Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11]CCN2C=CN=N2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:26][C:27]1[N:28]=[C:29]([CH:32]=[CH:33][C:34]2[CH:39]=[CH:38][C:37]([S:40]([F:45])([F:44])([F:43])([F:42])[F:41])=[CH:36][CH:35]=2)[O:30][CH:31]=1.[I-].[K+]>CC(=O)CC>[F:43][S:40]([F:41])([F:42])([F:44])([F:45])[C:37]1[CH:38]=[CH:39][C:34](/[CH:33]=[CH:32]/[C:29]2[O:30][CH:31]=[C:27]([CH2:26][O:1][C:2]3[CH:3]=[CH:4][C:5]([S:8]([NH2:11])(=[O:9])=[O:10])=[CH:6][CH:7]=3)[N:28]=2)=[CH:35][CH:36]=1
Reactant: O=S(=O)(NCCn1ccnn1)c1ccc(O)cc1
Reactant: FS(F)(F)(F)(F)c1ccc(C=Cc2nc(CCl)co2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CCC(C)=O
Product: NS(=O)(=O)c1ccc(OCc2coc(/C=C/c3ccc(S(F)(F)(F)(F)F)cc3)n2)cc1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A mixture of 145 mg (0.54 mmol) 4-hydroxy-N-(2-[1,2,3]triazol-1-yl-ethyl)-benzenesulfon-amide and 117 mg (0.36 mmol) cesium carbonate in 10 ml butanone was stirred at 60° C. for 30 min, then 207 mg (0.6 mmol) 4-chloromethyl-2-[2-(4-pentafluorosulfanyl-phenyl)-vinyl]-oxazole and 100 mg (0.6 mmol) potassium iodide were added and stirring at 60° C. continued overnight. After evaporation, the residue was mixed with 15 ml water and extracted thrice with 15 ml ethyl acetate. The combined extracts were dried, evaporated and the product purified on silica. Elution with heptane/ethyl acetate 1:5 yielded 148 mg (43%) N-(2-[1,2,3]triazol-1-yl-ethyl)-(4-{2-[(E)-2-(4-pentafluorosulfanyl-phenyl)-vinyl]-oxazol-4-ylmethoxy}-benzene-sulfonamide as white solid melting at 170–172° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1.[CH3:9][Mg+].[Br-]>C1COCC1>[CH3:1][C:2]1[N:3]=[C:4]([CH:7]([OH:8])[CH3:9])[S:5][CH:6]=1
Reactant: C[Mg+]
Reactant: Cc1csc(C=O)n1
Agent: [Br-]
Solvent: C1CCOC1
Product: Cc1csc(C(C)O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
To a solution of 4-methylthiazole-2-carbaldehyde of preparation 94 (5.8 g, 45.6 mmol) in anhydrous THF (100 mL) was added a THF solution of MeMgBr (3M, 30.4 mL, 91.3 mmol) drop-wise at −60° C. under N2, and the mixture was warmed to room temperature and stirred for another 2 hours. TLC (petroleum ether:EtOAc 2:1) showed the reaction was completed. The mixture was quenched by saturated NH4Cl solution (120 mL), and extracted with EtOAc (100 mL×3). The combined organic extracts were washed with brine (50 mL), dried over sodium sulfate and concentrated in vacuum to give the residue which was purified by a silica gel column eluting with petroleum ether:EtOAc=20:1-8:1 to give the title compound as a yellow oil (3.4 g, 50%).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[S:6][CH:7]=1.[OH:14][C:15]1[CH:36]=[CH:35][C:18]([CH2:19][O:20]/[N:21]=[C:22](/[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)\[CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C.CCCCCC.O>[C:29]1(/[C:22](=[N:21]/[O:20][CH2:19][C:18]2[CH:35]=[CH:36][C:15]([O:14][CH2:2][C:3]3[N:4]=[C:5]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[S:6][CH:7]=3)=[CH:16][CH:17]=2)/[CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: ClCc1csc(-c2ccccc2)n1
Reactant: COC(=O)CC/C(=N\OCc1ccc(O)cc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)CC/C(=N\OCc1ccc(OCc2csc(-c3ccccc3)n2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 63.6 %

