Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NN1CCCC1.[CH3:7][N:8]([CH3:29])[C:9]([CH:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:26]3[C:21](=[CH:22][C:23]([F:27])=[CH:24][CH:25]=3)[N:20]=[C:19]([Cl:28])[N:18]=2)[CH2:13][CH2:12]1)=[O:10].Cl.[NH2:31][C@H:32]1[CH2:36][CH2:35][N:34]([C:37](=[O:50])[CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][C:46]([F:49])([F:48])[F:47])=[CH:41][CH:40]=2)[CH2:33]1.C(N(CC)C(C)C)(C)C>C(Cl)(Cl)Cl.C(=O)([O-])O.[Na+].C(O)CCC>[ClH:28].[CH3:7][N:8]([CH3:29])[C:9]([CH:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:26]3[C:21](=[CH:22][C:23]([F:27])=[CH:24][CH:25]=3)[N:20]=[C:19]([NH:31][C@H:32]3[CH2:36][CH2:35][N:34]([C:37](=[O:50])[CH2:38][C:39]4[CH:40]=[CH:41][C:42]([O:45][C:46]([F:47])([F:48])[F:49])=[CH:43][CH:44]=4)[CH2:33]3)[N:18]=2)[CH2:13][CH2:12]1)=[O:10]
Reactant: N[C@H]1CCN(C(=O)Cc2ccc(OC(F)(F)F)cc2)C1
Reactant: CN(C)C(=O)C1CCN(c2nc(Cl)nc3cc(F)ccc23)CC1
Agent: Cl
Agent: NN1CCCC1
Agent: O=C([O-])O
Solvent: ClC(Cl)Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)C1CCN(c2nc(N[C@H]3CCN(C(=O)Cc4ccc(OC(F)(F)F)cc4)C3)nc3cc(F)ccc23)CC1
Temperature: 120 °C
Yield: 23.7 %

Procedure:
A mixture of 2,4-dichloro-7-fluoroquinazoline (250 mg), piperidine-4-carboxylic acid dimethylamide (189 mg), triethylamine (0.24 mL), THF (6 mL), and DMF (4 mL) was stirred at room temperature for 13 h. The reaction mixture was diluted with a mixture of chloroform and saturated aqueous sodium hydrogencarbonate, and then the aqueous layer was extracted 3 times with chloroform. The organic layer was dried with anhydrous sodium sulfate, the desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=7:3) to obtain colorless solid 1-(2-chloro-7-fluoroquinazolin-4-yl)piperidine-4-carboxylic acid dimethylamide (407 mg). (2) A mixture of 1-(2-chloro-7-fluoroquinazolin-4-yl)piperidine-4-carboxylic acid dimethylamide (250 mg), 1-((S)-3-aminopyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone mono hydrochloride (265 mg), N,N-diisopropylethylamine (0.32 mL), and n-butanol (1.2 mL) was heated at 120° C. for 57 h with stirring. The reaction mixture was diluted with a mixture of chloroform and saturated aqueous sodium hydrogencarbonate, and then the aqueous layer was extracted with chloroform. The organic layer was dried with anhydrous sodium sulfate, the desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH silica gel, hexane/ethyl acetate=4:1−ethyl acetate, and silica gel, chloroform/methanol=95:5). The resulting purification product was dissolved in ethyl acetate (2.0 mL), followed by addition of a solution (0.1 mL) of 4 M HCl in ethyl acetate, and the mixture was stirred at room temperature for 3.5 h. The solvent was evaporated under reduced pressure to obtain the amorphous title compound (110 mg).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19].[NH4+:21].[OH-].CCOC(C)=O.O>C1COCC1>[NH2:21][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19]
Reactant: [NH4+]
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(F)c([N+](=O)[O-])c1
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(NC(=O)OC(C)(C)C)c1ccc(N)c([N+](=O)[O-])c1
Temperature: 150 °C
Yield: 76.4 %

