Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]2([CH2:21][NH:22][C:23](=[O:28])[CH2:24][CH2:25][CH2:26]Cl)[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].O>CN(C)C=O>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]2([CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][C:23]3=[O:28])[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCCCl)NCC1(CCN2CCN(Cc3ccccc3)CC2)CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCCN1CC1(CCN2CCN(Cc3ccccc3)CC2)CCCC1
Temperature: 70 °C
Reaction time: 5 h

Procedure:
To a stirred solution of N-[[1-[2-(4-benzyl-1-piperazinyl)ethyl]cyclopentyl]methyl]-4-chlorobutanamide (664 mg) in dimethylformamide(5.5 ml) was added sodium hydride(60% in oil, 98 mg) at room temperature and the mixture was stirred at 70° C. for 5 hours. After cooling down, water (3 ml) was added and the organic layers were extracted with ethyl acetate (15 ml). The extract was washed with brine (4 ml), dried over magnesium sulfate filtered and concentrated in vacuo. The residue was purified by column chromatography (NH2 gel, 230-400 mesh/20 g/hexane:ethyl acetate=2:1-1:2) to give a yellow oil (408 mg/67%).
Reaction SMILES: [F:1][C:2]1([F:56])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[CH:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=4)[CH2:15][C:14]([CH3:29])([CH3:28])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:35][CH2:34][N:33]([C:36]4[N:41]=[CH:40][C:39]([CH2:42][OH:43])=[CH:38][N:37]=4)[CH2:32][CH2:31]3)[C:9]=2[CH:44]([F:55])[C:45]2[CH:50]=[CH:49][C:48]([C:51]([F:54])([F:53])[F:52])=[CH:47][CH:46]=2)[CH2:4][CH2:3]1.[CH3:57]O>>[F:56][C:2]1([F:1])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[CH:16]([O:18][CH2:19][C:20]4[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=4)[CH2:15][C:14]([CH3:28])([CH3:29])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:31][CH2:32][N:33]([C:36]4[N:41]=[CH:40][C:39]([CH2:42][O:43][CH3:57])=[CH:38][N:37]=4)[CH2:34][CH2:35]3)[C:9]=2[CH:44]([F:55])[C:45]2[CH:46]=[CH:47][C:48]([C:51]([F:53])([F:52])[F:54])=[CH:49][CH:50]=2)[CH2:4][CH2:3]1
Reactant: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCN(c5ncc(CO)cn5)CC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Reactant: CO
Product: COCc1cnc(N2CCC(c3nc4c(c(C5CCC(F)(F)CC5)c3C(F)c3ccc(C(F)(F)F)cc3)C(OCc3ccc(OC)cc3)CC(C)(C)C4)CC2)nc1

Procedure:
Reactions similar to those of Reference Example 21 were performed except for using methanol instead of ethanol, and from 72 mg (0.092 mmol) of 4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-[1-[5-(hydroxymethyl)pyrimidin-2-yl]piperidin-4-yl]-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 17, 48 mg of the title compound was obtained as a foam (yield: 66%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.[C:6]([O:10][C:11]([N:13]1[CH2:19][CH2:18][CH2:17][N:16]([C:20]2[N:24]([CH2:25][CH2:26]OS(C)(=O)=O)[C:23]3[CH:32]=[CH:33][CH:34]=[CH:35][C:22]=3[N:21]=2)[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]>>[C:6]([O:10][C:11]([N:13]1[CH2:19][CH2:18][CH2:17][N:16]([C:20]2[N:24]([CH2:25][CH2:26][N:1]3[CH:5]=[CH:4][N:3]=[N:2]3)[C:23]3[CH:32]=[CH:33][CH:34]=[CH:35][C:22]=3[N:21]=2)[CH2:15][CH2:14]1)=[O:12])([CH3:7])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3n2CCOS(C)(=O)=O)CC1
Reactant: c1c[nH]nn1
Product: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3n2CCn2ccnn2)CC1

