Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[O:6][C@@H:5]([CH2:7][NH:8][C:9]([CH3:27])([CH3:26])[CH2:10][C:11]([NH:13][C@@H:14]2[CH2:20][CH2:19][C:18]3[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=3[NH:16][C:15]2=[O:25])=[O:12])[CH2:4][O:3]1.[CH3:29][NH:30][C:31]([NH:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41]1[CH:46]=[CH:45][C:44]([CH2:47]O)=[CH:43][CH:42]=1)=[O:32]>>[CH3:1][C:2]1([CH3:28])[O:6][C@@H:5]([CH2:7][NH:8][C:9]([CH3:27])([CH3:26])[CH2:10][C:11]([NH:13][C@@H:14]2[CH2:20][CH2:19][C:18]3[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=3[N:16]([CH2:47][C:44]3[CH:43]=[CH:42][C:41]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=4[CH2:34][NH:33][C:31]([NH:30][CH3:29])=[O:32])=[CH:46][CH:45]=3)[C:15]2=[O:25])=[O:12])[CH2:4][O:3]1
Reactant: CNC(=O)NCc1ccccc1-c1ccc(CO)cc1
Reactant: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2NC1=O)NC[C@H]1COC(C)(C)O1
Product: CNC(=O)NCc1ccccc1-c1ccc(CN2C(=O)[C@H](NC(=O)CC(C)(C)NC[C@H]3COC(C)(C)O3)CCc3ccccc32)cc1

Procedure:
Prepared from 3-[[2,2-dimethyl-1,3-dioxolan-4(S)-yl]methyl]amino-3-methyl- N-[2,3,4,5-tetrahydro-2-oxo-1H-benzazepin-3(R)-yl]butanamide (Step B) and 2'-[[(methylamino)carbonyl]amino]methyl-1,1'-biphenyl-4-methanol, methanesulfonate ester (Example 48, Step I) according to the procedure described in Example 35, Step H.1H NMR (200 MHz, CD3OD): δ 1.14 (s, 6H), 1.28 (s, 3H), 1.34 (s, 3H), 2.07 (m, 1H), 2.20-2.42 (m, 3H), 2.48-2.76 (m, 4H), 2.64 (s, 3H), 3.64 dd; 8, 6 Hz; 1H), 4.05 (dd; 8, 6 Hz; 1H), 4.14 (s, 2H), 4.20 (m, 1H), 4.40 (dd; 12, 8 Hz; 1H), 4.94 (d, 15 Hz, 1H), 5.27 (d, 15 Hz, 1H), 7.10-7.40 (m, 12H). FAB-MS: calculated for C37H46N5O5 641; found 642 (M+H, 80%).
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([NH:14][C:15]3[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=3)[N:12]=2)[N:7]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:6]=1)=[O:4].[C:33]([CH2:35][C:36]([NH:38][CH2:39][CH3:40])=[O:37])#[N:34].N1CCCCC1>CO>[C:33]([C:35](=[CH:19][C:18]1[CH:21]=[CH:22][C:15]([NH:14][C:11]2[N:12]=[C:13]3[C:5]([C:3](=[O:4])[C:2]([CH3:32])([CH3:1])[CH3:31])=[CH:6][N:7]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:8]3=[N:9][CH:10]=2)=[CH:16][CH:17]=1)[C:36]([NH:38][CH2:39][CH3:40])=[O:37])#[N:34]
Reactant: CCNC(=O)CC#N
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccc(C=O)cc3)nc12
Solvent: C1CCNCC1
Solvent: CO
Product: CCNC(=O)C(C#N)=Cc1ccc(Nc2cnc3c(n2)c(C(=O)C(C)(C)C)cn3COCC[Si](C)(C)C)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 96.7 %

