Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[O:11])=[CH:5][CH:4]=1.[C:12]1([C:18]2[O:19][CH2:20][CH:21]([OH:30])[CH:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:23]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClCCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([O:30][CH:21]2[CH2:20][O:19][C:18]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:23][CH:22]2[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:11])=[CH:7][CH:8]=1
Reactant: COc1ccc(N=C=O)cc1
Reactant: OC1COC(c2ccccc2)=NC1c1ccccc1
Solvent: ClCCCl
Product: COc1ccc(NC(=O)OC2COC(c3ccccc3)=NC2c2ccccc2)cc1
Yield: 25.9 %

Procedure:
4-Methoxyphenyl isocyanate (1 g) is added at a temperature in the region of 20° C. to a solution, maintained under an argon atmosphere, of (4RS, 5RS)-2,4-diphenyl-5,6-dihydro-4H-1,3-oxazin-5-ol (1.7 g) in 1,2-dichloroethane (20 cc). The solution obtained is stirred under reflux for 4 hours and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is purified by chromatography on silica (0.063-0.2 mm; 40 g) contained in a column 2 cm in diameter, collecting 20-cc fractions. Fractions 2 to 6, eluted with a mixture of ethyl acetate and cyclohexane (3:7 by volume), are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization in diisopropyl ether, (4RS, 5RS)-5-(4-methoxyphenylcarbamoyloxy)-2,4-diphenyl-5,6-dihydro-4H-1,3-oxazine (0.7 g), m.p. 140° C., is obtained.
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([CH3:8])O[C:4](=[O:9])[CH:3]=1.[F:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=1>C(O)CCC>[F:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][N:16]2[C:6]([CH3:8])=[CH:7][C:2]([NH:16][CH2:15][C:14]3[CH:17]=[CH:18][C:11]([F:10])=[CH:12][CH:13]=3)=[CH:3][C:4]2=[O:9])=[CH:13][CH:12]=1
Reactant: Cc1cc(O)cc(=O)o1
Reactant: NCc1ccc(F)cc1
Solvent: CCCCO
Product: Cc1cc(NCc2ccc(F)cc2)cc(=O)n1Cc1ccc(F)cc1
Yield: 30.1 %

Procedure:
A mixture of 4-hydroxy-6-methylpyrone (5.0 g, 0.04 mol) and 4-fluorobenzylamine (10.0 g. 0.08 mol) in n-butanol (25.0 mL) was heated to reflux for 24 hours under argon atmosphere. The resulting solution was concentrated to dryness under reduced pressure. The residue was triturated with ethyl acetate and filtered. It was thoroughly washed with ethyl acetate and dried to afford the title compound as a pale yellow powder (4.1 g. 30%). 1H-NMR (CD3OD, 400 MHz) δ 7.33 (q, 2H), 7.04 (m, 5H), 5.85 (d, 1H, J=2.0 Hz), 5.44 (d, 2H, J=2.4 Hz), 5.20 (s, 1H), 4.29 (s, 2H), 2.17 (s, 3H); ES-HRMS m/z 341.1488 (M+H calculated for C20H19N2OF2 requires 341.1460).
Reaction SMILES: N1C=CC([N:7]2[CH2:12][CH2:11][CH:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9][CH2:8]2)=CC=1.[Li+].[OH-].O>C1COCC1>[N:7]1[CH:12]=[CH:17][C:16]([O:15][C:13]([CH:10]2[CH2:9][CH2:8][NH:7][CH2:12][CH2:11]2)=[O:14])=[CH:9][CH:8]=1
Reactant: CCOC(=O)C1CCN(c2ccncc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(Oc1ccncc1)C1CCNCC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 33-1 (10 g, 42.7 mmol) in THF (50 mL) was treated with 1N LiOH (47 mL, 47.0 mmol) and water (50 mL). The resulting solution was stirred at ambient temperature for 12 h. The solution was concentrated and the aqueous residue was cooled to 0° C., then adjusted to pH=6 with 1N HCl. The resulting solid was collected by filtration and dried in vacuo to afford 33-2 as a white solid. 1H NMR (D2O) δ 7.95 (d, J=6.8 Hz, 2HO, 6.73 (d, J=6.8 Hz, 2h), 3.76 (d, J=12.8 Hz, 2HO, 2.81 (m, 2H), 2.20 (m, 1H), 1.85 (d, J=12.9 Hz, 2H), 1.55 (m, 2H). ##STR165## Ethyl 4-(Pyridyl)(piperidin-4-yl)-carbonylamino-3-methylphenoxyacetate (33-3)
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[C:13]3[C:14](=[O:17])[NH:15][CH2:16][C:12]=3[CH:11]=[C:10]([NH:18][C@@H:19]3[CH2:24][CH2:23][CH2:22][CH2:21][C@@H:20]3[NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[N:9]=2)[CH:5]=[N:4]1)[CH3:2].[B-](F)(F)(F)[F:34].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(Cl)Cl>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[C:13]3[C:14](=[O:17])[NH:15][CH2:16][C:12]=3[C:11]([F:34])=[C:10]([NH:18][C@@H:19]3[CH2:24][CH2:23][CH2:22][CH2:21][C@@H:20]3[NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[N:9]=2)[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1cc(-c2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)cc3c2C(=O)NC3)cn1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: ClCCl
Product: CCn1cc(-c2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)c(F)c3c2C(=O)NC3)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 28 %