Procedure:
Prepare by the method of Preparation 28 using triazole (0.045 g, 1.13 mmol) and 1-(t-butoxycarbonyl)-4-(1-(2-methanesulfonyloxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (0.33 g, 0.75 mmol) to give 1-(t-butoxycarbonyl)-4-(1-(2-(1H-triazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepane: Rf=0.32 (silica gel, 5% methanol/dichloromethane/0.5% concentrated aqueous ammonia).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:11]=[C:12]([NH:16][C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])[CH:13]=[CH:14][CH:15]=2)[CH2:6][CH2:5]1.[C:22]1([CH:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:29](Cl)=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1>[C:32]1([CH:28]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:29]([NH:1][CH2:2][CH2:3][N:4]2[CH2:9][CH2:8][CH:7]([C:10]3[CH:11]=[C:12]([NH:16][C:17](=[O:21])[CH:18]([CH3:19])[CH3:20])[CH:13]=[CH:14][CH:15]=3)[CH2:6][CH2:5]2)=[O:30])[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCN)CC2)c1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCNC(=O)C(c3ccccc3)c3ccccc3)CC2)c1
Temperature: 23 °C
Reaction time: 8 h
Yield: 23.6 %

Procedure:
A mixture of N-{3[1-(2-aminoethyl)-4-piperidinyl]phenyl}-2-methylpropanamide (20.0 mg, 0.0700 mmol), diphenylacetyl chloride (23.0 mg, 0.110 mmol), and TEA (20.0 mg, 0.140 mmol) in THF (2 mL) was stirred overnight at 23° C. The crude product was purified by preparative TLC using CH2Cl2/MeOH/isopropyl amine (19:1:0.2) to give the desired product (8.0 mg, 47%). 1H NMR (400 MHz, CDCl3) δ 7.53 (s, 1H) 7.37–7.20 (m, 13H), 6.97–6.92 (m, 1H) 6.67 (s, 1H) 4.98 (s, 1H), 3.43 (q, 2H, J=5.9 Hz), 2.90 (d, 2H, J=11.6 Hz), 2.57–2.42 (m, 4H), 2.11 (t, 2H, J=10.4 Hz), 1.75 (d, 2H, J=12.4 Hz), 1.70–1.58 (m, 2H), 1.25 (d, 6H, J=6.7 Hz); ESMS m/e: 484.2 (M+H)+.
Reaction SMILES: [CH2:1](O)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:23][C:24]1[C:28]2=[N:29][CH:30]=[CH:31][CH:32]=[C:27]2[NH:26][N:25]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.O.C1(C)C=CC=CC=1>[Br:23][C:24]1[N:25]([CH2:1][CH3:2])[N:26]=[C:27]2[CH:32]=[CH:31][CH:30]=[N:29][C:28]=12
Reactant: CCO
Reactant: Brc1n[nH]c2cccnc12
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: CCn1nc2cccnc2c1Br
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a solution of ethanol (0.118 ml) and triphenylphosphine (530 mg) in THF (3 ml) was added 3-bromo-1H-pyrazolo[4,3-b]pyridine (200 mg), and the mixture was heated at 50° C. A toluene solution (1.9 M, 1.06 ml) of DIAD was added dropwise at 50° C., and the mixture was stirred for 30 min. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (71 mg).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]([NH:12][C:13]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:16](=[O:23])[O:15][N:14]=1)([CH:9]([CH3:11])[CH3:10])[C:5]([O:7]C)=O.[O:24]1CCCC1.S(=O)(=O)(O)O>O.C(Cl)Cl>[OH:15][N:14]1[C:5](=[O:7])[C:4]([CH:9]([CH3:11])[CH3:10])([CH3:3])[N:12]=[C:13]1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:16]([OH:23])=[O:24]
Reactant: C1CCOC1
Reactant: COC(=O)C(C)(Nc1noc(=O)c2ccccc12)C(C)C
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC(C)C1(C)N=C(c2ccccc2C(=O)O)N(O)C1=O
Temperature: 45 °C
Reaction time: 36 h
Yield: 76 %

Procedure:
Sodium hydroxide (0.58 g, 0.0145 mol) in water is added to a solution of methyl 2,3-dimethyl-2-[(1-oxo-2,3-benzoxazin-4-yl)amino]butyrate (2.0 g, 0.00689 mol) and tetrahydrofuran under a nitrogen atmosphere. The reaction mixture is stirred at 45° C. for 36 hours then at room temperature for 6 days. The reaction mixture is concentrated in vacuo to give an oil. The oil is dissolved into water. The aqueous solution is cooled with an ice-bath and concentrated sulfuric acid is added until a pH of about 1 is obtained then the solution is extracted with ethyl acetate. The combined ethyl acetate extracts are dried with anhydrous magnesium sulfate and concentrated in vacuo to give a pale yellow solid. The solid is added to boiling methylene chloride and after 2/3 of the methylene chloride has evaporated, the mixture is filtered to give the title compound as a white solid (1.44 g, 76%), mp 186°-188° C., identified by IR and NMR spectral analyses.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][NH:11]2)[OH:9])=[CH:4][CH:3]=1.[CH3:16][N:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1>>[CH3:16][N:17]1[CH2:22][CH2:21][C:20]2([N:11]3[CH2:12][CH2:13][CH2:14][CH2:15][CH:10]3[CH:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[O:9]2)[CH2:19][CH2:18]1
Reactant: OC(c1ccc(Cl)cc1)C1CCCCN1
Reactant: CN1CCC(=O)CC1
Product: CN1CCC2(CC1)OC(c1ccc(Cl)cc1)C1CCCCN12