Procedure:
To a 20 ml vial 4-[[7-(2,2-dimethylpropanoyl)-5-(2-trimethylsilylethoxymethyl)-pyrrolo[2,3-b]pyrazin-2-yl]amino]benzaldehyde (30 mg, 0.070 mmol) was dissolved in methanol (5 ml) and 2-cyano-N-ethyl-acetamide (11.38 mg, 0.1000 mmol) and piperdine (0.01 ml, 0.1300 mmol) were added. The reaction mixture was stirred at room temperature for 5 hr. The solvent was evaporated, the residue was loaded on a silica gel column and eluted with CH2Cl2 to MeOH 0-2, 3% to yield 37 mg of 2-cyano-3-[4-[[7-(2,2-dimethylpropanoyl)-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazin-2-yl]amino]phenyl]-N-ethyl-prop-2-enamide.
Reaction SMILES: [CH2:1]([NH:3][C:4]([N:6]1[CH2:10][C:9]([CH3:12])([CH3:11])[CH:8]=[N:7]1)=[S:5])[CH3:2].I[CH3:14]>CO>[CH3:14][S:5][C:4]([N:6]1[CH2:10][C:9]([CH3:11])([CH3:12])[CH:8]=[N:7]1)=[N:3][CH2:1][CH3:2]
Reactant: CCNC(=S)N1CC(C)(C)C=N1
Reactant: CI
Solvent: CO
Product: CCN=C(SC)N1CC(C)(C)C=N1
Temperature: 50 °C
Yield: 7.8 %

Procedure:
15 g (1 mol equiv.) 4,4-Dimethyl-4,5-dihydro-pyrazole-1-carbothioic acid ethylamide was dissolved in 300 mL methanol, 50.4 mL (10 mol equiv.) iodomethane was added and the reaction mixture was heated at 50° C. for 3 hours. Volatiles were removed in vacuo. The residue was taken up in DCM and extracted with 5% aqueous NaHCO3. The organic layer was washed twice with water, dried over Na2SO4, filtered and evaporated to dryness to give 15.5 g (96%) N-ethyl-4,4-dimethyl-4,5-dihydro-pyrazole-1-carboximidothioic acid methyl ester. 1H NMR (400 MHz, CDCl3) δ 1.16 (t, J=7.3 Hz, 3H), 1.20 (s, 6H), 2.45 (s, 3H), 3.49 (s, 2H), 3.53 (q, J=7.3 Hz, 2H), 6.66 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[N:7]=[CH:6][NH:5][C:4]2=[N:8][C:9]([NH2:11])=[CH:10][C:3]=12.[C:12](Cl)(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14]>N1C=CC=CC=1>[OH:1][C:2]1[N:7]=[CH:6][NH:5][C:4]2=[N:8][C:9]([NH:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:10][C:3]=12
Reactant: Nc1cc2c(O)nc[nH]c-2n1
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Nc1cc2c(O)nc[nH]c-2n1
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
A mixture of 3.0 g (0.02 mole) of 4-hydroxy-6-aminopyrrolo[2,3-d]pyrimidine and 8.4 g (0.07 mol) of pivaloyl chloride in 40 mL of pyridine is stirred for 30 minutes at from 80° to 90° C., the mixture then evaporated to dryness, and the residue dissolved in 30 mL of methanol. Addition of 10% aqueous ammonia yields 4.2 g (89%) of 4-hydroxy-6-pivaloylaminopyrrolo[2,3-d]pyrimidine which can be further purified by chromatography through silica gel, eluting with 8% methanol in methylene chloride. mp 295° C. 1NMR (d6 -DMSO) δ 1.20(s, 9H), 6.37(d, J=3.4 Hz, 1H), 6.92(d, J=3.4 Hz, 1H), 10.78 (s, 1H), 11.56 (s, 1H), 11.82 (s, 1H). Anal. Calc. for C11H14N4O2 : C, 56.40; H, 6.02; N, 23.92. Found: C, 56.16; H, 6.01; N, 23.67.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=2)=[N:4][C:3]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)(=O)C.[Zn]>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([NH2:13])=[CH:11][CH:12]=2)=[N:4][C:3]=1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Cc1oc(-c2ccc([N+](=O)[O-])cc2)nc1-c1ccccc1
Agent: [Zn]
Solvent: CC(=O)O
Product: Cc1oc(-c2ccc(N)cc2)nc1-c1ccccc1
Reaction time: 1.5 h

