Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Si:5]([CH3:24])([CH3:23])[O:6][CH:7]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:8][CH2:9][CH:10]1[NH:14][C:13](=[O:15])[CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:35][O:36][C:37](=[O:48])[C:38]1[CH:43]=[CH:42][C:41]([CH2:44][CH2:45][CH2:46]Br)=[CH:40][CH:39]=1>CN(C=O)C>[CH3:35][O:36][C:37](=[O:48])[C:38]1[CH:43]=[CH:42][C:41]([CH2:44][CH2:45][CH2:46][N:14]2[C:13](=[O:15])[CH2:12][CH2:11][CH:10]2[CH2:9][CH2:8][CH:7]([O:6][Si:5]([C:1]([CH3:3])([CH3:2])[CH3:4])([CH3:24])[CH3:23])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:40][CH:39]=1
Reactant: COC(=O)c1ccc(CCCBr)cc1
Reactant: CC(C)(C)[Si](C)(C)OC(CCC1CCC(=O)N1)Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CCCN2C(=O)CCC2CCC(Cc2ccccc2)O[Si](C)(C)C(C)(C)C)cc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 70.3 %

Procedure:
To a solution of 5-[3-(tert-butyl-dimethyl-silanyloxy)-4-phenyl-butyl]-pyrrolidin-2-one (3.20 g, 9.21 mmol) in DMF (30 mL) at 0° C. was added NaHMDS (1M in THF, 11.5 mL, 11.5 mmol). After 1 h, 4-(3-bromo-propyl)-benzoic acid methyl ester (2.84 g, 11.0 mmol) was added and the reaction mixture was stirred at 70° C. for 18 h. The DMF was removed in vacuo and the residue was dissolved in EtOAc. The organic solution was washed with water, dried (MgSO4), filtered and concentrated. The residue was purified by medium pressure chromatography (30% EtOAc in hexanes) to yield 3.39 g of 4-(3-{2-[3-(tert-butyl-dimethyl-silanyloxy)-4-phenyl-butyl]-5-oxo-pyrrolidin-1-yl}-propyl)-benzoic acid methyl ester. 1H NMR (CDCl3) (selected peaks) δ7.92 (m, 2H), 7.25-7.09 (m, 7H), 3.86 (s, 3H), 3.80 (m, 1H), 3.61 (m, 1H), 3.46 (m, 1H), 2.90 (m, 1H), 2.78-2.57 (m, 4H), 2.38-2.18 (m, 2H), 0.83 (s, 9H); MS 524.1 (M+1).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@@H:21](/[CH:35]=[CH:36]/[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]SCCCCCCC)[C@@:22]([OH:34])([CH2:30][CH2:31][O:32][CH3:33])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:20])[C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[CH:51]1[CH:56]=[C:55](Cl)[CH:54]=[C:53]([C:58](OO)=O)[CH:52]=1.[S:62]([O-:66])([O-])(=[O:64])=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@@H:21](/[CH:35]=[CH:36]/[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][S:62]([CH2:58][CH2:53][CH2:52][CH2:51][CH2:56][CH2:55][CH3:54])(=[O:66])=[O:64])[C@@:22]([OH:34])([CH2:30][CH2:31][O:32][CH3:33])[C:23]([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[O:24])=[O:20])[C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S([O-])([O-])=S
Reactant: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCSCCCCCCC)[C@@](O)(CCOC)C(=O)OC(C)(C)C)C(=O)OC)cc1
Agent: [Na+]
Solvent: ClCCl
Product: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCS(=O)(=O)CCCCCCC)[C@@](O)(CCOC)C(=O)OC(C)(C)C)C(=O)OC)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl (E)-(2S,3S)-3-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-11-heptylsulfanyl-2-hydroxy-2-(2-methoxy-ethyl)-undec-4-enoate (No. 6804240; 50.9 mg, 0.0709 mmol) was dissolved in dichloromethane (3.4 mL), and the mixture was cooled to 0° C. mCPBA (72% content, 34.0 mg, 0.142 mmol) was added, and the mixture was stirred at 0° C. for 30 minutes. After completing the reaction, the progress of the reaction was stopped by adding an aqueous solution of 10% sodium thiosulfate, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate, water, and a saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off under reduced pressure to obtain 56.1 mg of tert-butyl (E)-(2S,3S)-3-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-11-(heptane-1-sulfonyl)-2-hydroxy-2-(2-methoxy-ethyl)-undec-4-enoate (No. 6804464; ESI (LC/MS positive mode) m/z 750 (M+H); Rt 2.15 min.).
Reaction SMILES: Br[C:2]1[N:6]([S:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=1.[CH3:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:25][N:17]([CH2:16][C:4]1[CH:3]=[C:2]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[CH3:26])[N:6]([S:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH:5]=1)[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21]
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Reactant: Cc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccccc1-c1cc(CN(C)C(=O)OC(C)(C)C)cn1S(=O)(=O)c1cccnc1
Temperature: 105 °C
Reaction time: 18 h
Yield: 68.2 %

