Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[C@@:10]3([CH2:25][C@H:24]3[C:26]([OH:28])=[O:27])[N:9]=2)=[CH:4][CH:3]=1.ClC1C=CC(C2C3C(C)=C(C)SC=3N3C(C)=NN=C3[C@]3(CC3C=O)N=2)=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:14]3[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[C@:10]3([CH2:25][CH:24]3[C:26]([OH:28])=[O:27])[N:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=N[C@]1(C[C@H]1C(=O)O)c1nnc(C)n1-2
Agent: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=N[C@@]1(CC1C=O)c1nnc(C)n1-2
Product: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=N[C@@]1(CC1C(=O)O)c1nnc(C)n1-2

Procedure:
A procedure analogous to that set forth for Compound 228 was followed, with the exception that (1R)-4′-(4-chlorophenyl)-2′,3′,9′-trimethylspiro[cyclopropane-1,6′-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine]-2-carbaldehyde was used as starting material. LRMS (M+H)+: 413 m/z.
Reaction SMILES: [P:1]([O:5][C@H:6]1[O:14][C@H:13]([CH2:15][OH:16])[C@@H:11]([OH:12])[C@H:9]([OH:10])[C@H:7]1[OH:8])([O-:4])([O-:3])=[O:2].[Na+].[Na+].O>C(O)C>[P:1]([O:5][C@H:6]1[O:14][C@H:13]([CH2:15][OH:16])[C@@H:11]([OH:12])[C@H:9]([OH:10])[C@H:7]1[OH:8])([OH:4])([OH:3])=[O:2]
Reactant: O=P([O-])([O-])O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=P(O)(O)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 2160 h

Procedure:
A 3.76-gram portion of disodium α-D-glucose-1-phosphate was dissolved in 33.3 ml of a 0.3 M solution of cis-[Pt(NH3)2 -(H2O)2 ](NO3)2. The resulting solution had an initial pH of 5.2. The solution was stoppered with a porous plug and then stirred for 90 days at room temperature, turning deep blue in color. During that period, water was periodically added to maintain the solution volume at 40 ml. At the end of the three month period, 60 ml of ethanol were added to the solution and a dark blue material was precipitated by placing the mixture in a freezer overnight. The supernatant was decanted, and the precipitate was washed with 70% ethanol, and then it was redissolved in 40 ml of water. The solution was filtered; and the blue material was reprecipitated by the addition of 50 ml ethanol to the solution. After overnight storage in a freezer, additional decanting, washing, and drying by the procedures described in Example 1, there were obtained 2.548 grams of the above-identified complex as a dark blue solid.
Reaction SMILES: [Cl-].[Cl:2][CH:3]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]CCCCCC)[CH2:4][CH2:5][N+:6]([CH2:9][CH:10]([OH:12])[CH3:11])([CH3:8])[CH3:7].[Cl-].ClC(CCCCC)CC[N+](CC(O)C)(C)C>>[Cl-:2].[Cl:2][CH:3]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:4][CH2:5][N+:6]([CH2:9][CH:10]([OH:12])[CH3:11])([CH3:8])[CH3:7]
Reactant: CCCCCCCCCCCCCCCC(Cl)CC[N+](C)(C)CC(C)O
Agent: CCCCCC(Cl)CC[N+](C)(C)CC(C)O
Agent: [Cl-]
Product: CCCCCCCCCC(Cl)CC[N+](C)(C)CC(C)O

Procedure:
3-chloro-2-hydroxypropyl dimethyloctadecyl ammonium chloride; 3-chloro-2-hydroxypropyldimethyloctyl ammonium chloride;
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH2:5]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18])[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].N1C=CC=CC=1>ClCCl>[C:1]([O:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[O:11][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])(=[O:3])[CH3:2]
Reactant: CCCCCCOc1ccccc1O
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCOc1ccccc1OC(C)=O
Reaction time: 1 h
Yield: 94.8 %

