Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([S:8]([NH:11][CH3:12])(=[O:10])=[O:9])=[N:6][CH:7]=1.[OH:13][CH2:14][C@@H:15]1[O:19][C:18]([C:20]2[NH:24][C:23]([C:25]3[CH:26]=[C:27]([OH:37])[CH:28]=[C:29]([O:31][C@@H:32]([CH3:36])[CH2:33][O:34][CH3:35])[CH:30]=3)=[CH:22][CH:21]=2)=[N:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C.C(OCC)(=O)C>[OH:13][CH2:14][C@@H:15]1[O:19][C:18]([C:20]2[NH:24][C:23]([C:25]3[CH:26]=[C:27]([CH:28]=[C:29]([O:31][C@@H:32]([CH3:36])[CH2:33][O:34][CH3:35])[CH:30]=3)[O:37][C:2]3[N:3]=[CH:4][C:5]([S:8]([NH:11][CH3:12])(=[O:10])=[O:9])=[N:6][CH:7]=3)=[CH:22][CH:21]=2)=[N:17][CH2:16]1
Reactant: COC[C@H](C)Oc1cc(O)cc(-c2ccc(C3=NC[C@H](CO)O3)[nH]2)c1
Reactant: CNS(=O)(=O)c1cnc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CNS(=O)(=O)c1cnc(Oc2cc(O[C@@H](C)COC)cc(-c3ccc(C4=NC[C@H](CO)O4)[nH]3)c2)cn1
Reaction time: 4 h
Yield: 53.6 %

Procedure:
5-Bromo-N-methylpyrazine-2-sulfonamide (147 mg, 0.58 mmol) synthesized in Example (128b) and 3-{5-[(5R)-5-(Hydroxylmethyl)-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-[(1S)-2-methoxy-1-methylethoxy]phenol (262 mg, 0.76 mmol) synthesized in Example (125g) were dissolved in acetonitrile (6 mL), and potassium carbonate (161 mg, 1.17 mmol) was added, followed by stirring for 4 hours under nitrogen atmosphere. Water (20 mL) was added to the reaction solution, and extraction was carried out twice with ethyl acetate (20 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=0%-3.5%) to afford the desired compound (161 mg, yield 54%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21](O)=[O:22])=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[NH2:32][C@@H:33]([CH2:35][OH:36])[CH3:34].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CCOC(C)=O.CN(C=O)C>[OH:36][CH2:35][C@H:33]([NH:32][C:21]([C:20]1[C:14]2[C:15](=[N:16][CH:17]=[C:12]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:8]([CH3:11])[N:7]=3)[N:13]=2)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:31])[CH3:30])[CH:19]=1)=[O:22])[CH3:34]
Reactant: C[C@@H](N)CO
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](CO)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.8 %

Procedure:
In a 20 mL scintillation vial, 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (400 mg, 0.87 mmol), D-alaninol (131 mg, 1.75 mmol), HBTU (431 mg, 1.14 mmol), HOBt (153 mg, 1.14 mmol) and DIPEA (0.31 ml, 1.75 mmol) were combined with DMF (6 ml) to give a light yellow solution. After stirring at room temperature overnight, the reaction mixture was diluted with EtOAc (50 mL) and washed with sat NaHCO3 (3×25 mL) and H2O (3×25 mL). The organic layer were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 4 g, 0% to 10% MeOH in DCM with 0.1% NH4OH) to provide 250 mg (56%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-2-hydroxy-1-methyl-ethyl)-amide as an off-white solid. MS: (M+H)+=516.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]([CH3:17])[C:5]([NH:7][C:8]1[O:12][N:11]=[C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:9]=1)=[O:6].[OH-].[K+]>O.C(O)C>[CH3:14][C:13]([C:10]1[CH:9]=[C:8]([N:7]2[CH2:2][CH2:3][CH:4]([CH3:17])[C:5]2=[O:6])[O:12][N:11]=1)([CH3:16])[CH3:15]
Reactant: CC(CCCl)C(=O)Nc1cc(C(C)(C)C)no1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC1CCN(c2cc(C(C)(C)C)no2)C1=O
Yield: 87.3 %