Procedure:
to a suspension of 5-methyl-2-(4-nitrophenyl)-4-phenyloxazole (1.20 g, 4.3 mmol) in acetic acid at room temperature was added all at once zinc dust (0.59 ml, 64 mmol). An exotherm developed. The mixture was stirred vigorously for 90 minutes then filtered. The filtrate was concentrated under reduced pressure, diluted with toluene then concentrated under reduced pressure to afford a yellow oily solid (1.1 g, quant.). ESI+ m/z=251.1 [MH]+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[O:5][C:6]=1[CH2:7][OH:8].ClCCl.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(=O)([O-])O.[Na+]>[CH3:1][C:2]1[N:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:13][CH:14]=2)[O:5][C:6]=1[CH:7]=[O:8]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)oc1CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)oc1C=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
[4-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-methanol (2.42 g, 9.41 mmol) and 100 mL dichloromethane are stirred at room temperature. Dess-Martin periodinane (8.0 g, 18.8 mmol) is added and the resulting mixture is stirred 4 hr at room temperature. The mixture is diluted with 100 mL saturated sodium hydrogen carbonate. The organic layer is separated, washed with 50 mL each of water and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude product is purified by silica gel chromatography eluting with a mixture of 8:2 hexanes:ethyl acetate affording 4-methyl-2-(4-trifluoromethyl-phenyl)-oxazole-5-carbaldehyde as a white solid, 2.12 g, 89%. MS (M++1) 256.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[NH:18][C:19]([CH3:24])=[C:20]([Cl:23])[C:21]=2[Cl:22])=[O:16])[CH:10]([N:25]=[N+:26]=[N-:27])[CH2:9]1)=O)(C)(C)C>Cl.CO>[ClH:22].[N:25]([C@H:10]1[C@@H:11]([NH:14][C:15]([C:17]2[NH:18][C:19]([CH3:24])=[C:20]([Cl:23])[C:21]=2[Cl:22])=[O:16])[CH2:12][CH2:13][NH:8][CH2:9]1)=[N+:26]=[N-:27]
Reactant: Cc1[nH]c(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2N=[N+]=[N-])c(Cl)c1Cl
Agent: Cl
Solvent: CO
Product: Cc1[nH]c(C(=O)N[C@H]2CCNC[C@H]2N=[N+]=[N-])c(Cl)c1Cl
Reaction time: 2 h

Procedure:
tert-butyl-3-azido-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidine-1-carboxylate (Intermediate 271, 967 mg; 2.3 mmol) was dissolved in 4N HCl in dioxanes (20 ml) and methanol (10 ml). The solution was stirred for 2 hours and monitored by LC/MS. Upon completion the solvent was removed and the crude reaction mixture was azeotroped with methanol to remove excess HCl. No further purification. LC/MS (ES+)[(M+H)+]: 317, 319 for C11H14Cl2N6O.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:9]3=[CH:11][C:12](=[O:15])[CH2:13][CH2:14][C:8]3([CH2:16][CH2:17][CH3:18])[O:7][C:6]=2[CH:5]=[C:4](O)[C:3]=1[Cl:20].Br[CH2:22][C:23]([O:25]CC)=[O:24]>CN(C)C=O>[Cl:1][C:2]1[C:10]2[C:9]3=[CH:11][C:12](=[O:15])[CH2:13][CH2:14][C:8]3([CH2:16][CH2:17][CH3:18])[O:7][C:6]=2[CH:5]=[C:4]([CH2:22][C:23]([OH:25])=[O:24])[C:3]=1[Cl:20]
Reactant: CCCC12CCC(=O)C=C1c1c(cc(O)c(Cl)c1Cl)O2
Reactant: CCOC(=O)CBr
Solvent: CN(C)C=O
Product: CCCC12CCC(=O)C=C1c1c(cc(CC(=O)O)c(Cl)c1Cl)O2
Temperature: 65 °C

