Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[C:10]([Cl:12])[N:9]=[C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:7]=1)=[O:4].[C:19]1(/[CH:25]=[CH:26]/[CH2:27][N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:12][C:10]1[N:9]=[C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:31]2[CH2:32][CH2:33][N:28]([CH2:27]/[CH:26]=[CH:25]/[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:29][CH2:30]2)[CH:11]=1
Reactant: C(=C/c1ccccc1)\CN1CCNCC1
Reactant: O=C(CBr)Nc1cc(Cl)nc(-c2ccccc2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(CN1CCN(C/C=C/c2ccccc2)CC1)Nc1cc(Cl)nc(-c2ccccc2)n1
Reaction time: 3 h

Procedure:
To a stirred solution of 2-bromo-N-(6-chloro-2-phenylpyrimidin-4-yl)acetamide (0.80 g in 40 ml acetonitrile) was added [(2E)-3-phenylprop-2-enyl]piperazine (0.50 g in 10 ml acetonitrile). After 3 hrs, N,N-diisopropylethylamine was added (428 μl in 10 ml acetonitrile) and the reaction stirred for a further 2 hrs after which time a precipitate of the title compound appeared. This was used crude in the next step. m/z (ES+) 448 (MH)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:15]2=[N:16][C:17]3[C:18](=[C:19]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[CH:20]=[CH:21][CH:22]=3)[N:14]2[CH2:13][CH:12]([NH2:28])[CH2:11][CH2:10]1.C(N(CC)CC)C.[C:36](OC(=O)C)(=[O:38])[CH3:37].C(=O)(O)[O-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:15]2=[N:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[C:18]=3[N:14]2[CH2:13][CH:12]([NH:28][C:36](=[O:38])[CH3:37])[CH2:11][CH2:10]1
Reactant: CC(=O)OC(C)=O
Reactant: CCN(CC)c1cccc2nc3n(c12)CC(N)CCN3c1ccc(Cl)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCN(CC)c1cccc2nc3n(c12)CC(NC(C)=O)CCN3c1ccc(Cl)cc1Cl
Yield: 41.5 %

Procedure:
To a mixture of 1-(2,4-dichlorophenyl)-N7,N7-diethyl-2,3,4,5-tetrahydro-1H-[1,3]diazepino[1,2-a]benzimidazole-4,7-diamine (59.5 mg, 0.142 mmol) and triethylamine (0.0396 mL, 0.284 mmol) in tetrahydrofuran (1.4 mL) was added acetic anhydride (0.161 mL, 0.170 mmol) at 0° C. After the resultant mixture was stirred at 0° C. for 1 hr, aqueous sodium bicarbonate was added and the mixture was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 50-100% ethyl acetate/n-hexane gradient mixture to give a solid, which was recrystallized from ethyl acetate to afford the title compound as a colorless solid (27.1 mg, 0.0589 mmol, 41%).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[C:17]([N:18]2[N:22]=[CH:21][CH:20]=[N:19]2)=[CH:16][CH:15]=[C:14]([CH3:23])[N:13]=1)=[O:11].Br[C:25]1[C:30]([F:31])=[CH:29][C:28]([Cl:32])=[CH:27][N:26]=1>>[Cl:32][C:28]1[CH:29]=[C:30]([F:31])[C:25]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[C:17]([N:18]3[N:22]=[CH:21][CH:20]=[N:19]3)=[CH:16][CH:15]=[C:14]([CH3:23])[N:13]=2)=[O:11])=[N:26][CH:27]=1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)n1
Reactant: Fc1cc(Cl)cnc1Br
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc(Cl)cc2F)n1