Procedure:
Two grams of 4-chloro-N-[3-(1,1-dimethylethyl)-5-isoxazolyl]-2-methylbutanamide was added by portion to a stirring solution of 0.6 g of powdered potassium hydroxide dissolved in 2 ml of water and 5 ml of ethanol. The reaction mixture was heated to reflux for 15 minutes, cooled and poured into 20 ml of water. The precipitated solid was collected by filtration to afford 1.5 g of 1-[3-(1,1-dimethylethyl)-5-isoxazolyl]-3-methyl-2-pyrrolidinone. Yield 87%. mp 73°-75° C.
Reaction SMILES: C[Si]([N:5]=[N+:6]=[N-:7])(C)C.[N:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:33]=[CH:32][C:19]([O:20][CH2:21][C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=3)=[CH:18][CH:17]=2)=[CH:10][CH:9]=1>>[N:8]1[CH:9]=[CH:10][C:11]([C:14]2[NH:7][N:6]=[N:5][C:15]=2[C:16]2[CH:17]=[CH:18][C:19]([O:20][CH2:21][C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=3)=[CH:32][CH:33]=2)=[CH:12][CH:13]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: C(#Cc1ccc(OCc2ccc3ccccc3n2)cc1)c1ccncc1
Product: c1ccc2nc(COc3ccc(-c4nn[nH]c4-c4ccncc4)cc3)ccc2c1
Temperature: 150 °C
Yield: 85.2 %

Procedure:
Trimethylsilylazide (730 mg, 6.4 mmol) and 2-((4-(2-(pyridin-4-yl)ethynyl)phenoxy)methyl)quinoline (360 mg) were combined in a screw cap sealed tube and heated behind a safety shield in a 150° C. bath for 72 h. The mixture was concentrated and the yellow residue triturated with ether (2×10 mL) leaving a yellow solid (346 mg) which was chromatographed on silica eluted with a gradient of 0.5%-2% methanol in dichloromethane giving a yellow solid (210 mg,52%). 1H NMR (CDCl3 with a drop of CD3OD, 400 mHz) δ 8.54 (d, 2H, J=6.2 Hz), 8.23 (d, 1H, J=8.7 Hz), 8.07 (d, 1H, J=8.7 Hz), 7.84 (d, 1H, J=7.9 Hz), 7.74 (ddd, 1H, J=8.4, 7, 1Hz), 7.69 (d, 1H, J=8.7 Hz), 7.63 (d, 2H, J=6.2 Hz), 7.56 (ddd, 1H), 7.41 (m, 2H), 7.09 (m, 2H), 5.41 (s, 2H). MS (AP+) m/e 380 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([Cl:15])[CH:14]=1)[O:5][CH:6]([CH2:10][CH3:11])[C:7](O)=[O:8].C1C=CC=CC=1.C(Cl)([Cl:24])=O.Cl>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([Cl:15])[CH:14]=1)[O:5][CH:6]([CH2:10][CH3:11])[C:7]([Cl:24])=[O:8]
Reactant: O=C(Cl)Cl
Reactant: CCC(Oc1cc(Cl)cc(Cl)c1)C(=O)O
Agent: Cl
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CCC(Oc1cc(Cl)cc(Cl)c1)C(=O)Cl
Temperature: 35 °C

