Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13]C)=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([O:21][C@@H:22]2[CH2:26][CH2:25][CH2:24][C@H:23]2[OH:27])=[CH:17][CH:16]=1.[OH-].[Na+].Cl>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:16]=[CH:17][C:18]([O:21][C@@H:22]2[CH2:26][CH2:25][CH2:24][C@H:23]2[OH:27])=[CH:19][CH:20]=1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(O[C@@H]4CCC[C@H]4O)cc3)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1c[nH]c2cc(Cl)c(-c3ccc(O[C@@H]4CCC[C@H]4O)cc3)cc12
Temperature: 75 °C

Procedure:
A solution of (±)-methyl 6-chloro-5-(4-{[trans-2-hydroxycyclopentyl]oxy}phenyl)-1H-indole-3-carboxylate (32 mg, 0.083 mmol) in methanol (0.845 mL) was treated with 1N aqueous sodium hydroxide (0.291 mL, 0.291 mmol). The solution was heated to 75° C. in a sealed vial for 24 hours. The cooled reaction mixture was poured into 0.3N HCl (7 mL) and extracted with ethyl acetate (3×5 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The crude product was purified using reverse-phase chromatography to give the title compound. MS (ES−) 370.0 (M−H)−. Retention time: 1.66 min; Waters Xbridge dC18 5 μm 4.6×50 mm, 95% H2O/5% MeCN linear to 5% H2O/95% MeCN over 4.0 min, HOLD at 5% H2O/95% MeCN to 5.0 min. (0.03% NH4OH). Flow: 2.0 mL/min.
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([C:10]([OH:12])=[O:11])[CH2:3]2.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[C:27]1([CH:33]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>CN(C=O)C.CCOCC>[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([C:10]([O:12][CH:33]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:11])[CH2:3]2
Reactant: O=C(O)C1CN2CCC1CC2
Reactant: OC(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: O=C(OC(c1ccccc1)c1ccccc1)C1CN2CCC1CC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 31.1 %

Procedure:
Quinuclidine-3-carboxylic acid hydrochloride (114 mg, 0.60 mmol), EDC (156 mg, 0.81 mmol), and HOBT (125 mg, 0.81 mmol) were suspended in dry DMF (5 ml). Diphenylmethanol (100 mg, 0.54 mmol) and DIPEA (332 μl, 1.90 mmol) were added, and the mixture was stirred at room temperature for 24 hours. Quinuclidine-3-carboxylic acid hydrochloride (52.0 mg, 0.27 mmol), EDC (52.0 mg, 0.27 mmol), and HOBT (41.6 mg, 0.27 mmol) followed by DIPEA (95 μl, 0.54 mmol) were added again, and the mixture was stirred for 4 days. The reaction was then portioned between sat. NaHCO3 and Et2O. The organic layer was separated, washed again with sat. NaHCO3, water and brine, dried over Na2SO4, filtered, and evaporated to afford benzhydryl quinuclidine-3-carboxylate (54 mg, racemic mixture). The compound was used as such in the next step.
Reaction SMILES: C(O)(=O)C.CO[N:7]=[C:8]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[NH:10][C:9]1=[O:20]>[Pd].C(OCC)(=O)C>[NH2:7][CH:8]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[NH:10][C:9]1=[O:20]
Reactant: CON=c1c(=O)[nH]c2ccccc2[nH]c1=O
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: NC1C(=O)Nc2ccccc2NC1=O
Temperature: 70 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
Wet 10% Pd/C (37.5 g) with glacial acetic acid (HOAc, 3.75 L). Add 1,5-dihydro-benzo[b][1,4]diazepine-2,3,4-trione 3-(O-methyl-oxime) (150 g, 0.684 mol), and subject the resulting mixture to catalytic hydrogenation under 50 psi H2 at ambient temperature for ˜18 hours until complete by HPLC. Remove the catalyst by filtration over glass fiber paper/Hyflo and rinse with HOAc (2 L). Concentrate the filtrate in vacuo to obtain the crude product as an amber waxy solid. Treat the solid with ethyl acetate (EtOAc, 3 L) and heat to 70° C. with stirring for 1 hour. Allow the slurry to cool to ambient temperature, then force cool to 0° C. Isolate the product by filtration and dry to afford 109.9 g (84%) of the title compound: 1H NMR (300 MHz, DMSO-d6) δ 10.48 (bs, 2H), 7.18 (m, 4H), 3.75 (s, 1H), ˜3.5 (bs, 2H); 13C NMR (75 MHz, DMSO-d6) δ 167.9, 164.5, 129.2, 125.1, 122.2, 55.8, 55.7; IR (KBr) 3375, 3306, 3282, 3047, 2750, 1697, 1670, 1559, 1500, 1433, 1411, 1337, 1307, 1258, 1183 cm−1; V (EtOH) λmax 217 nm (ε 33772), 285 nm (ε 3210); HRMS (ES+) exact mass calc'd for C9H9N3O2 192.0773, Found 192.0768.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C@H:7]([NH:12][C:13](=[O:22])[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6]2.S(Cl)([Cl:25])=O>C(Cl)Cl>[Cl:25][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C@H:7]([NH:12][C:13](=[O:22])[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6]2
Reactant: O=S(Cl)Cl
Reactant: O=C(N[C@H]1Cc2ccc(CO)cc2C1)OCc1ccccc1
Solvent: ClCCl
Product: O=C(N[C@H]1Cc2ccc(CCl)cc2C1)OCc1ccccc1
Reaction time: 1 h
Yield: 99.6 %

