Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P([O-])(OC1C=CC=CC=1)OC1C=CC=CC=1.[NH2:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:19]=1[C:20]([OH:22])=O.[C:28]([O:32][C:33]([NH:35][C@@H:36]([CH3:40])[C:37](O)=O)=[O:34])([CH3:31])([CH3:30])[CH3:29].[NH2:41][C:42]1[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=1>N1C=CC=CC=1.CCCCCC>[Cl:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:18]2[C:19]=1[C:20](=[O:22])[N:41]([C:42]1[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=1)[C:37]([C@@H:36]([NH:35][C:33](=[O:34])[O:32][C:28]([CH3:31])([CH3:30])[CH3:29])[CH3:40])=[N:17]2
Reactant: Nc1cccnc1
Reactant: Nc1cccc(Cl)c1C(=O)O
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: [O-]P(Oc1ccccc1)Oc1ccccc1
Solvent: c1ccncc1
Solvent: CCCCCC
Product: C[C@H](NC(=O)OC(C)(C)C)c1nc2cccc(Cl)c2c(=O)n1-c1cccnc1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
Diphenyl phosphite (1.9 mL, 10 mmol) was added to a solution of 2-amino-6-chlorobenzoic acid (495 mg, 2.9 mmol) and (S)-2-(tert-butoxycarbonylamino)propanoic acid (710 mg, 3.77 mmol) in pyridine (3 mL). The reaction mixture was stirred at 40° C. for 2 hours. 3-Aminopyridine (274 mg, 3.48 mmol) was then added to the reaction mixture, which was then stirred at 55° C. for 12 hours. The reaction mixture was cooled to room temperature and loaded onto a hexane primed SiO2 column. The title compound was then purified by eluting with EtOAc in hexanes (0-50%) to afford (S)-tert-butyl 1-(5-chloro-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazolin-2-yl)ethylcarbamate as a solid. ES/MS m/z=401.1 (M+H+).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[F:13][C:14]1[CH:15]=[C:16]([CH:26]([NH:28][C:29]([C:31]2[N:32]=[C:33](Cl)[O:34][CH:35]=2)=[O:30])[CH3:27])[CH:17]=[C:18]([F:25])[C:19]=1[NH:20][S:21]([CH3:24])(=[O:23])=[O:22].C([O-])([O-])=O.[Cs+].[Cs+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:25][C:18]1[CH:17]=[C:16]([CH:26]([NH:28][C:29]([C:31]2[N:32]=[C:33]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([C:1](=[O:3])[CH3:2])[CH:5]=3)[O:34][CH:35]=2)=[O:30])[CH3:27])[CH:15]=[C:14]([F:13])[C:19]=1[NH:20][S:21]([CH3:24])(=[O:23])=[O:22]
Reactant: CC(=O)c1cccc(B(O)O)c1
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(=O)c1cccc(-c2nc(C(=O)NC(C)c3cc(F)c(NS(C)(=O)=O)c(F)c3)co2)c1
Yield: 38.2 %

Procedure:
3-Acetylphenylboronic acid (42.6 mg, 0.26 mmol) and 2-chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted using Pd(PPh3)2Cl2 (7 mg, 0.01 mmol), Cs2CO3 (127 mg, 0.39 mmol) as described above to give the title compound (23 mg, 38%) after purification by flash chromatography on silica gel (hexane: EtOAc=1:1).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[S:17]([C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][CH:21]=1)(=[O:19])=[O:18]>>[CH2:9]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[S:17]([C:20]1[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:28][CH:29]=1)(=[O:19])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Product: O=C(O)c1ccc(S(=O)(=O)N(Cc2ccccc2)Cc2ccccc2)cc1