Procedure:
A stirred mixture of 1,2-dichloro-3-hydroxy-8-oxo-5a-propyl-5a,6,7,8-tetrahydrodibenzofuran (0.4 g) potassium carbonate (0.2 g) and ethyl bromoacetate (200 μl) in N,N-dimethylformamide (7 ml) was heated at 65° C. for 1 1/4 hours. The reaction mixture was poured into ice water and the solid ester which precipitated was removed by filtration then dissolved in methanol (15 ml) containing water (1 ml) and 10N sodium hydroxide (1 ml). After 1/2 hour the methanol solution was poured into dilute aqueous hydrochloric acid, extracted with ether which was washed with water, brine, dried over MgSO4 and evaporated in vacuo. Trituration of the residue with methylene chloride gave 0.35 g of (1,2-dichloro-8-oxo-5a-propyl-5a,6,7,8-tetrahydrodibenzofuran-3-yl)acetic acid which melted at 248°-250° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH:15]3[CH:19]([C:20]([F:23])([F:22])[F:21])[CH2:18][NH:17][CH2:16]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][C:31]=2[C:33](O)=[O:34])[CH:26]=[CH:25]1.Cl.CN(C)CCCN=C=NCC>CN(C1C=CN=CC=1)C.C(Cl)Cl>[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][C:31]=2[C:33]([N:17]2[CH2:18][CH:19]([C:20]([F:21])([F:23])[F:22])[CH:15]([CH2:14][N:11]3[CH2:12][CH2:13][CH:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[CH2:9][CH2:10]3)[CH2:16]2)=[O:34])[CH:26]=[CH:25]1
Reactant: O=C(O)c1cccc2cc[nH]c12
Reactant: Fc1ccc(C2CCN(CC3CNCC3C(F)(F)F)CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(c1cccc2cc[nH]c12)N1CC(CN2CCC(c3ccc(F)cc3)CC2)C(C(F)(F)F)C1

Procedure:
A solution of 0.12 g (0.36 mmol) of 3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(RS)-(trifluoromethyl)pyrrolidine, 0.069 g (0.43 mmol) of indole-7-carboxylic acid, 0.088 g (0.72 mmol) of DMAP and 0.097 g (0.5 mmol) of 1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (Aldrich) in 10 mL of CH2Cl2 was stirred at rt for 4 h. The reaction mixture was concentrated and the residue was purified by chromatography (silica, acetone:hexanes, 1:5) to give the title compound. 1H NMR (key peaks) (CDCl3) δ9.96 (s, 1H), 7.82 (d, 1H, J=8.0 Hz), 7.44 (d, 1H, J=7.5 Hz), 7.32 (t, 1H, J=3.0 Hz), 7.17-7.21 (m, 3H), 7.03 (t, t, 2H, J=8.5 Hz), 6.62-6.63 (m, 1H); Mass Spectrum (ESI) m/e=474 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](=O)[N:13]=1.Cl.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][NH2:29])=[CH:24][CH:23]=1.C(N(CC)CC)C>C(O)C>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([C:11]2[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=2[OH:9])[N:28]([C:25]2[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[CH:23][CH:24]=2)[N:29]=1
Reactant: COc1ccc(NN)cc1
Reactant: O=c1nc(-c2ccccc2O)oc2ccccc12
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc(-n2nc(-c3ccccc3O)nc2-c2ccccc2O)cc1

Procedure:
5 g of 2-(2-hydroxyphenyl)benz[e][1,3]oxazin-4-one, 3.7 g of 4-methoxyphenylhydrazine hydrochloride and 3 ml of triethylamine are boiled under reflux for 2 h in 75 ml of ethanol. The mixture is cooled, poured onto water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. The residue is crystallized from isopropanol. After drying, 3,5-bis(2-hydroxyphenyl)-1-(4-methoxyphenyl)-1H-[1,2,4]triazole remains as colorless crystals of m.p. 179-181° C.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)C.CC(C)=O.S(=O)(=O)(O)O>O>[F:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][CH:4]=[O:3])=[CH:8][CH:9]=1
Reactant: CCOC(COc1ccc(F)cc1)OCC
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: O
Product: O=CCOc1ccc(F)cc1
Temperature: 25 °C
Yield: 93.9 %

