Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[CH:9][C:8](=[O:18])[C:4]([C:5]([OH:7])=[O:6])=[C:3]1[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1.[OH-].[Na+:27]>CO>[CH3:1][N:2]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)=[CH:9][C:8](=[O:18])[C:4]([C:5]([O-:7])=[O:6])=[C:3]1[C:19]1[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=1.[Na+:27]
Reactant: Cn1c(-c2ccc(F)cc2)cc(=O)c(C(=O)O)c1-c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1c(-c2ccc(F)cc2)cc(=O)c(C(=O)[O-])c1-c1ccc(F)cc1
Yield: 84.4 %

Procedure:
3.45 gms of 1-methyl-2,6-di(4'-fluorophenyl)-4-oxonicotinic acid was mixed with 0.445 gms of NaOH and 70 mls of methanol. Evaporation of the solvent provided 3.1 gms of sodium 1-methyl-2,6-di(4'-fluorophenyl)-4-oxonicotinate as a glassy solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]=[N:18][S:19]([CH:22]=[CH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:21])=[O:20])=[C:9]1[CH3:30])([CH3:4])([CH3:3])[CH3:2].[CH:32]([Mg]Br)=[CH2:33]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:31])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]([NH:18][S:19]([CH:22]=[CH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:21])=[O:20])[CH:32]=[CH2:33])=[C:9]1[CH3:30])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(C=NS(=O)(=O)C=Cc2ccccc2)c2ccccc2n1CC(=O)OC(C)(C)C
Reactant: C=C[Mg]Br
Solvent: Cc1ccccc1
Product: C=CC(NS(=O)(=O)C=Cc1ccccc1)c1c(C)n(CC(=O)OC(C)(C)C)c2ccccc12
Temperature: 0 °C

Procedure:
The product of step b) (2.2 g, 5 mmol) was treated with 100 mL toluene. The slurry was stirred at 0° C. and treated with Me3AI (3.8 mL of 2 M in toluene) followed by vinyl magnesium bromide (10 mL of 1 M). The reaction was warmed to rt and stirred for 10 minutes. The reaction was cooled to 0° C., quenched with aqueous acetic acid, and partitioned between water and EtOAc (200 mL each). The organic layer was washed with 1 M NaOH, dried over MgSO4 and purified over silica gel (30% EtOAc/Hex) to give 1.25 g of the sub-title compound as an oil.
Reaction SMILES: [O:1]([CH:8]([CH3:13])[C:9](=[N:11]O)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>CCOCC>[O:1]([CH:8]([CH:9]([NH2:11])[CH3:10])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=NO)C(C)Oc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CC(N)C(C)Oc1ccccc1
Reaction time: 4 h

Procedure:
A solution of 3-phenoxybutan-2-one oxime (28.8 g.) in dry ether (150 ml.) was added dropwise, over 45 minutes, to a stirred, refluxing mixture of lithium aluminium hydride (6.3 g.) in dry ether (100 ml.). Stirring and heating were continued for 4 hours and the mixture was cooled and treated cautiously with water (6.3 ml.) followed by 15% aqueous sodium hydroxide (6.3 ml.), and finally, water (18.9 ml.). The mixture was stirred for 30 minutes and then filtered. The filtrate was extracted with 2N-hydrochloric acid (150 ml.) and the acid extract was made strongly basic with sodium hydroxide and extracted with ether. The ether extract was dried over anhydrous potassium carbonate, evaporated, and distilled to give a fraction, b.p. 118°-124°/14 mm. Redistillation gave pure 2-phenoxybut-3-ylamine, b.p. 116°-118°/14 mm.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.[CH:16]([NH2:18])=[O:17]>O>[OH:1][C:2]1[CH:3]=[C:4]([CH:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:18][CH:16]=[O:17])[CH:13]=[CH:14][CH:15]=1
Reactant: O=C(c1ccccc1)c1cccc(O)c1
Reactant: NC=O
Solvent: O
Product: O=CNC(c1ccccc1)c1cccc(O)c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 4525.6 %