Procedure:
A solution of tert-Butyl (1S,2R)-2-(4-(1-ethyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclohexylcarbamate (69.7 mg, 0.158 mmol) in DCM (5 mL) was cooled to 0° C. SELECTFLUOR® (84 mg, 0.237 mmol) was added. The mixture was left stirring in an ice bath and was allowed to warm slowly to RT with stirring overnight. Additional SELECTFLUOR® (2 eq) was added and the reaction was stopped after 2 h. After removal of solvent, the residue was diluted with EtOAc (10 mL) and washed with saturated aq NaHCO3 (5 mL), water (5 mL), and brine (5 mL). The organic layers were combined, dried over Na2SO4, and concentrated to a brown residue. The resulting crude material was reconstituted in MeOH/DCM (6 mL) and was purified via preparative HPLC. The fractions were collected and ACN was removed via rotary evaporation. The resulting aq solution was neutralized with saturated aq NaHCO3, washed with EtOAc (2×200 mL), dried over Na2SO4, and filtered. The organic phase was stripped to dryness via rotary evaporation to yield the title compound (20 mg, 28%). [M+H] calc'd for C23H31FN6O3, 459. found, 459.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([N+:13]([O-:15])=[O:14])[C:9](O)=[N:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2].S(Cl)([Cl:18])=O>CN(C)C=O>[Cl:18][C:9]1[C:8]([N+:13]([O-:15])=[O:14])=[CH:7][C:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[CH:11][N:10]=1
Reactant: O=S(Cl)Cl
Reactant: CCS(=O)(=O)c1cnc(O)c([N+](=O)[O-])c1
Solvent: CN(C)C=O
Product: CCS(=O)(=O)c1cnc(Cl)c([N+](=O)[O-])c1