Procedure:
To (S)-benzyl 5-(hydroxymethyl)-2,3-dihydro-1H-inden-2-ylcarbamate (5.72 mmol, 1.7 g) was added DCM (34.9 mL) followed by sulfurous dichloride (11.43 mmol, 1.360 g). The reaction was stirred for one hour before removing the solvent in vacuo. DCM was added (5 mL) before removing the solvent in vacuo, this procedure was followed a further twice to give a yellow solid (1.8 g, 100%). 1H NMR (400 MHz, CDCl3) δ 2.81 (m, 2H), 3.30 (m, 2H), 4.56 (m, 3H), 4.95 (brs, 1H), 5.12 (s, 2H), 7.19 (d, 2H), 7.25 (m, 1H), 7.33 (m, 5H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[NH:17][N:16]=[N:15][N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C)C=O.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[N:17]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:16]=[N:15][N:14]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nnn[nH]1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nnnn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To a solution of crude compound A in N,N-dimethyl-formamide (5 mL) is added K2CO3 (1.16 g, 8.4 mmol) and benzyl bromide (665 uL, 5.6 mmol). The solution is stirred at room temperature for 1 hr. The mixture is diluted with EtOAc and washed with brine. The organic layer is dried and concentrated under vacuum. The residue is purified by flash column chromatography (Hexanes/EtOAc) to provide 404 mg of the title compound M+H+=330, and 401 mg of the other region isomer (S)-2-(1-Benzyl-1H-tetrazol-5-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (C). M+H+=330. Combined yield is 87% for 2 steps.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH2:4][CH2:3]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:20][NH:21][C:22]([N:24]1[C:32]2[C:27](=[CH:28][C:29]([O:33][C:34]3[CH:39]=[CH:38][N:37]=[C:36]([NH:40][C:41]([N:43]4[CH2:48][CH2:47][C:46](=O)[CH2:45][CH2:44]4)=[O:42])[CH:35]=3)=[CH:30][CH:31]=2)[CH:26]=[CH:25]1)=[O:23]>ClCCl>[CH3:20][NH:21][C:22]([N:24]1[C:32]2[C:27](=[CH:28][C:29]([O:33][C:34]3[CH:39]=[CH:38][N:37]=[C:36]([NH:40][C:41]([N:43]4[CH2:48][CH2:47][CH:46]([N:2]5[CH2:5][CH2:4][CH2:3]5)[CH2:45][CH2:44]4)=[O:42])[CH:35]=3)=[CH:30][CH:31]=2)[CH:26]=[CH:25]1)=[O:23]
Reactant: CNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)N4CCC(=O)CC4)c3)ccc21
Reactant: C1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: CNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)N4CCC(N5CCC5)CC4)c3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.8 %