Procedure:
Prepared as in example 5-27 from dibenzylamine and methyl 4-(chlorosulfonyl)-benzoate (Example 5-10c). MS (M−H, 380.1); 1H NMR (400 MHz, DMSO-d6): δ, ppm: 4.52 (s, 4H), 7.10 (m, 4H), 7.25 (m, 6H), 8.00 (d, 2H, J=8.4 Hz), 8.15 (d, 2H-J=8.4 Hz), 13.5 (s, broad, 1H).
Reaction SMILES: C([O:4][C@@H:5]([CH3:52])[C:6]([N:8]([CH2:35][C@H:36]1[C@@H:40]([F:41])[CH2:39][N:38](C(OCC2C=CC=CC=2)=O)[CH2:37]1)[C@@H:9]([C:14]1[N:18]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)[N:17]=[C:16]([C:27]2[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=2[F:34])[N:15]=1)[C:10]([CH3:13])([CH3:12])[CH3:11])=[O:7])(=O)C.C(=O)([O-])[O-].[K+].[K+]>CCOC(C)=O.CO.[Pd]>[F:34][C:28]1[CH:29]=[CH:30][C:31]([F:33])=[CH:32][C:27]=1[C:16]1[N:15]=[C:14]([C@H:9]([N:8]([CH2:35][C@H:36]2[C@@H:40]([F:41])[CH2:39][NH:38][CH2:37]2)[C:6](=[O:7])[C@@H:5]([OH:4])[CH3:52])[C:10]([CH3:11])([CH3:12])[CH3:13])[N:18]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)[N:17]=1
Reactant: CC(=O)O[C@@H](C)C(=O)N(C[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1F)[C@@H](c1nc(-c2cc(F)ccc2F)nn1Cc1cccc(F)c1)C(C)(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: C[C@H](O)C(=O)N(C[C@@H]1CNC[C@@H]1F)[C@@H](c1nc(-c2cc(F)ccc2F)nn1Cc1cccc(F)c1)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
To a solution of (3R,4R)-benzyl 3-(((S)-2-acetoxy-N-((R)-1-(3-(2,5-difluorophenyl)-1-(3-fluorobenzyl)-1H-1,2,4-triazol-5-yl)-2,2-dimethylpropyl)propanamido)methyl)-4-fluoropyrrolidine-1-carboxylate (2.24 g, 3.09 mmol) in degassed EtOAc (25 mL, 0.1 M solution) was added Pd/C (224 mg, 10 wt %) under anhydrous N2 atmosphere. After flushed with hydrogen gas, the reaction mixture equipped with a hydrogen gas balloon was stirred at room temperature for overnight. The reaction mixture was filtered through Celite® pad that was washed with EtOAc. The volatile organic filtrate was removed in vacuo to give the crude amine. Then, the crude product was dissolved in MeOH (200 mL, 0.015 M solution) followed by addition of anhydrous potassium carbonate (4.2 g, 30.9 mmol). The reaction was then stirred for 15 min at room temperature. After white precipitate was removed by filtration, the organic filtrate was concentrated in vacuo. The crude product was purified by preparative reverse phase HPLC. The combined fractions of the product were neutralized with saturated NaHCO3 solution, which was then extracted with EtOAc (200 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The dried product was then dissolved in acetonitrile and water (1:1 ratio) and lyophilized for 48 h. The white powdery (S)—N—((R)-1-(3-(2,5-difluorophenyl)-1-(3-fluorobenzyl)-1H-1,2,4-triazol-5-yl)-2,2-dimethylpropyl)-N-(((3S,4R)-4-fluoropyrrolidin-3-yl)methyl)-2-hydroxypropanamide was obtained in 57% yield (962 mg, over 3 steps) as a free amine 1H NMR (CD3OD, 400 MHz): 7.81 (1H, m), 7.40-7.16 (5H, m), 7.06 (1H, m), 6.12 (1H, s), 5.44 (2H, m), 4.77 (2H, m), 3.87 (1H, m), 2.82 (2H, m), 2.28 (1H, m), 2.17 (1H, m), 1.95 (1H, m), 1.43 (3H, m), 1.22 (1H, m), 0.91 (9H, s). LC/MS (uplc): MH+ 548.3, 0.94 min.
Reaction SMILES: [OH:1][C@@H:2]([CH2:6][O:7][S:8]([CH3:11])(=[O:10])=[O:9])[CH2:3][C:4]#[N:5].[ClH:12].[H][H]>CO.[Pd]>[ClH:12].[OH:1][C@@H:2]([CH2:6][O:7][S:8]([CH3:11])(=[O:10])=[O:9])[CH2:3][CH2:4][NH2:5]
Reactant: CS(=O)(=O)OC[C@H](O)CC#N
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CS(=O)(=O)OC[C@H](O)CCN

