Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](/[C:3](=[C:9](\OCC)/[CH3:10])/[C:4]([O:6][CH2:7][CH3:8])=O)#[N:2].[OH2:14].[NH2:15][NH2:16]>C(O)(=O)C>[NH2:2][C:1]1[NH:16][N:15]=[C:9]([CH3:10])[C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:14]
Reactant: CCOC(=O)/C(C#N)=C(\C)OCC
Reactant: NN
Reactant: O
Solvent: CC(=O)O
Product: CCOC(=O)c1c(C)n[nH]c1N
Temperature: 110 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
A mixture of (E)-ethyl 2-cyano-3-ethoxybut-2-enoate (4.4 g, 24.02 mmol, 1.00 equiv) and hydrazine hydrate (3 mL) in acetic acid (40 mL) was stirred at 110° C. for 2 h. The resulting mixture was cooled to room temperature and concentrated under vacuum. Water (20 mL) was added to the residue and the resulting solution extracted with 2×20 mL of dichloromethane. The combined organic layers was washed with 2×40 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with 0-50% of ethyl acetate in petroleum ether to give 2.1 g (52%) of ethyl 5-amino-3-methyl-1H-pyrazole-4-carboxylate as a yellow oil. 1H-NMR (300 MHz, CDCl3): δ 6.76 (br s, 2H), 4.30 (q, J=7.2 Hz, 2H), 2.41 (s, 3H), 1.35 (t, J=7.2 Hz, 3H) ppm. LCMS (method D, ESI): RT=0.98 min, m/z=170.0 [M+H]+.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]=O)[CH:3]=1.[NH2:11][CH2:12][CH2:13][CH2:14][NH:15][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23].[BH4-].[Na+]>CO>[C:4]1([CH2:5][NH:11][CH2:12][CH2:13][CH2:14][NH:15][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[CH:7]=[CH:8][CH:9]=[C:2]([CH2:1][NH:11][CH2:12][CH2:13][CH2:14][NH:15][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24])[CH:3]=1
Reactant: O=Cc1cccc(C=O)c1
Reactant: CC(C)(C)OC(=O)NCCCNCCCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCCNCCCNCc1cccc(CNCCCNCCCNC(=O)OC(C)(C)C)c1
Reaction time: 24 h

Procedure:
Isophthalaldehyde (1.07 g, 7.99 mmol) and MeOH (50 mL) were added to a round-bottom flask. To the solution was added tert-butyl (3-((3-aminopropyl)amino)propyl)carbamate (3.69 g, 16.0 mmol) and the reaction mixture was stirred for 24 h. Sodium borohydride (1.21 g, 32.0 mmol) was added portionwise and stirred for 1 h. The reaction mixture was concentrated under reduced pressure, and aq. NaOH (10%, 150 mL) and EtOAc (150 mL) were added. The layers were separated, and the aqueous layer was extracted with EtOAc (150 mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the desired product as a clear oil. The intermediate was carried forward without further purification.
Reaction SMILES: CN(C=[C:5]([C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][C:12]=1[N+:21]([O-:23])=[O:22])[C:6](=[O:10])[CH2:7][CH2:8][CH3:9])C>O1CCOCC1>[N+:21]([C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][C:11]=1[CH2:5][C:6](=[O:10])[CH2:7][CH2:8][CH3:9])[C:15]([O:17][CH3:18])=[O:16])([O-:23])=[O:22]
Reactant: CCCC(=O)C(=CN(C)C)c1ccc(C(=O)OC)cc1[N+](=O)[O-]
Solvent: C1COCCO1
Product: CCCC(=O)Cc1ccc(C(=O)OC)cc1[N+](=O)[O-]
Yield: 89.2 %