Procedure:
The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone and 2-bromo-3-fluoro-5-chloropyridine. ESI-MS (m/z): 444 [M+1]+.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[N:13][C:12]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)[CH2:5][CH2:4]1.C([OH:31])(C)C>O1CCCC1.O.OOS([O-])=O.[K+]>[F:17][C:15]1[CH:14]=[N:13][C:12]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25]([CH3:26])=[O:31])[CH:20]=2)=[C:11]([CH:16]=1)[C:10]([NH:9][C@H:6]1[CH2:7][CH2:8][C@@H:3]([CH2:2][OH:1])[CH2:4][CH2:5]1)=[O:27]
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](CO)CC2)c1
Reactant: CC(C)O
Agent: O=S([O-])OO
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)c1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](CO)CC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-(cis-4-Hydroxymethyl-cyclohexyl)-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide (120 mg, 0.307 mmol) was dissolved in a solvent mixture of isopropyl alcohol (4 ml), tetrahydrofuran (1 ml) and water (0.5 ml) and oxone™ (132 mg, 0.215 mmol) was added. The reaction was stirred at room temperature for 2 h. The reaction mixture was diluted with water (5 ml) and extracted with dichloromethane (3×10 ml). The combined organic extracts were dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane:methanol (98:2 increasing to 97:3, by volume). The resulting foam was triturated with diethylether (5 ml) to give the product (108 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[OH-].[K+].Br[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1>CN1CCCC1=O.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: COc1ccc(CCBr)cc1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1ccc(CCn2c3c(c4cc(Cl)ccc42)CN(C)CC3)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 5.6 %

Procedure:
8-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.22 g, 0.001 mol) was dissolved in N-methyl 2-pyrolidone (3.0 mL). Powdered potassium hydroxide (0.224 g, 0.004 mol) was added and heated at 100 deg C. for 3 h. 1-(2-Bromo-ethyl)-4-methoxy-benzene (0.214 g, 0.001 mol) was added at the same temperature and stir for 6 h. at RT. Reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3×50 mL). Organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure using rotary evaporator. The crude was purified through column chromatography (4% MeOH:DCM in silica 100-200 mesh, Diameter of column—2.5 cm, Height of silica—approx. 5 inch) to provide the desired compound as light yellow oil (0.02 g, 6% yield). 8-Chloro-5-[2-(4-methoxy-phenyl)ethyl]-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.020 g, 0.0564 mol) was dissolved in THF (1.0 mL), A solution of oxalic acid dihydrate (0.007 g, 0.0564 mol) in 1.5 mL THF was added and stirred for 30 min at RT. The precipitate was filtered and dried to give oxalate salt as white solid (0.01 g, 40% yield).
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16](=[O:32])/[CH:17]=[CH:18]/[CH:19]3[CH2:24][CH2:23][N:22]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:21][CH2:20]3)=[CH:12][CH:11]=2)=[N:4][CH:5]=[N:6][C:7]=1[CH3:8].C(O)C.[H][H]>[Pt]=O.O1CCOCC1>[CH3:1][C:2]1[C:3]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([C:16](=[O:32])[CH2:17][CH2:18][CH:19]3[CH2:20][CH2:21][N:22]([CH2:25][C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH2:23][CH2:24]3)=[CH:14][CH:15]=2)=[N:4][CH:5]=[N:6][C:7]=1[CH3:8]
Reactant: [H][H]
Reactant: Cc1ncnc(Nc2ccc(C(=O)/C=C/C3CCN(Cc4ccccc4)CC3)cc2)c1C
Agent: O=[Pt]
Solvent: CCO
Solvent: C1COCCO1
Product: Cc1ncnc(Nc2ccc(C(=O)CCC3CCN(Cc4ccccc4)CC3)cc2)c1C
Yield: 47.3 %

Procedure:
0.82 g of (E)-N-(5,6-dimethylpyrimidin-4-yl)-4-[3-(1-benzylpiperidin-4-yl)propenoyl]aniline obtained in Example 1 was added to a mixed solvent of 30 ml of ethanol and 40 ml of dioxane, and then 0.05 g of platinum oxide was added thereto. The mixture was stirred in a hydrogen stream at room temperature for 3.5 hours. After the catalyst was removed by filtration, the filtrate was condensed under reduced pressure. The obtained residue was applied to silica gel column chromatography to obtain 0.39 g of the title compound as pale yellow powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33](=[O:51])[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]2[CH:45]=[CH:44][N:43]=[C:42]([N:46]3[CH2:50][CH2:49][CH2:48][CH2:47]3)[CH:41]=2)[CH:35]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:18])([F:17])[F:19])[C:11]([C:20]([F:22])([F:23])[F:21])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33](=[O:51])[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]2[CH:45]=[CH:44][N:43]=[C:42]([N:46]3[CH2:47][CH2:48][CH2:49][CH2:50]3)[CH:41]=2)[CH:35]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccnc(N3CCCC3)c2)c1
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1N
Product: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2ccnc(N3CCCC3)c2)c1