Procedure:
By a similar operation as in Reference Example 79 and using tert-butyl {[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (300 mg), (2-methylphenyl)boronic acid (190 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222 mg), the title compound was obtained as a pale-yellow oil (yield 210 mg, 68%). More specifically, a suspension of tert-butyl {[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (300 mg), (2-methylphenyl)boronic acid (190 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222 mg) in 1,2-dimethoxyethane (10 mL) and water (7.5 mL) was stirred at 105° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=7:1→3:1) to give the title compound as a pale-yellow oil (yield 210 mg, 68%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[C:10]([CH3:15])=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:6][CH:7]=1.C(N(CC)CC)C.Cl[C:24]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:25]>C(Cl)Cl>[CH3:15][C:10]1[C:9]([O:8][C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:24](=[O:25])[O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:7][N:6]=2)=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cc1ncccc1Oc1ccc(N)cn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ncccc1Oc1ccc(NC(=O)Oc2ccccc2)cn1
Temperature: -20 °C
Reaction time: 1 h
Yield: 55.7 %

Procedure:
5-Amino-2-(2-methylpyridin-3-yloxy)pyridine (D9, 60.3 g, 0.3 mole) in dry CH2Cl2 (2.5L) was cooled to −20° C. under argon. Triethylamine (46 ml, 0.33 mole) was added, followed dropwise by phenyl chloroformate (41 ml, 0.33 mole) and the mixture was stirred at −20° C. for 1 hour. After warming to ambient temperature, the mixture was washed with dil. aq. NaHCO3, dried (Na2SO4) and evaporated in vacuo. The residue was recrystallised from ethyl acetate/60-80° petroleum ether to afford the title compound (53.7 g, 56%) as a pink solid.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[C:6]([F:9])[N:5]=[C:4]([C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])[CH:3]=1.[OH-].[NH4+:17].O>CN1C(=O)CCC1>[NH2:17][C:2]1[C:7]([F:8])=[C:6]([F:9])[N:5]=[C:4]([C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])[CH:3]=1
Reactant: [NH4+]
Reactant: CC(C)OC(=O)c1cc(F)c(F)c(F)n1
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)OC(=O)c1cc(N)c(F)c(F)n1
Reaction time: 8 h
Yield: 68 %

Procedure:
Isopropyl 4,5,6-trifluoropicolinate (17.52 g, 80 mmol) was dissolved in NMP (175 g) in a 500 mL flask equipped with a stirring bar. The mixture was blanketed with nitrogen and then ammonium hydroxide (10.70 g 176 mmol, 28% in water) was added to the flask dropwise at room temperature, and the reaction was stirred overnight. To the reaction was added water (190 mL) and the resulting slurry was cooled in an ice bath and stirred for 5 hours. The solid was collected by filtration and the cake washed with water. Vacuum drying provided the isopropyl 4-amino-5,6-difluoropicolinate as an off-white solid (11.7 g, 68% yield, 96% HPLC purity): mp 167-168° C.; 1H NMR (THF-d8, 300 MHz) δ 7.25 (d, 1H, J=6 Hz), 6.07 (s, 2H), 5.01 (m, 1H, J=6 Hz), 1.20 (d, 6H, J=6.3 Hz); 13C NMR (THF-d8, 75 MHz, 1H decoupled) δ 162.9 (s), 151.5 (dd, J=228 Hz, 12 Hz), 146.1 (dd, J=9 Hz, 6 Hz), 140.4 (dd, J=17 Hz, 5 Hz), 134.5 (dd, J=251 Hz, 32 Hz), 111.9 (m), 68.4 (s), 21.0 (s).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][CH2:12][C@H:13]2[CH2:17][CH2:16][CH2:15][NH:14]2)=[CH:5][C:4]=1[N:18]=[CH:19][N:20]([CH3:22])[CH3:21])#[N:2].Br[CH2:24][CH2:25][O:26][C:27]([CH3:30])([CH3:29])[CH3:28].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:27]([O:26][CH2:25][CH2:24][N:14]1[CH2:15][CH2:16][CH2:17][C@@H:13]1[CH2:12][O:11][C:6]1[C:7]([O:9][CH3:10])=[CH:8][C:3]([C:1]#[N:2])=[C:4]([N:18]=[CH:19][N:20]([CH3:21])[CH3:22])[CH:5]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OCCBr
Reactant: COc1cc(C#N)c(N=CN(C)C)cc1OC[C@H]1CCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C#N)c(N=CN(C)C)cc1OC[C@H]1CCCN1CCOC(C)(C)C
Yield: 55.6 %