Procedure:
Utilizing the procedure described in Example 1 above, alpha-(4-chlorophenyl)-2-piperidinemethanol (10 g) is reacted with 1-methyl-4-piperidone (7 g) to yield hexahydro-1'-methyl-1-(4-chlorophenyl)spiro[3H-oxazolo[3,4-a]pyridine-3,4'-piperidine]; mp 122°-124° C., after chromatography over silica gel with ethyl acetate.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[C:9](O)=[O:10])[CH:5]=[CH:4][CH:3]=[N:2]1.S(Cl)(Cl)=O.C[N:20](C=O)C.C([O-])(=O)C.[NH4+]>C1C=CC=CC=1>[N:1]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[C:9]([NH2:20])=[O:10])[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: CN(C)C=O
Reactant: O=C(O)c1cccc(-n2cccn2)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: NC(=O)c1cccc(-n2cccn2)c1
Yield: 80 %

Procedure:
To a suspension of 3-(1H-pyrazol-1-yl)-benzoic acid [see WO 00/21951] (104 g, 0.55 mol) in anhydrous benzene (500 ml) was added thionyl chloride (85 g, 0.715 mol) and DMF (0.5 ml). The mixture was heated at reflux for 3 hours, then evaporated under reduced pressure. The residue was dissolved in anhydrous THF (100 ml) and evaporated. The residue was dissolved in anhydrous acetone (600 ml), and treated with ammonium acetate (77 g, 1 mol). The mixture was heated at reflux for 12 hours, solvent was evaporated and the residue treated with cold water (2000 ml). The resulting precipitate was filtered, washed with cold water (200 ml) and recrystallised from absolute ethanol (600 ml) to give 3-(1H-pyrazol-1-yl)benzamide (82 g, 80%). A solution of this material (82 g, 0.44 mol) in THF was added dropwise to a solution of LiAlH4 (25 g, 0.66 mol) in anhydrous THF (800 ml). The mixture was heated at reflux for 4 hours, cooled and quenched by the sequential addition of water (25 ml), 15% aqueous NaOH (25 ml), and water (50 ml). The inorganic by-products were filtered off and washed several times with diethyl ether (overall volume 1000 ml). The combined filtrates were dried over Na2SO4, filtered and evaporated. The residue was dissolved in methanol (400 ml), the solution was treated with activated carbon (10 g), and the mixture was refluxed for 40 minutes, then filtered and evaporated. The residue was treated with 1N HCl in ether (1000 ml), and the precipitate formed was filtered, washed with ether and dried to give the title compound (53 g, 70%).
Reaction SMILES: [C:1](Cl)(=O)C.[CH2:5]([O:7][C:8]1[CH:9]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]=[CH:21][C:22](=[O:26])[C:23]([OH:25])=[O:24])=[CH:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)[CH3:6]>CO>[CH3:1][O:24][C:23](=[O:25])[C:22](=[O:26])[CH:21]=[CH:20][C:17]1[CH:18]=[CH:19][C:14]([C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([O:7][CH2:5][CH3:6])[CH:9]=2)=[CH:15][CH:16]=1
Reactant: CC(=O)Cl
Reactant: CCOc1cccc(-c2ccc(C=CC(=O)C(=O)O)cc2)c1
Solvent: CO
Product: CCOc1cccc(-c2ccc(C=CC(=O)C(=O)OC)cc2)c1
Yield: 38.4 %

Procedure:
Acetyl chloride (2.0 mL, 28.7 mmol) was slowly added to methanol (10.0 mL) at 0° C. under stirring. A solution of 4-(3′-ethoxy-biphenyl-4-yl)-2-oxo-3-butenoic acid (2.5 g, 8.4 mmol) prepared in Step 2 in methanol (10.0 mL) was added to the reaction mixture at room temperature. The reaction mixture was stirred at room temperature for 1 hour, additionally at 80° C. for 16 hours, and then filtered at room temperature to give 1.0 g of the titled compound as a yellow solid.
Reaction SMILES: COC1C=CC(C[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([OH:19])[CH:17]=[CH2:18])=CC=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[CH2:18]=[CH:17][CH:16]([OH:19])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][OH:8]
Reactant: C=CC(O)CCCCCCCOCc1ccc(OC)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: C=CC(O)CCCCCCCO

