Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]([CH3:13])[CH2:3][N:4]1[CH:8]=[C:7]([C:9]([OH:11])=O)[N:6]=[C:5]1[CH3:12].[NH2:14][C@@H:15]([CH3:31])[CH2:16][N:17]1[CH:21]=[CH:20][C:19]([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[C:24]([Cl:30])[CH:23]=2)=[N:18]1.CN(C=O)C>C(Cl)Cl>[Cl:30][C:24]1[CH:23]=[C:22]([C:19]2[CH:20]=[CH:21][N:17]([CH2:16][C@@H:15]([NH:14][C:9]([C:7]3[N:6]=[C:5]([CH3:12])[N:4]([CH2:3][C@H:2]([OH:1])[CH3:13])[CH:8]=3)=[O:11])[CH3:31])[N:18]=2)[CH:29]=[CH:28][C:25]=1[C:26]#[N:27]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: Cc1nc(C(=O)O)cn1C[C@@H](C)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)cn1C[C@@H](C)O
Yield: 76.8 %

Procedure:
The title compound was prepared using the procedure described in Example 3(h) starting from (R)-1-(2-hydroxypropyl)-2-methyl-1H-imidazole-4-carboxylic acid (1.059 mmol, 195 mg) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-benzonitrile (0.882 mmol, 230 mg) using DMF (2 ml) as the solvent. DCM was added and evaporated. The residue was purified by flash chromatography. The product was further purified by dissolving it in MeOH/DCM and washing twice with 1 M NaHCO3. The separated organic phase was dried, purified and evaporated. 289 mg of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.02-1.10 (m, 6H), 2.34 (s, 3H), 3.70-3.91 (m, 3H), 4.22-4.48 (m, 3H), 4.92 (d, 1H), 6.95 (d, 1H), 7.47 (s, 1H), 7.83 (d, 1H), 7.97-8.00 (m, 2H), 8.04 (d, 1H), 8.09-8.13 (m, 1H).
Reaction SMILES: [N:1]([CH2:4][CH2:5][N:6]([C:15](=[O:21])[C:16](OCC)=[O:17])[N:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[N+]=[N-].[H][H]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].C(O)C>[C:9]1([CH:8]=[N:7][N:6]2[CH2:5][CH2:4][NH:1][C:16](=[O:17])[C:15]2=[O:21])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCOC(=O)C(=O)N(CCN=[N+]=[N-])N=Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCO
Product: O=C1NCCN(N=Cc2ccccc2)C1=O

Procedure:
2 g. of the ethyl ester product from part (d) are dissolved in 100 ml. of ethanol. 0.5 g. of Lindlar catalyst are added and the reaction mixture is stirred for four hours at room temperature under two atmospheres of hydrogen. At intervals the reaction mixture is filtered. After completion of the slow absorption of hydrogen, the reaction solution is flooded with nitrogen and then heated to a boil. This mixture is filtered while hot and after cooling 1 g. of crude product is obtained from the filtrate. Recrystallization from water yields as white crystals purified 1-[(phenylmethylene)amino]-2,3-piperazinedione; m.p. 229°-231°.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([O:11][CH3:12])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[CH2:13]([O:15][C:16](=[O:26])[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[N:20]=1)[CH3:14]>>[CH2:13]([O:15][C:16](=[O:26])[CH:17]=[C:18]([C:2]1[CH:10]=[C:9]2[C:5]([C:6]([O:11][CH3:12])=[N:7][NH:8]2)=[CH:4][CH:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[N:20]=1)[CH3:14]
Reactant: COc1n[nH]c2cc(Br)ccc12
Reactant: CCOC(=O)C=Cc1cccc(C)n1
Product: CCOC(=O)C=C(c1ccc2c(OC)n[nH]c2c1)c1cccc(C)n1

Procedure:
3-(3-Methoxy-1H-indazol-6-yl)-3-(6-methyl-pyridin-2-yl)-acrylic acid ethyl ester CCLIII was prepared from 6-bromo-3-methoxy-1H-indazole and 3-(6-methyl-pyridin-2-yl)-acrylic acid ethyl ester using the procedure described for preparation of 3-(3-Cyano-1H-Indol-4-yl)-3-phenyl-acrylic acid ethyl esterLVIII (Example 14).
Reaction SMILES: Cl.[NH2:2]O.C(=O)(O)[O-].[Na+].[Cl:9][C:10]1[N:15]=[C:14]([NH:16][C:17]([NH:19]C(=O)OCC)=S)[C:13]([O:25][CH3:26])=[CH:12][N:11]=1>O.C(O)(C)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>[Cl:9][C:10]1[N:15]2[N:19]=[C:17]([NH2:2])[N:16]=[C:14]2[C:13]([O:25][CH3:26])=[CH:12][N:11]=1
Reactant: NO
Reactant: CCOC(=O)NC(=S)Nc1nc(Cl)ncc1OC
Agent: Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC(C)(C)O
Product: COc1cnc(Cl)n2nc(N)nc12
Reaction time: 0.08 h