Procedure:
3-Hydroxybenzophenone (25 g, 126.1 mmol) in formamide (130 mL, 3.3 mmol) was heated to 180° C. for 18 hours. The reaction was allowed to cool slightly then poured into ice-cooled water and stirred for 30 minutes, filtered and washed with water. The solid was stirred in water (60 mL) and ethanol (60 mL) and heated to 50° C. for 1 hour, then allowed to cool. The solid was filtered and washed with water to give the title compound as a brown solid (33.94 g, 118%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[CH:13][N:14]=[C:15](Cl)[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(#N)C>[CH2:1]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[CH:13][N:14]=[C:15]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: Clc1ncnc2c1CN(Cc1ccccc1)CC2
Solvent: CC#N
Product: c1ccc(CN2CCc3ncnc(Nc4ccccc4)c3C2)cc1
Temperature: 180 °C

Procedure:
6-Benzyl-4-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (Intermediate 2, 1.0 g, 3.86 mmol) was dissolved in anhydrous acetonitrile (3 mL) and aniline was added (0.39 mL, 4.24 mmol). The mixture was heated at 180° C. for 600 s in a microwave (Emrys Optimizer model, Personal Chemistry). The solvents were removed under vacuum to give the desired product as a beige powder (1.5 g, quant.). The crude product was used as such for the subsequent step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:14][N:13]([CH3:15])[CH2:12][CH2:11][C:7]=3[NH:8][C:9]=2[CH:10]=1.N1CCC[C@H]1C(O)=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[CH:33]=[C:34]([C:36]1[CH:37]=[CH:38][C:39]([CH3:42])=[N:40][CH:41]=1)[CH3:35]>CN(C=O)C.[Cu]I>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:14][N:13]([CH3:15])[CH2:12][CH2:11][C:7]=3[N:8](/[CH:33]=[C:34](/[C:36]3[CH:41]=[N:40][C:39]([CH3:42])=[CH:38][CH:37]=3)\[CH3:35])[C:9]=2[CH:10]=1
Reactant: CN1CCc2[nH]c3cc(Cl)ccc3c2C1
Reactant: CC(=CBr)c1ccc(C)nc1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C/C(=C\n1c2c(c3ccc(Cl)cc31)CN(C)CC2)c1ccc(C)nc1
Temperature: 80 °C

Procedure:
7-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (176 mg, 0.8 mmol) was dissolved in DMF (5 mL). Copper (I) iodide (19 mg, 0.10 mmol), L-proline (23 mg, 0.20 mmol) and potassium phosphate (424 mg, 2.00 mmol) were added and the reaction mixture was stirred for min. at RT. 5-(1-Bromoprop-1-en-2-yl)-2-methylpyridine (212 mg, 1 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated overnight at 80° C. (prolonged heating in some cases was required). DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh). The product was further purified by HPLC. 1H NMR (CDCl3, TFA salt) δ (ppm): 9.10 (s, 1H), 8.30 (d, 1H), 7.65 (d, 1H), 7.38 (d, 1H), 7.18 (d, 1H), 7.10 (m, 2H), 4.80 (d, 1H), 4.18 (d, 1H), 3.90 (m, 1H), 3.30 (m, 2H), 3.10 (s, 3H), 2.98 (m, 1H), 2.82 (s, 3H), 2.05 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:20]2[C:19]([CH3:21])=[CH:18][N:17]=[C:16]([NH2:22])[C:15]=2[N:14]=[C:13]1[CH2:23][O:24][CH2:25][CH3:26]>>[NH2:22][C:16]1[C:15]2[N:14]=[C:13]([CH2:23][O:24][CH2:25][CH3:26])[N:12]([CH2:11][CH2:10][CH2:9][CH2:8][NH:7][C:3](=[O:4])[N:2]([CH3:6])[CH3:1])[C:20]=2[C:19]([CH3:21])=[CH:18][N:17]=1
Reactant: CN(C)C(=O)Cl
Reactant: CCOCc1nc2c(N)ncc(C)c2n1CCCCN
Product: CCOCc1nc2c(N)ncc(C)c2n1CCCCNC(=O)N(C)C