Procedure:
A mixture of 4-(chloromethyl)-2-phenylthiazole (368 mg), methyl E-4-(4-hydroxybenzyloxyimino)-4-phenylbutyrate (500 mg), potassium carbonate (442 mg) and N,N-dimethylformamide (10 ml) was stirred at room temperature for 18 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to silica gel chromatography to obtain methyl E-4-phenyl-4-[4-(2-phenyl-4-thiazolylmethoxy)benzyloxyimino]butyrate (494 mg, yield 63%) as a colorless oil from an ethyl acetate-hexane (2:9, v/v)-eluted fraction.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C[Si]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])(C)C.[CH3:21][N:22]1[C:26]([C:27]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][O:37]3)=[CH:31][CH:30]=2)=O)=[CH:25][N:24]=[CH:23]1>C1COCC1>[CH3:21][N:22]1[C:26]([C:27]([C:29]2[CH:30]=[CH:31][C:32]([O:35][CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][O:37]3)=[CH:33][CH:34]=2)=[CH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:25][N:24]=[CH:23]1
Reactant: CCOC(=O)C[Si](C)(C)C
Reactant: Cn1cncc1C(=O)c1ccc(OC2CCCCO2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C=C(c1ccc(OC2CCCCO2)cc1)c1cncn1C
Temperature: -45 °C
Reaction time: 0.33 h
Yield: 118.4 %

Procedure:
To a solution of lithium bis(trimethylsilyl)amide (6.8 mmol, 1 M in THF) was added ethyl trimethylsilylacetate (6.5 mmol) dropwise at −78° C. After 20 minutes at −78° C., a solution of 4.2 (5.9 mmol) in THF (20 mL) was added dropwise. The reaction was maintained at −78° C. for 3 hours and at −45° C. for 2 hours. The reaction was quenched with saturated NH4Cl (aq) at 0° C. and warmed to room temperature. The mixture was extracted with EtOAc (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford crude 4.3 (2.49 g). MS ESI (pos.) m/e 357.2 (M+H).
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]2[C:12]3[CH:13]=[C:14]([C:18]#[C:19][C:20]([OH:23])([CH3:22])[CH3:21])[C:15]([F:17])=[CH:16][C:11]=3[O:10][CH2:9][CH2:8][N:7]2[C:24]=1[C:25]([OH:27])=O)(=[O:3])[NH2:2].[NH2:28][CH:29]1[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]1>>[F:17][C:15]1[C:14]([C:18]#[C:19][C:20]([OH:23])([CH3:22])[CH3:21])=[CH:13][C:12]2[C:6]3[N:7]([C:24]([C:25]([NH:28][CH:29]4[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]4)=[O:27])=[C:4]([C:1]([NH2:2])=[O:3])[N:5]=3)[CH2:8][CH2:9][O:10][C:11]=2[CH:16]=1
Reactant: CC(C)(O)C#Cc1cc2c(cc1F)OCCn1c-2nc(C(N)=O)c1C(=O)O
Reactant: CN1CCC(N)CC1
Product: CN1CCC(NC(=O)c2c(C(N)=O)nc3n2CCOc2cc(F)c(C#CC(C)(C)O)cc2-3)CC1