Procedure:
To an aqueous solution of 10-((4-methoxybenzyl)oxy)-1-decene-3-ol (590 mg, 2.02 mmol, 1.00 eq.) in methylene chloride (20.0 mL) and saturated sodium bicarbonate (10.0 mL), was added DDQ (687 mg, 3.03 mmol, 1.50 eq.) at room temperature. The mixture was allowed to react at the same temperature for 5 hours, and then the reaction solution was poured into 10% aqueous sodium thiosulfate solution. The organic phase was extracted with ethyl acetate, and then the resulting organic phase was washed with 10% aqueous sodium thiosulfate solution, a saturated aqueous sodium bicarbonate solution, and a saturated salt solution. The washed organic phase was dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=70:30) to obtain 1-decene-3,10-diol as shown below (324 mg, 1.88 mmol, 93%).
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([C:11]([OH:13])=[O:12])[OH:10])[OH:8])[OH:6])[OH:4].[NH2:14][C@H:15]([C:23]([OH:25])=[O:24])[CH2:16][CH2:17][CH2:18][NH:19][C:20]([NH2:22])=[O:21]>[Ni]>[C:11]([CH:9]([OH:10])[CH:7]([OH:8])[CH:5]([OH:6])[CH:3]([OH:4])[CH2:2][NH:14][C@H:15]([C:23]([OH:25])=[O:24])[CH2:16][CH2:17][CH2:18][NH:19][C:20]([NH2:22])=[O:21])([OH:13])=[O:12]
Reactant: NC(=O)NCCC[C@H](N)C(=O)O
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(=O)O
Agent: [Ni]
Product: NC(=O)NCCC[C@H](NCC(O)C(O)C(O)C(O)C(=O)O)C(=O)O

Procedure:
The product was made from D-glucuronic acid and L-(+)-citrulline using Raney nickel as a catalyst under the conditions of the above example. A brownish, highly viscous oil was obtained.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:9]=[N:10][C:11]([S:14]([CH3:17])(=O)=O)=[N:12][CH:13]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24]C(S)=[CH:22][CH:21]=1>C(C(C)=O)C>[Cl:7][C:8]1[CH:9]=[N:10][C:11]([S:14][C:17]2[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)=[N:12][CH:13]=1
Reactant: COc1ccc(S)cc1
Reactant: CS(=O)(=O)c1ncc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COc1ccc(Sc2ncc(Cl)cn2)cc1
Yield: 96.7 %

Procedure:
Potassium carbonate (5.8 g) was added to a solution of 5-chloro-2-methylsulphonylpyrimidine (6.7 g) and 4-methoxythiophenol (5.0 g) in methyl ethyl ketone (50 ml) and the mixture was stirred and boiled under reflux for 3 hours. The solvent was evaporated under reduced pressure and the residue partitioned between chloroform and 5% sodium hydroxide aqueous solution. The chloroform extracts were dried (Mg SO4) and evaporated under reduced pressure to give 5-chloro-2-(4-methoxyphenylthio)pyrimidine (8.5 g) as a colourless solid, m.p. 75° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH2:20][C:21]([OH:23])=[O:22])(=[O:19])=[O:18])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:24](C1C=CC(S(C2C=CC(CC(O)=S)=CC=2)(=O)=O)=CC=1)C>>[CH2:1]([C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH2:20][C:21]([OH:23])=[O:22])(=[O:19])=[O:18])=[CH:13][CH:12]=2)(=[O:9])=[O:10])=[CH:4][CH:3]=1)[CH3:24]
Reactant: CCc1ccc(S(=O)(=O)c2ccc(CC(O)=S)cc2)cc1
Reactant: Cc1ccc(S(=O)(=O)c2ccc(S(=O)(=O)CC(=O)O)cc2)cc1
Product: CCc1ccc(S(=O)(=O)c2ccc(S(=O)(=O)CC(=O)O)cc2)cc1

