Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([C:13]#[N:14])=[C:4]([CH3:12])[C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[C:15](Cl)(=O)C(Cl)=O.CN(C=O)C>ClCCl>[Br:1][C:2]1[C:3]([C:13]#[N:14])=[C:4]([CH3:12])[C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:15])=[O:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1c(O)c(C(=O)O)cc(Br)c1C#N
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1cc(Br)c(C#N)c(C)c1O
Reaction time: 3 h
Yield: 53.8 %

Procedure:
To a solution of 5-bromo-4-cyano-2-hydroxy-3-methylbenzoic acid (7.40 g) in dichloromethane (70.0 mL) were added oxalyl chloride (3.91 g) and DMF (0.20 mL) under ice-cooling, and the mixture was stirred for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with THF. To this mixture was added dropwise a solution of triethylamine (5.66 g) in methanol (50.0 mL) under ice-cooling, and the mixture was stirred for 20 min. The reaction mixture was poured into 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (4.20 g).
Reaction SMILES: [I-].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]2[CH2:14][CH2:13][N+:12]([CH3:15])=[C:11]2SC)=[CH:5][N:4]=1.[N:18]#[C:19][NH2:20]>C(O)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]2[CH2:14][CH2:13][N:12]([CH3:15])[C:11]2=[N:20][C:19]#[N:18])=[CH:5][N:4]=1
Reactant: CSC1=[N+](C)CCC1Cc1ccc(Cl)nc1
Reactant: N#CN
Agent: [I-]
Solvent: CCO
Product: CN1CCC(Cc2ccc(Cl)nc2)C1=NC#N

Procedure:
A mixture of 3.7 g of 3-(2-chloropyrid-5-yl-methyl)-1-methyl-2-methylthio-1-azacyclopent-1-enylium iodide and 2.5 g of cyanamide in 20 ml of ethanol is boiled at reflux for 6 hours. The mixture is concentrated by evaporation in vacuo and the residue is chromatographed on silica gel using dichloromethane/methanol (19:1) as eluant. The title compound having a melting point of 53-54° C. (compound 6.4) is obtained.
Reaction SMILES: O1CCCC1.[Si]([O:13][CH2:14][C:15]1[CH:16]=[C:17]([C:21]2([OH:44])[CH2:26][CH2:25][N:24]([CH2:27][C:28]34[CH2:43][CH:35]([C:36]5[CH:37]=[CH:38][C:39]([Cl:42])=[CH:40][C:41]=53)[C:34]3[C:29]4=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:23][CH2:22]2)[CH:18]=[N:19][CH:20]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O>[Cl:42][C:39]1[CH:38]=[CH:37][C:36]2[CH:35]3[CH2:43][C:28]([CH2:27][N:24]4[CH2:23][CH2:22][C:21]([C:17]5[CH:18]=[N:19][CH:20]=[C:15]([CH2:14][OH:13])[CH:16]=5)([OH:44])[CH2:26][CH2:25]4)([C:29]4[C:34]3=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:41]=2[CH:40]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1cncc(C2(O)CCN(CC34CC(c5ccccc53)c3ccc(Cl)cc34)CC2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: OCc1cncc(C2(O)CCN(CC34CC(c5ccccc53)c3ccc(Cl)cc34)CC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.3 %