Procedure:
Acetyl chloride (2.4 g, 30.1 mmol) was added dropwise to vigorously stirred mixture of 2-hexyloxyphenol (5.0 g, 25.8 mmol) and pyridine (5 ml) in dichloromethane (50 ml). The mixture was stirred for 1 hour and poured onto water. The organic layer was separated, dried (MgSO4), concentrated to give crude product which was purified by column chromatography on silica gel using dichloromethane petroleum spirit (1:3) as eluent to give title compound as a colourless oil (5.78 g, 95%). Found: C, 71.00; H, 8.35. C14H20O3 requires C, 71.19; H, 8.47. δH (CHCl3) 7.21-7.15 (m, 1H, ArH), 7.05-7.01 (m, 1H, ArH), 6.97-6.89 (m, 2H, ArH), 3.97 (t, J 6.5, 2H, OCH2), 2.30 (s, 3H, COCH3), 1.78-1.71 (m, 2H, ArOCH2CH2), 1.57-1.30 (m, 6H, CH2), 0.90 (t, J 6.9, 3H, CH2CH3). MS (FAB), 236 (M+, 53%), 194 (100%), 153 (27%), 110 (34%), 85 (7%), 55 (7%).
Reaction SMILES: B.[F:2][C:3]1[CH:4]=[C:5]([CH:10]2[CH2:15][C:14](=[CH2:16])[CH2:13][CH2:12][N:11]2[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH:6]=[CH:7][C:8]=1[F:9].[OH-:27].[Na+].OO>O1CCCC1>[F:2][C:3]1[CH:4]=[C:5]([C@H:10]2[CH2:15][C@@H:14]([CH2:16][OH:27])[CH2:13][CH2:12][N:11]2[C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: C=C1CCN(C(=O)OCc2ccccc2)C(c2ccc(F)c(F)c2)C1
Reactant: [OH-]
Agent: B
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CC[C@H](CO)C[C@@H]1c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.6 %

Procedure:
A solution of borane (1 M in tetrahydrofuran, 4.58 mL) was added to a solution of phenylmethyl 2-(3,4-difluorophenyl)-4-methylidenepiperidine-1-carboxylate (0.79 g, 2.3 mmol) in tetrahydrofuran (20 mL) at 0° C. The reaction mixture was slowly warmed to room temperature and stirred for 18 hours. The mixture was then cooled to 0° C., and 2M sodium hydroxide solution (2.6 mL, 5.2 mmol) then hydrogen peroxide solution (30% in water, 1.2 mL) were added sequentially. The mixture was warmed to room temperature and stirred for 1.5 hours. The reaction mixture was quenched with saturated sodium bicarbonate solution (10 mL), diluted with water (20 mL), and partitioned with ethyl acetate (20 mL). The organic portion was separated and washed twice with saturated sodium bisulfite solution (20 mL), water, then brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (20% to 90% ethyl acetate in hexanes gradient) to give (±)-phenylmethyl (2R,4S)-2-(3,4-difluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate (0.57 g, 69% yield), MS (EI) for C20H21F2NO3: 362 (MH+).
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH:13]([C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1)=[O:14]>>[Cl:1][C:2]1[N:3]([C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:13]=[O:14])[CH:20]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: O=Cc1c(Cl)[nH]c2ccccc12
Reactant: O=Cc1cccc(B(O)O)c1
Product: O=Cc1cccc(-n2c(Cl)c(C=O)c3ccccc32)c1
Yield: 99 %