Procedure:
The intended 4-(4-ethylphenylsulfonyl)phenylsulfonyl acetic acid was prepared in the same manner as in the synthesis of 4-(4-methylphenylsulfonyl)phenylsulfonyl acetic acid of Example 6 except that 104 g of 4-(4-ethylphenylsulfonyl)phenylthio acetic acid was used in place of 100 g of 4-(4-methylphenylsulfonyl)phenylthio acetic acid. The yield was 97.1 g. NMR (heavy methanol): δ8.3-8.1 (m, 4H), 7.9 (d, 2H), 7.4 (d, 2H), 4.4 (s, 2H), 2.7 (q, 2H), 1.2 (t, 3H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([Cl:14])[N:3]=1.Cl.[Sn].[NH4+].[OH-]>C(O)(=O)C>[Cl:14][C:4]1[N:3]=[CH:2][C:11]2[C:6]([CH:5]=1)=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2
Reactant: COc1ccc2cc(Cl)nc(Cl)c2c1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COc1ccc2cc(Cl)ncc2c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 20.7 %

Procedure:
1,3-dichloro-7-methoxyisoquinoline (1.14 g, 5.00 mmol) was suspended in glacial acetic acid (6 mL) and concentrated HCl (2 mL), then treated with tin powder (1.77 g, 15.0 mmol) and stirred at 60° C. for 3 hours. The resulting mixture was basified to pH=9 with concentrated NH4OH and then extracted with ethyl acetate (10 mL×3). The combined organic layer was washed with saturated NaHCO3 solution (20 mL), dried over Na2SO4 and concentrated in vacuo, followed by silica gel column (EtOAc/PE=20:1) to give Intermediate 12 (200 mg, yield 21%) as a solid. 1H NMR (DMSO 300 MHz): δ 9.00 (s, 1H), 7.94 (s, 1H), 8.87 (d, J=9.0 Hz, 1H), 7.53 (d, J=2.7 Hz, 1H), 7.46 (dd, J=9.0, 2.7 Hz, 1H), 3.89 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[N:12][C:13]([C:16]#[N:17])=[CH:14][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].OS([O-])(=O)=O.[K+].CO>[Pd].O>[NH2:17][CH2:16][C:13]1[N:12]=[CH:11][C:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(C#N)nc1
Agent: [Pd]
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1ccc(CN)nc1
Temperature: 25 °C