Procedure:
A tetrahydrofuran solution (15 mL) of 4-(5-(tert-butyldimethylsilyl)oxymethyl-3-pyridyl)-1-(2-chloro-9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)piperidin-4-ol (1.70 g, 3.04 mmol) was cooled to 0° C. under nitrogen and treated with tetrabutylammonium fluoride (1.0N in tetrahydrofuran, 3.20 mL, 3.20 mmol, 1.05 eq). The reaction was warmed to room temperature and stirred at that temperature for 3 h. Water (15 mL) was added and the resulting aqueous phase was extracted with ethyl acetate (3×15 mL). Combined organic extracts were dried over anhydrous sodium sulfate, filtered, and reduced to an oil. This procedure resulted in 1.20 g (89%) of the title compound. TLC analysis (Rf 0.11, 5% methanol in diethyl ether). No additional purification was required. 1H NMR (CDCl3, 250 MHz) 8.62 (s, 1H), 8.42 (s, 1H), 7.84 (s, 1H), 7.21 (m, 4H), 6.94 (m, 3H), 4.69 (s, 2H), 4.27 (s, 1H), 3.44 (s, 2H), 2.90 (m, 2H), 2.74 (m, 2H), 2.62 (d, J=1.3 Hz, 2H), 2.11 (m, 2H), 1.76 (m, 2H) MS (CI, CH4) m/z 447 (M+1,100), 449 (32), 475 (M+29,19), 429 (71), 431 (25) The free base was dissolved in ether and acidified with ethereal HCl. The hydrochloride salt was filtered, rinsed with fresh ether and dried in vacuo (room temperature, 10 pascal, 18 h) to yield a white solid, mp 235°-240° C. (dec).
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[C@@H:26]([OH:27])[CH2:25][CH2:24][C@@:23]2([CH3:28])[C@H:3]1[CH2:4][CH:5]=[C:6]1[C@@H:22]2[CH2:21][CH2:20][C@@:19]2([CH3:29])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[C@H:11]([CH3:18])[CH2:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16].[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>N1C=CC=CC=1>[C:31]([O:27][C@H:26]1[CH2:25][CH2:24][C@@:23]2([CH3:28])[C@@H:3]([CH2:4][CH:5]=[C:6]3[C@@H:22]2[CH2:21][CH2:20][C@@:19]2([CH3:29])[C@H:7]3[CH2:8][CH2:9][C@@H:10]2[C@H:11]([CH3:18])[CH2:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C:2]1([CH3:1])[CH3:30])(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=CC[C@H]4C(C)(C)[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=CC[C@H]4C(C)(C)[C@@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
4,4-Dimethyl-5α-cholest-7-en-3β-ol [prepared according to J. Biol. Chem., 233:1343 (1958)]was converted to the title compound with benzoyl chloride in pyridine at ambient temperature for 18 hours. 3β-benzoyloxy-4,4-dimethyl-5α-cholest-7-ene had an mp of 160°-161° C. (from CH2Cl2/MeOH).
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=1[CH2:6][CH:7]([NH2:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([O-:3])=[O:2].[CH:19]1([C:25](Cl)=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C1(C)C=CC=CC=1.N1C=CC=CC=1>[CH:19]1([C:25]([NH:14][CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N+:1]([O-:3])=[O:2])=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: NC(Cc1ccccc1[N+](=O)[O-])c1ccccc1
Reactant: O=C(Cl)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: O=C(NC(Cc1ccccc1[N+](=O)[O-])c1ccccc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10.0 g of 2-nitro-α-phenylphenethylamine in 75 ml of toluene is added dropwise to a stirred, cooled solution of 14.4 ml of cyclohexylcarbonyl chloride in 75 ml of toluene and 25 ml of pyridine. After complete addition the mixture is stirred at room temperature for 2 hours. The mixture is allowed to stand overnight, after which the tan precipitate is collected and washed with 100 ml of ether. The precipitate is recrystallized from 350 ml of methanol to give yellow needles, mp 210°-212° C. of N-cyclohexanecarbonyl-2-nitro-α-phenylphenethylamine.
Reaction SMILES: O.[OH-].[Li+].[C:4]([O:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH:28]([O:34][CH2:35][CH3:36])[C:29]([O:31]CC)=[O:30])=[CH:23][CH:22]=2)=[CH:14][CH:13]=1)=[O:10])([CH3:7])([CH3:6])[CH3:5]>O.C1COCC1>[C:4]([O:8][C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][O:20][C:21]2[CH:22]=[CH:23][C:24]([CH2:27][CH:28]([O:34][CH2:35][CH3:36])[C:29]([OH:31])=[O:30])=[CH:25][CH:26]=2)=[CH:16][CH:17]=1)=[O:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: CCOC(=O)C(Cc1ccc(OCCc2ccc(NC(=O)OC(C)(C)C)cc2)cc1)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(Cc1ccc(OCCc2ccc(NC(=O)OC(C)(C)C)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.7 %