Procedure:
2-Carbamoyl-9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-3-carboxylic acid (0.05 g) was reacted with 4-amino-1-methylpiperidine similar to as described in Example 2 to afford 17.8 mg of 9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-N3-(1-methyl-4-piperidyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide following reverse phase hplc purification. MS (Q1) 470 (M)+. 1H NMR (400 MHz, DMSO) δ 11.37 (d, J=7.0 Hz, 1H), 8.60 (d, J=8.5 Hz, 1H), 8.39 (s, 1H), 7.88 (s, 1H), 7.02 (d, J=10.6 Hz, 1H), 6.45 (s, 1H), 5.47 (s, 1H), 5.07-4.93 (m, 2H), 4.63-4.46 (m, 2H), 2.98-2.81 (m, 2H), 2.48-2.39 (m, 1H), 2.36 (s, 3H), 1.98-1.87 (m, 2H), 1.65-1.52 (m, 2H), 1.49 (s, 6H).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:19]=[CH:18][C:8]([O:9][C:10]2[S:11][C:12]([C:15]([NH2:17])=[O:16])=[CH:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].Cl[C:21]([S:23]Cl)=[O:22]>C1(C)C=CC=CC=1>[CH:1]([O:4][C:5]1[CH:19]=[CH:18][C:8]([O:9][C:10]2[S:11][C:12]([C:15]3[O:16][C:21](=[O:22])[S:23][N:17]=3)=[CH:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc(Oc2ncc(C(N)=O)s2)cc1
Reactant: O=C(Cl)SCl
Solvent: Cc1ccccc1
Product: CC(C)Oc1ccc(Oc2ncc(-c3nsc(=O)o3)s2)cc1
Yield: 92.3 %

Procedure:
A mixture of Example 100A (1.89 g, 0.0066 mol) and chlorocarbonylsulfenyl chloride (0.64 g, 0.01 mol) in toluene was heated at reflux for 6 hours. The solvent was removed and the residue was purified on silica gel (5˜30% ethyl acetate in hexane) to give 2.05 g of product as an off-white solid (92% yield). 1H NMR (300 MHz, CDCl3) δ ppm 1.36 (d, J=6.25 Hz, 6H) 4.46-4.63 (m, 1H) 6.89-6.98 (m, 2H) 7.14-7.24 (m, 2H) 7.80 (s, 1H). MS (ESI), M/Z: 369.0 (M+32)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:7]([OH:9])=O)([O-:3])=[O:2].[C:15]([C:19]1[CH:34]=[CH:33][C:22]([C:23]([NH:25][C:26]2[C:27]([NH2:32])=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:24])=[CH:21][CH:20]=1)([CH3:18])([CH3:17])[CH3:16]>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:7]([NH:32][C:27]1[C:26]([NH:25][C:23](=[O:24])[C:22]2[CH:33]=[CH:34][C:19]([C:15]([CH3:17])([CH3:16])[CH3:18])=[CH:20][CH:21]=2)=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:9])([O-:3])=[O:2]
Reactant: COc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: CC(C)(C)c1ccc(C(=O)Nc2ccccc2N)cc1
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)c2ccc(C(C)(C)C)cc2)cc1[N+](=O)[O-]
Yield: 0.1 %

Procedure:
Using the procedure described in Example 102, Part A, 3-nitro-4-methoxybenzoic acid (2.8 mmol) and N1-(4-tert-butylbenzoyl)-1,2-benzenediamine (1.9 mmol) yielded 0.70 mg (84%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH:15]=O)[CH:12]=[C:11]([Cl:17])[C:10]=1[F:18])([CH3:4])([CH3:3])[CH3:2].[CH2:20]([NH:22][CH2:23][CH3:24])[CH3:21].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH2:15][N:22]([CH2:23][CH3:24])[CH2:20][CH3:21])[CH:12]=[C:11]([Cl:17])[C:10]=1[F:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCNCC
Reactant: CC(C)(C)OC(=O)NCc1cc(C=O)cc(Cl)c1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCN(CC)Cc1cc(Cl)c(F)c(CNC(=O)OC(C)(C)C)c1
Reaction time: 8 h

