Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([CH3:26])=[C:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[C:10](=[O:17])[NH:11]2.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].I[CH:40]([CH3:42])[CH3:41]>O>[CH3:1][O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([CH3:26])=[C:9]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=1)[C:10]([O:17][CH:40]([CH3:42])[CH3:41])=[N:11]2
Reactant: COC(=O)COc1ccc(Cl)c2[nH]c(=O)c(Cc3ccc(F)cc3)c(C)c12
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(Cl)c2nc(OC(C)C)c(Cc3ccc(F)cc3)c(C)c12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of [8-chloro-3-(4-fluorobenzyl)-4-methyl-2-oxo-1,2-dihydroquinolin-5-yloxy]acetic acid methyl ester (0.020 g), N,N-dimethylformamide (1.0 mL), potassium carbonate (0.020 g) and 2-iodopropane (0.050 g) was stirred at room temperature for 4 hour. The mixture was diluted with water (20 mL), extracted with ethyl acetate and the combined extracts washed with water and saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent removed under reduced pressure and the residue purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (1:9 by volume) to afford title compound as a cream solid, 0.023 g.
Reaction SMILES: [OH:1][C:2]1([CH:13]2[CH2:18][NH:17][CH2:16][CH2:15][NH:14]2)[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.C(N(CC)C(C)C)(C)C.[N+:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[S:37](Cl)(=[O:39])=[O:38])([O-:30])=[O:29]>C1COCC1>[OH:1][C:2]1([CH:13]2[CH2:18][N:17]([S:37]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[N+:28]([O-:30])=[O:29])(=[O:38])=[O:39])[CH2:16][CH2:15][NH:14]2)[CH2:3][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:5]1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC(O)(C2CNCCN2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(O)(C2CN(S(=O)(=O)c3ccccc3[N+](=O)[O-])CCN2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.5 %

Procedure:
To a solution of 1,1-dimethylethyl 3-hydroxy-3-piperazin-2-ylazetidine-1-carboxylate (227 mg, 0.88 mmol) and N,N-diisopropylethylamine (436 μL, 2.64 mmol) in THF (5 mL) was added 2-nitrobenzenesulfonyl chloride (195 mg, 0.88 mmol). The mixture was stirred at room temperature for 2 hours. The solution was concentrated and the residue was purified by column chromatography (95% dichloromethane: 5% methanol) to provide 1,1-dimethylethyl 3-hydroxy-3-{4-[(2-nitrophenyl)sulfonyl]piperazin-2-yl}azetidine-1-carboxylate as a white foam (308 mg, 0.70 mmol, 79% yield). 1H NMR. (400 MHz, CDCl3): 7.98 (m, 1H), 7.72 (m, 2H), 7.64 (m, 1H), 3.96 (d, 1H), 3.94 (d, 1H), 3.85 (d, 1H), 3.79 (d, 1H), 3.79-3.73 (m, 2H), 3.11 (m, 1H), 3.05 (dd, 1H), 3.00 (br s, 1H), 2.94 (dt, 1H), 2.78 (dt, 1H), 2.68 (dd, 1H), 1.45 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=2)=[C:4]([Cl:17])[CH:3]=1.[NH2:18][OH:19]>CN(C=O)C>[Br:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([CH:11]=[N:18][OH:19])=[CH:9][CH:8]=2)=[C:4]([Cl:17])[CH:3]=1
Reactant: O=Cc1ccc(Oc2ccc(Br)cc2Cl)cc1
Reactant: NO
Solvent: CN(C)C=O
Product: ON=Cc1ccc(Oc2ccc(Br)cc2Cl)cc1

Procedure:
20 mg (0.06 mmol) of 4-(4-bromo-2-chloro-phenoxy)-benzaldehyde were stirred with 20 μL (0.33 mmol) of hydroxylamine solution (50% in water) in 2 mL f DMF at 80° C. for 1 h. The reaction mixture was purified by chromatography (reversed phase).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[S:8][C:9]=1[CH2:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[C:14]([Cl:20])[CH:13]=1)[CH2:2][CH2:3][CH3:4].[BH4-].[Na+]>CO>[CH2:1]([C:5]1[N:6]=[C:7]([C:21]2[CH:22]=[CH:23][C:24]([C:27]([F:29])([F:28])[F:30])=[CH:25][CH:26]=2)[S:8][C:9]=1[CH2:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][OH:17])=[C:14]([Cl:20])[CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(C=O)c(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(CO)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
3.0 g 4-[4-Butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-chloro-benzaldehyde were dissolved in 100 ml methanol and 300 mg sodium borohydride were added. The reaction mixture was stirred at room temperature for two hours, then the solvent was removed in vacuo and the residue dissolved in 100 ml ethyl acetate. This solution was washed three times with 30 ml brine, dried over MgSO4 and the solvent was removed in vacuo to provide 3.0 g {4-[4-Butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-chloro-phenyl}-methanol as pale yellow solid.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][CH:21]=3)[NH:16][C:15]2=[O:23])[CH2:10][CH2:9]1)C1C=CC=CC=1.[ClH:24]>O1CCOCC1>[ClH:24].[NH:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][CH:21]=3)[NH:16][C:15]2=[O:23])[CH2:10][CH2:9]1
Reactant: O=c1[nH]c2ncncc2n1C1CCN(Cc2ccccc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=c1[nH]c2ncncc2n1C1CCNCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 7-(1-benzylpiperidin-4-yl)-7,9-dihydro-8H-purin-8-one (1.2 g, 3.7 mmol) in 4 N hydrogen chloride in dioxane (50 mL), was stirred vigorously at room temperature for 3 h. The reaction was concentrated in vacuo to give the title compound as a white solid. MS: m/z=220 (M+1)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][C:16]1[CH:17]=[C:18](O)[CH:19]=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:18]2[CH:19]=[CH:20][C:21]([N+:22]([O-:24])=[O:23])=[C:16]([CH3:15])[CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(O)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 6 h
Yield: 59.9 %