Procedure:
Hydroxylamine hydrochloride (280 mg, 4 eq), and sodium bicarbonate (210 mg, 2.5 eq) were combined in water (5 mL) and stirred for 5 minutes. Ethyl [(2-chloro-5-methoxypyrimidin-4-yl)amino]carbonothioylcarbamate (2) (290 mg, 1.0 mmol), suspended in t-butanol (15 mL) was added at room temperature. The reaction was stirred at room temperature for 5 hours, and then treated with 10 drops of saturated aqueous sodium carbonate solution. The reaction slurry was then filtered, and the product solids washed with water and dried to obtain the title compound as a off white solid (330 mg, 83%) that was identical in HPLC retention to previously described 5-chloro-8-methoxy[1,2,4]triazolo-[1,5-c]pyrimidin-2-amine (4).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[C:14]([O:18][C:19](=O)[O:20]C(C)(C)C)([CH3:17])([CH3:16])[CH3:15]>O1CCCC1>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:20])[CH2:10][CH2:9]1
Reactant: Oc1ccccc1N1CCNCC1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccccc2O)CC1
Temperature: 60 °C

Procedure:
To a stirred suspension of 1-(2-hydroxyphenyl)piperazine 19 (1.78 g, 0.01 mol) in 20 mL tetrahydrofuran (in a round bottom flask fitted with a gas bubbler) was added a solution of di-tert-butylcarbonate (2.62 g, 0.012 mol) in 10 mL tetrahydrofuran at room temperature. Soon it became a clear solution and a gas was evolved. The resulting mixture was heated at 60° C. for 6 h. The progress of the reaction was monitored by thin layer chromatography (TLC). The solvent was evaporated, the residue was dissolved in 100 mL ethyl acetate and washed with 100 mL water, dried over sodium sulphate (Na2SO4) and evaporated to give tert-Butyl 4-(2-hydroxyphenyl)piperazine-1-carboxylate 20 which was purified by triturating with hexanes. White solid, 2.5 g (92%). 1H NMR (400 MHz, CDCl3): δ 1.49 (s, 9H); 2.81(t, J=4.8 Hz, 4H); 3.58 (t, J=4.8 Hz, 4H); 6.84-6.88 (m, 1H); 6.94-6.99 (m, 1H); 7.06-7.12 (m, 2H).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH:40]([OH:48])[C:41]5[CH:46]=[C:45]([CH3:47])[CH:44]=[CH:43][N:42]=5)=[CH:36][CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:49]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:58])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH:40]([OH:48])[C:41]5[CH:46]=[C:45]([CH3:47])[CH:44]=[CH:43][N+:42]=5[O-:58])=[CH:36][CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:49]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cc(C)ccn4)cc2)CCN3C(=O)C(F)(F)F)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cc(C)cc[n+]4[O-])cc2)CCN3C(=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.1 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(4-methylpyridin-2-yl) methyl]phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.6 g) was dissolved in dichloromethane (20 ml), and to the solution was added 3-chloroperbenzoic acid (0.3 g) under ice-cooling and the mixture was stirred overnight at room temperature. An aqueous solution of sodium thiosulfate was added to the mixture. The mixture was concentrated, and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/methanol/triethylamine), to give 7-[4-(2-butoxyethoxy) phenyl]-N-[4-[hydroxy(4-methyl-1-oxidopyridin-2-yl)methyl]phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.32 g) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[C:7](=[CH:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)[CH2:6]2.ClC1C=CC=C(C(OO)=[O:30])C=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[C:7](=[CH:15][C:16]1[CH:21]=[CH:20][N+:19]([O-:30])=[CH:18][CH:17]=1)[CH2:6]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cc2c(cc1OC)C(=O)C(=Cc1ccncc1)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc2c(cc1OC)C(=O)C(=Cc1cc[n+]([O-])cc1)C2
Reaction time: 4 h
Yield: 94.6 %