Procedure:
A solution of methyl 4-(1-dimethylaminomethylene-2-oxopentyl)-3-nitrobenzoate (172 mg) in dioxane (9 ml) was refluxed For 4 days. The resulting mixture was evaporated in vacuo, and the residue was purified by thin layer chromatography with a mixture of hexane and ethyl acetate (2:1) to give methyl 3-nitro-4-(2-oxopentyl)benzoate (127 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)=[CH:12][C:13]#[N:14])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[S:22](Cl)(=[O:25])(=[O:24])[NH2:23].C(Cl)Cl.O>CC(N(C)C)=O>[C:13]([CH:12]=[C:11]([C:15]1[CH:16]=[C:17]([O:21][S:22](=[O:25])(=[O:24])[NH2:23])[CH:18]=[CH:19][CH:20]=1)[C:5]1[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)#[N:14]
Reactant: COc1cc(OC)cc(C(=CC#N)c2cccc(O)c2)c1
Reactant: NS(=O)(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Solvent: O
Product: COc1cc(OC)cc(C(=CC#N)c2cccc(OS(N)(=O)=O)c2)c1
Reaction time: 15 h
Yield: 89 %

Procedure:
To a solution of 3-(3,5-dimethoxy-phenyl)-3-(3-hydroxy-phenyl) -acrylonitrile (280 mg, 1 mmol) in dimethylacetamide (4 mL) was added a solution of sulfamic chloride in methylene chloride (1 mL, 2.3 mmol/mL, 2.3 mmol) at room temperature. After 15 h, water (30 mL) was added to the mixture. The aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers was washed with water (50 mL), brine (50 mL) and dried over magnesium sulfate. Removal of solvent and chromatography gave (E/Z) sulfamic acid 3-[2-cyano-1-(3,5-dimethoxy-phenyl)-vinyl]-phenyl ester (320 mg, 89% yield): mp, 301-303° C.; 1H NMR (DMSO-d6) δ 3.73 (s, 6H, 2CH3), [3.76 (s)], [6.41 (s)], 6.44 (s, 1H, CH), 6.49-6.51 (m, 2H, Ar), 6.63-6.67 (m, 1H, Ar), 7.22 (brs, 1H, Ar), 7.38-7.65 (m, 3H, Ar), 8.07 (brs, 2H, NH2); Anal. Calcd for C17H16N2O5S+0.1H2O: C, 56.38; H, 4.51; N, 7.73. Found: C, 56.23; H, 4.36; N, 7.55.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[O:20]1[CH2:24][CH2:23][CH2:22][CH:21]1[CH2:25][NH2:26]>>[O:20]1[CH2:24][CH2:23][CH2:22][CH:21]1[CH2:25][NH:26][S:16]([C:14]1[S:15][C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])=[CH:12][CH:13]=1)(=[O:18])=[O:17]
Reactant: NCC1CCCO1
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Product: CCc1cc(-c2ccc(S(=O)(=O)NCC3CCCO3)s2)c(C)[nH]c1=O
Yield: 39.5 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with (tetrahydrofuran-2-yl)methylamine as described in Step 5, Example 24 to give the title compound as a yellow solid (39.5% yield). LC/MS: RT 2.63 min; m/e 383 (M+H); 1H NMR (CDCl3, δ, ppm): 11.21 (H, br), 7.50 (1H, d), 7.23 (1H, s), 6.90 (1H, d), 4.98 (1H, t), 4.00 (1H, q), 3.80 (2H, m), 3.30 (1H, m), 3.05 (1H, m), 2.6 (2H, dd), 2.40 (3H, s), 1.87 (3H, m), 1.23 (3H, t).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:43])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([O:34][CH2:35]C(OC(C)(C)C)=O)[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][CH:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2].C[Mg]Br.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[OH:34][C:31]([CH3:32])([CH3:30])[CH2:35][O:34][C@H:31]1[CH2:32][CH2:33][C@H:28]([N:18]2[C:17](=[O:43])[C:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:4]4[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=4)=[CH:10][CH:11]=3)=[C:21]([CH2:22][CH2:23][CH3:24])[N:20]3[N:25]=[CH:26][CH:27]=[C:19]23)[CH2:29][CH2:30]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)OC(C)(C)C)CC2)c2ccnn12
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2ccnn12
Reaction time: 2 h