Procedure:
Azetidine hydrochloride (179 mg, 2.00 mmol) and sodium triacetoxyborohydride (434 mg, 2.05 mmol) were added to a dichloromethane (3.7 ml) solution of N1-methyl-5-(2-(4-oxopiperidin-1-ylcarbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide (555 mg, 1.36 mmol) synthesized in Example 40, and stirred overnight at room temperature. The reaction mixture was partitioned between ethyl acetate and water; and the organic layer was dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure; and the residue was purified by use of silica gel column chromatography (Fuji Silysia NH, ethyl acetate-methanol system). The resultant was washed with a solvent mixture of ether-hexane=1:1; and the solid was filtered off to yield crystals of the title compound (5 mg), and a mixture (410 mg) including the title compound.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:23])=[C:11]([NH:13][C:14]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][N:17]=3)=[O:15])[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.Cl.Cl[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1>>[CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:23])=[C:11]([NH:13][C:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=4)=[CH:18][N:17]=3)=[O:15])[CH:12]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(O)cn1
Reactant: ClCc1ccccn1
Agent: Cl
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(OCc2ccccn2)cn1

Procedure:
The title compound was prepared from N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-hydroxypyridine-2-carboxamide and 2-chloromethyl-pyridine hydrochloride according to the method described for Example 4; NMR Spectrum: (DMSOd6) 0.58 (m, 2H), 0.69 (m, 2H), 2.32 (s, 3H), 2.86 (m, 1H), 5.40 (s, 2H), 7.33 (m, 1H), 7.39 (m, 1H), 7.58 (m, 2H), 7.72 (m, 1H), 7.88 (m, 1H), 8.13 (m, 1H), 8.21 (m, 1H), 8.36 (m, 1H), 8.51 (m, 1H), 8.61 (m, 1H), 10.14 (s, 1H); Mass Spectrum: M+H+ 403.
Reaction SMILES: C(OC([NH:11][CH:12]1[N:18]=[C:17]([CH:19]([CH3:21])[CH3:20])[C:16]2[CH:22]=[CH:23][CH:24]=[CH:25][C:15]=2[NH:14][C:13]1=[O:26])=O)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[NH2:11][CH:12]1[N:18]=[C:17]([CH:19]([CH3:21])[CH3:20])[C:16]2[CH:22]=[CH:23][CH:24]=[CH:25][C:15]=2[NH:14][C:13]1=[O:26]
Reactant: CC(C)C1=NC(NC(=O)OCc2ccccc2)C(=O)Nc2ccccc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)C1=NC(N)C(=O)Nc2ccccc21
Reaction time: 1 h
Yield: 85.1 %

Procedure:
To a suspension of Pd—C (5 wt %, 1.60 g) in methanol (60 ml) was added dropwise a solution of (3RS)-3-benzyloxycarbonylamino-2,3-dihydro-5-isopropyl-1H-1,4-benzodiazepin-2-one (8.00 g) in methanol (60 ml) and then ammonium formate (5.56 g) at room temperature. The reaction mixture was stirred at the same temperature for 1 hour. The catalyst was filtered on Celite®. The filtrate was concentrated in vacuo. The residue was taken up with ethyl acetate (100 ml) and saturated aqueous sodium hydrogen carbonate (100 ml). The organic layer was washed with a brine (100 ml). Dryness over sodium sulfate and evaporation gave (3RS)-3-amino-2,3-dihydro-5-isopropyl-1H-1,4-benzodiazepin-2-one (4.21 g). The product was used in a following reaction step without further purification.
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].[F:9][C:10]1[C:15](B(O)O)=[CH:14][CH:13]=[CH:12][N:11]=1.Br[C:20]1[CH:33]=[CH:32][C:31]2[O:30][C:29]3[C:24](=[CH:25][C:26]([C:34]4[CH:39]=[CH:38][N:37]=[C:36]([F:40])[CH:35]=4)=[CH:27][CH:28]=3)[C@@:23]3([N:45]=[C:44]([NH2:46])[CH2:43][O:42][CH2:41]3)[C:22]=2[CH:21]=1>O1CCOCC1.O.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[F:9][C:10]1[C:15]([C:20]2[CH:33]=[CH:32][C:31]3[O:30][C:29]4[C:24](=[CH:25][C:26]([C:34]5[CH:39]=[CH:38][N:37]=[C:36]([F:40])[CH:35]=5)=[CH:27][CH:28]=4)[C@@:23]4([N:45]=[C:44]([NH2:46])[CH2:43][O:42][CH2:41]4)[C:22]=3[CH:21]=2)=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: OB(O)c1cccnc1F
Reactant: NC1=N[C@@]2(COC1)c1cc(Br)ccc1Oc1ccc(-c3ccnc(F)c3)cc12
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: NC1=N[C@]2(COC1)c1cc(-c3ccnc(F)c3)ccc1Oc1ccc(-c3cccnc3F)cc12
Temperature: 120 °C
Yield: 68.5 %