Procedure:
To a solution of 5-(ethylsulfonyl)-3-nitropyridin-2-ol (Step C, 575 mg, 2.5 mmol) in thionyl chloride (7 mL) was added N,N-dimethylformamide (one drop). The mixture was stirred under reflux for 2 h and concentrated to afford the crude title compound as a white solid.
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]2[O:22][CH:21]=[C:20]([C:23]3[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=3)[C:15]=2[CH:16]=[N:17][C:18]=1[NH2:19])[CH3:11].[CH:29]([N:32]=[C:33]=[O:34])([CH3:31])[CH3:30].CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:19][C:18]1[N:17]=[CH:16][C:15]2[C:20]([C:23]3[CH2:24][CH2:25][N:26]([C:33]([NH:32][CH:29]([CH3:31])[CH3:30])=[O:34])[CH2:27][CH:28]=3)=[CH:21][O:22][C:14]=2[C:13]=1[O:12][C@@H:10]([C:3]1[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[Cl:1])[CH3:11]
Reactant: CC(C)N=C=O
Reactant: C[C@@H](Oc1c(N)ncc2c(C3=CCNCC3)coc12)c1c(Cl)ccc(F)c1Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)NC(=O)N1CC=C(c2coc3c(O[C@H](C)c4c(Cl)ccc(F)c4Cl)c(N)ncc23)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a flask were added 7-[(R)-1-(2,6-Dichloro-3-fluorophenyl)ethoxy]-3-(1,2,3,6-tetrahydropyridin-4-yl)-furo[3,2-c]pyridin-6-ylamine (10.0 mg, 0.0237 mmol), isopropyl isocyanate (0.00371 g, 0.0436 mmol), DIPEA (33 μL, 0.19 mmol) and DMF (1 mL) and the reaction mixture was stirred at rt for 15 min. Purification by HPLC followed by prep TLC in 5% NH3 in DCM afforded the title compound. 1H NMR (400 MHz, CD3OD): δ=1.17 (d, J=6.6 Hz, 6H), 1.88 (d, J=6.8 Hz, 3H), 2.49 (br. s., 2H), 3.63 (t, J=5.7 Hz, 2H), 3.87-3.99 (m, 1H), 4.06 (d, J=2.5 Hz, 2H), 6.13 (d, J=7.6 Hz, 1H), 6.25 (br. s., 1H), 6.49 (d, J=6.8 Hz, 1H), 7.21 (t, J=8.6 Hz, 1H), 7.39 (dd, J=9.0, 4.9 Hz, 1H), 7.63 (s, 1H). MS (ES+): m/z 507.04/509.06 (100/71) [MH+]. HPLC: tR=3.14 min (ZQ3, polar—5 min).
Reaction SMILES: F[B-](F)(F)F.[F:6][C:7]([F:18])([F:17])[O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]#[N:16])=[CH:11][CH:10]=1.[Cl:19][CH:20](C(C)=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22]>N1C=CC=CC=1.O>[Cl:19][C:20](=[N:16][NH:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][C:7]([F:17])([F:18])[F:6])=[CH:14][CH:13]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: N#[N+]c1ccc(OC(F)(F)F)cc1
Agent: F[B-](F)(F)F
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)C(Cl)=NNc1ccc(OC(F)(F)F)cc1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 89.5 %

Procedure:
4-Trifluoromethoxybenzenediazonium tetrafluoroborate (63) (4.33 g, 15.7 mmol) was added to a solution of ethyl 2-chloroacetoacetate (64) (2.35 g, 14.3 mmol) in pyridine (6 mL) and water (6 mL) at −5° C. The mixture was stirred at −5° C. for 0.5 h and the precipitate was filtered and washed with ice cold water. Recrystallisation from EtOH/water gave ethyl 2-chloro{[4-(trifluoromethoxy)phenyl]hydrazono}ethanoate (65) (3.977 g, 82%) as pale orange needles: mp 128-130° C.; 1H NMR [(CD3)2SO] δ 10.68 (s, 1H), 7.43 (d, J=9.2 Hz, 2H), 7.34 (d, J=9.2 Hz, 2H), 4.30 (t, J=7.1 Hz, 2H), 1.30 (q, J=7.1 Hz, 3H). APCI MS m/z 309, 311 [M−H]−.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:12][CH:13]([O:19][CH:20]([CH3:22])[CH3:21])[C:14]([O:16]CC)=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[N:31]=[C:32]=[O:33]>>[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[NH:31][C:32]([O:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:12][CH:13]([O:19][CH:20]([CH3:21])[CH3:22])[C:14]([OH:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])=[O:33]
Reactant: CCOC(=O)C(Cc1ccc(OC)c(CCO)c1)OC(C)C
Reactant: O=C=Nc1ccc(F)cc1F
Product: COc1ccc(CC(OC(C)C)C(=O)O)cc1CCOC(=O)Nc1ccc(F)cc1F