Procedure:
Lithium hydroxide hydrate (77 mg; 1.85 mmole) in water (5.5 ml) was slowly added to a solution of ethyl 3-{4-[2-(4-tert-butoxycarbonylaminophenyl)ethoxy]phenyl}-2-ethoxypropanoate (0.77 g; 1.68 mmole) in THF (7.6 ml). After stirring at room temperature for 4 hours the reaction mixture was kept in a freezer for 4 days. THF was removed by evaporation in vacuo. More water was added and the mixture was acidified with hydrochloric acid to pH1. The product was extracted with ethyl acetate, washed twice with water, dried (sodium sulfate), filtered and the solvent was evaporated in vacuo to give 0.712 g (98.7% yield) of the desired product.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH2:26][C:27]([O:29]C)=O)=[N:4][CH:5]=[C:6]([NH:8][C:9]2[N:25]=[C:12]3[CH:13]=[CH:14][CH:15]=[C:16]([NH:17][C@H:18]4[CH2:23][CH2:22][C@@H:21]([OH:24])[CH2:20][CH2:19]4)[N:11]3[N:10]=2)[CH:7]=1>ClCCl.CO.[Ni]>[OH:24][C@@H:21]1[CH2:22][CH2:23][C@H:18]([NH:17][C:16]2[N:11]3[N:10]=[C:9]([NH:8][C:6]4[CH:7]=[C:2]5[NH:1][C:27](=[O:29])[CH2:26][C:3]5=[N:4][CH:5]=4)[N:25]=[C:12]3[CH:13]=[CH:14][CH:15]=2)[CH2:19][CH2:20]1
Reactant: COC(=O)Cc1ncc(Nc2nc3cccc(N[C@H]4CC[C@@H](O)CC4)n3n2)cc1N
Agent: [Ni]
Solvent: ClCCl
Solvent: CO
Product: O=C1Cc2ncc(Nc3nc4cccc(N[C@H]5CC[C@@H](O)CC5)n4n3)cc2N1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Methyl cis-2-(3-amino-5-(5-(4-hydroxycyclohexylamino)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)pyridin-2-yl)acetate. To a mixture of diethyl cis-2-(3-amino-5-(5-(4-hydroxycyclohexylamino)-[1,2,4]triazolo[1,5-c]pyridin-2-ylamino)pyridin-2-yl)malonate (120.0 mg, 0.23 mmol) in a mixture of dichloromethane (10 mL) and methanol (50 mL) was added Raney nickel (100 mg), and the mixture was stirred under hydrogen at room temperature for 24 hours. LCMS analysis showed that the major product was the desired product (if the reaction was not completed, just kept the hydrogenation until the reaction was completed). The mixture was filtered, concentrated under reduced pressure, and purified on silica gel column (eluting with 1-2% dichloromethane in methanol) to give methyl cis-2-(3-amino-5-(5-(4-hydroxycyclohexylamino)-[1,2,4]triazolo[1,5-c]pyridin-2-ylamino)pyridin-2-yl)acetate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]O)=[C:4]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:3]=1.P(Br)(Br)([Br:16])=O.P(Br)(Br)Br>[Cl-].[Na+].O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:16])=[C:4]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:3]=1
Reactant: CS(=O)(=O)c1cc(Br)ccc1CO
Reactant: O=P(Br)(Br)Br
Agent: BrP(Br)Br
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CS(=O)(=O)c1cc(Br)ccc1CBr
Temperature: 130 °C
Reaction time: 8 h
Yield: 160.5 %

Procedure:
To a solution of (4-bromo-2-methanesulfonyl-phenyl)-methanol (preparation 112) (100 mg, 0.38 mmol) in POBr3 (542 mg, 1.89 mmol) was added PBr3 (511 mg, 1.89 mmol). After the addition, the reaction mixture was stirred at 130° C. overnight. TLC (petroleum ether:EtOAc 1:1) showed the reaction was complete. The reaction was cooled to room temperature and then poured into brine (10 mL) and extracted with EtOAc (10 mL×2). The combined organic layers were washed with brine (10 mL×2), dried over sodium sulfate and concentrated in vacuo to give crude 4-bromo-1-bromomethyl-2-methanesulfonyl-benzene (200 mg, 80%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[CH:16]=[CH:15][S:14][C:13]=2Br)=[O:11])[C:5]([OH:8])=[CH:6][CH:7]=1.[C:18](=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][C:13]3[S:14][C:15]([CH3:18])=[CH:16][C:12]=3[C:10](=[O:11])[NH:9][C:4]=2[CH:3]=1
Reactant: O=C(Nc1cc(Cl)ccc1O)c1ccsc1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cc2c(s1)Oc1ccc(Cl)cc1NC2=O
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 20.1 %