Procedure:
2-Chloro-1H-indole-3-carboxaldehyde is reacted with 3-formylphenylboronic acid as described in Step 1 of Example 29 to afford 2-chloro-1-(3-formylphenyl)-1H-indole-3-carboxaldehyde (99% yield) as a white solid. ESI/MS 284 (M+H); RT=3.37 min; NMR 10.15 (1H, s); 10.12 (1H, s); 8.23 (3H, m); 7.98 (2H, m); 7.41 (2H, m); 7.18 (1H, d, J=9 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2([OH:35])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][C:24]=1[C:36]([F:39])([F:38])[F:37].C1(C)C=CC(S(O)(=O)=O)=CC=1.Cl>O.C1(C)C=CC=CC=1>[ClH:22].[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)[CH2:9][CH2:10][CH:11]([N:32]3[CH2:33][CH2:34][C:29]([C:26]4[CH:27]=[CH:28][C:23]([Cl:22])=[C:24]([C:36]([F:38])([F:37])[F:39])[CH:25]=4)([OH:35])[CH2:30][CH2:31]3)[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: OC1(c2ccc(Cl)c(C(F)(F)F)c2)CCNCC1
Reactant: O=C1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: OC1(c2ccc(Cl)c(C(F)(F)F)c2)CCN(C2CCC(c3ccc(F)cc3)(c3ccc(F)cc3)CC2)CC1

Procedure:
A mixture of 14.3 g of 4,4-bis(p-fluorophenyl)cyclohexanone, 14 g of 4-(4-chloro-3-trifluoromethylphenyl)-4-piperidinol, 0.5 g of p-toluenesulfonic acid and 100 ml of toluene is stirred under reflux for 145 hours, water formed being removed as an azeotropic mixture with toluene. The toluene is then removed, and the residual oil is dissolved in 100 ml of 90% methanol. To the solution is added slowly 19 g of sodium borohydride under cooling. After the addition is complete, the methanol is removed under reduced pressure, water is added to the residue, and the aqueous mixture is extracted with chloroform. The extract is washed with water and dried over sodium sulfate. The residual oil is purified by column chromatography on silica gel using a mixture of chloroform and methanol (9:1) as an eluent. The objective base thus obtained is converted in a conventional manner into the hydrochloride. Thus is obtained 1-[4,4-bis(p-fluorophenyl)cyclohexyl]-4-(4-chloro-3-trifluoromethylphenyl)-4-piperidinol hydrochloride as colorless crystals, melting at 274°-277° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH2:6][C:7]2[CH:8]=[CH:9][C:10]([NH2:14])=[N:11][C:12]=2[CH3:13])[CH2:3][CH2:2]1.[F:15][C:16]1[CH:17]=[CH:18][C:19]([CH3:26])=[C:20]([S:22](Cl)(=[O:24])=[O:23])[CH:21]=1>>[CH:1]1([CH2:4][O:5][CH2:6][C:7]2[CH:8]=[CH:9][C:10]([NH:14][S:22]([C:20]3[CH:21]=[C:16]([F:15])[CH:17]=[CH:18][C:19]=3[CH3:26])(=[O:23])=[O:24])=[N:11][C:12]=2[CH3:13])[CH2:3][CH2:2]1
Reactant: Cc1ccc(F)cc1S(=O)(=O)Cl
Reactant: Cc1nc(N)ccc1COCC1CC1
Product: Cc1ccc(F)cc1S(=O)(=O)Nc1ccc(COCC2CC2)c(C)n1

Procedure:
This material was prepared in analogy to example 1 from 5-cyclopropylmethoxymethyl-6-methyl-pyridin-2-ylamine (0.053 g) and 5-fluoro-2-methyl-benzenesulfonyl chloride (0.058 g) as a light yellow solid (0.063 g). MS (ESI−): 363.3 ([M−H]−)
Reaction SMILES: N1C=CN=C1.[C:6]([Si:10]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)Cl)([CH3:9])([CH3:8])[CH3:7].[OH:24][CH:25]([C:39]1[S:40][CH:41]=[CH:42][N:43]=1)[C@H:26]1[CH2:31][CH2:30][CH2:29][N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27]1>ClCCl>[Si:10]([O:24][C@@H:25]([C:39]1[S:40][CH:41]=[CH:42][N:43]=1)[C@H:26]1[CH2:31][CH2:30][CH2:29][N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:36])[CH3:37])=[O:33])[CH2:27]1)([C:6]([CH3:9])([CH3:8])[CH3:7])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Si:10]([O:24][C@H:25]([C:39]1[S:40][CH:41]=[CH:42][N:43]=1)[C@H:26]1[CH2:31][CH2:30][CH2:29][N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:36])[CH3:37])=[O:33])[CH2:27]1)([C:6]([CH3:9])([CH3:8])[CH3:7])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](C(O)c2nccs2)C1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]([C@@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c2nccs2)C1
Product: CC(C)(C)OC(=O)N1CCC[C@H]([C@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c2nccs2)C1
Temperature: 0 °C