Procedure:
Using the method of Examples 147-164, dimethylcarbamyl chloride was reacted with 1-(4-aminobutyl)-2-(ethoxymethyl)-7-methyl-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired compound. The observed accurate mass was 349.2334.
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH3:14])=[CH:10][C:9]([CH2:15][CH2:16][CH:17]=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][N:29]([CH2:17][CH2:16][CH2:15][C:9]2[CH:10]=[C:11]([CH2:12][CH2:13][CH3:14])[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=2)[CH2:28][CH2:27]1
Reactant: CCCc1cc(CCC=O)nn1-c1ccccc1
Reactant: Fc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(CCCN2CCN(c3ccccc3F)CC2)nn1-c1ccccc1

Procedure:
96 mg (66%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-5-propyl-1H-pyrazol-3-yl)propanal (80 mg, 0.330 mmol), 1-(2-fluorophenyl)piperazine (59 mg, 0.330 mmol), DIPEA (0.090 mL, 0.495 mmol) and NaBH(OAc)3 (210 mg, 0.990 mmol).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C@H:8]1[CH2:13][CH2:12][C@@H:11]([N:14]=[N+:15]=[N-:16])[CH2:10][C@H:9]1[CH2:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([S:27][CH3:28])=[CH:23][CH:22]=1)(=[O:20])=[O:19])([CH3:4])([CH3:3])[CH3:2].[CH3:30][Si]([N-][Si](C)(C)C)(C)C.[K+].COS(OC)(=O)=O>C1COCC1>[C:1]([O:5][C:6](=[O:29])[N:7]([C@H:8]1[CH2:13][CH2:12][C@@H:11]([N:14]=[N+:15]=[N-:16])[CH2:10][C@H:9]1[CH2:17][S:18]([C:21]1[CH:22]=[CH:23][C:24]([S:27][CH3:28])=[CH:25][CH:26]=1)(=[O:19])=[O:20])[CH3:30])([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1ccc(S(=O)(=O)C[C@@H]2C[C@H](N=[N+]=[N-])CC[C@@H]2NC(=O)OC(C)(C)C)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: COS(=O)(=O)OC
Product: CSc1ccc(S(=O)(=O)C[C@@H]2C[C@H](N=[N+]=[N-])CC[C@@H]2N(C)C(=O)OC(C)(C)C)cc1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
±(1S*,2R*,4R*)-[4-Azido-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cyclohexyl]-carbamic acid tert-butyl ester, from Example (55d) (389 mg) was dissolved in THF (3 ml) and cooled to −78° C. prior to the slow addition of a solution of 0.5M KHMDS in THF (2.65 ml). After 20 min, Me2SO4 (0.15 ml) was added. The reaction was warmed to rt and stirred for 2 h before the solution was quenched with sat. NH4Cl. This was extracted twice with EtOAc. The combined organic layer was dried, filtered, and concentrated. Flash chromatography of the resulting residue gave ±(1S*,2R*,4R*)-[4-azido-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cyclohexyl]-methyl-carbamic acid tert-butyl ester (207 mg): 1H NMR (CDCl3, δppm, 300 mHz) 1.39 (s, 9H), 1.55-1.93 (m, 4H), 2.00 (m, 1H), 2.52 (s, 3H), 2.65 (m, 1H), 2.80 (s, 3H), 3.00 (m, 2H), 3.81 (m, 3H), 7.34 (d, 2H), 7.80 (d, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C:11]2[CH:10]=[CH:9][C:8]([C:12]#[C:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5](=O)[CH2:4][CH2:3]1.[C:25]([Si](C)(C)C)#[N:26]>B(F)(F)F.CCOCC>[C:25]([C:5]1[C:6]2[CH:7]=[C:8]([C:12]#[C:13][C:14]3[CH:15]=[CH:16][C:17]([C:18]([OH:20])=[O:19])=[CH:21][CH:22]=3)[CH:9]=[CH:10][C:11]=2[C:2]([CH3:24])([CH3:1])[CH2:3][CH:4]=1)#[N:26]
Reactant: C[Si](C)(C)C#N
Reactant: CC1(C)CCC(=O)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21
Agent: FB(F)F
Solvent: CCOCC
Product: CC1(C)CC=C(C#N)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21
Temperature: 80 °C