Procedure:
The title compound was prepared from [2-amino-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J6) (281 mg, 0.75 mmol) and 3-oxo-3-[3-(2-pyrrolidin-1-yl-pyridin-4-yl)-phenyl]-propionic acid tert-butyl ester (Example K63) (275 mg, 0.75 mmol) according to the general procedure M. Obtained as a light yellow amorphous substance (419 mg, 84%).
Reaction SMILES: [NH4+].[Cl-].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-])=O)=[CH:6][CH:5]=1>[Fe].CCO>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[C:12]([NH2:17])=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccccc1Nc1ccc(Cl)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: Nc1ccccc1Nc1ccc(Cl)cc1
Temperature: 70 °C
Yield: 93.3 %

Procedure:
To a mixture of EtOH (100 ml) and NH4Cl saturated solution (15 ml), N-(4-chlorophenyl)-2-nitrobenzenamine (5.0 g, 20.1 mmol) was added, followed by iron powder (4.0 g). The reaction mixture was heated at 70° C. for 2 h. The solid was filtered and the filtrate was extracted by EA (100 mL×3), dried over Na2SO4. After the solvent was removed, the mixture was purified by Combi-flash (PE:EA=5:1) to give N1-(4-chlorophenyl)benzene-1,2-diamine (4.1 g, 93.2%) as a light yellow solid. LRMS (M+H+) m/z: calcd 218.06. found 218. 1H NMR (300 MHz, CD3OD): δ 6.52-6.59 (m, 3H), 6.70-6.74 (m, 1H), 6.81-6.87 (m, 1H), 6.90-6.99 (m, 3H).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][CH2:12][C:13]2[NH:23][C:16]3[N:17]=[C:18]([NH2:22])[NH:19][C:20](=[O:21])[C:15]=3[CH:14]=2)=[CH:8][CH:9]=1)=[O:4].[OH-].[Na+].CO.C(Cl)(Cl)Cl>CO>[NH2:22][C:18]1[NH:19][C:20](=[O:21])[C:15]2[CH:14]=[C:13]([CH2:12][CH2:11][CH2:10][C:7]3[S:6][C:5]([C:3]([OH:4])=[O:2])=[CH:9][CH:8]=3)[NH:23][C:16]=2[N:17]=1
Reactant: COC(=O)c1ccc(CCCc2cc3c(=O)[nH]c(N)nc3[nH]2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Nc1nc2[nH]c(CCCc3ccc(C(=O)O)s3)cc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.7 %

Procedure:
To a solution of 8 (300 mg, 0.9 mmol) in MeOH (10 mL) was added 1 N NaOH (10 mL) and the mixture was stirred under N2 at room temperature for 16 h. TLC showed the disappearance of the starting material (Rf=0.56) and one major spot at the origin (MeOH/CHCl3 1:5). The reaction mixture was evaporated to dryness under reduced pressure. The residue was dissolved in water (10 mL), the resulting solution was cooled in an ice bath, and the pH was adjusted to 3-4 with dropwise addition of 1 N HCl. The resulting suspension was frozen in a dry ice-acetone bath, thawed to 4-5° C. in the refrigerator, and filtered. The residue was washed with a small amount of cold water and dried in vacuum using P2O5 to afford 254 mg of 9 as white powder. 1H NMR (DMSO-d6): δ 1.89-1.96 (m, 2H), 2.49-2.55 (t, J=7.2 Hz, 2H), 2.80-2.84 (t, J=7.2 Hz, 2H), 5.88 (s, 1H), 5.98 (s, 2H), 6.92-6.93 (d, J=3.6 Hz, 1H), 7.55-7.56 (d, J=3.6 Hz, 1H), 10.14 (s, 1H), 10.83 (s, 1H) 12.86 (br, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16]C)=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Li+].[OH-].Cl>C1COCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(-c2ccc(F)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2ccc(F)cc2)cc1

