Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC1(F)CCN(C(C2NC3=NC=C(OC4CCN(C(C)C)CC4)C=C3C=2)=O)CC1.[CH3:30][O:31][C:32]([C:34]1[N:51]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[C:37]2=[N:38][C:39]([Cl:50])=[C:40]([O:42]CC3C=CC=CC=3)[CH:41]=[C:36]2[CH:35]=1)=[O:33]>>[CH3:30][O:31][C:32]([C:34]1[N:51]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[C:37]2=[N:38][C:39]([Cl:50])=[C:40]([OH:42])[CH:41]=[C:36]2[CH:35]=1)=[O:33]
Reactant: COC(=O)c1cc2cc(OCc3ccccc3)c(Cl)nc2n1C(=O)OC(C)(C)C
Agent: CC(C)N1CCC(Oc2cnc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Product: COC(=O)c1cc2cc(O)c(Cl)nc2n1C(=O)OC(C)(C)C

Procedure:
The title compound was synthesized in analogy to example 9, intermediate b), through hydrogenation of 5-benzyloxy-6-chloro-pyrrolo[2,3-b]pyridine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester to give the compound as a white solid (62%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH:13]([N+:15]([O-])=O)[CH2:12][N:11]([CH3:18])[CH2:10][CH:9]1[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20](O)(=[O:22])[CH3:21]>C(O)C.[Ni]>[C:20]([NH:15][CH:13]1[CH2:14][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:9]([CH3:19])[CH2:10][N:11]([CH3:18])[CH2:12]1)(=[O:22])[CH3:21]
Reactant: CC(=O)O
Reactant: CC1CN(C)CC([N+](=O)[O-])CN1Cc1ccccc1
Agent: [Ni]
Solvent: CCO
Product: CC(=O)NC1CN(C)CC(C)N(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-Benzyl-2,4-dimethyl-6-nitrohexahydro-1H-1,4-diazepine (5.1 g) is dissolved in ethanol (100 ml) and acetic acid (5 ml) and hydrogenerated over Raney-nickel (about 1 g) at 25° C. After the calculated amount of the hydrogen is absorbed, the catalyst is filtered off. The filtrate is evaporated under reduced pressure. The residue is dissolved in chloroform (100 ml), and acetic anhydride (4.0 g) is added to the solution. The reaction mixture is stirred for 2 hours at 25° C., diluted with aqueous sodium hydroxide solution, and extracted with chloroform. The organic layer is washed successively with water, aqueous sodium hydroxide solution, and saturated aqueous sodium chloride solution, and dried over magnesium sulfate. The solvent is evaporated under reduced pressure, the residue is chromatographed on silica gel with.elution of chloroform-methanol (9:1). Fractions containing the object compound are pooled and evaporated under reduced pressure to give 6-acetylamino-1-benzyl-2,4-dimethylhexahydro-1H-1,4-diazepine (1.8 g) as an oil. The above compound is dissolved in 10% hydrochloric acid (20 ml) and is refluxed for 2 hours. After cooling, the reaction mixture is basified with aqueous sodium hydroxide solution and extracted with chloroform. The organic layer is washed successively with water and saturated aqueous sodium chloride solution, and dried over magnesium sulfate. The solvent is evaporated under reduced pressure to give the title compound (1.5 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH2:11]([O:13][C:14](=[O:19])[C:15](Br)([CH3:17])[CH3:16])[CH3:12].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:11]([O:13][C:14](=[O:19])[C:15]([O:10][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:9][C:6]=1[CH:7]=[O:8])([CH3:17])[CH3:16])[CH3:12]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: O=Cc1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(Cl)cc1C=O
Temperature: 110 °C
Yield: 57.5 %