Procedure:
71.8 g. (0.288 moles) of α-(3,5-dichlorophenoxy) butyric acid and 75 ml. of benzene are placed in a 500 ml. flask to which a dropping funnel with dry-ice condenser is attached. The slurry is stirred and the 0.2 ml. dimethyl formamide is added. The mixture is heated to 35° C. and 10 g. of phosgene is condensed into the mixture to initiate reaction. The start of the reaction is evidenced by HCl evolution and foaming. 26.0 g. more phosgene is added in 5 gm. increments. At the conclusion of the reaction (HCl evolution ceasing), the reaction mixture is evaporated leaving a residual liquid α-(3,5-dichlorophenoxy) butyryl chloride 77.6 g., ND20 = 1.5345
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[C:32]([O:36][CH2:37][CH3:38])(=[O:35])[CH2:33][OH:34].[CH3:39][C:40]([CH3:47])([CH3:46])[C:41](=O)[CH2:42][C:43]#[N:44]>C1COCC1>[CH3:39][C:40]([CH3:47])([CH3:46])/[C:41](/[O:34][CH2:33][C:32]([O:36][CH2:37][CH3:38])=[O:35])=[CH:42]/[C:43]#[N:44]
Reactant: CCOC(=O)CO
Reactant: CC(C)(C)C(=O)CC#N
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)CO/C(=C\C#N)C(C)(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 80.5 %

Procedure:
A 0° C. solution of triphenylphosphine (2.72 g, 10.4 mmol, 1.3 equiv) in anh. THF (50 mL) was treated with diethyl azodicarboxylate (1.81 g, 10.4 mmol, 1.3 equiv), ethyl glycolate (1.08 g, 10.4 mmol, 1.3 equiv) and 4,4-dimethyl-3-oxopentanenitrile (1.00 g, 8.0 mmol). The resulting solution was allowed to warm to room temperature, stirred for 15 h and concentrated under reduced pressure. The residue was purified by flash chromatography (11 cm×22 cm SiO2, gradient from 5% EtOAc/hex to 8% EtOAc/hex) to afford (Z)-4,4-dimethyl-3-(ethoxycarbonylmethoxy)pentenenitrile (1.36 g, 80%) as a colorless oil: TLC (5% EtOAc/hexanes) Rf0.26; 1H NMR (CDCl3) δ1.12 (s, 9H), 1.28 (t, J=7.0 Hz, 3H), 4.24 (q, J=7.0 Hz, 2H), 4.55 (s, 1H), 5.00 (s, 2H); 13C NMR (CDCl3) δ13.9, 27.8, 38.2, 61.5, 67.1, 67.3, 117.0, 167.1, 180.7; CI-LRMS m/z (rel abundance) 212 (M+H, 100%). Anal. Calcd for C11H17NO3: C, 62.54; H, 8.11; N, 6.63. Found: C, 62.57; H, 7.90; N, 6.47.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH:6]([C:8]([OH:10])=[O:9])[CH2:5][N:4]=[CH:3]1.C(Cl)(=O)C(Cl)=O.[CH2:17](O)[C:18]#[C:19][CH3:20]>C1C=CC=CC=1.O>[CH2:17]([O:9][C:8]([CH:6]1[CH2:7][NH:2][CH:3]=[N:4][CH2:5]1)=[O:10])[C:18]#[C:19][CH3:20]
Reactant: CC#CCO
Reactant: O=C(O)C1CN=CNC1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: c1ccccc1
Product: CC#CCOC(=O)C1CN=CNC1
Yield: 61 %

Procedure:
1,4,5,6-tetrahydropyrimidine-5-carboxylic acid hydrochloride (1 g, 6 mmol) was suspended in a solution of oxalyl chloride (1.5 mL, 17 mmol) in benzene (10 mL), heated with stirring under reflux for 2.5 h, and then evaporated to dryness in vacuo after cooling, to give an orange-yellow residue. A mixture of the acid chloride (04 g) and 2-butyn-l-ol (20 mL, excess) was stirred at room temperature overnight. After stirring overnight, the solvents were removed in vacuo to give a brownish residue. The residue was taken up in water (100 mL), stirred at room temperature for 2 h and filtered. The brown residue obtained on removal of the solvents in vacuo was recrystallized (ethanol/ether) to give a brown viscous oil (0.3 g, 61%) of 5-(2-butynyloxycarbonyl)-1,4,5,6-tetrahydropyrimidine as the hydrochloride salt. 1H NMR (D2O): δ 1.5 (t, 3H, CH3), 3.1 (m, 1H), 3.5 (d, 4H), 3.9 (q, 2H, OCH2), 7.9 (s, 1H, amidine-H). Anal. (C9H13N2O2Cl) C, H, N.
Reaction SMILES: C(O)(=O)C.[N:5]1[CH:10]=[CH:9][C:8]([C:11]([CH3:23])=[CH:12][C:13]([O:15]CC2C=CC=CC=2)=[O:14])=[CH:7][CH:6]=1>CO>[N:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:23])[CH2:12][C:13]([OH:15])=[O:14])=[CH:7][CH:6]=1
Reactant: CC(=CC(=O)OCc1ccccc1)c1ccncc1
Solvent: CO
Solvent: CC(=O)O
Product: CC(CC(=O)O)c1ccncc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.6 %