Procedure:
Using ethyl 3-[3-(2-hydroxyethyl)-4-methoxyphenyl]-2-isopropoxypropanoate and 2,4-difluorophenylisocyanate, the title compound was obtained in the same manner as described in Example 148.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([N:24]2[CH2:28][CH2:27][CH2:26][S:25]2(=[O:30])=[O:29])[CH:3]=1.C([N:34]1[CH2:38][CH2:37][NH:36][C:35]1=[O:39])(=O)C>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:34]4[CH2:38][CH2:37][NH:36][C:35]4=[O:39])=[CH:3][C:4]=3[N:24]3[CH2:28][CH2:27][CH2:26][S:25]3(=[O:30])=[O:29])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: CC(=O)N1CCNC1=O
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3N3CCCS3(=O)=O)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCNC4=O)cc3N3CCCS3(=O)=O)CC2)c(C)c1
Yield: 16 %

Procedure:
Using [4-bromo-2-(1,1-dioxo-1λ6-isothiazolidin-2-yl)phenyl][4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (247 mg) described in Preparation Example 166 and 1-acetylimidazolidin-2-one (96 mg) and by the reaction and treatment in the same manner as in Example 638, the title compound (40 mg) was obtained.
Reaction SMILES: C[O:2][C:3](=[O:39])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:13][CH:12]=2)=[C:6]([NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)[CH:5]=1.[Li+].[OH-]>C1COCC1>[C:21]([O:20][C:18]([NH:17][C:14]1[CH:15]=[CH:16][C:11]([O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:39])=[O:2])=[CH:5][C:6]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:37])[CH3:38])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:12][CH:13]=1)=[O:19])([CH3:23])([CH3:22])[CH3:24]
Reactant: COC(=O)c1ccc(Oc2ccc(NC(=O)OC(C)(C)C)cc2)c(Nc2ncnc3nc(C(C)C)ccc23)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)c1ccc2c(Nc3cc(C(=O)O)ccc3Oc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Temperature: 25 °C
Reaction time: 21 h
Yield: 97.2 %

Procedure:
To a suspension of 4-(4-tert-butoxycarbonylamino-phenoxy)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-benzoic acid methyl ester (4.30 g, 8.1 mmol) in THF (43 mL) was added aqueous LiOH [prepared from LiOH monohydrate (1.08 g) and H2O (11 mL)] dropwise at room temperature. The mixture was stirred at room temperature for 21 hours. Additional aqueous LiOH [prepared from LiOH monohydrate (0.70 g) and H2O (7 mL)] was added at room temperature. The mixture was mixture was stirred at 35° C. for 6 hours, and then evaporated. The aqueous mixture was diluted with 150 mL of H2O, washed with AcOEt, and treated with active charcoal. The mixture was filtered and the filtrate was carefully acidified to pH 4-5 with 1N HCl under stirring. The resulting solid was collected by filtration, washed with H2O, and dried at 40° C. for 1 day under reduced pressure to give the title compound as pale yellow crystal (4.06 g, 97%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])=[CH:5][CH:4]=1.[C:18]([O:22][C:23]([NH:25][C:26]([CH3:44])([CH3:43])[CH2:27][C:28]([NH:30][C@@H:31]1[CH2:37][CH2:36][C:35]2[CH:38]=[CH:39][CH:40]=[CH:41][C:34]=2[NH:33][C:32]1=[O:42])=[O:29])=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[N+:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:33]2[C:34]3[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=3[CH2:36][CH2:37][C@@H:31]([NH:30][C:28](=[O:29])[CH2:27][C:26]([NH:25][C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:24])([CH3:44])[CH3:43])[C:32]2=[O:42])=[CH:4][CH:5]=1)([O-:17])=[O:16]
Reactant: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2NC1=O)NC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccccc1-c1ccc(CBr)cc1
Product: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3[N+](=O)[O-])cc2)C1=O)NC(=O)OC(C)(C)C