Procedure:
5-Chloro-2-hydroxy-benzaldehyde (7 g, 45 mmol), 2-bromo-2-methyl-propionic acid ethyl ester (11.4 g, 58 mmol), K2CO3 (18.6 g, 135 mmol) and KI (0.97 g, 5.8 mmol) were mixed in DMF (20 mL). Then the reaction mixture was heated at 110° C. for 3 h. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in ethyl acetate and washed with 1N NaOH. Then the organic layer was separated, dried over Na2SO4 and concentrated to give title compound (7 g)
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=O.[CH2:12]([O:14][C:15](=[O:18])[CH2:16][SH:17])[CH3:13].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:12]([O:14][C:15]([C:16]1[S:17][C:2]2[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=2[CH:4]=1)=[O:18])[CH3:13]
Reactant: COc1ccc(F)c(C=O)c1
Reactant: CCOC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(OC)ccc2s1
Temperature: 80 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
A solution of 2-fluoro-5-methoxy-benzaldehyde (4.35 g, 28.2 mmol) in DMF (30 mL) is added mercapto-acetic acid ethyl ester (3.71 mL, 33.9 mmol) and K2CO3 (7.86 g, 57.0 mmol). The resulting suspension is stirred at 80° C. for 60 min and quenched with water (300 mL). The mixture is extracted with EtOAc (2×200 mL), and the organic layer is dried over Na2SO4, concentrated, and purified by silica gel column chromatography (10% EtOAc/Hex), to give the title compound as an oil (4.40 g, 66%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[O:5][C:6]1[N:11]=[CH:10][C:9]([CH:12]=O)=[CH:8][CH:7]=1.[N+:17]([CH3:20])([O-:19])=[O:18].C([O-])(=O)C.[NH4+].[BH4-].[Na+].C(=O)([O-])O.[Na+]>O.C(O)(=O)C.CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH2:20][N+:17]([O-:19])=[O:18])=[CH:10][N:11]=1
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc(Oc2cccc(F)c2)nc1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CC(=O)O
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])CCc1ccc(Oc2cccc(F)c2)nc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 65.6 %

Procedure:
To an acetic acid (20 mL) solution of 6-(3-fluoro-phenoxy)-pyridine-3-carbaldehyde (2.47 g, 11.4 mmol) described in Manufacturing Example 71-1-2 was added nitromethane (3.09 mL, 57.0 mmol) and ammonium acetate (1.76 g, 22.8 mmol), which was stirred for 6 hours at 100° C. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure. To a dimethyl sulfoxide (35 mL) and acetic acid (5 mL) solution of the residue was added sodium borohydride (681 mg, 17.1 mmol), which was stirred for 40 minutes at room temperature. Sodium hydrogencarbonate and water were added to the reaction mixture at room temperature while cooling appropriately, which was then extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=2:1) to obtain the title compound (1.96 g, 66%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][N:15]2C(=O)C3=CC=CC=C3C2=O)=[CH:7][CH:6]=1>CN.CO>[OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])=[CH:7][CH:6]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCc1ccc(OCCO)cc1
Agent: CN
Solvent: CO
Product: NCCCCc1ccc(OCCO)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 3.4 %

Procedure:
The crude protected amine 114 (1.2 g, 35 mmol) was dissolved in 40 mL of a 2 N solution of methyl amine in dry methanol and the reaction mixture was stirred overnight at room temperature. After this time the solvent was removed under reduced pressure and the residue was purified by flash chromatography (silica gel, 5:1:0.1 chloroform/methanol/concentrated ammonium hydroxide) to give free amine 115 (0.25 g, 35%) as a clear oil. 1H NMR (300 MHz, DMSO-d6) δ 1.58 (m, 4H), 2.55 (m, 2H), 2.73 (m, 2H), 3.83 (m, 2H), 3.97 (m, 2H), 6.83 (d, 2H), 7.07 (d, 2H), 7.82 (s, 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:13][N:12]=[C:11]2[C:7]=1[CH2:8][CH:9]1[C:14]([CH3:16])([CH3:15])[CH:10]12)=O)C.[NH3:17]>>[CH3:15][C:14]1([CH3:16])[CH:9]2[CH2:8][C:7]3[C:11]([CH:10]12)=[N:12][NH:13][C:6]=3[C:4]([NH2:17])=[O:3]
Reactant: N
Reactant: CCOC(=O)c1[nH]nc2c1CC1C2C1(C)C
Product: CC1(C)C2Cc3c(n[nH]c3C(N)=O)C21
Temperature: 100 °C