Procedure:
Next, methanol (31 ml) and acetic acid (0.71 ml, 12.4 mmol) were added to benzyl 3-(4-pyridyl)-2-butenoate (1.75 g, 6.20 mmol), and a nitrogen gas was bubbled through the mixture at room temperature for 10 minutes. A catalytic amount of 10% palladium on carbon was added to the mixture, and the whole was stirred under a hydrogen atmosphere at room temperature overnight. An insoluble matter was filtered out, and the filtrate was concentrated under reduced pressure. The resulting crystals were filtered off with acetone to give 0.61 g (60%) of 3-(4-pyridyl)butyric acid as pale yellow crystals.
Reaction SMILES: C([O:3][C:4](=[O:19])[C:5]1[CH:10]=[CH:9][C:8]([P:11]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][CH:6]=1)C.[OH-].[Li+]>CO.O>[CH2:17]([O:16][P:11]([C:8]1[CH:9]=[CH:10][C:5]([C:4]([OH:19])=[O:3])=[CH:6][CH:7]=1)([O:13][CH2:14][CH3:15])=[O:12])[CH3:18]
Reactant: CCOC(=O)c1ccc(P(=O)(OCC)OCC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCOP(=O)(OCC)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-(diethoxyphosphoryl)-benzoic acid ethyl ester (2b) (2.46 g, 8.59 mmol) in methanol (86 mL) was slowly added lithium hydroxide (monohydrate, 0.36 g, 8.59 mmol) in water (86 mL). The resulting reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated to remove methanol and diluted with brine, then extracted with EtOAc (3×100 mL) until the aqueous layer showed little or no evidence of product by HPLC. The combined organics were dried over Na2SO4 and concentrated on a rotary evaporator. The desired product was purified by crystallization from hexane/ethyl acetate (2.37 g), m.p. 101° C. 1H NMR (300 MHz, CDCl3) δ (ppm)): 1.27 (t, J=7.03 Hz, 6H), 4.03 (q, J=7.03 Hz, 4H), 7.85 (m, 2H), 8.09 (m, 2H), 12.65 (bs, 1H). 31P NMR (121 MHz, CDCl3) δ21.611.
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][CH:10](O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:13](=[O:26])[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=1.[NH:27]1[C:36]2[C:31](=[CH:32][C:33]([O:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])=[CH:34][CH:35]=2)[CH2:30][CH2:29][CH2:28]1>>[CH3:1][CH:2]1[CH2:11][CH:10]([N:27]2[C:36]3[C:31](=[CH:32][C:33]([O:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])=[CH:34][CH:35]=3)[CH2:30][CH2:29][CH2:28]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:13](=[O:26])[C:14]1[CH:15]=[C:16]([O:24][CH3:25])[C:17]([O:22][CH3:23])=[C:18]([O:20][CH3:21])[CH:19]=1
Reactant: COc1cc(C(=O)N2c3ccccc3C(O)CC2C)cc(OC)c1OC
Reactant: CCOC(=O)CCCCOc1ccc2c(c1)CCCN2
Product: CCOC(=O)CCCCOc1ccc2c(c1)CCCN2C1CC(C)N(C(=O)c2cc(OC)c(OC)c(OC)c2)c2ccccc21
Yield: 36.3 %