Procedure:
A mixture of 4-fluorophenoxyacetaldehyde diethyl acetal (30.0 g., 0.131 mole) acetone (150 ml.), water (150 ml.), and concentrated sulfuric acid (0.8 ml.) is refluxed overnight (ca. 16 hours). The mixture is allowed to cool to room temperature, and is then extracted with methylenechloride four times. The combined extracts are washed with aqueous sodium bicarbonate and dried over anhydrous magnesium sulfate. The solvent is stripped off on a rotary evaporator and the oil residue is subsequently distilled in vacuo at 70°/0.05 mm to give the title compound (19.0 g., 0.123 mole, 94%). ir (neat) 3.23, 3.50, 3.63, 5.71, 6.62, 7.00, 8.00, 8.24, 9.07, 9.38, 12.03, 12.51, 13.12μ; pmr (CCl4) δ 4.37 (2H, d, J=1Hz), 6.6-7.1 (4H, m), 9.68 (1H, t, J=1Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([N:28]5[CH2:33][C@H:32]([CH3:34])[NH:31][C@H:30]([CH3:35])[CH2:29]5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1.Br[CH2:37][CH2:38][F:39].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([N:28]5[CH2:33][C@H:32]([CH3:34])[N:31]([CH2:37][CH2:38][F:39])[C@H:30]([CH3:35])[CH2:29]5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1
Reactant: C[C@@H]1CN(c2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)C[C@H](C)N1
Reactant: FCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C[C@@H]1CN(c2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)C[C@H](C)N1CCF
Temperature: 120 °C
Reaction time: 1 h
Yield: 27.7 %

Procedure:
A mixture of 2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (150 mg 0.3 mmol), 1-Bromo-2-fluoro-ethane (65 mg, 0.45 mmol) and Cesium carbonate (200 mg, 0.6 mmol) in N,N-Dimethyl-formamide (2 mL) was stirred at 120° C. for 1 h under the irradiation of microwave. The reaction mixture was filtered over celite and purified by pre-TLC (Hexanes/EtOAc=1:1) to afford 45 mg of 315 (yield: 28%). 1H NMR (CDCl3, 400 MHz): δ8.23 (s, 1H), 7.51-7.46 (m, 1H), 7.10-6.93 (m, 4H), 6.46 d, J=8.8 Hz, 1H), 4.52 (t, J=5.6 Hz, 2H), 4.40 (t, J=5.6 Hz, 2H), 4.18 (t, J=4.8 Hz, 2H), 3.85-3.82 (m, 2H), 3.07-2.94 (m, 4H), 2.70 (d, J=6.0 Hz, 2H), 2.55-2.49 (m, 2H), 1.22-1.34 (d, J=6.0 Hz, 6H). LC-MS (ESI): m/z=541 [M+H]+
Reaction SMILES: CC([CH:5]1[CH2:10][N:9]([CH2:11][CH2:12][C:13]2[CH:22]=[CH:21][C:16]3[C:17](=[O:20])[O:18][CH2:19][C:15]=3[C:14]=2[CH3:23])[CH2:8][CH2:7][N:6]1C([O-])=O)(C)C.[ClH:27]>O1CCOCC1>[ClH:27].[CH3:23][C:14]1[C:15]2[CH2:19][O:18][C:17](=[O:20])[C:16]=2[CH:21]=[CH:22][C:13]=1[CH2:12][CH2:11][N:9]1[CH2:10][CH2:5][NH:6][CH2:7][CH2:8]1
Reactant: Cc1c(CCN2CCN(C(=O)[O-])C(C(C)(C)C)C2)ccc2c1COC2=O
Agent: Cl
Solvent: C1COCCO1
Product: Cc1c(CCN2CCNCC2)ccc2c1COC2=O