Procedure:
N′-(2-cyano-4-methoxy-5-[(2R)-pyrrolidin-2-ylmethoxy]phenyl)-N,N-dimethylimidoformamide (1.23 g, 4.06 mmol) in dimethylformamide (13 ml) was reacted with 2-(2-bromoethoxy)-2-methylpropane (809 mg, 4.47 mmol) in the presence of potassium carbonate (842 mg, 6.1 mmol) at 50° C. for 5 hours. The solvent was then evaporated, and the residue purified by chromatography on silica gel, eluting with dichloromethane:methanol (98:2) then (95:5), to yield N′-(5-{[(2R)-1-(2-tert-butoxyethyl)pyrrolidin-2-yl]methoxy}-2-cyano-4-methoxyphenyl)-N,N-dimethylimidoformamide (908 mg, 56% yield):
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N+:8]([O-:18])[CH2:9][C:10]3[N:11]([N:12]=[C:13]([C:15]([OH:17])=O)[N:14]=3)[C:5]=2[S:4][C:3]=1[CH3:25].C(N(CC)CC)C.C(Cl)(=O)OCC.[NH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>O.O1CCCC1>[CH3:1][C:2]1[C:6]2[C:7]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N+:8]([O-:18])[CH2:9][C:10]3[N:11]([N:12]=[C:13]([C:15]([N:39]4[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]4)=[O:17])[N:14]=3)[C:5]=2[S:4][C:3]=1[CH3:25]
Reactant: C1CCNCC1
Reactant: Cc1sc2c(c1C)C(c1ccccc1)=[N+]([O-])Cc1nc(C(=O)O)nn1-2
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1sc2c(c1C)C(c1ccccc1)=[N+]([O-])Cc1nc(C(=O)N3CCCCC3)nn1-2
Reaction time: 0.08 h

Procedure:
To a mixture of 178 mg. of 7,8-dimethyl-6-phenyl-4H-thieno[3,2-f]-s-triazolo[1,5-a][1,4]diazepine-2-carboxylic acid 5-oxide, 0.1 ml. of triethylamine and 5 ml. of tetrahydrofuran is added 0.07 ml. of ethyl chlorocarbonate under stirring and cooling on an ice-sodium chloride bath, and the mixture is stirred for 5 minutes. Then, to the mixture is added 0.07 ml. of piperidine, followed by stirring for 30 minutes, and water is added to the resulting mixture. Then, the mixture is extracted with ethyl acetate. The ethyl acetate layer is washed with water, dried over sodium sulfate and then the solvent is evaporated. Thereafter, addition of ether to the residue gives 7,8-dimethyl-6-phenyl-2-piperidinocarbonyl-4H-thieno[3,2-f]-s-triazolo[1,5-a][1,4]diazepine-5-oxide as crystals. Recrystallization from ethyl acetate gives colorless prisms melting at 213° to 214° C.
Reaction SMILES: [CH2:1]([N:4]([C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH:10]=O)[CH2:5][CH:6]=[CH2:7])[CH:2]=[CH2:3].[C:16]1([NH:22][NH2:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CO>[C:16]1([NH:22][N:23]=[CH:10][C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[N:4]([CH2:5][CH:6]=[CH2:7])[CH2:1][CH:2]=[CH2:3])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NNc1ccccc1
Reactant: C=CCN(CC=C)c1ccccc1C=O
Solvent: CO
Product: C=CCN(CC=C)c1ccccc1C=NNc1ccccc1