Procedure:
To a solution of (R)-3-hydroxy-4-(methanesulfonyloxy)butyronitrile (14.6 g) in methanol (60 ml), 10 wt. % Pd on carbon (2.5 g) and conc. hydrochloric acid (15 ml) were added. The mixture was stirred in a hydrogen atmosphere of 4.0 kg/cm2 at room temperature for 8 hours. After filtrating off the catalyst, the mixture was evaporated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (Wako Gel C200, an eluent: methanol/acetone (volume ratio of 1/9) to obtain pure (R)-3-hydroxy-4-(methanesulfonyloxy)butylamine hydrochloride (14.4 g). Yield, 80 %.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH:26]1([C:29](O)=[O:30])[CH2:28][CH2:27]1.CCN=C=NCCCN(C)C>>[CH:26]1([C:29]([NH:1][C:2]2[CH:3]=[C:4]([C:8]3[C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=4)[NH:10][N:9]=3)[CH:5]=[CH:6][CH:7]=2)=[O:30])[CH2:28][CH2:27]1
Reactant: O=C(O)C1CC1
Reactant: NC(=O)c1ccc2c(c1)c(-c1cccc(N)c1)nn2C1CCCCO1
Agent: CCN=C=NCCCN(C)C
Product: NC(=O)c1ccc2[nH]nc(-c3cccc(NC(=O)C4CC4)c3)c2c1
Yield: 24.4 %

Procedure:
Following Example 290, the reaction of 3-(3-aminophenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxamide (600 mg, 1.79 mmol) with cyclopropanecarboxylic acid (0.43 mL, 0.46 g, 5.4 mmol) and EDCI (1.06 g, 5.4 mmol) furnished 140 mg (26% yield) of the title compound. 1H NMR (DMSOd6) δ 13.4 (br s, 1H), 10.4 (s, 1H), 8.6 (s, 1H), 8.2 (s, 1H), 8.1 (br s, 1H), 7.9 (dd, 1H), 7.75 (m, 2H), 7.6 (d, 1H), 7.5 (t, 1H), 7.35 (s, 1H), 1.9–1.68 (m, 1H), 0.8 (m, 4H); ES-MS (m/z) 321 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([O:11][C@@H:12]1[O:38][C@H:37]([CH2:39][O:40][C:41](=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43])[C@@H:29]([O:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C@H:21]([O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[C@H:13]1[O:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])=[N:5][NH:6]2.[CH2:47]=[CH:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C>[C:49]1(/[CH:48]=[CH:47]/[C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[C:4]([O:11][C@@H:12]2[O:38][C@H:37]([CH2:39][O:40][C:41](=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43])[C@@H:29]([O:30][C:31](=[O:36])[C:32]([CH3:33])([CH3:34])[CH3:35])[C@H:21]([O:22][C:23](=[O:28])[C:24]([CH3:25])([CH3:26])[CH3:27])[C@H:13]2[O:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])=[N:5][NH:6]3)[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Oc2n[nH]c3cccc(Br)c23)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Reactant: C=Cc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Oc2n[nH]c3cccc(/C=C/c4ccccc4)c23)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Yield: 64.6 %