Procedure:
4-[(5,6-Dimethoxy-1-indanon-2-ylidene)methyl]pyridine (2.5 g) was dissolved in methylene chloride (60 ml) and chilled. m-Chloroperbenzoic acid (2.0 g) was added to reaction mixture and then stirred for 4 hours. Solid obtained was filtered. The wet solid so obtained was stirred with 10% sodium bicarbonate solution. The solid was filtered, washed with acetone and then dried to get the title compound (2.5 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)[CH3:2].[N+:13]([O-:16])([OH:15])=[O:14].[N:17]#[C:18][NH2:19]>C(O)C>[N+:13]([O-:16])([OH:15])=[O:14].[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:18]([NH2:19])=[NH:17])=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: N#CN
Solvent: O=[N+]([O-])O
Solvent: CCO
Product: CCOC(=O)c1ccc(NC(=N)N)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
4-aminobenzoic acid ethyl ester (20 g, 0.121 mol), nitric acid (7.26 g, 0.121 mol), cyanamide (50%, 14 ml 0.182 mol) were mixed under reflux with ethanol (50 ml). After 24 hr, the mixture was cooled to RT, and then washed with ethanol to give the titled compound as crystalline solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:25]=[CH:24][C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH:12]=2)=[O:9])=[C:6]([Cl:26])[CH:5]=1.[NH:27]1[CH2:31][CH2:30][N:29]=[C:28]1N1C(C)=CC(C)=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:26][C:6]1[CH:5]=[C:4]([CH2:3][NH:2][C:28]2[NH:29][CH2:30][CH2:31][N:27]=2)[CH:25]=[CH:24][C:7]=1[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:12]=1)=[O:9]
Reactant: Cc1cc(C)n(C2=NCCN2)n1
Reactant: NCc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(CNC2=NCCN2)cc1Cl

Procedure:
100 mg of the crude HCl salt of 4-(aminomethyl)-2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide was reacted with 72 mg of 1-(4,5-dihydro-1H-imidazol-2-yl)-3,5-dimethyl-1H-pyrazole and 100 SL of DIPEA in 500 μL of DMF in the microwave at 150° C. for 5 minutes. The crude product was concentrated to dryness and purified by reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((4,5-dihydro-1H-imidazol-2-ylamino)methyl)benzamide. MS (Q1) 440 (M)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:11][CH2:12][CH2:13][CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][N:15]3[C:20]3[CH:25]=[CH:24][N:23]=[C:22]([N:26]4[CH:30]=[CH:29][N:28]=[CH:27]4)[N:21]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.CCN(C(C)C)C(C)C.[C:40](OC(=O)C)(=[O:42])[CH3:41]>C1COCC1>[C:40]([N:11]([CH2:10][C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][O:3][C:4]=2[CH:9]=1)[CH2:12][CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][N:15]1[C:20]1[CH:25]=[CH:24][N:23]=[C:22]([N:26]2[CH:30]=[CH:29][N:28]=[CH:27]2)[N:21]=1)(=[O:42])[CH3:41]
Reactant: c1cn(-c2nccc(N3CCCCC3CCNCc3ccc4c(c3)OCO4)n2)cn1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N(CCC1CCCCN1c1ccnc(-n2ccnc2)n1)Cc1ccc2c(c1)OCO2
Reaction time: 16 h
Yield: 59.5 %

Procedure:
To THF (3 mL) was added N-[(1,3-benzodioxol-5-yl)methyl]-1-[2-(1H-imidazol-1-yl)pyrimidin-4-yl]piperidine-2-ethanamine (8 mg, 0.03 mmol), Hünig's base (8 mg, 0.06 mmol), and acetic anhydride (4 mg, 0.04 mmol). After stirring for 16 hours, the solvent was removed in vacuo and the residue was chromatographed (CH2Cl2/MeOH. 19/1) to give 8 mg (60%) of N-acetyl-N-[(1,3-benzodioxol-5-yl)methyl]-1-[2-(1H-imidazol-1-yl)pyrimidin-4-yl]piperidine-2-ethanamine (the compound of formula (Igg)): 1H NMR (CDCl3) δ 8.48 (s, 1), 8.08 (d, 1), 7.76 (s, 1), 7.09 (s, 1), 6.66 (m, 3), 6.33 (m, 1), 5.94 (s, 1), 5.91 (s, 1), 4.43 (m, 3), 3.40 (m, 2), 2.11 (d, 3), 1.14 (m); MS: 450.0 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:23]3[O:22][C:21]([C:24]([O-])=[O:25])=[CH:20][C:19]=3[CH:18]=[CH:17][CH:16]=2)[CH2:11][CH2:10]1.[Li+].[NH2:28][CH:29]1[CH2:34][CH2:33][N:32]([C:35](=[O:37])[CH3:36])[CH2:31][CH2:30]1>>[C:35]([N:32]1[CH2:33][CH2:34][CH:29]([NH:28][C:24]([C:21]2[O:22][C:23]3[C:15]([N:12]4[CH2:13][CH2:14][N:9]([CH2:8][CH2:7][C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=5)[CH2:10][CH2:11]4)=[CH:16][CH:17]=[CH:18][C:19]=3[CH:20]=2)=[O:25])[CH2:30][CH2:31]1)(=[O:37])[CH3:36]
Reactant: O=C([O-])c1cc2cccc(N3CCN(CCc4ccccn4)CC3)c2o1
Reactant: CC(=O)N1CCC(N)CC1
Agent: [Li+]
Product: CC(=O)N1CCC(NC(=O)c2cc3cccc(N4CCN(CCc5ccccn5)CC4)c3o2)CC1