Procedure:
In a microwave vial, the potassium phosphate (0.071 g, 0.334 mmol), PdCl2(AmPhos)2 (7.88 mg, 0.011 mmol), 2-fluoropyridin-3-ylboronic acid (0.020 g, 0.139 mmol), and (R)-2′-bromo-7′-(2-fluoropyridin-4-yl)-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthen]-5-amine (0.049 g, 0.111 mmol) were suspended in dioxane (2 mL) and water (0.5 mL). Argon gas was blown through the vessel, which was sealed and heated by microwave at 120° C. for 30 min. The mixture was concentrated, and the residue was diluted with brine (15 mL), and the aqueous phase was extracted with 5% MeOH-dcm (3×25 mL). The organics were combined, dried over sodium sulfate and concentrated. The residue was purified by chromatography (3.5%-4.5% MeOH/DCM) to afford (R)-2′-(2-fluoropyridin-3-yl)-7′-(2-fluoropyridin-4-yl)-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthen]-5-amine (35 mg, 0.076 mmol). MS (m/z) 457 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([N+:15]([O-])=O)[CH:9]=2)=[O:4]>CO>[CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([NH2:15])[CH:9]=2)=[O:4]
Reactant: COC(=O)c1cc2ccc([N+](=O)[O-])cc2cn1
Solvent: CO
Product: COC(=O)c1cc2ccc(N)cc2cn1
Yield: 98.9 %

Procedure:
0.5 g (2.1 mmol) of 7-nitro-isoquinoline-3-carboxylic acid methyl ester in methanol (25 ml) was hydrogenated according to the general procedure C to provide 0.42 g of 7-amino-isoquinoline-3-carboxylic acid methyl ester in quantitative yield. LCMS: 203 (M+1)+
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]\[C@@H:9]2[CH2:25][N:13]3[CH2:14][CH2:15][N:16]([C:18]4[N:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=4)[CH2:17][C@@H:12]3[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>[Pd].C(O)C>[C:1]1([CH2:7][CH2:8][C@H:9]2[CH2:25][N:13]3[CH2:14][CH2:15][N:16]([C:18]4[N:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=4)[CH2:17][C@@H:12]3[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [H][H]
Reactant: Fc1cnc(N2CCN3C[C@@H](/C=C\c4ccccc4)CC[C@H]3C2)nc1
Agent: [Pd]
Solvent: CCO
Product: Fc1cnc(N2CCN3C[C@H](CCc4ccccc4)CC[C@H]3C2)nc1
Yield: 82.8 %