Procedure:
6.91 g (0.102 mol) of imidazole and 26.435 ml (0.201 mol) of tert-butyldiphenylchlorosilane were added successively at 22° C. to a solution of 19 g (0.058 mol) of tert-butyl (S)-3-(hydroxythiazol-2-yl-methyl)piperidine-1-carboxylate [diastereomer mixture] in 250 ml of dichloromethane. 250 ml of ice-water were added to the reaction mixture. The organic phase was dried over sodium sulfate, filtered and evaporated. The crude product was chromatographed over silica gel, giving 3.44 g of tert-butyl (S)-3-[(R)-(tert-butyldiphenylsilanyloxy)thiazol-2-ylmethyl]piperidine-1-carboxylate (rotation value in methanol [α]20D=+28.00) and 1.19 g of tert-butyl (S)-3-[(S)-(tert-butyldiphenylsilanyloxy)thiazol-2-ylmethyl]-piperidine-1-carboxylate (rotation value in methanol [α]20D=−1.3°); HPLC/MS (M+H)+=537.
Reaction SMILES: C(N(CC)CC)C.[O:8]=[C:9]1[N:15]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C@@H:25]([C:39](O)=[O:40])[CH2:26][C:27]3[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[C:30]([NH2:37])=[C:29]([Cl:38])[CH:28]=3)=[O:23])[CH2:18][CH2:17]2)[CH2:14][CH2:13][C:12]2[CH:42]=[CH:43][CH:44]=[CH:45][C:11]=2[NH:10]1.[CH3:46][N:47]1[CH2:52][CH2:51][CH:50]([N:53]2[CH2:58][CH2:57][NH:56][CH2:55][C@H:54]2[C:59]([O:61][CH2:62][CH3:63])=[O:60])[CH2:49][CH2:48]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[NH2:37][C:30]1[C:31]([C:33]([F:36])([F:35])[F:34])=[CH:32][C:27]([CH2:26][C@@H:25]([O:24][C:22]([N:19]2[CH2:20][CH2:21][CH:16]([N:15]3[CH2:14][CH2:13][C:12]4[CH:42]=[CH:43][CH:44]=[CH:45][C:11]=4[NH:10][C:9]3=[O:8])[CH2:17][CH2:18]2)=[O:23])[C:39]([N:56]2[CH2:57][CH2:58][N:53]([CH:50]3[CH2:49][CH2:48][N:47]([CH3:46])[CH2:52][CH2:51]3)[C@H:54]([C:59]([O:61][CH2:62][CH3:63])=[O:60])[CH2:55]2)=[O:40])=[CH:28][C:29]=1[Cl:38]
Reactant: CCOC(=O)[C@@H]1CNCCN1C1CCN(C)CC1
Reactant: Nc1c(Cl)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H]1CN(C(=O)[C@@H](Cc2cc(Cl)c(N)c(C(F)(F)F)c2)OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)CCN1C1CCN(C)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
0.25 mL (2.88 mmol) triethylamine were added to a mixture of 200 mg (0.36 mmol) (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 1f), 150 mg (0.58 mmol) ethyl(S)-1-(1-methyl-piperidin-4-yl)-piperazine-2-carboxylate (Example A10c) and 140 mg (0.44 mmol) TBTU in 2.0 mL DMF and the reaction mixture was stirred for 5 h at RT. This was purified by HPLC without any further working up; the fractions containing the product were combined and lyophilised.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[NH2:26][CH2:27][CH:28]([OH:33])[CH2:29][C:30]([OH:32])=[O:31]>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:26][CH2:27][CH:28]([OH:33])[CH2:29][C:30]([OH:32])=[O:31])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: NCC(O)CC(=O)O
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC(O)CC(=O)O)c2c1