Procedure:
To a solution of tert-butyl [(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propylpyrazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]acetate (38.0 g) in tetrahydrofuran (200 mL) was added dropwise methylmagnesium bromide (1 M tetrahydrofuran solution, 200 mL) at 0° C., and the mixture was stirred for 2 hr. The mixture was diluted with ethyl acetate, and then saturated aqueous ammonium chloride solution was added. The mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (32.1 g, 91%).
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1)(=[O:4])=[O:3].[N+:17]([C:20]1[CH:21]=[C:22](CCO)C=[CH:24][CH:25]=1)([O-:19])=[O:18].[N+](C1C=CC(S(Cl)(=O)=O)=CC=1)([O-])=O>>[N+:17]([C:20]1[CH:21]=[CH:22][C:1]([S:2]([O:5][CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=2)(=[O:3])=[O:4])=[CH:24][CH:25]=1)([O-:19])=[O:18]
Reactant: CS(=O)(=O)OCCc1cccc([N+](=O)[O-])c1
Reactant: O=[N+]([O-])c1cccc(CCO)c1
Agent: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Product: O=[N+]([O-])c1ccc(S(=O)(=O)OCCc2cccc([N+](=O)[O-])c2)cc1
Yield: 68 %

Procedure:
The title compound was prepared in 68% yield using a similar procedure to description D4 starting from 2-(3-nitro-phenyl)ethanol and 4-nitrobenzenesulfonyl chloride.
Reaction SMILES: [CH:1]1[C:13]2[N:12]([C:14]3[CH:19]=[C:18]([CH2:20]O)[C:17]([O:22][CH2:23][CH:24]([CH2:29][CH3:30])[CH2:25][CH2:26][CH2:27][CH3:28])=[CH:16][C:15]=3CO)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.O=P(Cl)(Cl)[Cl:35].CN(C=O)C.[CH:43]([Cl:46])(Cl)Cl>>[CH:1]1[C:13]2[N:12]([C:14]3[CH:19]=[C:18]([CH2:20][Cl:35])[C:17]([O:22][CH2:23][CH:24]([CH2:29][CH3:30])[CH2:25][CH2:26][CH2:27][CH3:28])=[CH:16][C:15]=3[CH2:43][Cl:46])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: ClC(Cl)Cl
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCC(CC)COc1cc(CO)c(-n2c3ccccc3c3ccccc32)cc1CO
Solvent: CN(C)C=O
Product: CCCCC(CC)COc1cc(CCl)c(-n2c3ccccc3c3ccccc32)cc1CCl
Reaction time: 12 h
Yield: 53 %

Procedure:
In a single-neck flask, 1.2 g (2.8×10−3 mol) of 2-(N-carbazolyl)-5-(2′-ethylhexyloxy)-1,4-bis(hydroxymethyl) benzene synthesized in the above step (7) was dissolved in 250 ml of absolute chloroform, and 0.26 ml (2.8×10−3 mol) of POCl3 and 0.21 ml (2.8×10−3 mol) of DMF stirred in 150 ml of chloroform were slowly added. The reaction was left to stand at room temperature for 12 hours, and then the reaction solution was washed several times with water, and water in the organic layer was removed with MgSO4 and vacuum-distilled. The oil so produced was purified by column chromatography using a hexane developing solution. Yield: 53% (0.7 g).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[OH:20].C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[Br:1][C:2]1[C:3]([O:20][C:14]2[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=2[F:12])=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: Oc1ccc(F)cc1F
Reactant: O=[N+]([O-])c1cnc(Cl)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cnc(Oc2ccc(F)cc2F)c(Br)c1
Yield: 94.2 %