Procedure:
(±)-1,1-Dimethyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ethyl ester (1.280 g, 5.81 mmol) was taken up in 7M methanolic ammonia (60 mL) in a sealed flask and heated to 100° C. for 18 hours. The resulting suspension was collected by vacuum filtration to give 1,1-dimethyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid amide as a cream solid. Solvent was removed from the mother liquor and the residue purified by preparative HPLC to give further (±)-1,1-dimethyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid amide as a cream solid. m/z (ES+): 192 [M+H]+, 175 [M−NH2]+; 1H NMR (CD3OD): δ 2.9–2.65 (m, 1H), 2.55 (t, 1H, J=19.9), 2.0–1.8 (m, 2H), 1.03 (s, 3H), 0.63 (s, 3H).
Reaction SMILES: OO.C([C@H]1COC(=O)N1[C:16](=[O:50])[C@@H:17]([CH3:49])[CH2:18][CH2:19][CH2:20][N:21]([C:26]1[N:31]=[C:30]2[O:32][C:33]([C:39]3[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=3)=[C:34]([C:35]([NH:37][CH3:38])=[O:36])[C:29]2=[CH:28][C:27]=1[CH:46]1[CH2:48][CH2:47]1)[S:22]([CH3:25])(=[O:24])=[O:23])C1C=CC=CC=1.[Li+].[OH-].S([O-])([O-])=[O:54].[Na+].[Na+].C(=O)(O)[O-].[Na+]>C1COCC1.O.O.CO.C(Cl)Cl>[CH:46]1([C:27]2[CH:28]=[C:29]3[C:34]([C:35](=[O:36])[NH:37][CH3:38])=[C:33]([C:39]4[CH:40]=[CH:41][C:42]([CH3:45])=[CH:43][CH:44]=4)[O:32][C:30]3=[N:31][C:26]=2[N:21]([CH2:20][CH2:19][CH2:18][C@H:17]([CH3:49])[C:16]([OH:54])=[O:50])[S:22]([CH3:25])(=[O:24])=[O:23])[CH2:47][CH2:48]1
Reactant: O=S([O-])[O-]
Reactant: CNC(=O)c1c(-c2ccc(C)cc2)oc2nc(N(CCC[C@H](C)C(=O)N3C(=O)OC[C@@H]3Cc3ccccc3)S(C)(=O)=O)c(C3CC3)cc12
Agent: O=C([O-])O
Agent: OO
Agent: [Li+]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)c1c(-c2ccc(C)cc2)oc2nc(N(CCC[C@H](C)C(=O)O)S(C)(=O)=O)c(C3CC3)cc12
Reaction time: 0.22 h

Procedure:
H2O2 (30%) (0.222 mL, 2.170 mmol) was added to a solution of 6-(N—((S)-5-((S)-4-benzyl-2-oxooxazolidin-3-yl)-4-methyl-5-oxopentyl)methylsulfonamido)-5-cyclopropyl-N-methyl-2-p-tolylfuro[2,3-b]pyridine-3-carboxamide (365 mg, 0.543 mmol) in 6.4 mL of 7:3 THF/water at 0° C. Added LiOH (26.0 mg, 1.085 mmol) Stirred at 0° C. for 15 min. Quenched with sodium sulfite (342 mg, 2.71 mmol) in 2 mL water followed by sodium bicarbonate (0.5 M) (5.43 mL, 2.71 mmol) Added DCM and extracted AQ layer Treated AQ layer with 1N HCl and then extracted with EtOAc. Concentrated Chiral HPLC using a 20-250 mm IA column running 40% EtOH in heptane gave 294 mg (0.572 mmol) desired enantiomer at 9.4 min. and 120 mg of undesired enantiomer at 13.3 min. The desired enantiomer was taken up in 2 mL MeOH and salted with 0.5 N KHCO3 and lyophylized.
Reaction SMILES: Cl.[C:2]1([S:8]([CH2:11][CH2:12][CH:13]([C:19](=[O:21])[CH3:20])C(OCC)=O)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C>[C:2]1([S:8]([CH2:11][CH2:12][CH2:13][C:19](=[O:21])[CH3:20])(=[O:9])=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(CCS(=O)(=O)c1ccccc1)C(C)=O
Agent: Cl
Solvent: CCO
Product: CC(=O)CCCS(=O)(=O)c1ccccc1
Temperature: 25 °C
Yield: 97.3 %