Procedure:
The title compound was prepared in analogy to Example 11-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 4-amino-3-hydroxybutanoic acid. MS obsd. (ESI+) [(M+H)+] 456. 1H NMR (400 MHz, CD3OD) δ ppm 8.10 (dd, J=7.83, 1.26 Hz, 1 H), 7.83-8.00 (m, 2 H), 7.80-7.67 (m, 2 H), 7.67-7.52 (m, 2 H), 6.32 (s, 1 H), 5.43-5.27 (m, 2 H), 4.55 (brs, 2 H), 4.39-4.23 (m, 1 H), 3.86-3.66 (m, 3 H), 3.57-3.40 (m, 1 H), 2.78-2.63 (m, 2 H), 2.50 (s, 3 H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=1.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[F:18][C:19]([F:30])([F:29])[C:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:22][CH:21]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CS(=O)(=O)c1ccc(-c2ccccc2Br)cc1
Product: CS(=O)(=O)c1ccc(-c2ccccc2-c2ccc(C(F)(F)F)cc2)cc1
Yield: 77.7 %

Procedure:
Following the general procedure outlined in Synthetic Scheme VI, 4.0 g (13 mmol) of 1-bromo-2-[4-(methylsulfonyl)phenyl]benzene (Example 4, Step 2) was reacted with 3.8 g (20 mmol) of 4-(trifluoromethyl)phenylboronic acid (Step 1). Purification by silica gel chromatography (Waters Prep-500A) with ethyl acetate/hexane (1:3) and subsequent recrystallization from ethyl acetate/hexane gave 3.80 g (77%) of 1-[4-(trifluoromethyl)phenyl]-2-[4-(methylsulfonyl)phenyl]benzene as a colorless solid: mp 172.8-173.5° C.; NMR (CDCl3) δ 3.06 (s, 3H), 7.23 (d, J=8 Hz, 2H), 7.33 (d, J=9 Hz, 2H), 7.41-7.46 (m, 2H), 7.48-7.54 (m, 4H), 7.81 (d, J=9 Hz, 2H). MS (ES): m/e 383 (M+Li); HRMS Calc'd for C20H15F3O2S: 376.0745. Found: 376.0766.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]2[N:15]=[C:16]([CH2:21][CH3:22])[C:17]([N+:18]([O-])=O)=[C:13]2[CH:12]=[CH:11][CH:10]=1.O.C(O)(=O)C>C(O)C.[Zn]>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]2[N:15]=[C:16]([CH2:21][CH3:22])[C:17]([NH2:18])=[C:13]2[CH:12]=[CH:11][CH:10]=1
Reactant: CCc1nn2c(-c3ccc(Cl)cc3Cl)cccc2c1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CCc1nn2c(-c3ccc(Cl)cc3Cl)cccc2c1N
Temperature: 60 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
7-(2,4-Dichlorophenyl)-2-ethyl-3-nitropyrazolo[1,5-a]pyridine (110 mg) was suspended in ethanol (6 mL), and then water (3 mL), acetic acid (1 mL) and zinc powder (220 mg) were added and the mixture was heated and stirred at 60° C. for 1 hour. The reaction mixture was filtered, water was added to the filtrate, extraction was performed with ethyl acetate and the extract was washed with saturated aqueous sodium hydrogencarbonate and brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure to obtain [7-(2,4-dichlorophenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]amine (90 mg) as crude crystals. These were dissolved in tetrahydrofuran (1 mL), and after adding propionaldehyde (0.059 mL) and 3 M aqueous sulfuric acid (0.294 mL), sodium borohydride (22.2 mg) was added in five portions while vigorously stirring on ice, and stirring was continued for 30 minutes. Water was added to the reaction mixture, extraction was performed with diethyl ether and the extract was washed with saturated sodium hydrogencarbonate and brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound (59 mg) was obtained from the n-hexane:ethyl acetate (100:1) fraction as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:24]([O-])=O)=[C:6]([CH:23]=1)[NH:7][C:8]1[S:12][C:11]2[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:10]=2[C:9]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[H][H]>[C].[Pd].C(OCC)(=O)C>[NH2:24][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:23][C:6]=1[NH:7][C:8]1[S:12][C:11]2[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:10]=2[C:9]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)c1c(Nc2cc(F)ccc2[N+](=O)[O-])sc2cc(C)ccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(Nc2cc(F)ccc2N)sc2cc(C)ccc12
Yield: 88.1 %