Procedure:
A mixture of 3-bromo-2-chloro-5-nitropyridine (0.237 g, 1 mmol), 2,4-difluorophenol (0.13 g, 1 mmol) and cesium carbonate (0.326 g, 1 mmol) in dimethyl sulfoxide (2 mL) was reacted in a Biotage microwave reactor at 80° C. for 30 minutes. The reaction mixture was partitioned between ethyl acetate and water, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0-20% ethyl acetate in heptanes) to provide 0.312 g (94%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([CH:6]=[C:7]([CH3:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].[Br:19]Br.CC1C(C)=NC2C(C=1)=CC=CC=2>ClC1C=CC=CC=1Cl.O>[Br:19][CH2:12][C:11]1[C:2]([Cl:1])=[CH:3][CH:4]=[C:5]2[C:10]=1[N:9]=[CH:8][C:7]([CH3:13])=[CH:6]2
Reactant: BrBr
Reactant: Cc1cnc2c(C)c(Cl)ccc2c1
Agent: CC(=O)[O-]
Agent: Cc1cc2ccccc2nc1C
Agent: [Na+]
Solvent: O
Solvent: Clc1ccccc1Cl
Product: Cc1cnc2c(CBr)c(Cl)ccc2c1

Procedure:
9.6 g of 7-chloro-3,8-dimethylquinoline are dissolved in 850 g of 1,2-dichlorobenzene, 6.2 g of sodium acetate, dissolved in 150 ml of water, and then 8 g of bromine are added, and the mixture is exposed to a 150 watt low pressure mercury lamp for from 5 to 6 hours at 15° C. The yield, determined chromatographically, is 80% of theory, based on converted dimethylquinoline. The selectivity of the reaction is 88% at a conversion of 91%. Table 1 sumarizes the result of varying the reaction conditions.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:23])[C:6]=1[C:7]1[CH:8]=[C:9]([NH2:22])[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][N:16]1[CH2:19][CH:18]([O:20][CH3:21])[CH2:17]1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:23])[C:6]=1[C:7]1[CH:8]=[C:9]([NH:22][C:32]([NH:31][C:28]2[CH:29]=[CH:30][C:25]([Cl:24])=[CH:26][CH:27]=2)=[O:33])[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][N:16]1[CH2:17][CH:18]([O:20][CH3:21])[CH2:19]1
Reactant: COC1CN(CCOc2ccc(N)cc2-c2c(Br)cnn2C)C1
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: ClCCl
Product: COC1CN(CCOc2ccc(NC(=O)Nc3ccc(Cl)cc3)cc2-c2c(Br)cnn2C)C1
Reaction time: 2 h
Yield: 92 %

Procedure:
To a solution of 3-(4-bromo-1-methyl-1H-pyrazol-5-yl)-4-(2-(3-methoxyazetidin-1-yl)ethoxy)benzenamine (39.2 mg, 0.103 mmol) in CH2Cl2 (4 mL) was added 4-chlorophenyl isocyanate (18.0 mg) and stirred for two hours. The resulting material was purified by HPLC. The product was dried in vacuo to afford the title compound as a white solid (50.7 mg, 92%). LCMS m/z (%)=534 (M+H79Br, 74), 536 (M+H81Br, 100). 1H NMR (400 MHz, DMSO-d6) δ: 8.79 (bs, 1H), 8.70 (bs, 1H), 7.60 (s, 1H), 7.52 (dd, J=8.95, 2.71 Hz, 1H), 7.47 (d, J=8.94 Hz, 2H), 7.35 (d, J=2.70 Hz, 1H), 7.31 (d, J=8.91 Hz, 2H), 7.09 (d, J=9.03 Hz, 1H), 4.02-3.86 (m, 2H), 3.83 (quint, J=5.80 Hz, 1H), 3.66 (s, 3H), 3.35-3.29 (m, 1H), 3.27-3.18 (m, 1H), 3.08 (s, 3H), 2.74-2.56 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:16]2[CH:17]=[C:18](C=CC(Cl)=O)[CH:19]=[CH:20][CH:21]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[OH:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1>>[OH:27][C:28]1[CH:34]=[CH:33][C:31]([NH:32][C:28](=[O:27])[C:29]([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([C:3]3[C:2]([CH3:1])=[CH:11][C:10]4[C:9]([CH3:12])([CH3:13])[CH2:8][CH2:7][C:6]([CH3:14])([CH3:15])[C:5]=4[CH:4]=3)[CH:17]=2)=[CH2:30])=[CH:30][CH:29]=1
Reactant: Cc1cc2c(cc1-c1cccc(C=CC(=O)Cl)c1)C(C)(C)CCC2(C)C
Reactant: Nc1ccc(O)cc1
Product: C=C(C(=O)Nc1ccc(O)cc1)c1cccc(-c2cc3c(cc2C)C(C)(C)CCC3(C)C)c1