Procedure:
A mixture of 0.15 g (0.44 mmol) of Z-(7R,9aS)-7-(2-phenyl)ethenyl-2-(5-fluoropyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine, 0.015 g of 10% palladium on carbon and 25 mL of ethanol was shaken under 40 psig of hydrogen gas in a Parr apparatus for 6 h. The mixture was filtered through Celite, and the filtrate concentrated to give 0.124 g (83%) of (7R,9aS)-7-(2-phenyl)ethyl-2-(5-fluoropyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine. mp (.HCl) 250–252° C. HRMS calcd for C20H26FN4O (MH+): 341.2142, found: 341.2126.
Reaction SMILES: [ClH:1].CC(C)=O.C(OC([N:13]1[CH2:18][CH2:17][N:16]([C:19]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N+:28]=3[O-:33])=[CH:23][CH:22]=2)=[O:20])[CH2:15][CH2:14]1)=O)(C)(C)C>ClCCl.C(O)C>[ClH:1].[N:16]1([C:19]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N+:28]=3[O-:33])=[CH:23][CH:22]=2)=[O:20])[CH2:17][CH2:18][NH:13][CH2:14][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(-c3cccc[n+]3[O-])cc2)CC1
Agent: Cl
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: CCO
Product: O=C(c1ccc(-c2cccc[n+]2[O-])cc1)N1CCNCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In dichloromethane (2.5 ml), 2-[4-[[4-(tert-butoxycarbonyl)piperazin-1-yl]carbonyl]phenyl]pyridine N-oxide was dissolved. To the resulting solution, a saturated solution of hydrochloride in ethanol (2.5 ml) was added, followed by stirring at room temperature for 1 hour. After the solvent was distilled off under reduced pressure, water was added to the residue, whereby an aqueous solution was obtained. Acetone was added to the aqueous solution until the solution became turbid. The precipitate was collected by filtration and washed with acetone, whereby the title compound (274 mg, 81%) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:14]=[CH:15][C:16]4[O:20][C:19]([C:21]5([NH:29]C(=O)OC(C)(C)C)[CH2:26][O:25]C(C)(C)[O:23][CH2:22]5)=[CH:18][C:17]=4[CH:37]=3)[N:9]=2)=[CH:4][C:3]=1[Cl:38].ClC1C=C(C2ON=C(C3C=CC4OC(C5(NC(=O)OC(C)(C)C)COC(C)(C)OC5)=CC=4C=3)N=2)C=CC=1OCCC>>[NH2:29][C:21]([C:19]1[O:20][C:16]2[CH:15]=[CH:14][C:13]([C:10]3[N:9]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([Cl:38])[CH:4]=4)[O:12][N:11]=3)=[CH:37][C:17]=2[CH:18]=1)([CH2:22][OH:23])[CH2:26][OH:25]
Reactant: CC(C)(C)OC(=O)NC1(c2cc3cc(-c4noc(-c5ccc(Br)c(Cl)c5)n4)ccc3o2)COC(C)(C)OC1
Agent: CCCOc1ccc(-c2nc(-c3ccc4oc(C5(NC(=O)OC(C)(C)C)COC(C)(C)OC5)cc4c3)no2)cc1Cl
Product: NC(CO)(CO)c1cc2cc(-c3noc(-c4ccc(Br)c(Cl)c4)n3)ccc2o1
Yield: 39 %

Procedure:
When the product of Step C was substituted for tert-butyl 5-(5-(5-(3-chloro-4-propoxyphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate in Example 36, Step E, the similar procedure afforded the title compound in 39% yield, as creamy solid. 1H-NMR (DMSO-d5) 8.31 (b, 2H); 8.05 (d, 1H, J=8.52 Hz); 8.00 (d, 1H, J=8.49 Hz); 7.94 (d, 1H, J=8.58 Hz); 7.68 (d, 1H, J=8.46 Hz); 6.91 (s, 1H); 4.88 (bs, 1H); 3.66 (bs, 2H); 3.58 (bs, 2H).
Reaction SMILES: [F:1][C:2]1[C:27](F)=[CH:26][C:5]2=[N:6][C:7]3[N:8]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=4[F:25])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[CH:32][CH:31]=1>CS(C)=O>[F:25][C:19]1[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:18]=1[N:8]1[C:7]2[N:6]=[C:5]3[CH:26]=[C:27]([N:39]4[CH2:38][CH2:37][N:36]([C:33]5[CH:32]=[CH:31][C:30]([F:29])=[CH:35][CH:34]=5)[CH2:41][CH2:40]4)[C:2]([F:1])=[CH:3][C:4]3=[CH:13][C:12]=2[C:11](=[O:14])[C:10]([C:15]([OH:17])=[O:16])=[CH:9]1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2nc3cc(F)c(F)cc3cc2c1=O
Solvent: CS(C)=O
Product: O=C(O)c1cn(-c2ccc(F)cc2F)c2nc3cc(N4CCN(c5ccc(F)cc5)CC4)c(F)cc3cc2c1=O
Yield: 63.9 %