Procedure:
To 1 mole of N,N-diallylaminobenzaldehyde in methanol, was added 1.2 moles of phenylhydrazine. The mixture was heated under reflux for about 2 hours to yield diallylaminobenzaldehyde N-phenylhydrazone (melting point: 63.5°-65.0° C.). Into a mixture of 5 cc of 5N sodium hydroxide solution and 20 cc of dimethyl sulfoxide, were added 5.0 g of said hydrazone and 4.8 g of allyl bromide. The mixture was stirred for 2 hours at room temperature. After completion of the reaction, 50 cc of water and ethyl acetate were added to the reaction mixture to extract the organic layer. The extract was freed from the ethyl acetate by distillation and the residue was recrystallized from 150 cc of alcohol to yield 3.8 g of pale yellowish white crystals melting at 38.5°-40.0° C.
Reaction SMILES: CC(O)C.C([C@](C(O)=O)(O)[C@](C(=O)C1C=CC=CC=1)(O)C(O)=O)(=O)C1C=CC=CC=1.[O:31]=[C:32]([N:46]1[CH2:51][CH2:50][N:49]2[C:52]([C:55]([F:58])([F:57])[F:56])=[N:53][N:54]=[C:48]2[CH2:47]1)[CH2:33][CH:34]([NH2:45])[CH2:35][C:36]1[CH:41]=[C:40]([F:42])[C:39]([F:43])=[CH:38][C:37]=1[F:44]>CO>[O:31]=[C:32]([N:46]1[CH2:51][CH2:50][N:49]2[C:52]([C:55]([F:58])([F:57])[F:56])=[N:53][N:54]=[C:48]2[CH2:47]1)[CH2:33][C@@H:34]([NH2:45])[CH2:35][C:36]1[CH:41]=[C:40]([F:42])[C:39]([F:43])=[CH:38][C:37]=1[F:44]
Reactant: NC(CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Agent: O=C(O)[C@](O)(C(=O)c1ccccc1)[C@](O)(C(=O)O)C(=O)c1ccccc1
Solvent: CC(C)O
Solvent: CO
Product: N[C@H](CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Temperature: 62.5 °C
Reaction time: 1 h

Procedure:
In a 100 mL three neck flask IPA (25 mL) and Dibenzoyl-D-tartaric acid (8.8 g) were taken. It was heated to 60-65° C. 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine (10 g, purity-91.8%) dissolved in methanol (30 mL) was added slowly into the reaction mixture at 60-65° C. It was stirred for 1 h at 60-65° C. Solid salt was precipitated. It was gradually cooled to room temperature and stirred for 3 h. The salt was filtered and washed with a mixture of IPA: MeOH (2:1). An enantiomerically enriched desired Dibenzoyl-D-tartaric acid salt of mixture of (2R) and (2S)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine was obtained (Wt.-7.2 g, % Y-38.4%, Purity by HPLC-98.2%, % Chiral purity by HPLC of S-isomer 71.7%).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][C:11](=[O:13])[CH2:10][C:9](=O)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:15][CH2:16][CH2:17]O.BrC1C(C)=CC(C)=CC=1C.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O1CCCC1>[C:1]1([CH:7]2[CH2:8][C:9]3[NH:15][CH:16]=[CH:17][C:10]=3[C:11](=[O:13])[CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NCCO
Reactant: O=C1CC(=O)CC(c2ccccc2)C1
Agent: Cc1cc(C)c(Br)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C1CC(c2ccccc2)Cc2[nH]ccc21
Temperature: 150 °C
Reaction time: 2 h
Yield: 0.7 %