Procedure:
In similar manner to Example 27(a), by reaction of 1.2 g (3.2 mmol) of 3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)phenylacryloyl chloride with 349 mg (3.2 mmol) of 4-hydroxyaniline, 810 mg of (57%) of N-(4-hydroxyphenyl)-3-(3,5,5,8,8-pentamethyl-5,6,7,6-tetrahydro-2-naphthyl)phenylacrylamide are obtained, with a melting point of 240-1° C.
Reaction SMILES: O[C:2]1([CH:7]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=2)[C:8]2[N:9]=[N:10][NH:11][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1.S(Cl)(Cl)=O>ClCCl>[C:2]1(=[C:7]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=2)[C:8]2[N:9]=[N:10][NH:11][CH:12]=2)[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: N#Cc1ccc(C(c2c[nH]nn2)C2(O)CCCC2)cc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: N#Cc1ccc(C(=C2CCCC2)c2c[nH]nn2)cc1
Reaction time: 2 h
Yield: 31.7 %

Procedure:
7.1 g of crude 4-[1-hydroxycyclopent-1-yl-1-(1,2,3-triazolyl)methyl]benzonitrile is dissolved at 0° in 50 ml of dichloromethane and stirred with 24 ml of thionyl chloride for 1 hour at 0°. Then the mixture is concentrated to dryness under vacuum, dissolved in 50 ml of dichloromethane, stirred with 32 ml of triethylamine for 2 hours, diluted with water, extracted three times with ethyl acetate, washed with water, dried over sodium sulfate, concentrated to dryness under vacuum, and chromatographed on silica gel with hexane/ethyl acetate, yielding 2.1 g of 4-[1-cyclopentylidene-1-(1,2,3-triazolyl)methyl]benzonitrile as the tree base, 108°-109° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:20])[N:7]3[CH:13]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH2:12][O:11][CH:8]32)=[CH:4][CH:3]=1.C([SiH](CC)CC)C.CCCCCC.C(OCC)(=O)C>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[OH:11][CH2:12][CH:13]([N:7]1[CH2:8][C:9]2[C:5](=[CH:4][CH:3]=[C:2]([CH3:1])[CH:10]=2)[C:6]1=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Cc1ccc2c(c1)C1OCC(c3ccccc3)N1C2=O
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: CC[SiH](CC)CC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1ccc2c(c1)CN(C(CO)c1ccccc1)C2=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
8-methyl-3-phenyl-2,3-dihydro-9bH-oxazolo[2,3-a]isoindol-5-one (5.20 g, 19.60 mmol) was taken up in anhydrous DCM (100 mL) under argon and cooled to minus 78EC. Triethylsilane (9.12 g, 78.40 mmol, 12.52 mL) was added via syringe followed by titanium tetrachloride in DCM (1.0M, 58.80 mmol, 58.80 mL). The solution was stirred at minus 78EC for 5 h then allowed to warm to room temp and stir for 12 h. The reaction was slowly poured into ice and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with saturated sodium bicarbonate, water, brine and dried over anhydrous magnesium sulfate. The solution was filtered and the solvent removed under reduced pressure. The product was isolated by flash chromatography. (1:1 hexane/ethyl acetate) Yield 4.72 g. 1H NMR (CDCl3, 300 MHz): δ 2.40 (s, 3H), 4.12-4.42 (m, 5H), 5.31 (dd, J=4, 8 Hz, 1H), 7.10-7.39 (m, 7H), 7.67 (d, J=8, 1H).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11]3=[CH:13][S:14][CH:15]=[C:10]3[C:9](SC)=[N:8][C:7]=2[CH:18]=1.O.[OH:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C(O)(=O)C>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11]3=[CH:13][S:14][CH:15]=[C:10]3[C:9]([N:26]3[CH2:27][CH2:28][N:23]([CH2:22][CH2:21][OH:20])[CH2:24][CH2:25]3)=[N:8][C:7]=2[CH:18]=1
Reactant: CSC1=Nc2cc(SC)ccc2Nc2cscc21
Reactant: OCCN1CCNCC1
Solvent: O
Solvent: CC(=O)O
Product: CSc1ccc2c(c1)N=C(N1CCN(CCO)CC1)c1cscc1N2