Procedure:
The compound was prepared according to the procedure disclosed in Example 1 starting from lithium 7-(4-(2-(pyridin-2-yl)ethyl)piperazin-1-yl)benzofuran-2-carboxylate (60 mg, 0.16 mmol) and 1-(4-amino-piperidin-1-yl)-ethanone (27 mg, 0.19 mmol). Yield: 39 mg (47%).
Reaction SMILES: [O-]CC.[Na+].[C:5](=[O:18])([O:9][C@@H:10]1[CH:15]2[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]2)[CH2:11]1)OCC.[C:19]1([C@H:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:28][CH2:27][NH:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C=CC=CC=1.CN(C=O)C>[CH:22]1[CH:21]=[CH:20][C:19]([C@@H:25]2[N:26]([C:5]([O:9][C@@H:10]3[CH:15]4[CH2:14][CH2:13][N:12]([CH2:17][CH2:16]4)[CH2:11]3)=[O:18])[CH2:27][CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:34]2=3)=[CH:24][CH:23]=1
Reactant: CCOC(=O)O[C@H]1CN2CCC1CC2
Reactant: c1ccc([C@@H]2NCCc3ccccc32)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(O[C@H]1CN2CCC1CC2)N1CCc2ccccc2[C@@H]1c1ccccc1
Yield: 12.1 %

Procedure:
In a mixture of 10 ml of toluene and 0.5 ml of DMF and in the presence of 0.21 g of sodium ethoxide, 1.00 g of ethyl (R)-quinuclidin-3-yl carbonate and 1.05 g of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline were stirred for 7 hours while evaporating the solvent, 20 ml of toluene and 20 ml of water were added thereto, and the thus obtained organic layer was washed with 20 ml of water and then mixed with 15 ml of 1 M hydrochloric acid aqueous solution. A 30 ml portion of EtOAc and 1 M sodium hydroxide aqueous solution were added to the obtained water layer. The thus obtained organic layer was dried with sodium sulfate, concentrated under a reduced pressure and then dried, and the thus obtained solid was purified by a silica gel column chromatography to obtain 0.22 g of solifenacin.
Reaction SMILES: C[O-].[Na+].Cl.Cl.[CH2:6]([NH:13][NH2:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:15]([C:17](=[C:20](SC)[NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:18]#[N:19])#[N:16]>CO.C(O)C>[NH2:19][C:18]1[N:13]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:14]=[C:20]([NH:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:17]=1[C:15]#[N:16]
Reactant: NNCc1ccccc1
Reactant: CSC(Nc1ccccc1)=C(C#N)C#N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: N#Cc1c(Nc2ccccc2)nn(Cc2ccccc2)c1N
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
With ice-cooling, 19.3 ml of a 5.4N sodium methanolate solution in 20 ml of methanol (purissimum) are added to 9.9 g of benzylhydrazine dihydrochloride in 20 ml of methanol (purissimum) and the reaction mixture is stirred for approx. 15 minutes at room temperature and then introduced into a solution of 4.65 g of 2-cyano-3-methylmercapto-3-phenylamino-acrylonitrile in 150 ml of absolute ethanol. The mixture is heated under reflux for approx. 17 hours and cooled to room temperature and insoluble material is filtered off with suction. The filtrate is concentrated by evaporation using a rotary evaporator and the brown oily residue is chromatographed on 190 g of silica gel, methylene chloride/ethyl acetate mixtures being used as eluant. 5-Amino-1-benzyl-4-cyano-3-phenylamino-pyrazole is obtained; m.p. 139-140° C., FAB-MS: (M+H)+ =290 (C17H15N5).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[C:12]([SH:23])=[N:13][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:15][CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.II>>[CH2:1]([N:8]1[C:9](=[O:10])[C:11]2[C:12](=[N:13][C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[N:15][CH:16]=2)[S:23]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCc1ccccc1)c1cnc(-c2ccccc2)nc1S
Agent: II
Product: O=c1c2cnc(-c3ccccc3)nc2sn1Cc1ccccc1
Yield: 87.6 %