Procedure:
To 76 mg (0.24 mmol) of 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-3-yl)ethynyl]benzoic acid (Compound 8) was added 0.06 ml (0.48 mmol) of cyanotrimethylsilane and 6 drops of boron trifluoride etherate. The resulting dark mixture was heated at 80° C. for 45 minutes, cooled to room temperature and purified by flash chromatography (silica, 50% EtOAc-hexane) to yield the title compound as a yellow solid.
Reaction SMILES: [C:1]([NH:9][C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:17]=2[N:19]2[CH2:24][CH2:23][N:22]([C:25](=[O:35])[CH2:26][NH:27]C(=O)OC(C)(C)C)[CH2:21][CH2:20]2)[NH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:27][CH2:26][C:25]([N:22]1[CH2:21][CH2:20][N:19]([C:17]2[C:16]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)=[CH:15][N:14]=[C:13]3[NH:12][CH:11]=[C:10]([NH:9][C:1](=[O:8])[C:2]4[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=4)[C:18]=23)[CH2:24][CH2:23]1)=[O:35]
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CCN(c2c(-c3ccccc3)cnc3[nH]cc(NC(=O)c4cccnc4)c23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCC(=O)N1CCN(c2c(-c3ccccc3)cnc3[nH]cc(NC(=O)c4cccnc4)c23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.2 %