Procedure:
A mixture of 5-phenylcyclohexane-1,3-dione (15.0 g), 2-aminoethanol (6.3 g), molecular sieves 4A (100 g) and tetrahydrofuran (200 ml) was refluxed for 12 hours and cooled, and insoluble materials were filtered off. Under reduced pressure, the solvent was evaporated to give oil, which was dissolved in dimethylformamide (5 ml). To the solution were added 2-bromomesitylene (0.20 g), tetrakistriphenylphosphine palladium (30 mg) and potassium carbonate (0.28 g), and the mixture was stirred at 150° C. for 2 hours and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and the solution was washed with sodium hydrogen carbonate solution, water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (EtOAc/hexane) to give colorless crystals of 6-phenyl-4,5,6,7-tetrahydroindol-4-one (0.11 g).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][N:18]=1)[C:13]([OH:15])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:52]1[CH2:57][CH2:56][O:55][CH2:54][CH:53]1[C:58]1[C:66]2[S:65][C:64]([NH2:67])=[N:63][C:62]=2[C:61]([O:68][CH3:69])=[CH:60][CH:59]=1>C1COCC1.C(Cl)(Cl)Cl>[O:52]1[CH2:57][CH2:56][O:55][CH2:54][CH:53]1[C:58]1[C:66]2[S:65][C:64]([NH:67][C:13](=[O:15])[C:12]3[CH:16]=[CH:17][N:18]=[C:10]([O:9][CH2:8][CH2:7][N:3]4[CH2:4][CH2:5][CH2:6][C:2]4=[O:1])[CH:11]=3)=[N:63][C:62]=2[C:61]([O:68][CH3:69])=[CH:60][CH:59]=1
Reactant: O=C(O)c1ccnc(OCCN2CCCC2=O)c1
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccnc(OCCN4CCCC4=O)c3)nc12

Procedure:
From 2-[2-(2-oxo-pyrrolidin-1-yl)-ethoxy]-isonicotinic acid, HATU and N-ethyldiisopropylamine in THF, then treatment with (+)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. [α]D20=+57.3° (c=1.03, CHCl3), ES-MS m/e (%): 499 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[S:13][C:12]3[CH:14]=[CH:15][C:16]4[C:21]([C:11]=3[NH:10][C:9]2=[O:22])=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:4][CH:3]=1.[OH-].[Na+].Br[CH2:26][CH2:27][CH2:28][Cl:29].O>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[S:13][C:12]3[CH:14]=[CH:15][C:16]4[C:21]([C:11]=3[N:10]([CH2:26][CH2:27][CH2:28][Cl:29])[C:9]2=[O:22])=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:4][CH:3]=1
Reactant: O=C1Nc2c(ccc3ccccc23)SC1c1ccc(Cl)cc1
Reactant: ClCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: O=C1C(c2ccc(Cl)cc2)Sc2ccc3ccccc3c2N1CCCCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.1 %

Procedure:
To a solution of 3-(4-chlorophenyl)-1H-naphtho-[2,1-b][1,4]thiazin-2(3H)-one (10.0 g) and 96% sodium hydroxide (1.96 g) in dimethylsulfoxide (150 ml) is added 1-bromo-3-chloropropane (6.78 g) under ice cooling, and the mixture is stirred at room temperature overnight. The reaction mixture is poured into water, and the mixture is extracted with ethyl acetate. The ethyl acetate layer is washed and distilled to remove the solvent. The residue is purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate=5:1) and further is recrystallized from methanol to give 3-(4-chlorophenyl)-1-(3-chloropropyl)-lH-naphtho[2,1-b][1,4]thiazin-2(3H)-one (8.04 g). M.p. 110°-112.5° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[C:11]([NH:16][C:17]([C:19]3[N:23]([CH3:24])[N:22]=[C:21]([CH3:25])[CH:20]=3)=[O:18])[CH:12]=[C:13]([CH3:15])[CH:14]=2)=[CH:4][CH:3]=1.[N:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:27]=[S:28]>CS(C)=O.O>[CH3:24][N:23]1[C:19]([C:17]([NH:16][C:11]2[CH:10]=[C:9]([CH:14]=[C:13]([CH3:15])[CH:12]=2)[O:8][C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:27]([NH:26][C:29](=[O:30])[O:31][CH2:32][CH3:33])=[S:28])=[N:7][CH:6]=2)=[O:18])=[CH:20][C:21]([CH3:25])=[N:22]1
Reactant: Cc1cc(NC(=O)c2cc(C)nn2C)cc(Oc2ccc(N)nc2)c1
Reactant: CCOC(=O)N=C=S
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)NC(=S)Nc1ccc(Oc2cc(C)cc(NC(=O)c3cc(C)nn3C)c2)cn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 104.2 %