Procedure:
To a solution of N-(3-chloro-6-hydroxyphenyl)-2-bromo-3-thiophenecarboxamide (4.1 g) in dimethyl sulfoxide (33 ml) was added potassium carbonate (3.3 g), and the mixture was stined at 140-150° C. for 75 minutes. The reaction system was cooled to room temperature and the reaction mixture was poured into ice water. The precipitated crystals were collected by filtration. The filtrate was extracted twice with chloroform, the organic layer was dried over sodium sulfate and the solvent was evaporated under reduced pressure. The residue and the above-mentioned crystals were combined and purified by silica gel column chromatography (chloroform:methanol=20:1, hexane:ethyl acetate=1:1-ethyl acetate:methanol=20:1). The obtained solid was collected by filtration from hexane-ethyl acetate to give 7-chloro-2-methylthieno[2,3-b][1,5]benzoxazepin-4(5H)-one (660 mg).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[CH2:8][N:9]([C:16]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][C:17]=1[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=O)[C:10](=[O:15])C(Cl)(Cl)Cl.C([O-])(=O)C.[NH4+:37]>C(O)(C)(C)C>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[CH2:8][N:9]1[C:16]2[C:17](=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[CH:28][CH:29]=2)[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:37][C:10]1=[O:15]
Reactant: O=C(c1ccccc1)c1cc([N+](=O)[O-])ccc1N(CC1CC2CCC1C2)C(=O)C(Cl)(Cl)Cl
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(C)(C)O
Product: O=c1nc(-c2ccccc2)c2cc([N+](=O)[O-])ccc2n1CC1CC2CCC1C2
Reaction time: 8 h

Procedure:
To a solution of 2.5 g of 2-[ N-(2-norbornylmethyl)trichloroacetamido]-5-nitrobenzophenone in 50 ml of tert-butyl alcohol was added 2 g of ammonium acetate and the resulting mixture was heated under reflux for 7 hours. Then 2 g of ammonium acetate was added thereto and the reaction was continued for additional 8 hours. The solvent was removed under reduced pressure, and the residue was extracted with chloroform. The chloroform extract was washed with water, dried over anhydrous sodium sulfate, and evaporated to dryness. The residual oil was crystallized from a mixture of carbon tetrachloride and diethyl ether to give 1-(2-norbornylmethyl)-4-phenyl-6-nitro-2(1H)-quinazolinone, m.p. 160°C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@H:10]([O:12][C:13]1[C:14]([NH2:28])=[N:15][CH:16]=[C:17](B2OC(C)(C)C(C)(C)O2)[CH:18]=1)[CH3:11].[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH:39]([N:42]2[CH:46]=[C:45](Br)[CH:44]=[N:43]2)[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O>[C:29]([O:33][C:34]([N:36]1[CH2:37][CH2:38][CH:39]([N:42]2[CH:46]=[C:45]([C:17]3[CH:16]=[N:15][C:14]([NH2:28])=[C:13]([O:12][C@@H:10]([C:3]4[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=4[Cl:1])[CH3:11])[CH:18]=3)[CH:44]=[N:43]2)[CH2:40][CH2:41]1)=[O:35])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(Br)cn2)CC1
Reactant: C[C@@H](Oc1cc(B2OC(C)(C)C(C)(C)O2)cnc1N)c1c(Cl)ccc(F)c1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: C[C@@H](Oc1cc(-c2cnn(C3CCN(C(=O)OC(C)(C)C)CC3)c2)cnc1N)c1c(Cl)ccc(F)c1Cl
Temperature: 87 °C
Reaction time: 16 h
Yield: 62.1 %