Procedure:
Using the procedure of Example 20, 2.0 g (6.22 mmol) of 4-mercapto-2-phenyl-pyrimidine-5-carboxylic acid benzylamide (from Preparation 42) was reacted with 1.74 g (6.8 mmol) of iodine to give 1.74 g of the title compound after crystallization from isopropanol, mp 166°-167° C.
Reaction SMILES: O=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[NH:3]1.[CH2:17]([N:24]1[CH2:29][C@@H:28]2[CH2:30][C@H:25]1[CH2:26][NH:27]2)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[NH4+].[OH-]>C1(C)C=CC=CC=1.Cl[Ti](Cl)(Cl)Cl>[CH2:17]([N:24]1[CH2:29][CH:28]2[CH2:30][CH:25]1[CH2:26][N:27]2[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[N:3]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C1Nc2ccccc2Oc2ccccc21
Reactant: c1ccc(CN2C[C@@H]3C[C@H]2CN3)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: c1ccc(CN2CC3CC2CN3C2=Nc3ccccc3Oc3ccccc32)cc1
Temperature: 25 °C
Yield: 49.1 %

Procedure:
To a solution of 11-oxo-dibenz[b,f][1,4]oxazepine (Aldrich) (0.149 g, 0.0007 mol) in dry toluene (10 mL), was added (1S,4S)-2-benzyl-2,5-diazabicyclo(2.2.1)heptane (0.54 g, 0.003 mol) and TiCl4 (0.75 mL, 0.0008 mol) via syringe. The mixture was stirred at room temperature for 30 rain then refluxed for 5 hrs. The reaction mixture was cooled and dumped into conc. NH4OH and extracted with CHCl3. The combined organic phases were dried (MgSO4) and concentrated in vacuo. The crude material was chromatographed (hexane:EtOAc, 1:1) to give 11-(2-benzyl-2,5-diazabicyclo(2.2.1) hept-5-yl)-dibenz[b,f][1,4]oxazepine (yield 0.131 g, mp 70°-72° C.).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([CH3:12])[CH2:10][OH:11])[C:5]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:37])(=[N:27][C:28](=[O:36])[NH:29][C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)=[O:26])=[CH:21][CH:20]=1>>[N:32]1[CH:33]=[CH:34][CH:35]=[C:30]([NH:29][C:28]([N:27]=[S:25]([C:22]2[CH:21]=[CH:20][C:19]([NH:18][C:2]3[N:7]=[C:6]([NH:8][C@H:9]([CH3:12])[CH2:10][OH:11])[C:5]([C:13]4[S:14][CH:15]=[CH:16][CH:17]=4)=[CH:4][N:3]=3)=[CH:24][CH:23]=2)([CH3:37])=[O:26])=[O:36])[CH:31]=1
Reactant: CS(=O)(=NC(=O)Nc1cccnc1)c1ccc(N)cc1
Reactant: C[C@H](CO)Nc1nc(Cl)ncc1-c1cccs1
Product: C[C@H](CO)Nc1nc(Nc2ccc(S(C)(=O)=NC(=O)Nc3cccnc3)cc2)ncc1-c1cccs1
Yield: 4 %

Procedure:
In the reaction of (R)-2-(2-chloro-5-(2-thienyl)pyrimidine-4-ylamino)propan-1-ol (30.7 mg, 0.11 mmol) with (RS)—S-(4-aminophenyl)-N-(pyridin-3-ylcarbamoyl)-S-methylsulphoximide (30 mg, 0.1 mmol) according to procedure 5c, the desired product is obtained in 4% yield (2.3 mg) after chromatographic purification (silica gel, dichloromethane/ethanol (0%-20% ethanol) and HPLC).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.[O:11]=[C:12]1[C:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:15][CH2:14][N:13]1[CH2:29][C:30](O)=[O:31].Cl.C(N=C=NCCCN(C)C)C>ClCCl>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:30](=[O:31])[CH2:29][N:13]1[CH2:14][CH2:15][C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:12]1=[O:11]
Reactant: c1ccc2c(c1)CCNC2
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)N1CCc2ccccc2C1
Reaction time: 8 h