Procedure:
1,1-Dimethylethyl-4-[2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazine-1-carboxylate (245 mg) was treated with 4N HCl in dioxane solution and the reaction was monitored until completion. The mixture was concentrated to afford 4-methyl-5-(2-piperazin-1-ylethyl)-2-benzofuran-1(3H)-one hydrochloride. The hydrochloride can be converted to free base as needed by partitioning between organic solvent (EtOAc, DCM, or 30% IPA/CHCl3) and saturated Na2CO3 solution. 1H-NMR (500 MHz, DMSO) δ ppm 12.4 (broad, 1H), 9.80 (broad, 2H), 7.71 (d, J=7.5 Hz, 1H), 5.53 (d, J=7.5 Hz, 1H), 5.44 (s, 2H), 3.81 (m, 2H), 3.64-3.27 (m, 10H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[Cl:20][C:21]1[CH:22]=[C:23]([S:28](Cl)(=[O:30])=[O:29])[CH:24]=[C:25]([Cl:27])[CH:26]=1>>[Cl:27][C:25]1[CH:24]=[C:23]([S:28]([NH:19][C:4]2[CH:5]=[N:6][C:7]([O:8][C:9]3[CH:10]=[N:11][C:12]4[C:17]([CH:18]=3)=[CH:16][CH:15]=[CH:14][CH:13]=4)=[C:2]([Cl:1])[CH:3]=2)(=[O:29])=[O:30])[CH:22]=[C:21]([Cl:20])[CH:26]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Reactant: Nc1cnc(Oc2cnc3ccccc3c2)c(Cl)c1
Product: O=S(=O)(Nc1cnc(Oc2cnc3ccccc3c2)c(Cl)c1)c1cc(Cl)cc(Cl)c1

Procedure:
The title compound was prepared by reacting 5-chloro-6-(quinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 1) and 3,5-dichlorobenzene-1-sulfonyl chloride.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[CH3:9][C:10]([CH3:15])([CH3:14])[C:11](Cl)=[O:12].O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:9][C:10]([CH3:15])([CH3:14])[C:11]([NH:8][C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][N:5]=1)=[O:12]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1ccnc(N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1ccnc(NC(=O)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Methyl-pyridin-2-ylamine (30 g, 0.28 mol) was dissolved in DCM (300 mL) and treated with TEA (41 mL) followed by trimethylacetyl chloride (38 mL) via a dropping funnel over 30 min. The mixture was allowed to stir overnight at RT, then poured into a separatory funnel with water (100 mL) and satd. aq. NaHCO3 (75 mL). The organic layer was extracted, washed with satd. aq. NaHCO3 (75 mL), dried over Na2SO4, and concentrated to give solid 2,2-dimethyl-N-(4-methyl-pyridin-2-yl)-propionamide (42 g, 0.22 mol). 1H NMR (CDCl3) δ 8.09 (m, 2 H), 7.93 (br s, 1 H), 6.83 (m, 1 H), 2.33 (s, 3H), 1.29 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[Br:18][C:19]1[O:23][C:22]([C:24](O)=[O:25])=[CH:21][CH:20]=1>>[Br:18][C:19]1[O:23][C:22]([C:24]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[O:25])=[CH:21][CH:20]=1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: O=C(O)c1ccc(Br)o1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccc(Br)o4)cc23)CC1
Yield: 47.5 %

Procedure:
Beginning with 10.0 mg (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 25.0 mg (0.131 mMol) 5-bromo-2-furoic acid, 8.4 mg (48%) of the title compound were recovered.
Reaction SMILES: [C:1]1([NH2:11])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>CCO>[C:1]1([NH:11][C:12](=[O:14])[CH3:13])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Nc1cccc2c1CCCC2
Reactant: CC(=O)OC(C)=O
Solvent: CCO
Product: CC(=O)Nc1cccc2c1CCCC2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 97.1 %

Procedure:
To a solution of commercially available 5,6,7,8-tetrahydronaphthylamine (2 g, 14 mmol) in EtOH (5 mL) at rt was slowly added acetic anhydride (1.28 mL, 13.6 mmol). After addition, the reaction mixture was stirred at rt for 5 min. The resulting suspension was filtered, the collected solid washed with hexane (5×) and dried under vacuum to furnish the title compound (2.5 g) as an off-white solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]([OH:30])[C@H:11]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:31][S:32](Cl)(=[O:34])=[O:33].O>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:31][S:32]([O:30][C@@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[C@H:11]([NH:22][C:23]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:29])[C:12]1[CH:13]=[CH:14][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:16][CH:17]=1)(=[O:34])=[O:33]
Reactant: CC(C)(C)OC(=O)N[C@H](c1ccc(C(F)(F)F)cc1)[C@@H](O)CO[Si](C)(C)C(C)(C)C
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](c1ccc(C(F)(F)F)cc1)[C@H](CO[Si](C)(C)C(C)(C)C)OS(C)(=O)=O
Temperature: 25 °C
Yield: 88 %