Procedure:
To a solution of N-{3-[(6-aminopyridin-3-yl)oxy]-5-methylphenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide (2.23 g, 5.43 mmol) in DMSO (30 mL) was added ethyl isothiocyanatoformate (770 μL, 6.52 mmol), and the mixture was stirred at room temperature for 12 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, hexane/ethyl acetate=100/0→50/50) to give the title compound (2.65 g, 88%) as a pale-yellow oil.
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:14]C(=O)OC(C)(C)C)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=1.[Cl:22]S([N:26]=[C:27]=[O:28])(=O)=O.O.C(=O)([O-])O.[Na+]>C(#N)C>[ClH:22].[C:27](=[O:28])([O:1][CH2:2][CH:3]([NH2:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:11])([F:12])[F:13])[CH:5]=1)[NH2:26]
Reactant: CC(C)(C)OC(=O)NC(CO)c1cccc(C(F)(F)F)c1
Reactant: O=C=NS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cl
Product: NC(=O)OCC(N)c1cccc(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
A solution of 1.00 g (3.28 mmol) of a compound from Example 59A in 20 ml of acetonitrile was cooled to −15° C. and admixed with 399 μl (4.59 mmol) of chlorosulphonyl isocyanate. After 10 min, 18 ml of water were added and the mixture was heated at 60° C. for 2 h. After cooling to RT, the solution was rendered alkaline (pH 9-10) by addition of saturated aqueous sodium hydrogen carbonate solution and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulphate and freed from the solvents on a rotary evaporator. For complete deprotection of the amino group, the residue was admixed with 15 ml of a 4M solution of hydrogen chloride in dioxane, and this mixture was stirred at RT for 5 min and concentrated on a rotary evaporator. Drying of the residue in an HV gave 785 mg (84% of theory) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH2:20][CH2:19][C:18]3[N:14]([C:15]4[N:29]=[CH:28][CH:27]=[CH:26][C:16]=4[C:17]=3[CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CI.[C:32]([O-])(=O)C.[NH4+].C(OCC)(=O)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:32])[C@@H:12]2[CH2:20][CH2:19][C:18]3[N:14]([C:15]4[N:29]=[CH:28][CH:27]=[CH:26][C:16]=4[C:17]=3[CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH2:13]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CC(=O)[O-]
Reactant: COC(=O)Cc1c2n(c3ncccc13)C[C@H](NS(=O)(=O)c1ccc(F)cc1)CC2
Agent: [NH4+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)Cc1c2n(c3ncccc13)C[C@H](N(C)S(=O)(=O)c1ccc(F)cc1)CC2
Reaction time: 0.17 h

Procedure:
To a solution of methyl ((8R)-8-{[(4-fluorophenyl)sulfonyl]amino}-6,7,8,9-tetrahydropyrido[3,2-b]indolizin-5-yl)acetate (0.46 g, 1.1 mmol) in DMF (5.5 mL) was added at 0° C. under nitrogen 60% NaH in oil (0.04 g, 1.2 mmol, 1.1 equiv.). After a period of 10 min., methyl iodide (0.076 mL, 1.2 mmol, 1.1 equiv.) was added and the reaction mixture aged 1 h at room temperature. The reaction mixture was poured over 25% aqueous ammonium acetate solution and ethyl acetate. The organic phase was separated, dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by combiflash (hexane to 100% ethyl acetate) to provide 420 mg of the title compound.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]([NH:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([C:19]([NH2:21])=[NH:20])[CH2:15][CH2:14]1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:22]([CH2:25][C:26](=O)[CH3:27])(=O)[CH3:23]>>[CH2:2]([O:9][C:10]([NH:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([C:19]2[N:21]=[C:26]([CH3:27])[CH:25]=[C:22]([CH3:23])[N:20]=2)[CH2:15][CH2:14]1)=[O:11])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: N=C(N)[C@H]1CC[C@H](NC(=O)OCc2ccccc2)CC1
Reactant: CC(=O)CC(C)=O
Agent: Cl
Product: Cc1cc(C)nc([C@H]2CC[C@H](NC(=O)OCc3ccccc3)CC2)n1

Procedure:
Using trans-4-(benzyloxycarbonylamino)-1-cyclohexane-carboxamidine.hydrochloride (a compound of Reference Example 8-35 (5)) (348 mg) as a starting material, by reacting the same with acetylacetone according to the method of Libman et al. (J. Chem. Soc., p. 2305, 1952), trans-1-benzyloxycarbonylamino-4-(4,6-dimethylpyrimidin-2-yl)cyclohexane (220 mg) was obtained. By treating this compound (205 mg) with trimethylsilyl iodide in the same manner as in Reference Example 8-35 (7), trans-4-(4,6-dimethylpyrimidin-2-yl)cyclohexylamine (Reference Example 8-36 in Table 9) (129 mg) was obtained.