Procedure:
Hydrochloric acid was added (150 mL of 3 N) to a solution of ethyl 2-(2-benzenesulfonylethyl)-3-oxo-butyrate (21.7 g, 76.3 mmol) in 100 mL of ethanol and heated to reflux overnight. The reaction was cooled to ambient temperature and the mixture was concentrated under reduced pressure. The residue was extracted with several portions of ethyl acetate, and the combined organic layers were washed with saturated aqueous sodium bicarbonate, washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford 16.8 g of 5-benzenesulfonylpentan-2-one as a yellow oil.
Reaction SMILES: [Na].[CH2:2]([O:4][C:5](=[O:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)[CH3:3].[CH:15]([N+:18]1[CH2:22][CH2:21][CH2:20][C:19]=1N(C)C)([CH3:17])[CH3:16].COS([O-])(=O)=O.O>C(O)C.C(OCC)C>[CH2:2]([O:4][C:5]([C:6](=[C:19]1[CH2:20][CH2:21][CH2:22][N:18]1[CH:15]([CH3:17])[CH3:16])[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)=[O:14])[CH3:3]
Reactant: CC(C)[N+]1=C(N(C)C)CCC1
Reactant: CCOC(=O)Cc1ccc(Cl)cc1
Agent: COS(=O)(=O)[O-]
Agent: [Na]
Solvent: CCO
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)C(=C1CCCN1C(C)C)c1ccc(Cl)cc1
Reaction time: 0.5 h
Yield: 8.5 %

Procedure:
Add [dropwise, with stirring, at from 90°-100°, in a stream of nitrogen] a solution of 5.1 g of sodium in 100 ml of ethanol to a mixture of 32 g of 4-chlorophenylacetic acid ethyl ester and 59.13 g of 1-isopropyl-2-dimethylamino-1-pyrrolinium-methylsulfate. After completion of the addition, continue stirring for a further 30 minutes; then cool and take up with water (≈100 ml) and diethyl ether (≈150 ml). Collect the organic phase, extract the aqueous phase once again with diethyl ether, combine the ether extracts, dry and concentrate them to obtain a yield [45.6 g (92% of theory)] of crude title compound; recrystallize 5 g from ethanol/water to obtain 4.2 g of product with a m.p. of 70° to 71°.
Reaction SMILES: C([O:4][C@@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][C@H:17]([O:24]C(=O)C)[C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C:14]2=[O:28])[CH2:6]1)(=O)C.O.[OH-].[Li+].CO.O1CCCC1>C(OCC)(=O)C.O>[OH:4][C@@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][C@H:17]([OH:24])[C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C:14]2=[O:28])[CH2:6]1
Reactant: CC(=O)O[C@@H]1CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2C[C@H](OC(C)=O)[C@]2(C)C(=O)CC[C@@H]32)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: C[C@]12CC[C@@H](O)C[C@H]1CC[C@@H]1[C@@H]2C[C@H](O)[C@]2(C)C(=O)CC[C@@H]12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3α, 12α-diacetoxy-5β-androstan-17-one (5.5 g) and lithium hydroxide monohydrate (1.7 g) in a solution of methanol (20 ml), tetrahydrofuran (20 ml) and water (20 ml) is stirred at room temperature for about two hours, diluted with ethyl acetate and washed three times with water. The organic solution is dried over magnesium sulfate, filtered and concentrated in vacuo. Benzene is azeotroped from the residue to give the desired product which is used, without further treatment, for the next step.
Reaction SMILES: [N:1]1([CH2:5][CH2:6][CH2:7][N:8]2[C:16]([O:17][CH3:18])=[N:15][C:14]3[C:9]2=[N:10][C:11]([O:20][CH2:21][CH2:22][CH2:23][CH3:24])=[N:12][C:13]=3[NH2:19])[CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O.[CH2:32](OC1NC(N)=C2C(N=1)=NC(OC)=N2)[CH2:33][CH2:34]C.BrCCCBr.N1CCCCCC1>>[CH2:21]([O:20][C:11]1[N:10]=[C:9]2[C:14]([N:15]=[C:16]([O:17][CH3:18])[N:8]2[CH2:7][CH2:6][CH2:5][N:1]2[CH2:4][CH2:3][CH2:34][CH2:33][CH2:32][CH2:2]2)=[C:13]([NH2:19])[N:12]=1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCN3CCC3)c2n1
Reactant: CCCCOc1nc2nc(OC)nc-2c(N)[nH]1
Agent: BrCCCBr
Agent: C1CCCNCC1
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(CCCN3CCCCCC3)c2n1