Procedure:
To a solution of tert-butyl (1R,2R)-3-(tert-butyldimethylsilyloxy)-2-hydroxy-1-(4-(trifluoromethyl)phenyl)-propylcarbamate (14.50 g, 32.3 mmol) in 50 mL DCM at −15° C. were added TEA (4.57 g, 45.2 mmol), N,N-dimethylpyridin-4-amine (0.197 g, 1.61 mmol), and methanesulfonyl chloride (3.26 mL, 41.9 mmol). The mixture was allowed to warm to room temperature. Distilled water (200 mL) was added, and the aqueous phase was extracted into DCM (2×200 mL). The combined organic layers were washed with cold 5% HCl, saturated sodium bicarbonate, and water. The resulting product was then chromatographed eluting with 15% EtOAc in hexane. After removing the solvent, the product was obtained as a colorless oil (15 g, yield=88%). 1H NMR (400 MHz, CD3OD) δ ppm 0.11 (d, J=3.91 Hz, 6 H) 0.93-0.98 (m, 9 H) 1.44 (s, 9 H) 2.84 (s, 3H) 3.80-3.87 (m, 2H) 4.84-4.86 (m, 1H) 5.13 (d, J=5.28 Hz, 1H) 7.58 (d, J=8.02 Hz, 2H) 7.69 (d, J=8.22 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][CH2:6]2.C(OC(=O)C)(=O)C.[N+:27]([O-])([OH:29])=[O:28].C(=O)(O)[O-].[Na+]>[N+](C)([O-])=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[N+:27]([O-:29])=[O:28])[CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][CH2:6]2
Reactant: O=[N+]([O-])O
Reactant: COc1ccc2c(c1)CCN(C(=O)OC(C)(C)C)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: C[N+](=O)[O-]
Product: COc1cc2c(cc1[N+](=O)[O-])CN(C(=O)OC(C)(C)C)CC2
Reaction time: 3 h

Procedure:
To a solution of the product of Example 53D (2.46 g, 9.35 mmol) in nitromethane (30 mL) at −10° C. was added acetic anhydride (5.7 g, 56.1 mmol) and concentrated nitric acid (0.88 g, 14 mmol). After stirring for 3 hours, the mixture was adjusted to pH 7 with aqueous sodium bicarbonate solution and extracted with dichloromethane (2×100 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash chromatography eluting with 5:1 hexane:ethyl acetate to give the title compound. MS: 309 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.Br[CH2:14][C:15]#[C:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[CH2:14]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1)[C:15]#[C:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: O=c1ccc2ccc(O)cc2o1
Reactant: CCCCCC#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCCCCC#CCOc1ccc2ccc(=O)oc2c1

Procedure:
A solution of 7-hydroxycoumarin (0.324 g, 1.99 mmol) and 1-bromo-2-octyne (0.378 g, 1.99 mmol) in 200 ml of acetone was heated under reflux in the presence of anhydrous potassium carbonate (3 grams) for 24 hours. After the reflux period, the reaction mixture was cooled, filtered and the collected solid was washed with fresh acetone. The acetone washings and the filtrate were combined and the solvent evaporated under reduced pressure to yield a pale yellow viscous liquid. The crude product was dissolved in a minimum amount of ethyl acetate and petroleum ether added until the solution became cloudy. The cloudy solution was concentrated under reduced pressure and a white precipitate formed. This precipitate was collected by vacuum filtration and recrystallized from aqueous methanol to yield the title compound as shiny, colorless plates, m.p. 74°-75° C., 0.245 g, 50%. 1H-NMR: 0.8-2.2 (m, 11H, (CH2)4CH3), 4.7 (t, 2H, OCH2C C), 6.2 (d, 1H, C3 --H J=9.3 Hz), 6.8 (dd, 1H, C6 --H), 6.9 (d, 1H, C8 --H, J=2.1 Hz), 7.4 (dd, 1H, C5 --H, J=8.1 Hz), 7.6 (d, 1H, C4 --H, J=9.3 Hz).