Procedure:
tert-Butyl 2-(4-(3-(nicotinamido)-5-phenyl-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)-2-oxoethylcarbamate (0.013 g, 0.023 mmol) was placed in DCM (3 mL) at room temperature. TFA (0.5 mL) was then added, and the reaction was stirred at room temperature for 1 hour. The reaction was then concentrated to dryness. The resulting residue was dissolved in minimal DCM and added to a stirring solution of 1M HCl in ether. The resulting solid product was filtered, washed with ether and dried to give N-(4-(4-(2-amino acetyl)piperazin-1-yl)-5-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide (0.004 g, 38% yield) as the trihydrochloride salt. MS APCI (+) m/z 456 detected.
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:29])[CH2:7][CH:8]([C:12]2[CH:17]=[CH:16][C:15]([S:18][C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][N:20]=3)=[CH:14][CH:13]=2)[CH2:9][C:10]=1[OH:11])(=O)[CH2:2][CH3:3].Cl.[CH2:31]([O:33][NH2:34])[CH3:32].C([O-])(=O)C.[Na+]>C(Cl)Cl.C(O)C>[CH2:31]([O:33][N:34]=[C:1]([C:5]1[C:6](=[O:29])[CH2:7][CH:8]([C:12]2[CH:13]=[CH:14][C:15]([S:18][C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:26])=[O:27])=[CH:21][N:20]=3)=[CH:16][CH:17]=2)[CH2:9][C:10]=1[OH:11])[CH2:2][CH3:3])[CH3:32]
Reactant: CCON
Reactant: CCC(=O)C1=C(O)CC(c2ccc(Sc3ccc(S(C)(=O)=O)cn3)cc2)CC1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: CCON=C(CC)C1=C(O)CC(c2ccc(Sc3ccc(S(C)(=O)=O)cn3)cc2)CC1=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a slurry of 4.60 g (0.0107 mol) of 2-propionyl-3-hydroxy-5-(4-(5-(methylsulfonyl)-2-pyridylthio)phenyl)cyclohex-2-en-1-one in 100 mL of methylene chloride and 100 mL of 95 percent ethanol was added 1.35 g (0.0139 mol) of ethoxyamine hydrochloride and 1.31 g (0.0160 mol) of anhydrous sodium acetate. The slurry was stirred at ambient temperature for 12 hours and diluted with 100 mL of methylene chloride and washed thrice with 150 mL portions of water. The organic layer was dried over sodium sulfate and the solvent was removed in vacuo leaving 4.8 g (94.7 percent of theoretical) of the crude product. The product was purified by column chromatography using 5:95 acetone:methylene chloride as eluent and then trituration with diethyl ether affording 2.60 g (51.3 percent of theoretical) of the above named title compound, melting at 125.5°-128.5° C.; 1H NMR (CDCl3): δ 1.05-1.40 (m, 6H, CH3CH2 -- and CH3CH2O--), 2.55-3.55 (m, 11H, ring protons, CH 3 SO2 --, CH3CH2 --), 4.10 (q, 2H, CH3CH2O--), 6.9-8.85 (m, 7H, ArH), 15.0 (broad s, br, 1H, OH).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[CH:22]=[CH:21][C:15]3[CH2:16][CH2:17][NH:18][CH2:19][CH2:20][C:14]=3[CH:13]=2)=[CH:6][CH:5]=1.[C:24]1(=O)[CH2:28][CH2:27][CH2:26][CH2:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:5]=[CH:6][C:7]([CH2:10][O:11][C:12]2[CH:22]=[CH:21][C:15]3[CH2:16][CH2:17][N:18]([CH:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)[CH2:19][CH2:20][C:14]=3[CH:13]=2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(COc2ccc3c(c2)CCNCC3)cc1
Reactant: O=C1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)c1ccc(COc2ccc3c(c2)CCN(C2CCCC2)CC3)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-(2,3,4,5-Tetrahydro-1H-benzo[d]azepin-7-yloxymethyl)-benzoic acid methyl ester (D4) (2.83 g, 9.1 mmol) and cyclopentanone (1.6 ml, 18.2 mmol) were dissolved in dichloromethane (30 ml) and acetic acid (0.5 ml). Sodium triacetoxy borohydride (3.85 g, 18.2 mmol) was added and the solution was stirred at room temperature for 4 hours. The reaction mixture was washed with a saturated solution of sodium carbonate, the organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The crude mixture was purified by column chromatography eluting with a mixture of 0.880 ammonia:ethanol:dichloromethane (1:9:90) to afford the title compound (E88); MS (ES+) m/e 380 [M+H]+.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[C:3](=[N:4][CH:5]=[CH:6][C:7]=2[NH:10]C(=O)OC(C)(C)C)[O:2]1.FC(F)(F)C(O)=O>>[NH2:10][C:7]1[CH:6]=[CH:5][N:4]=[C:3]2[O:2][CH2:1][O:9][C:8]=12
Reactant: CC(C)(C)OC(=O)Nc1ccnc2c1OCO2
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccnc2c1OCO2
Yield: 80 %

Procedure:
Using an analogous procedure to that described in the last paragraph of that portion of Example 1 that is concerned with the preparation of starting materials, tert-butyl 2,3-methylenedioxypyrid-4-ylcarbamate was reacted with trifluoroacetic acid to give 4-amino-2,3-methylenedioxypyridine in 80% yield; NMR Spectrum: (CDCl3) 3.98 (m, 2H), 5.98 (s, 2H), 6.24 (d, 1H), 7.44 (d, 1H); Mass Spectrum: M+H+ 139.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH:30]=[C:29](B(O)O)[CH:28]=[N:27]2)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].ClCCl>O1CCCC1.O>[F:14][C:13]1([F:15])[CH2:12][O:11][C:10]([NH2:16])=[N:9][C@@:8]1([C:6]1[CH:7]=[C:2]([C:29]2[CH:28]=[N:27][N:26]([C:23]3[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=3)[CH:30]=2)[CH:3]=[CH:4][C:5]=1[F:18])[CH3:17]
Reactant: C[C@]1(c2cc(Br)ccc2F)N=C(N)OCC1(F)F
Reactant: OB(O)c1cnn(-c2ccc(F)cc2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: C[C@]1(c2cc(-c3cnn(-c4ccc(F)cc4)c3)ccc2F)N=C(N)OCC1(F)F
Temperature: 80 °C
Yield: 47.9 %