Procedure:
A solution of 7,10-bis(methylthio)-4H-thieno-[3,4-b][1,5]benzodiazepine in excess N-(2-hydroxyethyl)-piperazine and glacial acetic acid is heated at 140°-160°C. for 2 days. The solution is poured into water and the product is collected.
Reaction SMILES: C([Li])CCC.[C:6]([Si:8]([CH3:11])([CH3:10])[CH3:9])#[CH:7].[N:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[N:14][CH:13]=1>C1COCC1.O>[N:12]1[CH:17]=[CH:16][C:15]([C:18]([OH:20])([C:7]#[C:6][Si:8]([CH3:11])([CH3:10])[CH3:9])[CH3:19])=[N:14][CH:13]=1
Reactant: CC(=O)c1ccncn1
Reactant: C#C[Si](C)(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(O)(C#C[Si](C)(C)C)c1ccncn1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of n-butyllithium (2.5M in hexane, 2.1 ml, 5.32 mmol) in THF (3 mL) at −78° C. was added dropwise ethynyl(trimethyl)silane (0.7 mL, 4.91 mmol). The reaction was stirred at −78° C. for 10 minutes and then 1-(pyrimidin-4-yl)ethanone (0.5 g, 4.09 mmol) was added in more THF (2 mL). The reaction was stirred at −78° C. to RT overnight. The mixture was diluted with water and the volatiles removed in vacuo. The product was then extracted with CHCl3:IPA (2:1 ratio, 2×25 mL). The organic phase was washed with water (20 mL), brine (20 mL); dried over Na2SO4 and the solvent removed in vacuo. Purification by column chromatography (Biotage), eluting with 0-100% EtOAc-heptane afforded 2-(pyrimidin-4-yl)-4-(trimethylsilyl)but-3-yn-2-ol; 1H NMR (500 MHz, CDCl3) delta 0.19 (9H, s), 1.78 (3H, s), 4.65 (1H, s), 7.65 (1H, dd, J=5.20, 1.10 Hz), 8.79 (1H, d, J=5.36 Hz), 9.20 (1H, s); LC-MS: m/z=+221 (M+H)+; and 2-(pyrimidin-4-yl)but-3-yn-2-ol; 1H NMR (500 MHz, CDCl3) delta 1.79 (3H, s), 2.62 (1H, s), 4.99 (1H, s), 7.67 (1H, dd, J=5.28, 0.87 Hz), 8.77 (1H, d, J=5.36 Hz), 9.19 (1H, s); LC-MS: m/z=+148.95 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[NH2:13])[C:6]([O:8][CH3:9])=[O:7].[Br:14]Br>CO.C(O)(=O)C>[Br:14][C:11]1[CH:10]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:12]=1[NH2:13])[C:6]([O:8][CH3:9])=[O:7]
Reactant: BrBr
Reactant: COC(=O)c1ccc(N)c(OC)c1
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1cc(Br)c(N)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 115.3 %