Procedure:
Prepared from 4-bromomethyl-2'-nitro-1,1'-biphenyl (Example 1, Step K) and 3-t-butoxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]-butanamide (Example 1, Step I) by the procedure described in Example 1, Step Q. 1H NMR (400 MHz, CDCl3): 1.34 (s, 6H), 1.41 (s, 9H), 1.83 (m, 1H), 2.35-2.70 (m, 5H), 4.50 (m, 1H), 4.84 (d, 15 Hz, 1H), 5.23 (d, 15 Hz, 1H), 5.27 (s, 1H), 6.64 (d, 7 Hz, 1H), 7.1-7.6 (m, 11H), 7.80 (d, 8 Hz, 1H). FAB-MS: calculated for C33H38N4O6 586; found 587(M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:32]([OH:34])=O)=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:35]([O:42][CH2:43][CH2:44][NH:45][CH:46]([CH3:48])[CH3:47])([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36].[Si](OCCN(C(C)C)C(C1C(OCC2C=CC=CC=2)=C(O)N=C(CC2(C3C=CC(C(F)(F)F)=CC=3)CCCC2)N=1)=O)(C(C)(C)C)(C)C>>[CH2:1]([O:8][C:9]1[C:10]([C:32]([N:45]([CH2:44][CH2:43][O:42][Si:35]([C:38]([CH3:40])([CH3:39])[CH3:41])([CH3:36])[CH3:37])[CH:46]([CH3:47])[CH3:48])=[O:34])=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[CH2:18][CH2:19][CH2:20][CH2:21]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1nc(CC2(c3cccc(C(F)(F)F)c3)CCCC2)nc(O)c1OCc1ccccc1
Reactant: CC(C)NCCO[Si](C)(C)C(C)(C)C
Agent: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(c3ccc(C(F)(F)F)cc3)CCCC2)nc(O)c1OCc1ccccc1
Product: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(c3cccc(C(F)(F)F)c3)CCCC2)nc(O)c1OCc1ccccc1

Procedure:
5-(Benzyloxy)-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-6-hydroxy-N-isopropyl-2-((1-(3-(trifluoromethyl)phenyl)cyclopentyl)methyl)pyrimidine-4-carboxamide (476) was synthesized from 5-(benzyloxy)-6-hydroxy-2-((1-(3-(trifluoromethyl)phenyl)cyclopentyl)methyl)pyrimidine-4-carboxylic acid (475) and [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-isopropyl-amine (8b) following the procedure described for 5-benzyloxy-2-[1-(4-trifluoromethyl-phenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-isopropylamide (245).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[O:8][CH2:7][C:6]3[CH:12]=[C:13]([C:15]([N:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=4[F:26])[CH3:18])=[O:16])[S:14][C:5]=3[C:4]=2[CH:3]=1.C([Li])CCC.CN(C)[CH:34]=[O:35].[Cl-].[NH4+]>O1CCCC1>[F:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[N:17]([CH3:18])[C:15]([C:13]1[S:14][C:5]2[C:4]3[CH:3]=[C:2]([CH:34]=[O:35])[CH:11]=[CH:10][C:9]=3[O:8][CH2:7][C:6]=2[CH:12]=1)=[O:16]
Reactant: CN(C)C=O
Reactant: CN(C(=O)c1cc2c(s1)-c1cc(Br)ccc1OC2)c1ccc(F)cc1F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN(C(=O)c1cc2c(s1)-c1cc(C=O)ccc1OC2)c1ccc(F)cc1F
Temperature: 24 °C
Reaction time: 0.25 h

Procedure:
To a solution of 8-bromo-N-(2,4-difluorophenyl)-N-methyl-4H-thieno[3,2-c]chromene-2-carboxamide 160bp (19.6 mg, 0.0449 mmol, 1 equiv) in tetrahydrofuran (1 mL) at −78° C. was added n-butyllithium (54 μL, 0.14 mmol, 3.0 equiv, 2.5 M in hexanes) dropwise. After 15 min, N,N-dimethylformamide (35 μL, 0.45 mmol, 10 equiv) was added. After 40 min, the reaction mixture was warmed to 24° C. for 50 min. Saturated aqueous ammonium chloride solution (5 mL) was added to the reaction mixture, and the resulting solution was extracted with ethylacetate (3×3 mL). The collected organic was dried over anhydrous sodium sulfate, filtered, and concentrated to afford the corresponding aldehyde, N-(2,4-difluorophenyl)-8-formyl-N-methyl-4H-thieno[3,2-c]chromene-2-carboxamide. LCMS (ESI) m/z: 386.
Reaction SMILES: C([NH:4][C:5]1[CH:18]=[CH:17][C:8]([C:9]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[S:10])=[CH:7][CH:6]=1)(=O)C.C(O)C.S(=O)(=O)(O)O>O>[NH2:4][C:5]1[CH:18]=[CH:17][C:8]([C:9]([N:11]2[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]2)=[S:10])=[CH:7][CH:6]=1
Reactant: CC(=O)Nc1ccc(C(=S)N2CCCCC2)cc1
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: O
Product: Nc1ccc(C(=S)N2CCCCC2)cc1
Temperature: 40 °C