Procedure:
Tert-butyl (1-(4-fluoro-3-nitrophenyl)ethyl)carbamate (500 g, 1.75 mmol) was stirred in THF (2 ml). NH4OH (0.978 ml, 7.0 mmol) was added and the reaction mixture was heated at 150° C. for 30 minutes using microwave (Biotage Initiator). NH4OH (0.6 00 ml) was added and then heated at 180° C. After cooling to room temperature, the reaction mixture was poured into EtOAc/water. The organic layer was washed with brine, dried over MgSO4 and evaporated. The resulting material was purified by flash chromatography on silica eluting with 0% to 50% EtOAc/Hexane to afford the title compound (376 mg, yield: 76%) 1H-NMR (400 MHz, CDCl3) δ 1.43-1.48 (m, 12H) 4.71 (br. s., 2H) 6.79 (d, 1H) 7.34 (dd, 1H) 8.05 (d, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][NH2:8])=[CH:5][N:4]=[CH:3]1.[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][N:20]([C:23]2[S:24][C:25]([C:29](O)=[O:30])=[C:26]([CH3:28])[N:27]=2)[C:19](=[O:32])[CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][N:20]([C:23]2[S:24][C:25]([C:29]([NH:8][CH2:7][C:6]3[N:2]([CH3:1])[CH:3]=[N:4][CH:5]=3)=[O:30])=[C:26]([CH3:28])[N:27]=2)[C:19](=[O:32])[CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)O
Reactant: Cn1cncc1CN
Product: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)NCc1cncn1C
Yield: 52 %

Procedure:
Following the procedure as described in Example 22, making variation only as required to use (1-methyl-1H-imidazol-5-yl)methanamine in place of benzo[b]thiophen-2-ylmethanamine to react with 2-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 52% yield: 1H NMR (300 MHz, DMSO-d6) δ 8.65-8.58 (m, 2H), 7.51 (s, 1H), 7.44-7.30 (m, 5H), 6.78 (s, 1H), 6.38 (dd, J=8.1, 2.6 Hz, 1H), 6.22 (d, J=2.6 Hz, 1H), 5.15 (s, 2H), 4.36 (d, J=5.3 Hz, 2H), 3.58 (s, 3H), 2.52 (s, 3H); MS (ES+) m/z 436.2 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:16])[C:8]([CH2:14][CH3:15])=[C:9]([C:12]#[N:13])[C:10]=1I)=[O:5])[CH3:2].[Br:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C([O-])([O-])=O.[Na+].[Na+].Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu].C(O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:16])[C:8]([CH2:14][CH3:15])=[C:9]([C:12]#[N:13])[C:10]=1[C:21]1[CH:22]=[CH:23][C:18]([Br:17])=[CH:19][CH:20]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(I)c(C#N)c(CC)n1C
Reactant: OB(O)c1ccc(Br)cc1
Agent: [Cu]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)c1c(-c2ccc(Br)cc2)c(C#N)c(CC)n1C
Temperature: 80 °C
Yield: 78.2 %

Procedure:
A 10 mL round bottom flask is charged with 4-cyano-5-ethyl-3-iodo-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (200 mg, 0.602 mmol, prepared in preparation 38) and absolute ethanol (4.0 mL). To this solution is added 4-bromophenylboronic acid (242 mg, 1.20 mmol) and 2M aqueous Na2CO3 solution (0.90 mL). This mixture is degassed under house vacuum for about 20 min until no bubbles produced. Nitrogen gas is recharged into the flask and Pd(PPh3)4 (56 mg, 0.048 mmol) is quickly added. The septum cap is well sealed with copper wire and teflon tape. The mixture in this sealed flask is then heated in oil bath at 80° C. for 18-20 hours. The mixture is cooled to room temperature. It is diluted in methylene chloride (20 mL) and poured into 0.1 M HCl solution (30 mL), pH is adjusted to 7-8 with sat. aq. NaHCO3 solution. The mixture is extracted with methylene chloride (2×30 mL), and diethyl ether (2×30 mL), the combined extracts are dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue is then purified by flash chromatography (silica gel, elution with 20% Et2O in hexanes) to provide the title compound (170 mg, 77%) as a light brown oil. Mass spectrum (m/e): 360.9 (M+1). Rf=0.4 (50% of Et2O in hexanes).
Reaction SMILES: C([Li])(C)(C)C.C(OC([N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([F:22])[CH:20]=2)[CH2:15][CH2:14]1)=O)(C)(C)C.[O:23]1CCC[CH2:24]1>>[F:22][C:19]1[C:20]([CH:24]=[O:23])=[C:21]2[C:16]([CH2:15][CH2:14][NH:13]2)=[CH:17][CH:18]=1
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(F)cc21
Agent: [Li]C(C)(C)C
Product: O=Cc1c(F)ccc2c1NCC2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 42 %