Procedure:
To a stirred solution of 3-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine (4.2711 g, 10.0 mmol) and 4-(4-bromo-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (3.9628 g, 12.0 mmol) in DME (40 mL) was added a solution of Na2CO3 (3.1787 g, 30.0 mmol) in water (10 mL). The solution was degassed and charged with nitrogen three times. To the solution was added Pd(PPh3J2CI2 (351 mg, 0.50 mmol). The reaction solution was degassed and charged with nitrogen again three times. The reaction solution was stirred at 87° C. oil bath for about 16 hours (or until consumption of the borane pinacol ester), cooled to ambient temperature and diluted with EtOAc (200 mL). The reaction mixture was filtered through a pad of celite and washed with EtOAc. The EtOAc solution was washed with brine, dried over Na2SO4, and concentrated. The crude product was purified on a silica gel column eluting with EtOAc/hexane system (0% EtOAc to 100% EtOAc) to afford 4-(4-{6-amino-5-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (3.4167 g, 65% yield, −95% purity) with a Rf of 0.15 (50% EtOAc/Hexanes). MS m/e 550 (M+1)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C.[C:37]([S:40][CH2:41][CH2:42][N:43]([CH2:52][CH2:53][CH:54]1[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]1)[C:44](=[O:51])[NH:45][C@@H:46]([CH3:50])[C:47]([OH:49])=O)(=[O:39])[CH3:38]>C(Cl)Cl>[C:37]([S:40][CH2:41][CH2:42][N:43]([CH2:52][CH2:53][CH:54]1[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]1)[C:44](=[O:51])[NH:45][C@@H:46]([CH3:50])[C:47]([N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)=[O:49])(=[O:39])[CH3:38]
Reactant: CN1CCNCC1
Reactant: CC(=O)SCCN(CCC1CCCCC1)C(=O)N[C@@H](C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(=O)SCCN(CCC1CCCCC1)C(=O)N[C@@H](C)C(=O)N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
In anhydrous methylene chloride (5 ml) are dissolved (2S)-2-[3-[2-(acetylthio)ethyl]-3-(2-cyclohexylethyl)ureido]propionic acid (Compound No. 7-1, 826 mg), N-methylpiperazine (0.27 ml) and 1-hydroxybenzotriazole (357 mg) under a nitrogen atmosphere. To the solution are added N-methylmorpholine (0.29 ml) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (506 mg) successively under ice cooling, and the mixture is stirred at room temperature overnight. The reaction mixture is concentrated under reduced pressure, a 5% aqueous sodium hydiogencarbonate solution (30 ml) is added to the resulting oily matter, and the whole is extracted with ethyl acetate. The organic layer is washed with water and saturated brine successively, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting oily matter is purified by silica gel column chromatography to give 801 mg (78%) of the titled compound (Compound No. 13-1).
Reaction SMILES: [H-].[Na+].Br[C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2.C([Li])CCC.[CH2:18]1[O:20][CH2:19]1>C1COCC1.CCCCCC>[OH:20][CH2:19][CH2:18][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: C1CO1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OCCc1ccc2[nH]ccc2c1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 54 %

Procedure:
To a cooled (0° C.) mixture of 1.56 g (38.9 mmol) of a 60% dispersion of sodium hydride in 10 mL THF is slowly added a solution of 5.05 g (25.9 mmol) 5-bromoindole (Acros) in 20 mL THF. After H2 evolution stopped (˜10 min) the mixture is cooled to −78° C., and 25.9 mL (64.8 mmol) of a 2.5 M hexane solution of n-butyllithium is added dropwise. After five minutes, added 16.8 mL (38.9 mmol) of a 2.3 M THF stock solution of ethylene oxide and removed cooling bath. After 90 minutes, quenched with 5 mL distilled water. The organic layer is then poured away from the inorganic salts and concentrated. The resulting residue is chromatographed (1:1 hexane:ethyl acetate) to provide 2.24 g of the product as a yellow oil in 54% yield. 1H NMR (CDCl3): δ 2.96 (2H, t, J=6.5 Hz), 3.88 (2H, m), 6.51 (1H, m), 7.06 (1H, dd, J1=8.5 Hz, J2=1.5 Hz), 7.19 (1H, m), 7.33 (1H, d, J=8.5 Hz), 7.49 (1H, s), 8.19 (1H, br). MS (EI) m/z 161 M+, 130 (M−CH2OH)+.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[CH:12]=[CH:11][C:7]([CH2:8][NH:9][NH2:10])=[CH:6][CH:5]=1.[CH3:13][C:14]([CH2:16][C:17]([C:19]([O:21][CH3:22])=[O:20])=O)=O>C(O)(=O)C>[CH3:13][C:14]1[N:9]([CH2:8][C:7]2[CH:11]=[CH:12][C:4]([CH3:3])=[CH:5][CH:6]=2)[N:10]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[CH:16]=1
Reactant: Cc1ccc(CNN)cc1
Reactant: COC(=O)C(=O)CC(C)=O
Agent: Cl
Solvent: CC(=O)O
Product: COC(=O)c1cc(C)n(Cc2ccc(C)cc2)n1
Temperature: 90 °C
Reaction time: 4 h
Yield: 44.8 %