Procedure:
A room temperature solution of Example 1A (10.0 g, 43.4 mmol) and saturated LiOH (50 mL) in THF (100 mL) was stirred for 16 hours, slowly adjusted to pH 2-4 with 6M HCl, diluted with ethyl acetate (200 mL), washed with water (100 mL) and brine (50 mL), dried (MgSO4), filtered, and concentrated to provide the desired product of sufficient purity for subsequent use. MS (ESI(−)) m/e 215 (M−H)−.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)OC(C)C)#[N:2].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][CH2:24][NH2:25]>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=1)=[N:25][CH2:24][CH2:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[O:16][CH3:15])#[N:2]
Reactant: COc1ccccc1CCN
Reactant: CC(C)OC(=NC#N)c1ccncc1
Solvent: CO
Product: COc1ccccc1CCN=C(NC#N)c1ccncc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.5 %

Procedure:
Isopropyl N-cyano-4-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved in methanol (10 ml), and 2-(2-methoxyphenyl)ethylamine (0.44 g, 2.9 mmol) was added. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residual concentrate was subjected to chromatography on a silica gel column (WAKO GEL C-200, 40 g) eluting with chloroform-methanol (100:1). The eluted fractions were concentrated under reduced pressure and crystallized from chloroform-diethyl ether to give the title compound (0.45 g, 1.6 mmol, yield: 61%) as colorless crystals.
Reaction SMILES: C[N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:11][CH:12]=2)[C:4](=[O:17])[N:3]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl.[F:25]C1C=CC(NN)=CC=1.C(N(CC)CC)C>C1C=CC=CC=1>[F:25][C:21]1[CH:22]=[CH:23][C:18]([N:3]2[C:4](=[O:17])[C:5]([C:7]3[CH:8]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:11][CH:12]=3)=[CH:6][NH:2]2)=[CH:19][CH:20]=1
Reactant: NNc1ccc(F)cc1
Reactant: Cn1cc(-c2cccc(C(F)(F)F)c2)c(=O)n1-c1ccccc1
Agent: Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: O=c1c(-c2cccc(C(F)(F)F)c2)c[nH]n1-c1ccc(F)cc1

Procedure:
A 5.5 gram portion of the atropic ester of Example 1 was combined with 3.5 grams of 4-fluorophenylhydrazine hydrochloride and 2 grams triethylamine in 50 ml. benzene. The mixture was stirred at reflux temperature for 5 hours, after which about half of the benzene was allowed to evaporate and an equivalent amount of meta-xylene was added. The mixture was then stirred at reflux overnight, and the reaction mixture was evaporated to dryness under vacuum. The residue was partitioned between ethyl acetate and water, and the organic layer was dried over sodium sulfate and evaporated to dryness. The residue was chromatographed on silica gel with ethyl acetate as the eluant. The product containing fractions were combined and evaporated to dryness to produce about 3.5 grams of crude intermediate, which was recrystallized from methanol to produce 2.7 grams of purified 1-(4-fluorophenyl)-4-(α,α,α-trifluoro-3-tolyl)-3-pyrazolin-5-one, m.p. 171°-173° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH2:9][C:10]#[N:11])[N:3]=1.C[O-].[Na+].[C:15](O)(=[O:17])C>CO>[NH2:1][C:2]1[N:7]=[C:6]([O:17][CH3:15])[CH:5]=[C:4]([CH2:9][C:10]#[N:11])[N:3]=1
Reactant: N#CCc1cc(Cl)nc(N)n1
Reactant: CC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(CC#N)nc(N)n1