Procedure:
Add tert-butyllithium (21.13 ml, 35.93 mmol, 1.7 M solution in heptane) to a solution of 1-(tert-butoxycarbonyl)-2,3-dihydro-6-fluoroindole (3.28 g, 13.82 mmol) in anhydrous tetrahydrofuran (100 ml) at −78 C. Stir for 20 minutes, quench with excess dimethylformamide, and stir for 1 hour at −78 C. Warm to room temperature, add saturated aqueous ammonium chloride, and extract with ethyl acetate. Concentrate the combined organic phases under reduced pressure and subject the residue to silica gel chromatography to provide the desired compound as a bright yellow solid (0.91 g, 42%).
Reaction SMILES: CCCCCC.C([Li])CCC.Br[C:13]1[CH:22]=[C:21]([Br:23])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]=1[O:24][CH3:25].CN(C)[CH:28]=[O:29].[Cl-].[NH4+]>C1COCC1>[Br:23][C:21]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([O:24][CH3:25])=[C:13]([CH:28]=[O:29])[CH:22]=1
Reactant: COc1c(Br)cc(Br)c2ccccc12
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1c(C=O)cc(Br)c2ccccc12
Reaction time: 0.5 h
Yield: 15.1 %

Procedure:
In a nitrogen stream, an n-butyllithium hexane solution (1.6 M, 56.9 ml, 91.1 mmol) was added dropwise to a solution of 2,4-dibromo-1-methoxy-naphthalene (30.3 g, 95.9 mmol) in THF (1,800 ml) at −78° C. and the reaction mixture was stirred at the same temperature for 30 minutes. To this mixture, N,N-dimethylformamide (8.9 ml, 115.1 mmol) was added at −78° C. The mixture was stirred at the same temperature for three hours, and then a saturated ammonium chloride aqueous solution was added thereto and the mixture was extracted with ether. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:8)] to obtain the title compound (3.85 g, 15%).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:19]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[C:18]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[N:17]=[C:16]3[NH:33][N:34]=[C:35]([C:36]#[N:37])[C:15]=23)=[CH:10][CH:9]=1.[OH-].[Na+]>C(OCC)C.O.C1COCC1>[NH2:37][CH2:36][C:35]1[C:15]2[C:16](=[N:17][C:18]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)=[C:19]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)[C:14]=2[C:11]2[CH:12]=[CH:13][C:8]([F:7])=[CH:9][CH:10]=2)[NH:33][N:34]=1
Reactant: N#Cc1n[nH]c2nc(-c3ccc(F)cc3)c(-c3ccncc3)c(-c3ccc(F)cc3)c12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: NCc1n[nH]c2nc(-c3ccc(F)cc3)c(-c3ccncc3)c(-c3ccc(F)cc3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.9 %

Procedure:
LiAlH4 (0.06 g, 1.5 mmol) and anhydrous diethyl ether (2 mL) were introduced into a volumetric flask. The mixture was cooled with an ice bath and a solution of 4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile (0.15 g, 0.4 mmol, obtained in example 65) in diethyl ether (1 mL) was added dropwise. THF (2 mL) was added and the mixture was stirred at room temperature overnight. It was cooled with an ice bath and successively water (0.1 mL), THF (0.2 mL), a 15% aqueous NaOH (0.1 mL) and water (0.3 mL) were added. The precipitate obtained was filtered and washed with THF. The solvent of the filtrate was evaporated. The residue obtained was purified by chromatography on silica gel using hexane-EtOAc mixtures of increasing polarity as eluent, to afford 71 mg of the title compound in solid form (yield: 47%).
Reaction SMILES: [CH:1]([N:4]([P:8]([N:10]([CH:14]([CH3:16])[CH3:15])[CH:11]([CH3:13])[CH3:12])Cl)[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:24][CH:25]([OH:27])[CH3:26]>C(OCC)C>[CH:25]([O:27][P:8]([N:10]([CH:14]([CH3:16])[CH3:15])[CH:11]([CH3:13])[CH3:12])[N:4]([CH:5]([CH3:7])[CH3:6])[CH:1]([CH3:3])[CH3:2])([CH3:26])[CH3:24]
Reactant: CC(C)O
Reactant: CC(C)N(C(C)C)P(Cl)N(C(C)C)C(C)C
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)OP(N(C(C)C)C(C)C)N(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 5.5 h