Procedure:
A solution of (3-chloro-2-fluoro-5-formyl-benzyl)-carbamic acid tert-butyl ester (200 mg, 0.7 mmol), diethylamine (51 mg, 0.7 mmol) and acetic acid (0.06 mL) in THF (mL) was stirred for 30 min at ambient temperature. After addition of sodium triacetoxyborohydride (368 mg, 1.7 mmol) the reaction was stirred overnight, quenched by addition of saturated aqueous NaHCO3 and extracted with EtOAc. The solvent was removed in vacuo and the residue was purified by RP-preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 30×100 mm, 5-100% CH3CN/H2O/20 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA, flow: 40 mL/min) to give the title compound. MS (LC-MS): 345.0 [M]+; tR (HPLC conditions c): 4.09 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:17]([O:19][CH3:20])=[O:18])[C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH:15]=O)=[CH:11][C:12]=3[C:13]=2[N:14]=1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>CN(C=O)C.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:17]([O:19][CH3:20])=[O:18])[C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH2:15][N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[CH:11][C:12]=3[C:13]=2[N:14]=1
Reactant: COC(=O)c1cc(Br)nc2c1[nH]c1ccc(C=O)cc12
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)c1cc(Br)nc2c1[nH]c1ccc(CN3CCOCC3)cc12
Reaction time: 0.08 h
Yield: 59 %

Procedure:
A suspension of methyl 2-bromo-8-formyl-5H-pyrido[3,2-b]indole-4-carboxylate (200 mg, 0.600 mmol) in DMF (1 mL) was stirred for 5 min and then diluted with DCM (10 mL). Morpholine (0.063 mL, 0.720 mmol) was added and the suspension was cooled in an ice bath. Sodium triacetoxyborohydride (344 mg, 1.62 mmol) was added and the suspension was left stirring for 0.5 hr. Acetic acid (0.069 mL, 1.20 mmol) was then added and the bath removed. The reaction was left stirring at RT overnight. It was diluted with DCM and washed with sat. aq. NaHCO3 solution followed by water (2×). After drying with sodium sulfate, the solvent was removed and radial chromatography (step gradient elution with DCM containing 0 to 3% MeOH) afforded methyl 2-bromo-8-(morpholinomethyl)-5H-pyrido[3,2-b]indole-4-carboxylate (143 mg, 0.354 mmol, 59% yield) as dark green solid. MS (ESI) m/z 436.10 (M+H). 1H NMR (400 MHz, chloroform-d) δ ppm 9.55 (1H, br. s.), 8.27 (1H, s), 7.94 (1H, s), 7.56 (1H, dd, J=8.31, 1.51 Hz), 7.45 (1H, d, J=8.31 Hz), 4.04 (3H, s), 3.66-3.74 (4H, m), 3.64 (2H, s), 2.46 (4H, br. s.).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][CH2:14][NH:13][C:12]2=[O:16])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]>O.[Rh]>[C:1]([NH:4][CH:5]1[CH2:6][CH2:7][CH:8]([N:11]2[CH2:15][CH2:14][NH:13][C:12]2=[O:16])[CH2:9][CH2:10]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(N2CCNC2=O)cc1
Agent: [Rh]
Solvent: O
Product: CC(=O)NC1CCC(N2CCNC2=O)CC1

Procedure:
A mixture of 4213 g of 1-(p-acetamidophenyl)-2-imidazolidinone in 39,000 ml of water and 2930 g of 5% rhodium on carbon 50% wet with water is hydrogenated at 40°. The hydrogenation mixture is filtered, and the filtrate is concentrated in vacuo to dryness. The resulting solid is air-dried and then powdered. The crude product is recrystallized from 12,000 ml of acetone to give 1-(4-acetamidocyclohexyl)-2-imidazolidinone, m.p. 211°-230° as a mixture of cis and trans isomers.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C@@H:9]1[CH2:21][CH2:22][CH2:23][C:24](O)=[O:25])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:10][C@@H:9]1[CH2:21][CH2:22][CH2:23][CH2:24][OH:25])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](CCCC(=O)O)C1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](CCCCO)C1
Reaction time: 8 h