Procedure:
Prepared similarly to Intermediate 20 from 2-(butyloxy)-8-(methyloxy)-1H-purin-6-amine trifluoroacetate, 1,3-dibromopropane and hexahydro-1H-azepine.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.[Cl:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21](Cl)=[O:22].O>ClCCl>[Br:1][C:2]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:3]=1[NH:4][C:21](=[O:22])[C:20]1[CH:24]=[CH:25][CH:26]=[C:18]([Cl:17])[CH:19]=1
Reactant: Nc1cc(Cl)ccc1Br
Reactant: O=C(Cl)c1cccc(Cl)c1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(Cl)ccc1Br)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.2 %

Procedure:
To a solution of 2-bromo-5-chloroaniline (0.380 g, 1.84 mmol) and triethylamine (0.768 mL, 5.52 mmol) in dichloromethane (15 mL) is added 3-chlorobenzoyl chloride (0.353 mL, 2.76 mmol) in a dropwise fashion. The resulting mixture is allowed to stir at room temperature for 2 h. Water (30 mL) is added and extracted with the mixture is extracted with dichloromethane 3×. The organic layer is combined, washed with brine 1×, dried (Na2SO4) and concentrated under vacuum to give 0.630 g of N-(2-bromo-5-chloro-phenyl)-3-chloro-benzamide in 99% yield.
Reaction SMILES: [CH3:1][C:2]([OH:6])([C:4]#[CH:5])[CH3:3].[Li]CCCC.[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH:16]=[O:17]>C1COCC1>[Cl:12][C:13]1[CH:14]=[C:15]([CH:16]([OH:17])[C:5]#[C:4][C:2]([CH3:3])([OH:6])[CH3:1])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: COc1ccc(C=O)cc1Cl
Reactant: C#CC(C)(C)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C(O)C#CC(C)(C)O)cc1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 25.3 %

Procedure:
To a −78° C. stirred solution of 2-methylbut-3-yn-2-ol (0.89 g, 10.710 mmol) in dry THF (50 mL), n-BuLi (16.0 mL, 27.001 mmol, 1.6 M in hexane) was added dropwise over 5 minutes under an inert atmosphere. The reaction mixture was stirred for 30 min at −78° C., and then a solution of 3-chloro-4-methoxybenzaldehyde (1.8 g, 10.710 mmol) in dry THF (10 mL) was added and stirring was continued for an additional 3 h at RT. The reaction mixture was then quenched with a saturated NH4Cl solution and extracted with EtOAc (2×50 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography eluting with 2-4% EtOAc in hexanes to afford 1-(3-chloro-4-methoxyphenyl)-4-methylpent-2-yne-1,4-diol (0.69 g, 26%) as a yellow syrup.
Reaction SMILES: Br[C:2]1[C:6]2[N:7]=[C:8]([Cl:12])[N:9]=[C:10]([NH2:11])[C:5]=2[S:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[N+:19]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)([O-:21])=[O:20].CC(C1C=C(C(C)C)C(C2C(P(C(C)(C)C)C(C)(C)C)=CC=CC=2)=C(C(C)C)C=1)C>O1CCOCC1>[Cl:12][C:8]1[N:9]=[C:10]([NH2:11])[C:5]2[S:4][CH:3]=[C:2]([C:26]3[CH:25]=[CH:24][CH:23]=[C:22]([N+:19]([O-:21])=[O:20])[CH:27]=3)[C:6]=2[N:7]=1
Reactant: Nc1nc(Cl)nc2c(Br)csc12
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Nc1nc(Cl)nc2c(-c3cccc([N+](=O)[O-])c3)csc12
Temperature: 90 °C
Reaction time: 6 h
Yield: 72.1 %