Procedure:
Bis(diisopropylamino)chlorophosphine (19, 250.1 g, 937 mmol) was dissolved in anhydrous ethyl ether (3.6 L) and triethylamine (190 g, 1.87 mol) was introduced. The turbid mixture was cooled at 0° C. and a solution of 2-propanol (225 g, 287 mL) in ether (200 mL) was added via a funnel. The resulting cloudy mixture was stirred at room temperature for 5.5 hours. The reaction was complete by checking with 31P NMR (δ=116.10 ppm, S). White solid (triethylamine HCl salt) was removed by filtration. The filtrate was concentrated to furnish a pale brown liquid (272 g, quantitative) and used for next step without further purification. Note that the P(III)-reagent can be purified by vacuum distillation (bp 84-86° C., 5 mm Hg) if desired to furnish a colorless clear oil. 1H NMR (CDCl3): δ 3.91 (m, 1H), 3.51 (m, 4 H), 1.19 (d, 6 H, J=6 Hz), 1.16 (24 H, m). 31P NMR (CDCl3): δ 116.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:27])[CH2:10][C:11]([C:13]1[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=1)=[O:12].[CH2:28]([O:30][C:31](=[O:34])[CH2:32]Br)[CH3:29].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C(=O)C>[CH2:28]([O:30][C:31](=[O:34])[CH2:32][O:8][C:6]1[CH:5]=[CH:4][C:3]([CH:9]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[CH2:10][C:11]([C:13]2[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=2)=[O:12])=[C:2]([F:1])[CH:7]=1)[CH3:29]
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(O)cc1F
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)COc1ccc(C(CC(=O)c2ccc(=O)n(C)c2)c2ccccc2C)c(F)c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 87.8 %

Procedure:
To a stirred solution of 5-[3-(2-fluoro-4-hydroxy-phenyl)-3-o-tolyl-propionyl]-1-methyl-1H-pyridin-2-one (71 mg) in N,N-dimethylacetamide (1.5 ml) were added ethylbromoacetate (36 mg) and cesium carbonate (69 mg). The mixture was stirred for 3.5 h at room temperature. Water was added and the mixture was extracted with diethyl ether. The organic phase was dried (MgSO4), filtered and concentrated to dryness. The product was purified by chromatography (SiO2, cyclohexane/ethyl acetate 1:0 to 0:1) to give the title compound (77 mg) as a light brown oil, MS (ESI+): m/z=452.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][CH2:8][C:9]1[CH:34]=[CH:33][C:12]2[N:13]([CH2:28][CH2:29][CH2:30][CH2:31][OH:32])[C:14]([CH2:16][N:17]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:19]([CH:26]=[CH2:27])=[N:18]3)=[N:15][C:11]=2[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6](=[O:35])[NH:7][CH2:8][C:9]1[CH:34]=[CH:33][C:12]2[N:13]([CH2:28][CH2:29][CH2:30][CH2:31][OH:32])[C:14]([CH2:16][N:17]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:19]([CH2:26][CH3:27])=[N:18]3)=[N:15][C:11]=2[CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C=Cc1nn(Cc2nc3cc(CNC(=O)OC(C)(C)C)ccc3n2CCCCO)c2ccccc12
Agent: [Pd]
Solvent: CO
Product: CCc1nn(Cc2nc3cc(CNC(=O)OC(C)(C)C)ccc3n2CCCCO)c2ccccc12
Yield: 92.5 %

Procedure:
To a solution of [1-(4-hydroxy-butyl)-2-(3-vinyl-indazol-1-ylmethyl)-1H-benzoimidazol-5-ylmethyl]-carbamic acid tert-butyl ester (115 mg, 0.24 mmol) in methanol (35 mL) was added 10% Pd/C (12 mg) and this suspension was rocked in a Parr shaker under a hydrogen atmosphere (45 psi) for 2 hrs. The catalyst was removed by filtration and the filtrate concentrated in vacuo to yield [2-(3-ethyl-indazol-1-ylmethyl)-1-(4-hydroxy-butyl)-1H-benzoimidazol-5-ylmethyl]-carbamic acid tert-butyl ester (106 mg, 92%) as a white foam:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([NH:18]C(=O)C)=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=[C:4]([Cl:22])[N:3]=1.Cl>[OH-].[Na+]>[NH2:18][C:15]1[CH:16]=[CH:17][C:12]([S:9]([NH:8][C:6]2[CH:7]=[C:2]([Cl:1])[N:3]=[C:4]([Cl:22])[CH:5]=2)(=[O:11])=[O:10])=[CH:13][CH:14]=1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2cc(Cl)nc(Cl)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccc(S(=O)(=O)Nc2cc(Cl)nc(Cl)c2)cc1
Yield: 93.4 %