Procedure:
Into a stirred solution of (S)-2-(3-carboxypropyl)-piperazine-1,4-dicarboxylic acid di-tert-butyl ester (0.596 g, 1.60 mmol) in THF add 1.0 M BH3 in THF (3.2 mL, 3.20 mmol) and continue stirring overnight. Concentrate the mixture under reduced pressure, dilute with H2O (30 mL) and extract with EtOAc (3×50 mL). Dry the organic layers with Na2SO4 filter concentrate under reduced pressure, azeotrope the residue with CH2Cl2/hexanes (1:2) and place the residue under vacuum to give the title compound: colorless solid (0.604 g), mass spectrum (m/e):359.12 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2(O)[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl>C1COCC1.O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:19][C:18]3[C:13]([CH:12]=2)=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(C2(O)Cc3ccccc3C2)cc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(C2=Cc3ccccc3C2)cc1
Yield: 63.3 %

Procedure:
To a solution of 2-(4-t-butyl-phenyl)-2-indanol (23.0 g, 86.5 mmol) in THF (200 mL) was added a solution of concentrated hydrochloric acid (40 mL) in water (60 mL). The solid was collected and washed with pentane (50 mL) and then tetrahydrofuran (50 mL) to give 13.6 g of 2-(4-t-butyl-phenyl)-1H-indene. 1H-N.M.R. (CDCl3) d 1.35 (s, 9H), d 3.78(br s, 2H), d 7.13-7.19(m, 2H),d 7.26 (br tt, J=7.4, 0.6 Hz, 1H), d 7.36-7.47(m, 4H), d 7.55-7.6(br d, J=6.7 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[O:14][C@H:13]3[CH2:15][C@H:16]([N:18]4C(=O)C5C(=CC=CC=5)C4=O)[CH2:17][C@H:12]3[CH2:11][O:10]2)=[CH:5][CH:4]=1.NN>CCO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[O:14][C@H:13]3[CH2:15][C@H:16]([NH2:18])[CH2:17][C@H:12]3[CH2:11][O:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C2OC[C@@H]3C[C@@H](N4C(=O)c5ccccc5C4=O)C[C@@H]3O2)cc1
Agent: NN
Solvent: CCO
Product: COc1ccc(C2OC[C@@H]3C[C@@H](N)C[C@@H]3O2)cc1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
A mixture of 2-[(4aS,6R,7aS)-2-(4-methoxyphenyl)-hexahydrocyclopenta[d][1,3]dioxin-6-yl]-1H-isoindole-1,3(2H)-dione (390. mg, 1.03 mmol), EtOH (11.3 mL) and hydrazine (0.0362 mL, 1.13 mmol) was stirred at 90° C. for 18 h. The resulting mixture was purified via silica gel chromatography eluting with a gradient of 10 to 50% MeOH in DCM. LC/MS: Rt=1.08 min, ES+ 250. (AA standard).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:12]([NH2:16])([CH3:15])([CH3:14])[CH3:13]>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:16][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CC(C)(C)N
Solvent: O
Product: CC(C)(C)NS(=O)(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
4-bromobenzenesulfonyl chloride (200 mg, 0.783 mmol) was dissolved in MC (10 ml), followed by dropwise addition of tert-butylamine (0.41 ml, 3.91 mmol) at 0° C., and then the resulting mixture was stirred at room temperature under nitrogen stream for 1 hour. Distilled water (15 ml) was added to the resulting reaction liquid, followed by extraction with MC (30 ml×2). The organic layer was dried over anhydrous sodium sulfate, followed by filtration and concentration, and then the residue thus obtained was dried under vacuum, to obtain 228 mg of white solid (100%).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].C(Cl)(Cl)Cl.[CH3:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[CH:20]([CH2:31][OH:32])[CH2:19]1>C(OCC)(=O)C>[CH3:8][S:9]([O:32][CH2:31][CH:20]1[CH:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19]1)(=[O:11])=[O:10]
Reactant: Cc1ccccc1C1CCN(C)CC1CO
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1ccccc1C1CCN(C)CC1COS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.83 h