Procedure:
A mixture of 4-bromo-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-indazole (75 mg), styrene (33 mg), triethylamine (0.073 mL), palladium (II) acetate (2 mg) and tris(2-methylphenyl)phosphine (6 mg) inacetonitrile (2 mL) was heated for reflux under an argon atmosphere overnight. The reaction mixture was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=3/1-2/1) to give the title compound (50 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[N:14]=[CH:15][C:16]([C:17]([O:19]CC)=[O:18])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[N:14]=[CH:15][C:16]([C:17]([OH:19])=[O:18])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnn2ccc(-c3ccc(Cl)cc3)nc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cnn2ccc(-c3ccc(Cl)cc3)nc12
Temperature: 70 °C
Yield: 100.5 %

Procedure:
A mixture of ethyl 5-(4-chloro-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylate (0.12 g, 0.4 mmol) and 0.5 N sodium hydroxide solution (4 mL) in methanol (4 mL) was heated to 70° C. for 2 h. The mixture was cooled, diluted with water (8 mL) and concentrated in vacuo. The aqueous solution was acidified to pH 2 by the addition of 3N HCl. The precipitate was isolated by filtration, washed with water, and dried to give 5-(4-chloro-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.11 g, 100%). Off-white solid. MS (ISN) 272.3 [(M−H)−]; mp 309-311° C.
Reaction SMILES: Cl.Cl.COC1C=CC(N2CCNCC2)=CC=1.C(Cl)(=O)CC(C)C.[F:24][C:25]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([F:33])=[CH:27][C:26]=1[N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.[CH2:40]([S:48](Cl)(=[O:50])=[O:49])[CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>>[F:24][C:25]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([F:33])=[CH:27][C:26]=1[N:34]1[CH2:39][CH2:38][N:37]([S:48]([CH2:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)(=[O:50])=[O:49])[CH2:36][CH2:35]1
Reactant: O=S(=O)(Cl)CCc1ccccc1
Reactant: COc1cc(F)c(N2CCNCC2)cc1F
Agent: CC(C)CC(=O)Cl
Agent: COc1ccc(N2CCNCC2)cc1
Agent: Cl
Product: COc1cc(F)c(N2CCN(S(=O)(=O)CCc3ccccc3)CC2)cc1F
Yield: 101.3 %

Procedure:
Production Example 3 was repeated except that 1-(4-methoxyphenyl)piperazine dihydrochloride and isovaleryl chloride were replaced with 1-(2,5-difluoro-4-methoxyphenyl)-piperazine (228 mg) and phenethylsulfonyl chloride (409 mg), respectively, to provide crude 4-(2,5-difluoro-4-methoxyphenyl)-1-phenethylsulfonylpiperazine (401 mg).
Reaction SMILES: Cl.[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]1[N:12]=[C:13]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[N:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[C:15]=12.CCN=C=NCCCN(C)C.Cl.C(N(CC)C(C)C)(C)C.[CH:48](O)=[O:49]>C(Cl)Cl>[NH2:20][C:16]1[C:15]2[N:14]([C:13]([CH:21]3[CH2:26][CH2:25][N:24]([CH:48]=[O:49])[CH2:23][CH2:22]3)=[N:12][C:11]=2[C:3]2[NH:2][C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:19]=[CH:18][N:17]=1
Reactant: O=CO
Reactant: Nc1nccn2c(C3CCNCC3)nc(-c3cc4ccccc4[nH]3)c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nccn2c(C3CCN(C=O)CC3)nc(-c3cc4ccccc4[nH]3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 432.5 %