Procedure:
To a solution of 1-t-butoxycarbonyl-4-hydroxypiperidine (6.04 g), 3-methyl-4-nitrophenol (4.59 g) and triphenylphosphine (10.20 g) in dichloromethane (100 ml) was added dropwise diethyl azodicarboxylate (6.1 ml) in an ice bath and the mixture was stirred at room temperature for 6 hours. The reaction mixture was concentrated in vacuo. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate=3/1 as an eluant to give the desired compound (6.04 g, yield 60%) as a pale yellow solid.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([NH2:15])=[CH:13][C:12]([C:16]([CH3:19])([CH3:18])[CH3:17])=[N:11]2)=[CH:6][C:5]=1[O:20][CH2:21][CH2:22][O:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][O:25]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[NH2:15][C:14]1[N:10]([C:7]2[CH:8]=[CH:9][C:4]([CH2:3][OH:2])=[C:5]([O:20][CH2:21][CH2:22][O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)[CH:6]=2)[N:11]=[C:12]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:13]=1
Reactant: COC(=O)c1ccc(-n2nc(C(C)(C)C)cc2N)cc1OCCOC1CCCCO1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(N)n(-c2ccc(CO)c(OCCOC3CCCCO3)c2)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 97.8 %

Procedure:
A solution of Intermediate 55b (1.72 g, 4.12 mmol) in THF (30 mL) was treated with LiAlH4 (2M in THF, 2.5 mL, 4.94 mmol) [CARE: gas evolution]. The reaction mixture was left to stir at RT for 5 h. The reaction was quenched slowly with water and the product was extracted with EtOAc. The organic phase was separated, washed with brine, dried over Na2SO4, and evaporated under reduced pressure to give the title compound (1.57 g, 95%). LCMS (Method 3): Rt 2.80 min, m/z 390 [MH+].
Reaction SMILES: C(OC[N:10]1[C:14]2[CH:15]=[N:16][NH:17][C:18](=[O:19])[C:13]=2[C:12]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[F:27])=[C:11]1[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH:35]([F:37])[F:36])=[C:30]([O:38][CH:39]2[CH2:41][CH2:40]2)[CH:29]=1)C1C=CC=CC=1.Cl.[H][H]>[Pd].C(O)C>[CH:39]1([O:38][C:30]2[CH:29]=[C:28]([C:11]3[NH:10][C:14]4[CH:15]=[N:16][NH:17][C:18](=[O:19])[C:13]=4[C:12]=3[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[CH:33]=[CH:32][C:31]=2[O:34][CH:35]([F:37])[F:36])[CH2:41][CH2:40]1
Reactant: [H][H]
Reactant: O=c1[nH]ncc2c1c(Cc1ccccc1F)c(-c1ccc(OC(F)F)c(OC3CC3)c1)n2COCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: O=c1[nH]ncc2[nH]c(-c3ccc(OC(F)F)c(OC4CC4)c3)c(Cc3ccccc3F)c12
Reaction time: 1 h
Yield: 88.9 %