Procedure:
1-(2,4-Difluorophenyl)-7-fluoro-8-[4-(4-fluorophenyl)piperazin-1-yl]-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid was prepared under the conditions of Example 1, but from 1.55 g of 7,8-difluoro-1-(2,4-difluorophenyl)-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid and 1.58 g of 4-(4-fluorophenyl)piperazine in 15 cm3 of dimethyl sulphoxide. After recrystallizing once from 55 cm3 of dimethylformamide, 1.4 g of 1-(2,4-difluorophenyl)-7-fluoro-8-[4-(4-fluorophenyl)piperazin-1-yl]-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid were obtained in the form of a yellow solid melting at about 322° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]([OH:14])[C:11]2[C:6](=[C:7](C)[C:8](OC)=[CH:9][CH:10]=2)[N:5]=1)[CH3:2].[Cl:18]C1C=CC=CC=1N>>[Cl:18][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([O:3][CH2:1][CH3:2])[CH:13]=[C:12]2[OH:14]
Reactant: CCOc1cc(O)c2ccc(OC)c(C)c2n1
Reactant: Nc1ccccc1Cl
Product: CCOc1cc(O)c2cccc(Cl)c2n1

Procedure:
8-Chloro-2-ethoxy-quinolin-4-ol was synthesized according to the method presented in the synthesis of 2-ethoxy-7-methoxy-8-methyl-quinolin-4-ol in Example 137 with the exception of utilizing 2-chloro-aniline.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:13][O:12][CH2:11][C@H:10]1[O:14][C:15]1[C:33]([F:34])=[CH:32][C:31]([N+:35]([O-])=O)=[CH:30][C:16]=1[CH2:17][N:18](C)[C:19](=O)OCC1C=CC=CC=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>CO.[Pd]>[Si:1]([O:8][C@H:9]1[CH2:13][O:12][CH2:11][C@H:10]1[O:14][C:15]1[C:16]([CH2:17][NH:18][CH3:19])=[CH:30][C:31]([NH2:35])=[CH:32][C:33]=1[F:34])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CN(Cc1cc([N+](=O)[O-])cc(F)c1O[C@@H]1COC[C@@H]1O[Si](C)(C)C(C)(C)C)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CNCc1cc(N)cc(F)c1O[C@@H]1COC[C@@H]1O[Si](C)(C)C(C)(C)C
Yield: 100 %

Procedure:
To 27F (138 mg, 0.372 mmol, 93% yield) in MeOH (5 mL) was added 10% Pd/C (50 mg) and the mixture was hydrogenated (1 atm) for 4 h at rt. The mixture was filtered and concentrated to give 27G (138 mg, 0.372 mmol, 93% yield) as a colorless oil. MS (ESI) m/z: 371.4 (M+H)+.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([S:12]([N:15]([CH3:29])[C@@H:16]2[CH2:24][CH2:23][CH2:22][C:21]3[N:20]([CH2:25][C:26]([OH:28])=[O:27])[N:19]=[CH:18][C:17]2=3)(=[O:14])=[O:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1.C(O)(=O)C>CS(C)=O>[CH3:29][N:15]([S:12]([C:4]1[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=[C:2]([N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[CH:3]=1)(=[O:13])=[O:14])[C@@H:16]1[CH2:24][CH2:23][CH2:22][C:21]2[N:20]([CH2:25][C:26]([OH:28])=[O:27])[N:19]=[CH:18][C:17]1=2
Reactant: C1CCNC1
Reactant: CN([C@@H]1CCCc2c1cnn2CC(=O)O)S(=O)(=O)c1cc(F)cc(C(F)(F)F)c1
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: CN([C@@H]1CCCc2c1cnn2CC(=O)O)S(=O)(=O)c1cc(N2CCCC2)cc(C(F)(F)F)c1
Temperature: 180 °C
Yield: 46.7 %