Procedure:
1.25 g (0.0035 mol) of N-[4-(2,6-dichloro-pyridin-4-yl-sulfamoyl)-phenyl]-acetamide were dissolved in 35 ml of 1N NaOH and boiled at reflux for 2 hours. After cooling the mixture was adjusted to pH 6 with 2N HCl and the precipitate which separated was filtered off. The material on the suction filter was washed well with water and dried. It was subsequently chromatographed on silica gel with ethyl acetate/hexane 1:2→1:1. There were obtained 1.04 g (93%) of 4-amino-N-(2,6-dichloro-pyridin-4-yl)-benzenesulfonamide as white crystals; m.p.: 209-211° C. (dec.).
Reaction SMILES: C[O-].[Na+].[CH3:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:28][C:29]([CH3:32])([OH:31])[CH3:30])[CH2:15][CH2:16]OS(C2C=CC(C)=CC=2)(=O)=O)(=[O:13])=[O:12])=[CH:7][CH:6]=1.O>CO>[CH3:30][C:29]1([CH3:32])[O:31][CH2:16][CH2:15][N:14]([S:11]([C:8]2[CH:9]=[CH:10][C:5]([CH3:4])=[CH:6][CH:7]=2)(=[O:13])=[O:12])[CH2:28]1
Reactant: Cc1ccc(S(=O)(=O)OCCN(CC(C)(C)O)S(=O)(=O)c2ccc(C)cc2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1ccc(S(=O)(=O)N2CCOC(C)(C)C2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93.1 %

Procedure:
Sodium methoxide (9.7 g) was added to a stirred solution of 1-{N-[(4-methylphenyl)sulfonyl]-N-[(4-methylphenyl)sulfonyloxyethyl]amino}-2-methyl-2-propanol (72.2 g) in methanol (350 ml) and the solution was stirred at room temperature for 1.5 h. A further amount of sodium methoxide (9.7 g) was then added and the mixture was stirred for an additional 30 min. The suspension was poured into water (1.2 l) and the mixture was stirred for 20 min. The colourless solid was filtered off, washed with water and dried in vacuo at 60° C. to give 2,2-dimethyl-4-[(4-methylphenyl)sulfonyl]morpholine (41.0 g). m.p. 95°-97° C.
Reaction SMILES: ClCCl.B(Br)(Br)Br.C[O:9][C:10]1[CH:11]=[CH:12][C:13]2[O:18][C:17]([CH3:20])([CH3:19])[C:16](=[O:21])[NH:15][C:14]=2[CH:22]=1>O>[OH:9][C:10]1[CH:11]=[CH:12][C:13]2[O:18][C:17]([CH3:19])([CH3:20])[C:16](=[O:21])[NH:15][C:14]=2[CH:22]=1
Reactant: COc1ccc2c(c1)NC(=O)C(C)(C)O2
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CC1(C)Oc2ccc(O)cc2NC1=O
Reaction time: 8 h
Yield: 80 %

Procedure:
A dichloromethane solution (36 ml) of 2M boron tribromide was added dropwise to a dichloromethane solution of 6-methoxy-2,2-dimethyl-4H-benzo[1,4]oxazin-3-one (5.0 g, 26 mmol) under ice cooling and the mixture was stirred overnight. Water was added to the reaction solution to decompose the reagents excessively present. The reaction solution was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1). The purified product was concentrated to dryness under reduced pressure to obtain 6-hydroxy-2,2-dimethyl-4H-benzo[1,4]oxazin-3-one (4.02 g) as white powder.
Reaction SMILES: [CH3:1][C:2]([CH3:26])([CH3:25])[CH2:3][NH:4][C:5]1[N:10]=[C:9]([NH:11][CH3:12])[N:8]=[C:7]([NH:13][C:14]2[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=2[CH3:24])[C:17]([NH:19][CH3:20])=[O:18])[CH:6]=1.C(=O)(O)[O-].[Na+].[Br:32]Br>C(Cl)Cl>[Br:32][C:6]1[C:7]([NH:13][C:14]2[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=2[CH3:24])[C:17]([NH:19][CH3:20])=[O:18])=[N:8][C:9]([NH:11][CH3:12])=[N:10][C:5]=1[NH:4][CH2:3][C:2]([CH3:26])([CH3:25])[CH3:1]
Reactant: CNC(=O)c1ccc(C)c(Nc2cc(NCC(C)(C)C)nc(NC)n2)c1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CNC(=O)c1ccc(C)c(Nc2nc(NC)nc(NCC(C)(C)C)c2Br)c1