Procedure:
At 0° C. 0.45 mL of triethylamine and 0.17 mL of methanesulfonyl chloride were added to chloroform (5 mL) solution of 237 mg of (3SR,4RS)-(1-methyl-4-o-tolylpiperidin-3-yl)-methanol obtained in Production Example 33-1. This was stirred at 0° C. for 50 minutes, diluted with ethyl acetate, washed with aqueous saturated sodium hydrogencarbonate solution, and dried with anhydrous sodium sulfate, and the solvent was evaporated off under reduced pressure to obtain 321 mg of 1-methyl-4-o-tolylpiperidin-3-ylmethyl methanesulfonate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[CH2:8][CH2:7][CH2:6]2.BrC1CCC2C(C=1)=CC=C(OC)C=2.Br[C:28]1[C:33]([N+:34]([O-:36])=[O:35])=[CH:32][CH:31]=[CH:30][C:29]=1[CH3:37]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10]([CH:9]=[C:8]([C:28]3[C:33]([N+:34]([O-:36])=[O:35])=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:37])[CH2:7][CH2:6]2)=[CH:11][CH:12]=1
Reactant: Cc1cccc([N+](=O)[O-])c1Br
Reactant: COc1ccc2c(c1)CCCC2=O
Agent: COc1ccc2c(c1)CCC(Br)=C2
Product: COc1ccc2c(c1)CCC(c1c(C)cccc1[N+](=O)[O-])=C2

Procedure:
Synthesized from 6-methoxy-1-tetralone according to an analogous synthetic method to Preparation Example 106, 3-bromo-7-methoxy-1,2-dihydronaphthalene (2.7 g) and 2-bromo-3-nitrotoluene (4.8 g) were used according to an analogous synthetic method to Preparation Example 107 to provide 7-methoxy-3-(2-methyl-6-nitrophenyl)-1,2-dihydronaphthalene (925 mg). This compound (920 mg) was used according to an analogous synthetic method to Example 30 to provide the title compound (740 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][CH2:6][N:7]1[CH:11]=[C:10]([N+:12]([O-])=O)[CH:9]=[N:8]1>[Pd].CO>[F:1][C:2]1[CH:3]=[C:4]([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([NH2:12])[CH:9]=[N:8]2)[CH:15]=[CH:16][CH:17]=1
Reactant: O=[N+]([O-])c1cnn(CCc2cccc(F)c2)c1
Agent: [Pd]
Solvent: CO
Product: Nc1cnn(CCc2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a round bottom flask 1-(3-fluorophenethyl)-4-nitro-1H-pyrazole (785 mg, 3.34 mmol), Pd/C (79 mg) and MeOH (10.0 mL, degassed) was added. The flask was evacuated and backfilled with H2 and the reaction mixture was stirred under H2-atmosphere at rt for 18 h. The reaction mixture was filtered over celite, washed with MeOH and the solvent was removed under reduced pressure to yield 1-[2-(3-Fluoro-phenyl)-ethyl]-1H-pyrazol-4-ylamine as a red oil which was used without further purification. LC-MS conditions B: tR=0.41 min; [M+MeCN+H]+=247.32.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[C:18]3[NH:20][C:21]([C:23]([C:25]4[CH:30]=[CH:29][N:28]=[C:27](Br)[CH:26]=4)=[O:24])=[N:22][C:17]3=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:32]([O:36][C:37]([N:39]1[C:43]([CH3:44])=[C:42](B2OC(C)(C)C(C)(C)O2)[C:41]([CH3:54])=[N:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33].[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[C:18]3[NH:20][C:21]([C:23]([C:25]4[CH:30]=[CH:29][N:28]=[C:27]([C:42]5[C:41]([CH3:54])=[N:40][N:39]([C:37]([O:36][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:38])[C:43]=5[CH3:44])[CH:26]=4)=[O:24])=[N:22][C:17]3=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nn(C(=O)OC(C)(C)C)c(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3nc(C(=O)c4ccnc(Br)c4)[nH]c3n2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nn(C(=O)OC(C)(C)C)c(C)c1-c1cc(C(=O)c2nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)nc3[nH]2)ccn1
Temperature: 120 °C
Yield: 97.1 %