Procedure:
1-(4-Acetamidothiobenzoyl)piperidine (131.2 g, 0.5 mole), ethanol (500 ml), water (1 l) and concentrated sulphuric acid (125 ml) were mixed together and refluxed for 16 hours with stirring; nearly all the solid dissolved during the first hour. The reaction mixture was cooled to about 40°C and filtered quickly to remove any insoluble material. The filtrate was then made alkaline with 6N sodium hydroxide solution using external ice-cooling. The yellow crystalline solid was filtered off, washed with water and dried in vacuo at a temperature of under 50°C. Recrystallisation of the crude product (91 g; m.p. 162°-164°) by dissolving in 6 volumes of warm chloroform (about 546 ml) followed by adding 5 volumes of petroleum ether (b.p. 40°-60°) (about 455 ml) yielded yellow crystals (85 g; 77.3%), m.p. 164°-165°.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH:11]1([C:14]([N:16]2[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18][CH2:17]2)=[O:15])[CH2:13][CH2:12]1.C(N(CC)CC)C>ClC(Cl)C.ClCCl>[CH:11]1([C:14]([N:16]2[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]2)=[O:15])[CH2:12][CH2:13]1
Reactant: O=C(C1CC1)N1CCC(O)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: O=C1CCN(C(=O)C2CC2)CC1
Yield: 75.9 %

Procedure:
66 g of oxalic chloride was dissolved in 500 ml of dichloroethane, into which 61 g of dimethyl sulfoxide was gradually dropped at -67° C. 44 g of 1-cyclopropanecarbonyl-4-hydroxypiperidine dissolved in 200 ml of dichloromethane was dropped into the above solution at -67° C. At -67° C., 131 g of triethylamine was further added, followed by returning to room temperature. The resultant salt was removed by filtration and the filtrate was once concentrated, after which water was added to the concentrate, followed by extraction with ethyl acetate and drying with anhydrous magnesium sulfate. Moreover, the aqueous phase was extracted with chloroform and dried similarly. The solvent was distilled off under reduced pressure and the resultant reside was purified by the use of silica gel column chromatography (elution solvent: ethyl acetate:hexane=3:7), thereby obtaining 33 g of the intended compound (yield 76%).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][CH2:9][CH2:10][S:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18]([NH:21]C(C)(C)C)(=[O:20])=[O:19]>ClC(Cl)Cl>[F:8][CH2:9][CH2:10][S:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18]([NH2:21])(=[O:19])=[O:20]
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1SCCF
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1ccccc1SCCF
Reaction time: 18 h