Procedure:
2-amino-4-chloro-6-pyrimidylacetonitrile (31.6 g, 204.6 mmol) was dissolved in methanol (500 ml) and then sodium methoxide in methanol (46.8 ml, 204.6 mmol) was added at 25° C. The resultant dark solution was heated at reflux for 1 hour and after this time TLC indicated complete reaction. The reaction was cooled and acidified to pH 6 with acetic acid and the mixture was filtered. The filtrated was concentrated and the residue was taken up in ethyl acetate and washed with water and brine and dried with magnesium sulfate. The brown solid was chromatographed on silica gel using 1:1 ethyl acetate/hexane as eluent to furnish two fractions. Fraction A furnished 6.9 g of pure subject as a yellow solid, m.p. 117°-118° C. Fraction B furnished 4.23 g of impure subject as a pink solid, m.p. 95°-98° C. NMR (fraction A) (90 mHz) D6-acetone δ 6.2-5.9 (bs, 2 H), 6.1 (s, 1 H), 3.9 (s, 3 H), 3.7 (s, 2 H). EXAMPLE 4
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[C:8]([O:12][C:13]([NH:15][C@@H:16]1[CH2:22][CH2:21][C@@H:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=2[F:30])[CH2:19][N:18]2[C:31]([C:34]([OH:36])=[O:35])=[CH:32][N:33]=[C:17]12)=[O:14])([CH3:11])([CH3:10])[CH3:9]>ClCCl.CO>[C:8]([O:12][C:13]([NH:15][C@@H:16]1[CH2:22][CH2:21][C@@H:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=2[F:30])[CH2:19][N:18]2[C:31]([C:34]([O:36][CH3:1])=[O:35])=[CH:32][N:33]=[C:17]12)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(C(=O)O)cnc21
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cnc2n1C[C@H](c1cccc(F)c1F)CC[C@H]2NC(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
(Trimethylsilyl)diazomethane (2.0 M in ether; 173 μL, 0.35 mmol) was added to a solution of (6S,9R)-9-[(tert-butoxycarbonyl)amino]-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepine-3-carboxylic acid (47 mg, 0.12 mmol) in dichloromethane (1.5 mL) and methanol (0.5 mL). After 1 h, additional (trimethylsilyl)diazomethane (2.0 M in diethyl ether; 50 μL, 0.10 mmol) was added. After 4 h, the reaction mixture was concentrated. MS 422.2 (M+1).
Reaction SMILES: [O:1]([CH2:19][C:20]([CH3:24])([CH3:23])[CH2:21][NH2:22])[Si:2]([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:26]([O:28][C:29]1[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=1)=[O:27].C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>ClCCl>[O:1]([CH2:19][C:20]([CH3:24])([CH3:23])[CH2:21][NH:22][C:26](=[O:27])[O:28][C:29]1[CH:30]=[CH:31][C:32]([N+:35]([O-:37])=[O:36])=[CH:33][CH:34]=1)[Si:2]([C:15]([CH3:16])([CH3:17])[CH3:18])([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(CN)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(CNC(=O)Oc1ccc([N+](=O)[O-])cc1)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reaction time: 0.75 h
Yield: 11.8 %

Procedure:
To a solution, at 0° C., of 0.120 g (3.51 mmol) of 3-(tert-butyldiphenylsilanoxy)-2,2-dimethylpropylamine in 25 ml of dichloromethane are added dropwise 1.42 g (7.03 mmol) of 4-nitrophenyl chloroformate (CAS 7693-46-1) dissolved in 5 ml of dichloromethane. 0.63 ml (3.5 mmol) of diisopropylethylamine is then added. Stirring is continued at 0° C. for 45 minutes, and the temperature of the mixture is then allowed to return to 0° C. over 1 hour. 20 ml of saturated aqueous sodium hydrogen carbonate solution are then added. The organic phase is separated out on a hydrophobic filter cartridge and the solvent is partially evaporated off under reduced pressure to a volume of about 8 ml. This solution is chromatographed on a column of silica gel, eluting with a mixture of 5 to 40% ethyl acetate in cyclohexane, to give 0.21 g of 4-nitrophenyl 3-(tert-butyldiphenylsilanoxy)-2,2-dimethylpropylcarbamate in the form of an oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([CH:12]([CH3:15])[CH2:13][NH2:14])=[CH:8][CH:7]=2)=[CH:2]1.[N:16]1([C:21](Cl)=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17]1>>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([CH:12]([CH3:15])[CH2:13][NH:14][C:21]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:22])=[CH:8][CH:7]=2)=[CH:2]1
Reactant: O=C(Cl)N1CCCC1
Reactant: CC(CN)c1ccc(-c2ccsc2)cc1
Product: CC(CNC(=O)N1CCCC1)c1ccc(-c2ccsc2)cc1