Procedure:
A solution of 1,2,3,4-tetrahydroisoquinoline (0.025 g, 0.186 mmol), 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 1C, 0.050 g, 0.169 mmol) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.049 g, 0.254 mmol) in dichloromethane (0.5 mL) was stirred at room temperature. After stirring overnight, the reaction was loaded directly onto a SF15-12 silica gel column (Analogix®, Burlington, Wis.), and the title compound was eluted using a gradient of 0.4% to 4.5% methanol/dichloromethane over 20 minutes (flow=30 mL/minute). 1H NMR (300 MHz, CDCl3) δ ppm 7.15-7.40 (m, 14H), 4.55-4.80 (m, 2H), 4.25 (s, 2H), 3.60-3.85 (m, 2H), 3.45-3.55 (m, 2H), 2.70-2.90 (m, 4H); MS (ESI+) m/z 411 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([C@@H:11]1[C@H:15]([C:16]([OH:18])=[O:17])[CH2:14][C:13](=[O:19])[O:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.[C:32](O)([CH3:35])([CH3:34])[CH3:33].Cl>C(Cl)(Cl)Cl.CN(C)C1C=CN=CC=1>[O:19]=[C:13]1[O:12][C@H:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[C@@H:15]([C:16]([O:18][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:17])[CH2:14]1
Reactant: CC(C)(C)O
Reactant: O=C1C[C@@H](C(=O)O)[C@@H](C(=O)OCc2ccccc2)O1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)[C@H]1CC(=O)O[C@@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
To 7.93 g of (2S,3R)-2-benzyloxycarbonyl-5-oxotetrahydrofuran-3-carboxylic acid in 75 ml of chloroform, 5.5 g of 4-dimethylaminopyridine, 8.6 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 5.7 ml of tert-butyl alcohol were successively added, and the resulting reaction solution was stirred at room temperature for 60 hours. The reaction solution was poured into 1N hydrochloric acid cooled with ice and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the desiccant was filtered off, the solvent was evaporated in vacuo, and the residue was purified by silica gel column chromatography [hexane/ethyl acetate=5/1] to give 6.48 g of the title compound as a white solid.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[N:3]1[C:9]1[N:13]2[CH:14]=[C:15]([O:18][C@H:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[C@@H:22]([NH2:29])[CH2:21][CH2:20]3)[CH:16]=[CH:17][C:12]2=[N:11][N:10]=1.ClC(Cl)(Cl)C[O:33][C:34](=O)[NH:35][C:36]1[N:37]([C:45]2[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][CH:46]=2)[N:38]=[C:39]([C:41]([CH3:44])([CH3:43])[CH3:42])[CH:40]=1>>[C:41]([C:39]1[CH:40]=[C:36]([NH:35][C:34]([NH:29][C@@H:22]2[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C@H:19]([O:18][C:15]3[CH:16]=[CH:17][C:12]4[N:13]([C:9]([N:3]5[C@H:2]([CH3:1])[CH2:7][CH2:6][CH2:5][C@@H:4]5[CH3:8])=[N:10][N:11]=4)[CH:14]=3)[CH2:20][CH2:21]2)=[O:33])[N:37]([C:45]2[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][CH:46]=2)[N:38]=1)([CH3:44])([CH3:42])[CH3:43]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5[C@H](C)CCC[C@@H]5C)n4c3)c3ccccc32)cc1

Procedure:
The title compound was prepared starting from Intermediate 96c and (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (for reference procedure see Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety) using analogous procedures to those described in Example 3. LCMS (Method 5): Rt 5.33 min, m/z 647 [MH+]. 1H NMR (400 MHz, CD3OD): 0.64-0.74 (6H, m), 1.34 (9H, s), 1.41-1.72 (3H, m), 1.75-2.19 (6H, m), 2.21-2.31 (1H, m), 2.42 (3H, s), 3.22-3.35 (2H, m), 4.90-4.98 (1H, m), 5.45 (1H, t, J=4.1 Hz), 6.37 (1H, s), 7.19-7.40 (9H, m), 7.62 (1H, dd, J=9.9, 0.8 Hz), 7.89 (1H, d, J=2.1 Hz).