Procedure:
Starting with 2-methyl-1-(3,4,5-trimethoxybenzoyl)-1,2,3,4-tetrahydro-4-quinolinol (1.3 g, 3.6 mmol) prepared in Reference Example 22 and ethyl 5-[(1,2,3,4-tetrahydro-6-quinolinyl)oxy]pentanoate (2.30 g, 8.28 mmol), the same procedure as shown in Example 1 was repeated to give the titled compound (806 mg, yield: 40%) as a colorless oil. (cis:trans=1:1.3)
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[C@@H:4]([C:5]#[C:6][C:7](=[O:14])[O:8]CC(Cl)(Cl)Cl)[C@H:3]1[C:15]([O:17][CH:18]([CH3:32])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:20]=1)=[O:16].C(O)(=O)C.O>C(Cl)Cl.[Zn]>[CH3:1][C:2]1([CH3:33])[C@@H:4]([C:5]#[C:6][C:7](=[O:8])[OH:14])[C@H:3]1[C:15]([O:17][C@H:18]([CH3:32])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:20]=1)=[O:16]
Reactant: CC(OC(=O)[C@@H]1[C@H](C#CC(=O)OCC(Cl)(Cl)Cl)C1(C)C)c1cccc(Oc2ccccc2)c1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: C[C@@H](OC(=O)[C@@H]1[C@H](C#CC(=O)O)C1(C)C)c1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
A solution of 4.16 g of the product of Step A in 4 ml of methylene chloride was admixed with 45 ml of acetic acid containing 10% of water and 0.53 g of zinc powder and the mixture was stirred for 30 minutes at room temperature. then another 0.53 g of zinc powder were added 4 times until The reaction was complete and after 3 hours contact, the mixture was filtered. The filtrate was extracted with methylene chloride and the organic phase was washed with water, dried and evaporated to dryness by azeotropic distillation with toluene to obtain 3.05 g of (R)α-methyl-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3-[3-oxo-3-hydroxy-1-propynyl]-cyclo-propane-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[C:26](I)=[N:25][C:24]4[C:19]3=[N:20][CH:21]=[N:22][C:23]=4[NH:28][CH3:29])=[CH:14][CH:13]=2)=[O:10])=[CH:4][C:3]=1[C:30]([F:33])([F:32])[F:31].[CH3:34][O:35][CH2:36][CH2:37][OH:38]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[C:26]([O:38][CH2:37][CH2:36][O:35][CH3:34])=[N:25][C:24]4[C:19]3=[N:20][CH:21]=[N:22][C:23]=4[NH:28][CH3:29])=[CH:14][CH:13]=2)=[O:10])=[CH:4][C:3]=1[C:30]([F:33])([F:32])[F:31]
Reactant: CNc1ncnc2c1nc(I)n2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: COCCO
Product: CNc1ncnc2c1nc(OCCOC)n2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1

Procedure:
The title compound can be prepared from 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-[4-(8-iodo-6-(methylamino)purin-9-yl)phenyl]urea and 2-methoxyethanol by the same techniques as in Example 136.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=2[O:2]1.Cl[Sn](Cl)(Cl)Cl.[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25](Cl)=[O:26]>C(Cl)Cl>[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25]([C:6]1[CH:7]=[C:8]2[O:9][CH2:1][O:2][C:3]2=[CH:4][C:5]=1[CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:26]
Reactant: COC(=O)Cc1ccc2c(c1)OCO2
Reactant: O=C(Cl)c1ccco1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)Cc1cc2c(cc1C(=O)c1ccco1)OCO2
Yield: 52 %