Procedure:
7-Bromo-2-chlorothieno[3,2-d]pyrimidin-4-amine (500 mg, 1.90 mmol) was dissolved in dioxane (10 mL) and then 2.0 N sodium carbonate (2.85 mL, 5.70 mmol) and 3-nitrophenylboronic acid (320 mg, 1.90 mmol) were added. After flowing nitrogen to the mixture solution for 10 minutes, Pd2(PPh3)Cl2 (80 mg, 0.11 mmol) and t-Butyl Xphos (73 mg, 0.17 mmol) were added. The reaction mixture solution was stirred at 90° C. for 6 hours, filtered with celite, and washed with ethyl acetate. The aqueous layer was separated from the organic layer and extracted with ethyl acetate. The organic layer was combined, washed with brine, dried with MgSO4, and then concentrated by filtering. Purification by silica gel chromatography (1/4 to 1/3 ethyl acetate/hexane) yielded the target compound (420 mg, 72% yield).
Reaction SMILES: [C:1]([NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8](S(C)(=O)=O)[N:7]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:20][C:21]12[CH2:27][C:24]([OH:28])([CH2:25][CH2:26]1)[CH2:23][CH2:22]2.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8]([NH:20][C:21]23[CH2:27][C:24]([OH:28])([CH2:25][CH2:26]2)[CH2:23][CH2:22]3)[N:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)Nc1nc(S(C)(=O)=O)ncc1C(N)=O
Reactant: NC12CCC(O)(CC1)C2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)Nc1nc(NC23CCC(O)(CC2)C3)ncc1C(N)=O
Temperature: 90 °C

Procedure:
4-(tert-Butylamino)-2-(methylsulfonyl)pyrimidine-5-carboxamide (0.165 g, 0.606 mmol; synthesis described herein), 4-aminobicyclo[2.2.1]heptan-1-ol hydrochloride (0.105 g, 0.644 mmol) and DIEA (0.337 ml 1.931 mmol) were mixed in DMF (8 mL) and heated at 90° C. overnight. The solvent was evaporated and the residue was purified by silica gel column chromatography (0-10% methanol in ethyl acetate) to give the desired product. (41 mg, 0.127 mmol, 21%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.43 (br. s., 0H) 8.32 (s, 1H) 7.07 (br. s., 1H) 4.88 (br. s., 1H) 1.94-2.14 (m, 2H) 1.61-1.87 (m, 6H) 1.49-1.60 (m, 2H) 1.42 (s, 9H). MS (ESI) m/z 320.0 [M+1]+
Reaction SMILES: [CH2:1]([NH:8][C:9]([O:11][CH2:12][C:13]1[S:17][C:16]([C:18]([O:20][CH3:21])=[O:19])=[C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:14]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:30]I>C1COCC1>[CH2:1]([N:8]([CH3:30])[C:9]([O:11][CH2:12][C:13]1[S:17][C:16]([C:18]([O:20][CH3:21])=[O:19])=[C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:14]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1sc(COC(=O)NCc2ccccc2)cc1-c1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1sc(COC(=O)N(C)Cc2ccccc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 53.2 %