Procedure:
A mechanically stirred suspension of 4-(methylbenzyl)hydrazine dihydrochloride (Step 3, 81.8 g, 391 mmol) and methyl acetopyruvate (51.2 g, 356 mmol) in acetic acid (825 mL) was warmed to 90° C. and stirred for 4 h. The solid gradually dissolved, leaving an orange solution. After being cooled to rt, the reaction mixture was concentrated to an orange oil. The organic residue was diluted with EtOAc, washed with water (1×250 mL), NaHCO3 (1×250 mL), and brine (1×250 mL), was dried (Na2SO4), filtered and concentrated to an orange oil. Purification with an ISCO CombiFlash Companion, using a gradient from 0% to 30% EtOAc in hexanes afforded the title compound as a yellow-orange oil (39 g, 45%): 1H NMR (300 MHz, d6-DMSO) δ 2.20 (s, 3H), 2.24 (s, 3H), 3.75 (s, 3H), 5.31 (s, 2H), 6.56 (s, 1H), 7.01 (d, 2H), 7.12 (d, 2H). ES-MS m/z 245.0 (MH)+, HPLC RT (Method A) 3.13 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]2[CH2:19][CH2:18][C:17]3[NH:16][C:15](=[O:20])[CH2:14][CH2:13][C:12]=3[CH2:11]2)=[CH:5][CH:4]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH:10]2[CH2:19][CH2:18][CH:17]3[CH:12]([CH2:13][CH2:14][C:15](=[O:20])[NH:16]3)[CH2:11]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(CC2CCC3=C(CCC(=O)N3)C2)cc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CC2CCC3NC(=O)CCC3C2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 46.3 %

Procedure:
3,4,5,6,7,8-Hexahydro-6-((4-methoxyphenyl)methyl)quinolin-2[1H]-one (1.5 g) (prepared according to Example 9) was dissolved in dichloromethane (50 ml) and cooled to 0° C. Triethylsilane (0.9 ml and trifluoroacetic acid (5 ml) were added and the mixture was stirred for 2 hours. The reaction mixture was then evaporated under reduced pressure, crystallised by addition of ether and recrystallised from acetonitrile to give the title compound (0.7 g), mp 194°-196° C.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=4[F:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:30][NH2:31]>>[CH3:30][NH:31][CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=3[F:29])[C:15]=2[O:14]1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4cccc(F)c4F)c3O2)cc1
Product: CNCC1Cc2cccc(-c3cccc(F)c3F)c2O1

Procedure:
The title compound was prepared (0.094 g, 84%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(2,3-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.095 g, 0.23 mmol) and methylamine (0.072 g, 2.3 mmol); mp 166-168° C.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9](/[CH:12]=[C:13]2/[C:14]([NH:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][OH:25])=[N:15][C:16](=[O:18])[S:17]/2)[CH2:8][CH2:7]1.O.[S:37]([C:41]1[CH:47]=[CH:46][C:44](C)=[CH:43][CH:42]=1)([OH:40])(=[O:39])=[O:38]>C(OCC)(=O)C>[C:3]1([CH3:2])[C:4]([S:37]([OH:40])(=[O:39])=[O:38])=[CH:26][CH:27]=[CH:28][CH:29]=1.[C:47]1([CH3:2])[C:41]([S:37]([OH:40])(=[O:38])=[O:39])=[CH:42][CH:43]=[CH:44][CH:46]=1.[F:35][C:2]([F:1])([F:34])[C:3]1[CH:29]=[C:28]([C:30]([F:32])([F:33])[F:31])[CH:27]=[CH:26][C:4]=1[CH2:5][N:6]1[CH2:7][CH2:8][CH:9](/[CH:12]=[C:13]2/[C:14]([NH:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][OH:25])=[N:15][C:16](=[O:18])[S:17]/2)[CH2:10][CH2:11]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C1N=C(NCCOCCO)/C(=C/C2CCN(Cc3ccc(C(F)(F)F)cc3C(F)(F)F)CC2)S1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccccc1S(=O)(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (5Z)-5-({1-[2,4-bis(trifluoromethyl)benzyl]piperidin-4-yl}methylidene)-4-{[2-(2-hydroxyethoxy)ethyl]amino}-1,3-thiazol-2(5H)-one (4.3 g) in ethyl acetate (40 ml) was added tosylic acid monohydrate (3.11 g), and the mixture was stirred at room temperature for 2 hr. The precipitate was collected by filtration, washed with ethyl acetate, and recrystallized from 2-butanone/heptane to give the title compound (4.4 g).