Procedure:
The title compound was prepared from methyl 3,4-methylenedioxyphenylacetate (336 mg, 1.73 mmol) in CH2Cl2 (10 mL), SnCl4 (1.0M solution in CH2Cl2 ; 2.8 mL, 2.8 mmol) and 2-furoyl chloride (200 μL, 1.92 mmol) as a solid (120 mg, 52% yield at 46% conversion). 1H NMR (CDCl3) 7.68 (brs, 1H), 7.17 (s, 1H), 7.11 (d, 1H, J=3.5), 6.83 (s, 1H), 6.57 (m, 1H), 6.06 (s, 2H), 3.78 (s, 2H), 3.64 (s, 3H).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:16](O)=[O:17])[S:10][C:11]=2[C:12]([F:15])([F:14])[F:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C1COCC1>[OH:17][CH2:16][C:9]1[S:10][C:11]([C:12]([F:15])([F:13])[F:14])=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:8]=1
Reactant: O=C(O)c1cc(-c2ccccc2)c(C(F)(F)F)s1
Solvent: C1CCOC1
Product: OCc1cc(-c2ccccc2)c(C(F)(F)F)s1
Temperature: 25 °C
Yield: 98.1 %

Procedure:
A solution of 2.10 g (7.7 mmol) of 4-phenyl-5-trifluoromethyl-thiophene-2-carboxylic acid (from Aldehyde 15, Step C) in 20 mL of THF was treated with 5.0 mL of 2.0 M borane dimethylsulfide complex in THF. The resulting solution was heated at reflux for 3 h, cooled to rt, quenched with 10 mL of MeOH and concentrated. Chromatography on a Biotage 40M cartridge using 9:1 v/v hexanes/EtOAc as the eluant afforded 1.95 g (98%) of the title compound: 1H NMR (500 Mhz) δ 2.05 (app s, 1H), 4.87 (s, 2H), 6.99 (s, 1H), 7.41 (app s, 5H).
Reaction SMILES: [O:1]1CCCC1.[C:6]1([Si:12]2([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[O:17][Si:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:15][Si:14]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[O:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N)CCCCC.Cl>O>[C:24]1([Si:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([OH:1])[O:17][Si:12]([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[O:13][Si:14]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[OH:15])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: C1CCOC1
Reactant: c1ccc([Si]2(c3ccccc3)O[Si](c3ccccc3)(c3ccccc3)O[Si](c3ccccc3)(c3ccccc3)O2)cc1
Agent: Cl
Solvent: CCCCCCN
Solvent: O
Product: O[Si](O[Si](O[Si](O)(c1ccccc1)c1ccccc1)(c1ccccc1)c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.5 h
Yield: 93 %

Procedure:
400 parts tetrahydrofuran and 55 parts hexaphenylcyclotrisiloxane were added to an Erlenmeyer flask, and dissolution was brought about. 3 parts hexylamine and 40 parts water were then added, and stirring was carried out for 30 minutes at room temperature. Conversion to the diol was confirmed by thin-layer chromatography, and the reaction solution was poured into 500 parts water and neutralized with dilute hydrochloric acid. The organic substance was precipitated with 600 parts of toluene, and this precipitate was repeatedly washed with water. Dehydration was then carried out with anhydrous sodium sulfate, and after filtration, the filtrate was condensed to 150 parts with a rotary evaporator. Hexane was then added to obtain crystals of hexaphenyltrisiloxane-1,5-diol in a yield of 93%.
Reaction SMILES: C([N:8]1[CH2:21][CH2:20][C:19]2[C:18]3[CH:17]=[CH:16][C:15]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:14][C:13]=3[NH:12][C:11]=2[CH2:10][CH2:9]1)C1C=CC=CC=1>C(O)(=O)C.C(O)C.[Pd]>[C:22]1([C:15]2[CH:16]=[CH:17][C:18]3[C:19]4[CH2:20][CH2:21][NH:8][CH2:9][CH2:10][C:11]=4[NH:12][C:13]=3[CH:14]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: c1ccc(CN2CCc3[nH]c4cc(-c5ccccc5)ccc4c3CC2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: c1ccc(-c2ccc3c4c([nH]c3c2)CCNCC4)cc1
Yield: 50.8 %