Procedure:
10.5 Grams (55 mmole) of methyl 3-methoxy-4-aminobenzoate was dissolved in 80 ml methanol, and 3.0 ml bromine (55 mmole) in 20 ml acetic acid was added dropwise at room temperature. The solution was stirred for three hours at room temperature and the solvents were evaporated under reduced pressure. The residue was treated with sodium bicarbonate solution and the product was filtered and air-dried to yield 16.5 grams of methyl 3-bromo-5-methoxy-4-aminobenzoate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.Cl[CH2:16][CH2:17][O:18][C:19](=[O:23])[C:20]([O-])=[O:21]>C(Cl)Cl>[O:21]=[C:20]([NH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)[C:19]([O:18][CH2:17][CH3:16])=[O:23]
Reactant: O=C([O-])C(=O)OCCCl
Reactant: Nc1cccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=O)Nc1cccnc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
To a solution 3-aminopyridine (3.00 g, 27.0 mmol) in methylene chloride (110 mL) at 23 ° C. was added triethylamine (7.53 mL, 54.0 mmol) and N,N-dimethylarninopyridine (330 mg, 2.70 mmol). The solution was cooled to 0° C. and chloroethyloxalate 4.42 g, 32.4 mmol) was added in a dropwise fashion. The reaction mixture was stirred at 0° C. for 2 hours and then quenched with water (30 mL) and partitioned. The organic portion was washed with 10% sodium bicarbonate solution (30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide 4.30 g of the title compound.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C1N=[CH:22][N:21](C(N2C=NC=C2)=O)[CH:20]=1.CNC>CN(C=O)C.C1COCC1.C(OCC)(=O)C>[CH3:20][N:21]([CH3:22])[C:16](=[O:18])[C@H:12]([CH:13]([CH3:15])[CH3:14])[NH:11][C:1]([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N(C)C
Reaction time: 0.83 h

Procedure:
To a stirred solution of 2.51 g (10 mmol) of Cbz-L-Valine (Bachem) in 20 mL of DMF was added 1.46 g (9 mmol) of CDI and the mixture was stirred for 50 min. To this mixture was added 6 mL (12 mmol) of dimethylamine (Aldrich) in 5 mL of THF and the reaction mixture was stirred for 18 hours. The mixture was taken up in 100 mL of ethyl acetate, washed with 10% HCl (3×40 mL), 10 mL of brine, and 20% potassium carbonate (2×50 mL), and dried over MgSO4. The mixture was filtered and concentrated to yield Cbz-L-valine N,N-dimethyl amide, which was hydrogenated under standard conditions with 10% Pd/C as the catalyst to remove the Cbz group and provide the title compound as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[C:16]([F:23])[CH:15]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:6][N:7]=1.[NH2:24][C@@H:25]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[CH:36]=1)[CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31].C(Cl)CCl.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[C:3]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH:24][C@@H:25]([C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[CH:36]=3)[CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:20])=[C:16]([F:23])[CH:15]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)NC[C@@H](N)c1cccc(Cl)c1
Reactant: Nc1ncc(C2CCOCC2)nc1-c1ccc(C(=O)O)c(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC[C@@H](NC(=O)c1ccc(-c2nc(C3CCOCC3)cnc2N)cc1F)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
To a solution of 4-(3-amino-6-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)-2-fluorobenzoic acid (35 mg, 0.110 mmol) in DMF (368 μL) was add (S)-tert-butyl (2-amino-2-(3-chlorophenyl)ethyl)carbamate (33.9 mg, 0.110 mmol), aza-HOBt (22.52 mg, 0.165 mmol), EDC (31.7 mg, 0.165 mmol), and DIEA (57.8 μL, 0.331 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was partitioned between EtOAc and water. The organic layer was washed by NaHCO3, water and brine, dried over anhydrous sodium sulfate, filtered off, and concentrated in vacuo yielding crude (S)-tert-butyl (2-(4-(3-amino-6-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)-2-fluorobenzamido)-2-(3-chlorophenyl)ethyl)carbamate (>99%).