Procedure:
To a solution of 1-(1H-Indol-2-yl)-3-piperidin-4-ylimidazo[1,5-α]pyrazin-8-amine hydrochloride (30.00 mg, 0.0068 mmol) in DCM (0.5 ml, 0.008 mol) was added N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (0.0195 g, 0.102 mmol), N,N-diisopropylethylamine (0.047 mL), 1-hydroxbenzotriaxole hydrate (0.0104 g, 0.0679 mmol) and formic acid (4.7 mg, 0.10 mmol). The reaction was stirred at rt overnight then diluted with DCM, washed with saturated NaHCO3 (2×25 mL) and brine (2×25), then dried over Na2SO4 and concentrated in vacuo. The material thus isolated was crystallized from EtOAc to afford 10.6 mg of desired product. 1H NMR (400 MHz, CDCl3): δ 2.04-2.12 (m, 4H), 2.99-3.00 (m, 1H), 3.27-3.32 (m, 2H), 3.85 (m, 1H), 4.49 (m, 1H), 5.70 (br, 2H), 6.80 (s, 1H), 7.13-7.24 (m, 4H), 7.45 (d, J=8.4 Hz, 1H), 7.65 (d, J=8.0 Hz, 1H), 8.10 (s, 1H), 8.97 (br, 1H). MS (ES+): m/z 361.16 [MH+].
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH:18]3[CH2:23][CH2:22][N:21](C#N)[CH2:20][CH2:19]3)=[N:10]2)=[CH:5][CH:4]=1.OS(O)(=O)=O.[OH-].[Na+]>O>[F:27][C:2]([F:1])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH:18]3[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]3)=[N:10]2)=[CH:5][CH:4]=1
Reactant: N#CN1CCC(c2nn(-c3ccc(C(F)(F)F)cc3)c3ccccc23)CC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: FC(F)(F)c1ccc(-n2nc(C3CCNCC3)c3ccccc32)cc1
Yield: 91.8 %

Procedure:
A stirred mixture of 4-[1-(4-trifluoromethylphenyl)-1H-indazol-3-yl]piperidine-1-carbonitrile of Example 101 (15 g, 0.041 moles) and 25% H2SO4 (100 ml) was refluxed for 20 hours. The mixture was cooled, poured into H2O, and basified with a 25% NaOH solution. The product was extracted (dichloromethane), dried (MgSO4), and concentrated which yielded 13 g (93%) of 1-[4(trifluoromethyl)phenyl]-3-(4-piperidinyl)-1H-indazole as an oil. A mixture of formic acid (1 ml, 0.027 moles) and acetic anhydride (2.4 ml, 0.025 moles) was warmed at 55° C. for 1.5 hours. The solution was cooled to 30° C. and a suspension of the indazole (4.0 g, 0.012 moles) in ether (10 ml) was added. The mixture was stirred at ambient temperature for 3.5 hours and then poured into H2O and basified with a 5% NaOH solution. The product was of an oil. The oil was purified on the high pressure liquid chromatograph (silica gel, 100% ethyl acetate) to yield 3.1 g (72%) of 1-formyl-4-[1-[4-(trifluoromethyl)phenyl]-1H-indazol-3-yl]piperidine, m.p. 109°-111° C.
Reaction SMILES: [CH:1]1([C:11]2[CH:12]=[C:13]([C:17](=[O:19])[CH3:18])[CH:14]=[CH:15][CH:16]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[C:20](OCC)(=[O:26])[C:21]([O:23]CC)=[O:22].[O-]CC.[Na+]>>[O:26]=[C:20]([CH2:18][C:17](=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)[CH:12]=1)[C:21]([OH:23])=[O:22]
Reactant: CC(=O)c1cccc(C2CCCc3ccccc32)c1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Product: O=C(O)C(=O)CC(=O)c1cccc(C2CCCc3ccccc32)c1