Procedure:
A mixture of 3-benzyl-8-phenyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (1.07 g, 3.0 mmol), glacial acetic acid (2 drops) and Pd/C (10%, 0.6 g) in ethanol (150 mL) was reacted in a manner similar to Example 8 to give 0.40 g (51%) of the title compound as a tan crystalline solid: mp 220-222° C.; 1H NMR (400 MHz, DMSO-d6) δ 10.41, 7.61-7.59, 7.46, 7.42-7.38, 7.28-7.22, 3.04-3.01, 2.96-2.94, 2.87-2.84; 13C NMR (100 MHz, DMSO-d6)δ 142.4, 138.2, 135.3, 133.0, 128.5, 128.4, 126.8, 126.0, 117.9, 117.5, 111.8, 108.8, 50.5, 48.8, 32.5, 28.0; IR (drift) 3305, 2929, 2918, 2893, 2827, 1468, 1324, 1242, 869, 814, 787, 762, 753, 743, 700 cm−1; MS (EI) m/z 262 (M+); HRMS (FAB) calcd for C18H18N2+H: 263.1548, found: 263.1543; Anal. Calcd for C18H18N2.0.1 C2H4O2: C, 81.46; H, 6.91; N, 10.44. Found: C, 81.11; H, 701; N, 10.35.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21](Br)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[F:24][C:25]1[N:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1>>[CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([C:28]5[CH:27]=[CH:26][C:25]([F:24])=[N:30][CH:29]=5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: OB(O)c1ccc(F)nc1
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(-c3ccc(F)nc3)ccc1-2
Yield: 50 %

Procedure:
Following the procedures for 128, 2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene was reacted with 6-fluoropyridin-3-ylboronic acid to give 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-(2-fluoropyrid-5-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (1.11 g, 50%). 1H NMR (400 MHz, DMSO) δ 8.64 (s, 1H), 8.47 (d, J=8.1, 1H), 8.38 (t, J=7.8, 1H), 8.12 (s, 1H), 7.61 (d, J=8.4, 1H), 7.49 (s, 1H), 7.30 (d, J=8.6, 1H), 5.84 (dd, J=13.2, 6.4, 1H), 4.43 (s, 2H), 3.49 (s, 2H), 1.57 (d, J=6.5, 6H). MS (ESI(+)): m/z 408.2 (M+H)
Reaction SMILES: C(#N)C.Cl[CH2:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7].[OH:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=1>C(N(CC)CC)C>[OH:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([O:21][CH2:5][C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:7])=[O:20])=[CH:17][CH:16]=1
Reactant: O=C(CCl)N1CCCCC1
Reactant: O=C(O)c1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(OCC(=O)N1CCCCC1)c1ccc(O)cc1
Yield: 83.9 %

Procedure:
To 100 ml of acetonitrile were added 7.75 g of N-(α-chloroacetyl)piperidine, 5.0 g of 4-hydroxybenzoic acid and 4.3 g (5.9 ml) of triethylamine, and the mixture was refluxed with heating for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. To the residue was added ice-water, and precipitated crystals were recrystallized from water to give 8.0 g of the title compound. Melting point: 160°-164° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][CH:8]=[CH:7][N:6]=1)=O.[H-].C([Al+]CC(C)C)C(C)C>C1COCC1>[NH2:11][C:10]1[C:5]([CH:3]=[O:2])=[N:6][CH:7]=[CH:8][N:9]=1
Reactant: COC(=O)c1nccnc1N
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: Nc1nccnc1C=O
Temperature: -78 °C
Reaction time: 4 h
Yield: 33.9 %

Procedure:
Methyl-3-aminopyrazine-2-carboxylate (11 g) was dissolved in THF and cooled to −78° C. Diisobutylaluminum hydride (1M in hexanes, 250 mL) was added, and the reaction stirred at −78° C. for 4 hours. The reaction was then warmed to 0° C. for one hour before being quenched slowly by addition of 1M hydrochloric acid. Ethyl acetate was added and the layers separated. The organic layer was dried over magnesium sulfate, filtered and concentrated. The residue was triturated in hexanes to afford title compound (3.0 g, 34%).