Procedure:
In a tube a mixture of (R)-4-(5-bromo-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A6.1) (60 mg, 186 μmol), 1-(4-fluorophenyl)-1H-pyrazol-4-ylboronic acid (39.0 mg, 186 μmol), and cesium carbonate (242 mg, 743 μmol) in tetrahydrofuran (4 ml) and water (2 ml) was purged with argon for minutes. Thereafter, [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (7.58 mg, 9.28 μmol) was added, the tube was sealed and the mixture heated at 80° C. for 16 hours. After evaporation, the residue was purified by chromatography on a silica-NH2 phase using a gradient of heptane/ethyl acetate=100:0 to 40:60 as the eluent. The (R)-5,5-Difluoro-4-{2-fluoro-5-[1-(4-fluoro-phenyl)-1H-pyrazol-4-yl]-phenyl}-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (36 mg, 48% yield) was obtained as a yellow solid. MS (ISP): m/z=405.0 [M+H]+.
Reaction SMILES: C[O:2][C:3]1[CH:20]=[CH:19][C:6]2[N:7]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([O:16]C)[C:11]=3[Br:18])[S:9][C:5]=2[CH:4]=1.B(Br)(Br)Br>>[OH:2][C:3]1[CH:20]=[CH:19][C:6]2[N:7]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[C:11]=3[Br:18])[S:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2nc(-c3cccc(OC)c3Br)sc2c1
Agent: BrB(Br)Br
Product: Oc1ccc2nc(-c3cccc(O)c3Br)sc2c1
Yield: 26.4 %

Procedure:
6-Methoxy-2-(2-bromo-3-methoxy-phenyl)-benzothiazole (0.144 g, 0.411 mmol) was treated with boron tribromide under standard condition to give 6-hydroxy-2-(2-bromo-3-hydroxy-phenyl)-benzothiazole (35 mg, 26% yield) as a yellow solid. Mass spec: MH+=322.
Reaction SMILES: [OH:1][C:2]1([CH2:8][O:9][C:10]2[CH:15]=[C:14]([CH3:16])[C:13]([C:17]3[C:22]([CH3:23])=[CH:21][CH:20]=[C:19]([C:24](OC)=[O:25])[CH:18]=3)=[C:12]([CH3:28])[CH:11]=2)[CH2:7][CH2:6][S:5][CH2:4][CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[OH:25][CH2:24][C:19]1[CH:20]=[CH:21][C:22]([CH3:23])=[C:17]([C:13]2[C:12]([CH3:28])=[CH:11][C:10]([O:9][CH2:8][C:2]3([OH:1])[CH2:3][CH2:4][S:5][CH2:6][CH2:7]3)=[CH:15][C:14]=2[CH3:16])[CH:18]=1
Reactant: COC(=O)c1ccc(C)c(-c2c(C)cc(OCC3(O)CCSCC3)cc2C)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(CO)cc1-c1c(C)cc(OCC2(O)CCSCC2)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.8 %