Procedure:
{(R)-4-[(3-Fluoro-5-trifluoromethyl-benzenesulfonyl)-methyl-amino]-4,5,6,7-tetrahydro-indazol-1-yl}-acetic acid (25 mg, 0.066 mmol) and pyrrolidine (47 mg, 0.66 mmol) were dissolved in dimethyl sulfoxide (1.5 mL). The mixture was heated in a microwave oven at 180° C. for 50 minutes. The resulting mixture was acidified with acetic acid to pH 4, and then filtered and purified by preparative HPLC to afford {(R)-4-[methyl-(3-pyrrolidin-1-yl-5-trifluoromethyl-benzenesulfonyl)-amino]-4,5,6,7-tetrahydro-indazol-1-yl}-acetic acid (15 mg, 48.5%) as a white powder. 1H NMR (400 MHz, CD3OD) δ ppm 7.24 (s, 1H), 7.14 (s, 1H), 6.98 (s, 1H), 6.41 (s, 1 H), 5.05 (t, 1H), 4.75 (s, 2H), 3.35 (t, 4H), 2.61 (s, 3H), 2.45 (m, 2H), 2.08-1.61 (m, 8H). MS calcd. for C21H25F3N4O4S 486, obsd. (ESI+) [(M+H)+] 487.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-])=O.C1CCCCC=1>C(O)C.[Pd]>[NH2:1][C:4]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:15][CH2:14]2)=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1cc(N2CCN(Cc3ccccc3)CC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: Nc1ccc(N2CCN(Cc3ccccc3)CC2)cc1C(=O)O
Yield: 87.7 %

Procedure:
The mixture of 6 g of 2-nitro-5-(4-benzylpiperazin-1-yl)benzoic acid, 15 mL of cyclohexene and 3 g of Pd/C (10%) is heated under reflux conditions in 120 mL of ethanol for 6 hours. The hot reaction mixture is filtered through celite filter. The filtrate is evaporated to obtain 4.8 g of the title compound. m.p.: 242° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[CH:11]=[CH:12][C:13]([O:15][CH3:16])=[O:14]>C(OP(OCC)OCC)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[CH:11]=[C:12]([C:13]([O:15][CH3:16])=[O:14])[NH:8]2
Reactant: COC(=O)C=Cc1c(C)cccc1[N+](=O)[O-]
Agent: CCOP(OCC)OCC
Product: COC(=O)c1cc2c(C)cccc2[nH]1
Yield: 72.1 %

Procedure:
Methyl 3-(2-methyl-6-nitrophenyl)propenoate (0.24 g, 1.1 mmol) was dissolved in triethylphosphite (1 mL) and heated under reflux for 20 h. The solvent was removed in vacuo and the crude product was purified by silica gel chromatography (EtOAc:hexane=8:92) to give 0.15 g (71% yield) of the title compound as a pale yellow solid:
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=O)=[CH:13][CH:14]=3)[C:9]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[N:8]2)=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.[O:31]=[C:32]1[N:36]([CH2:37][C:38]([OH:40])=[O:39])[C:35](=[O:41])[CH2:34][S:33]1>>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:34]4/[C:35](=[O:41])[N:36]([CH2:37][C:38]([OH:40])=[O:39])[C:32](=[O:31])[S:33]/4)=[CH:13][CH:14]=3)[C:9]([C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)=[N:8]2)=[C:4]([C:27]([F:29])([F:30])[F:28])[CH:3]=1
Reactant: O=Cc1ccc2c(c1)c(-c1ccc(F)cc1)nn2Cc1ccc(Cl)cc1C(F)(F)F
Reactant: O=C(O)CN1C(=O)CSC1=O
Product: O=C(O)CN1C(=O)S/C(=C\c2ccc3c(c2)c(-c2ccc(F)cc2)nn3Cc2ccc(Cl)cc2C(F)(F)F)C1=O

Procedure:
[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-3-(4-fluorophenyl)-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]acetic acid was prepared from 1-(4-chloro-2-trifluoromethylbenzyl)-3-(4-fluorophenyl)-1H-indazole-5-carbaldehyde and (2,4-dioxothiazolidin-3-yl)acetic acid following General Procedure F.