Procedure:
The title compound was prepared from 2-(4-(3-thienyl)phenyl)propylamine (see example 14) and pyrrolidine carbonyl chloride in a manner analogous to the procedure described in example 14. The NMR spectrum was consistent with the proposed title structure.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[S:3]([CH2:6][C:7]1([NH:13]S(C(C)(C)C)=O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)(=[O:5])=[O:4].Cl>CO.O1CCOCC1>[NH2:13][C:7]1([CH2:6][S:3]([N:2]([CH3:20])[CH3:1])(=[O:5])=[O:4])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: CN(C)S(=O)(=O)CC1(NS(=O)C(C)(C)C)CCCCC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CN(C)S(=O)(=O)CC1(N)CCCCC1
Reaction time: 0.5 h

Procedure:
The sulfinamide 1200-C (1.3 g) was dissolved in 40 mL of methanol and treated with 10 mL of 4M HCl solution in dioxane. The mixture was stirred for about 30 min until all the starting material had been consumed as determined by TLC (20% acetone in dichloromethane/hexanes, 1:1). The mixture was evaporated to dryness. Dichloromethane was added (15 mL) to make a cloudy solution. Upon addition of 100 mL of ether a white precipitated formed. The product 1200-D (1.02 g; 98%) was recovered by filtration using filter paper whatman #1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]4[O:21][CH2:20][O:19][C:17]4=[CH:18][C:13]=3[CH2:12][C:11](=[O:22])[NH:10][N:9]=2)=[CH:4][CH:3]=1.C1C(=O)N([Cl:30])C(=O)C1>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]4[O:21][CH2:20][O:19][C:17]4=[CH:18][C:13]=3[CH2:12][C:11](=[O:22])[NH:10][N:9]=2)=[CH:4][C:3]=1[Cl:30]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1ccc(C2=NNC(=O)Cc3cc4c(cc32)OCO4)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1ccc(C2=NNC(=O)Cc3cc4c(cc32)OCO4)cc1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 47.4 %

Procedure:
To a solution of 1-(4-aminophenyl)-7,8-methylenedioxy-3,5-dihydro-2,3-benzodiazepin-4(4H)-one (118 mg, 0.400 mmol) in DMF (3 mL) was added NCS (51 mg, 0.38 mmol). The mixture was stirred at room temperature for 20 h, diluted with EtOAc (50 mL), washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography (1:1 hexane/EtOAc) to afford the title compound as a tan solid (60 mg, 0.18 mmol, 45%), mp: 256°-258° C. 1H NMR (CDCl3) 8.50 (s, 1H), 7.54 (s, 1H), 7.32(d, J=8.3, 1H), 6.82 (s, 1H), 6.77 (d, J=8.3, 1H), 6.69 (s, 1H), 6.04 (s, 2H), 4.33 (s, 2H), 3.42 (s, 2H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8].S(Cl)([Cl:11])=O>C(Cl)(Cl)(Cl)Cl>[CH3:1][C:2]1([Cl:11])[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8]
Reactant: O=S(Cl)Cl
Reactant: CC1CCCCC1=O
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(Cl)CCCCC1=O

Procedure:
112 g of 2-methylcyclohexanone and 500 ml carbon tetrachloride are mixed in a three neck flask and 90 ml of thionyl chloride in 150 ml of carbon tetrachloride are added dropwise in the course of 60 minutes, under vigorous stirring while keeping the temperature at about 15° with a water bath. Stirring is maintained for a further 2 hours. The reaction medium is then washed three times with dilute hydrochloric acid, twice with a saturated solution of sodium bicarbonate and finally with a saturated solution of sodium chloride. The organic phase is separated, dried over sodium sulphate and the solvent is evaporated off under reduced pressure. The dry residue of 2-methyl-2-chlorocyclohexanone weighing about 180 g is purified by fractional distillation. The main fraction boils at 85°-90° (20 mm Hg); nD25 =1.4672.