Procedure:
To a solution of methyl 4′-[(4-hydroxytetrahydro-2H-thiopyran-4-yl)methoxy]-2′,6,6′-trimethylbiphenyl-3-carboxylate (191 mg, 0.48 mmol) in anhydrous tetrahydrofuran (3 mL) was added lithium aluminum hydride (34.2 mg, 0.72 mmol) under ice-cooling, and the mixture was stirred overnight at room temperature. Anhydrous tetrahydrofuran (10 mL) was added to the reaction solution, and the solution was ice-cooled. Sodium sulfate decahydrate (232 mg, 0.72 mmol) was added, and the mixture was stirred at room temperature for 2 hr. The precipitated insoluble material was filtered off through celite, and the filtrate was concentrated under reduced pressure to give the title compound (182 mg, yield 100%) as a colorless amorphous powder.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]([CH2:30][OH:31])[CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:39][CH2:40][CH2:41][CH2:42][C:43](Cl)=[O:44]>C(Cl)(Cl)Cl>[CH2:1]([O:8][C@H:9]([CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:30][O:31][C:43](=[O:44])[CH2:42][CH2:41][CH2:40][Cl:39])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCCCCCCCCCCCCCOC[C@H](CO)OCc1ccccc1
Reactant: O=C(Cl)CCCCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCOC[C@H](COC(=O)CCCCl)OCc1ccccc1
Temperature: 25 °C

Procedure:
A solution of 0.5 g of (S)-2-O-benzyl-1-O-octadecylglycerine and 0.16 ml of triethylamine in 2 ml of chloroform is added dropwise to a solution, cooled to 0° C., of 0.16 ml of 4-chlorobutyryl chloride in 1 ml of chloroform. The reaction mixture is stirred at room temperature, diluted with 5 ml of chloroform and washed in succession with 5 ml of 1N sodium hydroxide and 3×10 ml of water. The organic phase is dried and concentrated. The residue is chromatographed on silica gel while eluting with hexane-ether (19:1). There is obtained (R)-2-O-benzyl-1-O-(4-chlorobutyryl)-3-O-octadecylglycerine in the form of an oily residue.
Reaction SMILES: CC(OC([N:8]1[CH2:13][CH2:12][C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]1)=O)(C)C.[H][H].[ClH:25]>CO.[Rh]>[ClH:25].[CH:17]1([C:11]2([C:14]([OH:16])=[O:15])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)(c2ccccc2)CC1
Agent: [Rh]
Agent: Cl
Solvent: CO
Product: O=C(O)C1(C2CCCCC2)CCNCC1

Procedure:
4-Phenyl-1,4-piperidinedicarboxylic acid 1-(1,1-dimethylethyl) ester (8-2) (202 g, 0.662 mol) was dissolved in 1700 mL of 10% HCl in methanol and rhodium on alumina (25 g) was added. The mixture was placed on a high pressure hydrogenator using 1500 psi of hydrogen at 100° C. for 17 h. The resulting mixture was filtered through Celite using methanol to rinse and concentrated. The resulting solid was triturated with diethyl ether and filtered to afford title compound 8-3 as an off-white solid.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12]([C:14]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=O)=[CH:11][C:10]=2[CH:23]=1.O.NN.[OH-].[K+].[Na+].[Cl-]>C(O)CO>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12]([CH2:14][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[CH:11][C:10]=2[CH:23]=1
Reactant: O=C(c1ccc(F)cc1)c1cc2cc(C3OCCO3)ccc2o1
Agent: NN
Agent: [Cl-]
Agent: [K+]
Solvent: OCCO
Solvent: O
Product: Fc1ccc(Cc2cc3cc(C4OCCO4)ccc3o2)cc1
Temperature: 10 °C
Reaction time: 2 h
Yield: 42.9 %

Procedure:
To an ethylene glycol (5 mL) suspension of (5-[1,3]-dioxolan-2-yl-benzofuran-2-yl)-(4-fluoro-phenyl)-methanone (370 mg, 1.18 mmol) were added hydrazine monohydrate (165 mg, 2.8 mmol) and potassium hydroxide (152 mg, 2.71 mmol). After stirring this suspension for 2 hours at 10° C., this suspension was further stirred for 1 hour at 160° C. After allowing the reaction mixture to cool on standing, sat. NaCl was poured thereinto followed by extraction with ethyl acetate. The organic layer was separated followed by drying over anhydrous magnesium sulfate and concentrating under a reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to obtain 5-[1,3]-dioxolan-2-yl-2-(4-fluoro-benzyl)-benzofuran (151 mg, 43%).