Procedure:
In the same manner as in Starting Material Synthesis Example 19 and using ethyl 2-(5-fluoro-2-nitroanilino)-6-methylbenzo[b]thiophene-3-carboxylate (1.9 g), ethyl acetate (200 ml), 10% palladium-carbon (0.4 g) and hydrogen (60 atm kg/cm2), ethyl 2-(2-amino-5-fluoroanilino)-6-methylbenzo[b]thiophene-3-carboxylate (1.54 g) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](O)=O)=[CH:4][CH:3]=1.[CH3:12]N.N.[CH2:15]1[CH:24]2[CH:19](CCC3C=CC=C[C:23]=32)[NH:18][C:17](=[O:29])[CH2:16]1>C(O)CO.CC(O)C>[CH3:12][N:18]1[C:19]2[C@@:8]([CH3:9])([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][C:6]=3[CH2:23][CH:24]=2)[CH2:15][CH2:16][C:17]1=[O:29].[CH3:12][N:18]1[C@H:19]2[C@@:8]([CH3:9])([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][C:6]=3[CH2:23][CH2:24]2)[CH2:15][CH2:16][C:17]1=[O:29]
Reactant: CN
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: O=C1CCC2c3ccccc3CCC2N1
Agent: N
Solvent: OCCO
Solvent: CC(C)O
Product: CN1C(=O)CC[C@@]2(C)C1=CCc1cc(Cl)ccc12
Product: CN1C(=O)CC[C@]2(C)c3ccc(Cl)cc3CC[C@@H]12

Procedure:
By following the procedures described in Example 40, Steps A, B, C, D, E and F using p-chlorophenylacetic acid as the starting material and in Step F using methylamine rather than ammonia and 2-propanol rather than ethylene glycol, the compound (R)(+)-4-methyl-8-chloro-10b-methyl-1,2,3,4,6,10b-hexahydro-benzo[f]quinolin-3-one was prepared. This hexahydrobenzo[f]quinolin-3-one was reduced according to the procedure described in Example 40, Step G. The crude product was purified by chromatography on SiO2 (ethyl acetate as eluent) to afford 5.6 g of the title compound as a pale oil which solidified on standing. Melting point 60°-61° C.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:17]2[O:18][CH:19]=[C:20]([CH2:22][CH:23]([C:28]([C:30]3[C:35]([CH3:36])=[CH:34][CH:33]=[CH:32][N:31]=3)=[O:29])C(OC)=O)[N:21]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])C1C=CC=CC=1.Cl>C(O)C>[OH:8][C:9]1[CH:10]=[C:11]([C:17]2[O:18][CH:19]=[C:20]([CH2:22][CH2:23][C:28]([C:30]3[C:35]([CH3:36])=[CH:34][CH:33]=[CH:32][N:31]=3)=[O:29])[N:21]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16]
Reactant: COC(=O)C(Cc1coc(-c2ccc(OC)c(OCc3ccccc3)c2)n1)C(=O)c1ncccc1C
Agent: Cl
Solvent: CCO
Product: COc1ccc(-c2nc(CCC(=O)c3ncccc3C)co2)cc1O
Temperature: 80 °C