Procedure:
3-[6-(2,2-Dimethyl-propylamino)-2-methylamino-pyrimidin-4-ylamino]-4,N-dimethyl-benzamide (35 mg), aq. sat. sodium bicarbonate (0.05 mL) and bromine (21 mg) were stirred in methylene chloride (1 mL) at room temperature for overnight. The product (4 mg) was purified with preparative thin layer chromatography. MS (m/z): 435 (M+H).
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].Br[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].O.CCOCC>CN(C)C=O>[CH2:6]([S:1][C:2]#[N:3])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCBr
Reactant: N#C[S-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCCCCCCCSC#N
Reaction time: 1.5 h

Procedure:
To a mixture of potassium thiocyanate (5.07 g, 51.7 mmol) in 30 ml of dimethylformamide (DMF) is added 1-bromooctane (5.0 g, 4.5 ml, 25.8 mmol). The mixture is stirred at 45° for 1.5 hours. It is then cooled to 0° and water and ether are added. The ether layer is washed with water and brine and stripped to give octylthiocyanate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[CH2:12]([C:15]1[C:21]([OH:22])=[CH:20][CH:19]=[CH:18][C:16]=1[OH:17])[CH2:13][CH3:14]>OS(C(F)(F)F)(=O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([C:18]2[CH:19]=[CH:20][C:21]([OH:22])=[C:15]([CH2:12][CH2:13][CH3:14])[C:16]=2[OH:17])=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: CCCc1c(O)cccc1O
Agent: O=S(=O)(O)C(F)(F)F
Product: CCCc1c(O)ccc(C(=O)Cc2ccc(Cl)cc2)c1O

Procedure:
Using the procedure in Example 51, step 1, 4-chlorophenyl-acetic acid and 2-(n-propyl)resorcinol were condensed in triflic acid to form 4-(4-chlorophenylacetyl)-1,3-dihydroxy-2-(n-propyl)benzene.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.[NH:21]1[CH:25]=[CH:24][N:23]=[CH:22]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[N:21]1([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=3[N:12]=2)[CH:25]=[CH:24][N:23]=[CH:22]1
Reactant: c1c[nH]cn1
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc2oc(-c3ccncc3-n3ccnc3)nc2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 85.4 %

Procedure:
A mixture of 0.31 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.14 g of imidazole, 0.55 g of potassium carbonate and 2 ml of DMF was stirred while heating at room temperature for 1.5 hours, and then at 60° C. for 1.5 hours. The reaction mixture was cooled to room temperature, and then water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.31 g of 2-[3-(imidazole-1-yl)pyridin-4-yl]-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 56”).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:19]=[C:20]([F:22])[CH:21]=1)[CH2:5][C@H:6]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:7](=[O:10])[CH:8]=[CH2:9].[BH4-].[Na+].[Cl-].[Ce+3].[Cl-].[Cl-]>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:19]=[C:20]([F:22])[CH:21]=1)[CH2:5][C@H:6]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:16])([CH3:17])[CH3:15])[CH:7]([OH:10])[CH:8]=[CH2:9]
Reactant: C=CC(=O)[C@H](Cc1cc(F)cc(F)c1)NC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Ce+3]
Agent: [Cl-]
Solvent: CO
Product: C=CC(O)[C@H](Cc1cc(F)cc(F)c1)NC(=O)OC(C)(C)C

Procedure:
Ketone (2) was reduced with sodium borohydride/cerium chloride (Luche conditions) in methanol at 0° C. to provide the allylic alcohol 3 as a mixture of alcohol epimers (white solid).