Procedure:
25 ml of trifluoroacetic acid are added at a temperature of 0° C. to a solution of 3.88 g of 2-(2-fluoroethylthio)-N-tert.-butylphenylsulfonamide, obtained in accordance with Example P1, in 25 ml of trichloromethane. After stirring for 18 hours at a temperature of +25° C., the resulting brown reaction mixture is lyophilised. After chromatographic purification of the oily residue with 1) ethyl acetate/petroleum ether (1:1) over silica gel and 2) dichloromethane/acetone (9:1) over silica gel, the resulting fractions are concentrated by evaporation to give 1.5 g (60.5% of the theoretical yield) of crystalline 2-(2-fluoroethylthio)-phenylsulfonamide.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[CH2:9][CH:8]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][OH:26])[CH2:19][CH2:18]3)[C:7]=2[CH:27]=1)[CH3:2].[C:28](Cl)(=[O:40])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39].C(O)(=O)/C=C\C(O)=O>C1C=CC=CC=1.C(Cl)(Cl)Cl.CC(C)=O.[OH-].[NH4+]>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[CH2:9][CH:8]([N:17]3[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][CH2:25][O:26][C:28](=[O:40])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:21][CH2:22]3)[C:7]=2[CH:27]=1)[CH3:2]
Reactant: CCc1ccc2c(c1)C(N1CCN(CCCO)CC1)Cc1ccccc1S2
Reactant: CCCCCCCCCCCC(=O)Cl
Agent: O=C(O)/C=C\C(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Solvent: c1ccccc1
Product: CCCCCCCCCCCC(=O)OCCCN1CCN(C2Cc3ccccc3Sc3ccc(CC)cc32)CC1

Procedure:
In accordance with the general method described in the foregoing Examples, 10.15 grams of 8-ethyl-10-[4-(3-hydroxypropyl)piperazino]-10,11-dihydrodibenzo[b,f]thiepin was reacted with a solution of 12.5 grams of lauroyl chloride (dodecanoyl chloride) in a mixture of 60 milliliters of benzene and 20 milliliters of chloroform. By adding a solution of 6.15 grams of maleic acid in 60 milliliters of acetone to the crude product, 14.0 grams of 8-ethyl-10-[4-(3-dodecanoyloxypropyl)piperazino]-10,11-dihydrodibenzo[b,f]thiepin di(hydrogen maleate) was recovered. The salt, after recrystallization from acetone, had a melting point of 126°-128°C. Its elemental analysis corresponded to the empirical formula C43H60N2O10S. The free base was obtained in the form of a colorless very viscous oil which was very soluble in vegetable oils by dissolving the salt in a dilute aqueous ammonium hydroxide solution and extracting the resulting solution with benzene.
Reaction SMILES: [OH:1][CH2:2][N:3]1[C:8](=[O:9])[CH2:7][N:6]([CH2:10][CH2:11][N:12]2[CH2:17][C:16](=[O:18])[N:15]([CH2:19][OH:20])[C:14](=[O:21])[CH2:13]2)[CH2:5][C:4]1=[O:22].[C:23]1([C:28](Cl)=[O:29])[S:27][CH:26]=[CH:25][CH:24]=1>N1C=CC=CC=1>[C:23]1([C:28]([O:20][CH2:19][N:15]2[C:14](=[O:21])[CH2:13][N:12]([CH2:11][CH2:10][N:6]3[CH2:7][C:8](=[O:9])[N:3]([CH2:2][O:1][C:28](=[O:29])[C:23]4[S:27][CH:26]=[CH:25][CH:24]=4)[C:4](=[O:22])[CH2:5]3)[CH2:17][C:16]2=[O:18])=[O:29])[S:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C1CN(CCN2CC(=O)N(CO)C(=O)C2)CC(=O)N1CO
Reactant: O=C(Cl)c1cccs1
Solvent: c1ccncc1
Product: O=C(OCN1C(=O)CN(CCN2CC(=O)N(COC(=O)c3cccs3)C(=O)C2)CC1=O)c1cccs1
Temperature: 25 °C
Reaction time: 4 h
Yield: 76.5 %

Procedure:
To a mixture of 1,2-bis(4-hydroxymethyl-3,5-dioxopiperazin-1-yl)ethane (6.30 g, 22 m mol) and pyridine (60 ml), thenoyl chloride (6.45 g, 44 m mol) was added gradually at 0° C., and then the mixture was stirred for 4 hours at room temperature. The solvent was removed from the reaction mixture under reduced pressure, and the residue was extracted with chloroform. The extract solution was washed with 10% sulfuric acid solution and successively with water, and was dried over magnesium sulfate. The residue obtained by removing the solvent from the extract solution under reduced pressure was purified by silica gel column chromatography (ethyl acetate, Rf value=0.6) to give the titled compound (8.20 g; yield 70%).