Procedure:
To a solution of 170 (0.620 g, 1.625 mmol) in 10 mL of THF was added NaH (0.098 g, 2.438 mmol) and stirred at room temperature for 20 min. Then MeI (0.5 ml, 8.00 mmol) was added and stirred for an additional 2 hours at 50° C. The reaction mixture was cooled down at room temperature, quenched with 2 mL of MeOH, diluted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by ISCO (40 g column, 5%-30% ethyl acetate in hexanes) to yield in 53% (342 mg) compound 171 as colorless oil.
Reaction SMILES: Cl[CH2:2][C:3]([NH2:5])=[O:4].[OH:6][C:7]1[C:12]2[C:13]3[CH2:14][NH:15][CH2:16][CH2:17][C:18]=3[C:19]([CH3:22])([CH3:21])[O:20][C:11]=2[CH:10]=[C:9]([CH:23]([CH3:31])[CH:24]([CH3:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:8]=1.C(N(CC)CC)C>CN(C)C=O>[OH:6][C:7]1[C:12]2[C:13]3[CH2:14][N:15]([CH2:2][C:3]([NH2:5])=[O:4])[CH2:16][CH2:17][C:18]=3[C:19]([CH3:21])([CH3:22])[O:20][C:11]=2[CH:10]=[C:9]([CH:23]([CH3:31])[CH:24]([CH3:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:8]=1
Reactant: NC(=O)CCl
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CNCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CN(CC(N)=O)CC1
Reaction time: 17 h

Procedure:
A solution of 1.03 g (0.011 mole) of 2-chloroacetamide in 8 ml of dimethylformamide was added dropwise to a stirred solution of 3.57 g (0.01 mole) of 10-hydroxy-5,5-dimethyl-8-(1,2-dimethylheptyl)-1,2,3,4-tetrahydro-5H-[1]benzopyrano[4,3-c]pyridine in 12 ml of dimethylformamide and 1.11 g (0.011 mole) of triethylamine. After stirring for 17 hours, the mixture was diluted with 20 ml. of water and extracted with ether. The combined ether extracts were washed with water, dried over anhydrous sodium sulfate, and evaporated in vacuo. The residue was recrystallized from acetonitrile, m.p. 165°-168°.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:8]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)=[N:9][N:10]([CH2:12][C:13]([F:16])([F:15])[F:14])[CH:11]=2)=[CH:3][CH:2]=1.[N:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=[CH:26][C:25]=1[CH2:34]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH-].[Na+]>O1CCOCC1>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:8]([C:17]3[CH:18]=[CH:19][C:20]([O:23][CH2:34][C:25]4[CH:26]=[N:27][C:28]5[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=5)[N:24]=4)=[CH:21][CH:22]=3)=[N:9][N:10]([CH2:12][C:13]([F:15])([F:16])[F:14])[CH:11]=2)=[CH:3][CH:2]=1
Reactant: Oc1ccc(-c2nn(CC(F)(F)F)cc2-c2ccncc2)cc1
Reactant: OCc1cnc2ccccc2n1
Agent: [Na+]
Agent: [OH-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: FC(F)(F)Cn1cc(-c2ccncc2)c(-c2ccc(OCc3cnc4ccccc4n3)cc2)n1
Temperature: 60 °C
Yield: 47.3 %

Procedure:
To a solution of 4-[4-Pyridin4-yl-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl]-phenol (79 mg) and Quinoxalin-2-yl-methanol (50 mg) in dioxane (2 ml) was added triphenylphosphine (105 mg) and di-t-butyldiazacarboxalate (92 mg) and the reaction mixture heated at 60° C. After 18, the reaction mixture was poured into 1N NaOH, extracted with methylene chloride, dried magnesium sulfate, filtered and concentrated. Purification with MPLC biotage eluting with 2% methanol/0.5% ammonium hydroxide/60% ethyl acetate/hexanes provided the title compound (54 mg). 1H NMR (400 MHz, CDCl3) δ 9.09 (s, 1 H), 8.52 (m, 2H), 8.13 (m, 1H), 8.10 (m, 1H), 7.79 (m, 2 H), 7.73 (s, 1 H), 7.40 (d, J=8.7, Hz, 2 H), 7.24 (m, 2H), 7.04 (d, J=8.7 Hz, 2 H), 5.32 (s, 2H), 4.79 (q, J=8.3 Hz, 2 H); MS: (M+H m/z=462.1).