Procedure:
A 5.5 g quantity of methyl 2-[2-(3-benzyloxy-4-methoxy phenyl)oxazol-4-ylmethyl]-3-(3-methylpyridin-2-yl)-3-oxopropionate obtained in Example 135 was dissolved in 20 ml of ethanol, 80 ml of a 5N aqueous hydrochloric acid solution was added thereto, and the mixture was stirred with heating at 80° C. for 1.5 hours. While stirring with ice cooling, the reaction mixture was neutralized with 5 N aqueous sodium hydroxide solution, and ethyl acetate extraction was performed. The organic layer was washed twice with water, concentrated under reduced pressure, and the obtained crude crystals were recrystallized with a mixture of 20 ml of ethanol and 40 ml of n-hexane, thereby yielding 1.92 g of pale yellow powdery 3-[2-(3-hydroxy-4-methoxy phenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-one.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([C:11]([OH:13])=O)[S:10][C:5]2=[N:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:47][C:48]1[CH:49]=[C:50]([NH:55][C:56](=[O:67])[C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([C:63]([F:66])([F:65])[F:64])[CH:58]=2)[CH:51]=[CH:52][C:53]=1[CH3:54]>CN(C=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([C:11]([NH:47][C:48]3[CH:49]=[C:50]([NH:55][C:56](=[O:67])[C:57]4[CH:62]=[CH:61][CH:60]=[C:59]([C:63]([F:64])([F:65])[F:66])[CH:58]=4)[CH:51]=[CH:52][C:53]=3[CH3:54])=[O:13])[S:10][C:5]2=[N:4][CH:3]=1
Reactant: O=C(O)c1cc2nc(Cl)cnc2s1
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1NC(=O)c1cc2nc(Cl)cnc2s1
Temperature: 60 °C
Reaction time: 8 h
Yield: 77.8 %

Procedure:
A solution of 2-chlorothieno[3,2-b]pyrazine-6-carboxylic acid 23 (219 mg, 1.019 mmol), HATU (465 mg, 1.223 mmol) and DIPEA (0.337 mL, 2.039 mmol) in DMF (6 mL) was stirred for 15 min at rt. N-(3-amino-4-methylphenyl)-3-(trifluoromethyl)benzamide 67 (300 mg, 1.019 mmol) was added and stirred overnight at rt and overnight at 60° C. The reaction mixture was poured out in 3% citric acid solution and the resulting precipitate was collected and washed with water to give compound 2-chloro-N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)thieno[2,3-b]pyrazine-6-carboxamide 68 (389 mg, 78%). (m/z)=491 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[F:28])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([O:22]C)[C:10](=[O:21])[N:11]([CH3:20])[C:12]=2[C:16]([O:18]C)=O)[C:7]1=[O:24].[CH2:29]([NH:31][CH2:32][CH3:33])[CH3:30]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[F:28])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:22])[C:10](=[O:21])[N:11]([CH3:20])[C:12]=2[C:16]([N:31]([CH2:32][CH3:33])[CH2:29][CH3:30])=[O:18])[C:7]1=[O:24]
Reactant: CCNCC
Reactant: COC(=O)c1c2c(c(OC)c(=O)n1C)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2
Product: CCN(CC)C(=O)c1c2c(c(O)c(=O)n1C)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2

Procedure:
The title compound was prepared from methyl 6-(3-chloro-4-fluorobenzyl)-4-methoxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylate in a manner similar to that described in Example 12, Steps 12, 13 and 14, using diethyl amine in place of dimethylamine in the step corresponding to Step 13 of Example 12.