Procedure:
Isomer B: As described above, 0.048 g (0.19 mmol) of 1-[3-(1,2,3,4-tetrahydronaphthalen-1-yl)-phenyl]-ethanone (isomer B), 0.056 g (0.38 mmol) diethyl oxalate, and 0.026 g (0.38 mmol) sodium ethoxide were reacted to give the title compound which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[N:12][N:13]2[C:18]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)([CH2:22][CH3:23])[C:19]([OH:21])=[O:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:43][CH2:44][O:45][C:46](/[C:48](/[NH2:51])=[N:49]/O)=[O:47]>C(Cl)Cl.CCOC(C)=O>[NH2:51][C:48](=[N:49][O:20][C:19](=[O:21])[C:18]([N:13]1[C:14]2[C:10](=[C:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:17]=[CH:16][CH:15]=2)[CH:11]=[N:12]1)([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[CH2:22][CH3:23])[C:46]([O:45][CH2:44][CH3:43])=[O:47]
Reactant: CCC(C(=O)O)(c1ccc(Cl)cc1)n1ncc2c(NC(=O)OC(C)(C)C)cccc21
Reactant: CCOC(=O)/C(N)=N/O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)C(N)=NOC(=O)C(CC)(c1ccc(Cl)cc1)n1ncc2c(NC(=O)OC(C)(C)C)cccc21
Temperature: 25 °C
Reaction time: 7.5 h

Procedure:
To a suspension of 2-(4-((tert-butoxycarbonyl)amino)-1H-indazol-1-yl)-2-(4-chlorophenyl)butanoic acid from Step A above (0.16 g, 0.37 mmol) in DCM (1.5 mL) was added 1,1′-carbonyldiimdazole (0.13 g, 0.78 mmol) to give a clear solution. The mixture was stirred for 7.5 hours at RT followed by addition of ethyl 2-oximinooxamate (0.13 g, 0.93 mmol). After stirring at RT overnight, the resulting mixture was diluted with EtOAc, washed with saturated NaHCO3 solution, water and brine. The organic layer was separated, and concentrated. The resulting crude product was re-dissolved in a mixture of acetonitrile and water and dried in a lyophilized to give the title compound as light yellow solid. LC/MS m/z=544.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:13]([N:15]=[C:16]=[O:17])[CH3:14].C(N(CC)CC)C>CN(C)C=O>[C:11]([C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([NH:1][C:16]([NH:15][CH2:13][CH3:14])=[O:17])[S:3][C:4]=2[CH:10]=1)#[N:12]
Reactant: CCN=C=O
Reactant: N#Cc1ccc2nc(N)sc2c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCNC(=O)Nc1nc2ccc(C#N)cc2s1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
2-Amino-1,3-benzothiazole-6-carbonitrile (0.2 g) was dissolved in about 5 mL dimethylformamide. About 0.2 mL of ethylisocyanate was added, followed by about 0.3 mL triethylamine and the solution was heated to about 80° C. under good agitation. The solution was allowed to stir for about 4 hours then cooled to room temperature. The solvent was removed in vacuo and the solids were washed well with ether. The product was further purified by column chromatography and after drying in vacuo, about 0.14 grams was isolated. 1H NMR 1.1 (t, 3H, J=7.2 Hz), 3.2 (m, 2H), 6.8 (s, 1H), 7.7 (m, 2H), 8.4 (s, 1H), 11.0 (s, 1H), LC/MS 2.54 min, 247 (MH+), 245 (M−H−), lab RP-HPLC RT 7.8 minutes.
Reaction SMILES: Br[C:2]1[N:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[C:9]([O:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)(=[O:19])=[O:18])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[S:27]1(=[O:34])(=[O:33])[CH2:32][CH2:31][CH2:30][CH2:29][NH:28]1.N1C=CC=CC=1C1C=CC=CN=1.O.C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O>CN(C=O)C.O.[Cu-]=O>[O:33]=[S:27]1(=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29][N:28]1[C:2]1[N:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[C:9]([O:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)(=[O:19])=[O:18])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: O=S1(=O)CCCCN1
Reactant: COC(=O)c1nc(Br)c2cccnc2c1OS(=O)(=O)c1ccc(C)cc1
Agent: O=[Cu-]
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: c1ccc(-c2ccccn2)nc1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1nc(N2CCCCS2(=O)=O)c2cccnc2c1OS(=O)(=O)c1ccc(C)cc1
Temperature: 118 °C