Procedure:
The mixture of [4-[2-(2-bromo-pyridine-4-carbonyl)-3H-imidazo[4,5-b]pyridine-5-yl]-piperazine-1-carboxylic acid tert-butyl ester (Example 164) (100 mg, 0.205 mmole), 3,5-dimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazole-1-carboxylic acid tert-butyl ester (Example 167) (66 mg, 0.205 mmole), Pd(Ph3)4 (23 mg, 0.021 mmole), 2 molar of K3PO4 aqueous (0.21 ml, 0.41 mmole), and dioxane (3.0 ml) was degassed and heated to 120° C. for 40 minutes in microwave. Reaction solution was diluted with water and extracted with EtOAc. EtOAc layer was concentrated to afford 120 mg of crude 4-{2-[2-(1-tert-butoxycarbonyl-3,5-dimethyl-1H-pyrazol-4-yl)-pyridine-4-carbonyl]-3H-imidazo[4,5-b]pyridin-5-yl}-piperazine-1-carboxylic acid tert-butyl ester, which was dissolved in 3 ml of 2 molar HCl ether solution. The acidic solution was stirred for 2 hours, then solvent was removed. Residue was washed with EtOAc and was purified by using HPLC, eluting with 10 to 20% of acetonitrile in water (0.1% of NH4OH) to yield [2-(3,5-Dimethyl-1H-pyrazol-4-yl)-pyridin-4-yl]-(5-piperazin-1-yl-3H-imidazo[4,5-b]pyridine-2-yl)-methanon (20 mg, 24%) as a yellow solid. 1H NMR (400 MHz, CD3OD) δ 2.41 (s, 6H), 2.94 (m, 4H), 3.61 (m, 4H), 6.88 (d, J=9.03 Hz, 1H), 7.87 (d, J=9.03 Hz, 1H), 7.94 (d, J=5.02 Hz, 1H), 8.17 (s, 1H), 8.76 (d, J=5.02 Hz, 1H). HR-MS m/z 403.1981 (M+1).
Reaction SMILES: Cl.[CH2:2]([C:4]([S:30]([CH3:33])(=[O:32])=[O:31])([CH2:15][CH2:16][N:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:19][C:18]1=[O:29])[C:5]([NH:7][O:8]C1CCCCO1)=[O:6])[CH3:3]>ClCCl.CO>[CH2:2]([C:4]([S:30]([CH3:33])(=[O:32])=[O:31])([CH2:15][CH2:16][N:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:19][C:18]1=[O:29])[C:5]([NH:7][OH:8])=[O:6])[CH3:3]
Reactant: CCC(CCn1ccc(-c2ccccc2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CCC(CCn1ccc(-c2ccccc2)cc1=O)(C(=O)NO)S(C)(=O)=O
Reaction time: 2 h
Yield: 26.4 %

Procedure:
A solution of hydrochloric acid (0.5 mL, 4.0 M in 1,4-dioxane) was added dropwise to a solution of 2-ethyl-2-(methylsulfonyl)-4-(2-oxo-4-phenylpyridin-1(2H)-yl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (45 mg, 0.1 mmol) in dichloromethane (0.5 mL) and methanol (0.1 mL) at 0° C. After 2 h, the reaction was concentrated under reduced pressure. The resulting residue was triturated with diethyl ether, filtered, washed with heptane, and dried under reduced pressure to provide an off-white solid (10 mg, 27%). MS (LCMS) m/z 379.5 (M+1). 1H NMR (400 MHz, CDCl3) δ ppm 0.97 (t, J=7.5 Hz, 3H), 1.86-1.95 (m, 1H), 2.31-2.45 (m, 3H), 3.29 (s, 3H), 3.99-4.08 (m 1H), 4.53-4.63 (m, 1H), 6.69 (br d, J=5.6 Hz, 1H), 6.99 (br s, 1H), 7.44-7.49 (m, 4H), 7.55-7.60 (m, 2H).