Procedure:
Add 3-(tert-butoxycarbonylamino-methyl)-6-cyano-pyridine (10.81 g, 46.4 mmol), KHSO4 (18.9 g, 16.2 mmol), 5% Pd/C (Degussa type E101, 4 g) to a mixture of methanol (250 mL) and water (20 mL) in a pressure vessel. Flush the vessel three times with hydrogen and charge with hydrogen to 50 psi. Stir at room temperature, recharging to 50 psi hydrogen as necessary, until no change in pressure is observed. Add an aqueous NaOH solution (6.11 g of NaOH in 20 mL of water) to the mixture and stir for 15 min. Filter the mixture through glass microfiber filter paper. Dilute the filtrate with water and DCM. Separate the layers, and extract the aqueous layer with DCM. Wash the combined organic extracts with water and brine. Dry the organic solution over Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel (600 g) eluting with DCM/(chloroform:methanol:concentrated NH4OH 80:18:2) (1:0 to 7:3 gradient) to obtain 6-aminomethyl-3-(tert-butoxycarbonylamino-methyl)-pyridine as a clear oil [3.4 g, 31%, MS (ES+) m/z: 238 (M+H)+] and the desired intermediate 3-(tert-butoxycarbonylamino-methyl)-6-hydroxymethyl-pyridine as colorless oil (5.6 g, 52%). MS (ES+) m/z: 239 (M+H)+.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][NH:9][C:10]1[CH:15]=[C:14]([CH:16]([OH:39])[C:17]2[C:22]([NH:23][S:24]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[C:29]([C:34]([F:37])([F:36])[F:35])[CH:28]=3)(=[O:26])=[O:25])=[CH:21][C:20]([Cl:38])=[CH:19][N:18]=2)[CH:13]=[CH:12][N:11]=1)(C)(C)C>O=[Mn]=O.O1CCOCC1>[Cl:38][C:20]1[CH:21]=[C:22]([NH:23][S:24]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[C:29]([C:34]([F:35])([F:36])[F:37])[CH:28]=2)(=[O:26])=[O:25])[C:17]([C:16]([C:14]2[CH:13]=[CH:12][N:11]=[C:10]([NH:9][CH2:8][CH2:7][OH:6])[CH:15]=2)=[O:39])=[N:18][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)Nc2cc(Cl)cnc2C(O)c2ccnc(NCCO[Si](C)(C)C(C)(C)C)c2)cc1C(F)(F)F
Agent: O=[Mn]=O
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)Nc2cc(Cl)cnc2C(=O)c2ccnc(NCCO)c2)cc1C(F)(F)F
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To the dioxane (1 mL) solution of N-[2-({2-[2-(tert-butyl-dimethyl-silanyloxy)-ethylamino]-pyridin-4-yl}-hydroxy-methyl)-5-chloro-pyridin-3-yl]-4-methyl-3-trifluoromethyl-benzenesulfonamide from step 1, was added MnO2 (440 mg, 5 mmol). The mixture was stirred at 80° C. for 1 hour, filtered, concentrated. The deprotection was performed in 4 M HCl in dioxane (4 mL) and water (1 mL) for 1 hour at RT. The solvent was evaporated and the residue was purified with HPLC to give N-{5-chloro-2-[2-(2-hydroxy-ethylamino)-pyridine-4-carbonyl]-pyridin-3-yl}-4-methyl-3-trifluoromethyl-benzenesulfonamide: 1H NMR (400 MHz, CDCl3) δ 8.3 (s, 1H), 8.15 (d, 2H), 8.05 (s, 1H), 7.9 (d, 1H), 7.4 (d, 1H), 6.7 (m, 2H), 3.8 (m, 2H), 3.5 (m, 2H), 2.5 (s, 3H); MS m/z: 515 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:33]=[C:34]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]2[C:23](=[O:24])[C:22]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[CH:21][NH:20][CH:19]=2)=[O:17])=[CH:11][C:10]=1[F:32].[BH4-].[Na+]>CCO.C1COCC1>[CH:34]([NH:33][C:3]1[C:2]([Cl:1])=[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[C:23](=[O:24])[C:22]([C:25]4[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=4)=[CH:21][NH:20][CH:19]=3)=[O:17])=[CH:11][C:10]=2[F:32])[CH:6]=[CH:5][N:4]=1)([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: O=C(Nc1ccc(Oc2ccnc(N=C(c3ccccc3)c3ccccc3)c2Cl)c(F)c1)c1c[nH]cc(-c2ccc(F)cc2)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(Nc1ccc(Oc2ccnc(NC(c3ccccc3)c3ccccc3)c2Cl)c(F)c1)c1c[nH]cc(-c2ccc(F)cc2)c1=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 94.5 %

Procedure:
To a solution of N-(4-(3-chloro-2-(diphenylmethyleneamino)pyridin-4-yloxy)-3-fluorophenyl)-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxamide (Preparation 1G, 127 mg, 0.2 mmol) in EtOH (5 mL) and THF (5 mL) at 0° C., was added NaBH4 (300 mg, 7.93 mmol). The mixture was stirred at 0° C. for 3 h, and then at rt overnight. The reaction was quenched with water, extracted with DCM, and dried over MgSO4. After filtration and concentration in vacuo, 120 mg of the desired material was obtained as a white solid. MS (ESI+) m/z 635 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[CH:24]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH2:25].C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:19]([N:18]1[C:14]([C:12]2[N:13]=[C:6]3[N:7]([CH2:8][CH2:9][O:10][C:4]4[CH:3]=[C:2](/[CH:25]=[CH:24]/[S:26]([NH2:29])(=[O:28])=[O:27])[CH:23]=[CH:22][C:5]=43)[CH:11]=2)=[N:15][CH:16]=[N:17]1)([CH3:21])[CH3:20]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Reactant: C=CS(N)(=O)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(/C=C/S(N)(=O)=O)cc1OCC2
Temperature: 130 °C
Yield: 35.2 %

Procedure:
8-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene 194 (400 mg, 1.07 mmol), ethenesulfonic acid amide (172 mg, 1.60 mmol), triethylamine (223 μL, 1.60 mmol), tri-o-tolyl-phosphane (65 mg, 0.21 mmol) and palladium (II) acetate (12 mg, 0.05 mmol) were suspended in DMF (5 mL) and the reaction mixture degassed by bubbling argon through the suspension. The reaction mixture was heated at 130° C. for 16 h, before cooling to RT and diluting the mixture with ethyl acetate (10 mL). The resultant mixture was washed with water, extracted with ethyl acetate (2×10 mL) and the combined organic extracts washed with brine, dried (MgSO4) then concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, eluting with 0-10% methanol in DCM) to yield the title compound as a white solid (151 mg, 35%) LCMS: RT=2.69 min, [M+H]+=401.