Procedure:
To a slurry of methyl 5-bromo-8-{[(4-methylphenyl)sulfonyl]oxy}-1,6-naphthyridine-7-carboxylate (7.55 g, 17.27 mmol) in degassed DMF (20 mL) in a pressure tube was added 1,2-thiazinane-1,1-dioxide (2.8 g, 20.7 mmol, prepared as in White et al, J. Org Chem. 1987, 52: 2162) followed by 2,2′-bipyridine (3.24 g, 20.7 mmol) and copper (I) oxide powder (2.96 g, 20.7 mmol). The pressure tube was closed and heated to 118 degrees C. overnight. Celite (0.5 g) was added to the resulting slurry and this was filtered through a plug of DMF wetted celite. The solids were washed with more DMF (10 mL) and the filtrate transferred to a large Erlenmeyer flask (1L) fitted with a 2 inch stirring bar. The volume was brought up to 200 mL with chloroform and a solution of ethylenediaminetetraacetic acid monohydrate (13.3 g, 35.7 mmol) in 140 mL of water was added. The biphasic mixture was vigorously stirred, open to the air, for 3 hours. The organic phase was separated and retreated with another solution of ethylenediaminetetraacetic acid monohydrate (13.3 g, 35.7 mmol) in 140 mL of water overnight (16 hrs). The organic was separated and washed with water and dried over Na2SO4, filtered, and reduced to a small volume in vacuo. The product solidified during solvent reduction. The solid was broken up and dried to afford the desired product.
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2].[CH2:18](O)[CH2:19][CH2:20][CH2:21]CC.C(N(CC)CC)C.C1C(CCCCC(N)=O)SSC1>C(OC(C)(C)C)C>[CH2:1]([O:3][C@H:4]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)[C:5]([O:7][CH2:8][CH2:9][CH2:18][CH2:19][CH2:20][CH3:21])=[O:6])[CH3:2].[CH2:1]([O:3][C@@H:4]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2]
Reactant: CCCCCCO
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Agent: NC(=O)CCCCC1CCSS1
Solvent: CCN(CC)CC
Solvent: CCOC(C)(C)C
Product: CCCCCCOC(=O)[C@@H](Cc1ccc(O)cc1)OCC
Product: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Temperature: 25 °C

Procedure:
To a solution of ethyl (2RS) (+/−) 2-ethoxy-3-(4-hydroxyphenyl)propanoate in t-butyl ethyl ether (dried on 3 Å molecular sieve) (10 mg/ml) was added n-hexanol (2 equivalents), triethylamine (dried on 3 Å molecular sieve) (14 mol %), 4 Å molecular sieve, and Mucor miehei lipase Lipozyme IM (from Novo Nordisk) (20 mg). The reaction mixture was shaken at room temperature and analysed at different times. The reaction mixture was analysed by the gradient HPLC method 1 and by the chiral CE method 2.
Reaction SMILES: [CH2:1]=C1CCC2(OCCO2)CC1.O=[C:13]1[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]1.O1C2(CCC(=O)CC2)OCC1>>[CH2:1]=[C:13]1[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]1
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: C=C1CCC2(CC1)OCCO2
Agent: O=C1CCC2(CC1)OCCO2
Product: C=C1CCC(C(=O)OCC)CC1
Yield: 68.7 %

Procedure:
This intermediate was prepared following the procedure described Compound 31a. As starting material ethyl 4-oxocyclohexane-1-carboxylate replaced 1,4-dioxaspiro[4.5]decan-8-one. After the usual work-up procedure, the residue was purified by means of automated flash chromatography (SP01®TM-Biotage; gradient Petroleum Ether-EtOAc from 95:5 to 4:6) to give the title compound as a colorless oil. Yield: 68.7%.