Procedure:
To 330 ml of ethanol solution containing 4.28 g (7.62 mmol) of 1-benzyloxymethyl-2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-(2-fluorobenzyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Example 22-(a) were added 1.50 g of 5% palladium-active carbon and 3.8 ml of 2N hydrochloric acid, and then the mixture was stirred under 1 atm hydrogen atmosphere at 50° C. for 1 hour. After completion of the reaction, the reaction mixture was filtered, the filtrate was concentrated under reduced pressure, methanol and 28% aqueous ammonia were added to the obtained solid, and the mixture was stirred for 1 hour. Then, the solution was concentrated under reduced pressure, water was added to the obtained concentrate, and the precipitated solid was collected by filtration. The obtained solid was washed with water and dried under reduced pressure to obtain 2.99 g of the title compound as a white solid. (Yield: 89%)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([CH:10]=[C:11]2[C:16](=O)[C:15](=[CH:18][C:19]3[CH:24]=[C:23]([CH3:25])[C:22]([O:26][CH3:27])=[CH:21][C:20]=3[CH3:28])[CH2:14][O:13][CH2:12]2)=[C:5]([CH3:29])[CH:4]=1.[NH2:30][C:31]1[S:32][CH2:33][CH2:34][N:35]=1>C(Cl)(Cl)Cl.CCO>[CH3:27][O:26][C:22]1[C:23]([CH3:25])=[CH:24][C:19]([CH:18]2[N:35]3[CH2:34][CH2:33][S:32][C:31]3=[N:30][C:16]3[C:11](=[CH:10][C:6]4[CH:7]=[C:8]([CH3:9])[C:3]([O:2][CH3:1])=[CH:4][C:5]=4[CH3:29])[CH2:12][O:13][CH2:14][C:15]2=3)=[C:20]([CH3:28])[CH:21]=1
Reactant: NC1=NCCS1
Reactant: COc1cc(C)c(C=C2COCC(=Cc3cc(C)c(OC)cc3C)C2=O)cc1C
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: COc1cc(C)c(C=C2COCC3=C2N=C2SCCN2C3c2cc(C)c(OC)cc2C)cc1C
Yield: 46.9 %

Procedure:
A stirred solution of tetrahydro-3,5-bis[(4-methoxy-2,5-dimethylphenyl)methylene]-4H-pyran-4-one (3.0 g, 7.6 mmole) and 2-amino-2-thiazoline (1.0 g, 9.7 mmole) in 75 ml of CHCl3 is heated at reflux temperature for 72 hours. After cooling, the solution is filtered to remove a small amount of insoluble material. The solvent is evaporated to give an oily residue. A solution of this material in 25 ml of EtOH yields 1.7 g of light yellow solid, m.p. 195°-197°. Crystallization from 20 ml of 10% DMF/MeOH gives 1.3 g (35%) of cream colored solid, m.p. 196°-198°.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+].[CH2:22](O)[CH3:23]>>[CH2:22]([O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([CH3:11])=[C:2]([OH:1])[CH:3]=1)[CH3:23]
Reactant: CCO
Reactant: Cc1ccc(C(=O)O)cc1O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)c1ccc(C)c(O)c1

Procedure:
A mixture of 3-hydroxy-4-methylbenzoic acid (25.42 g, 167 mmol, TCl US) and concentrated sulfuric acid (3 mL) in absolute ethanol (180 mL) was heated at reflux for 20 hours. After cooling, solid sodium bicarbonate (10 g) was added to neutralize the acid. The mixture was partitioned between diethyl ether (2×400 mL) and water (2×300 mL). The organic layers were washed with brine (300 mL), combined, dried (MgSO4), filtered, and concentrated. The residue was recrystallized from hexanes to give 3-hydroxy-4-methyl-benzoic acid ethyl ester as white crystals in two crops. (Yield 29.14 g).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7](Br)[S:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1)=[O:4].[CH3:18][NH:19][CH3:20]>>[CH3:18][N:19]([CH3:20])[C:7]1[S:8][C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)=[C:5]([C:3]([OH:2])=[O:4])[N:6]=1
Reactant: COC(=O)c1nc(Br)sc1-c1cccc(F)c1
Reactant: CNC
Product: CN(C)c1nc(C(=O)O)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of 2-bromo-5-(3-fluoro-phenyl)-thiazole-4-carboxylic acid methyl ester with dimethylamine. LC-MS: tR=0.87 min; [M+H]+=267.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[C:11]([C:18]3[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:25])=[N:12][O:13][C:14]=2[CH:15]2[CH2:17][CH2:16]2)[CH:5]=[CH:4][C:3]=1[C:26]1([OH:40])[CH2:29][CH:28]([C:30]2[CH:31]=[C:32]([S:36](Cl)(=[O:38])=[O:37])[CH:33]=[CH:34][CH:35]=2)[CH2:27]1.[NH4+:41].[OH-]>CC#N>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[C:11]([C:18]3[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:25])=[N:12][O:13][C:14]=2[CH:15]2[CH2:17][CH2:16]2)[CH:5]=[CH:4][C:3]=1[C:26]1([OH:40])[CH2:29][CH:28]([C:30]2[CH:31]=[C:32]([S:36]([NH2:41])(=[O:38])=[O:37])[CH:33]=[CH:34][CH:35]=2)[CH2:27]1
Reactant: [NH4+]
Reactant: O=S(=O)(Cl)c1cccc(C2CC(O)(c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C4CC4)cc3Cl)C2)c1
Agent: [OH-]
Solvent: CC#N
Product: NS(=O)(=O)c1cccc(C2CC(O)(c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C4CC4)cc3Cl)C2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 10 %

Procedure:
To the solution of compound 5b (30 mg) in CH3CN (2 mL) was added NH4OH (0.3 mL). The mixture was stirred at rt for 1 h. Concentration to dryness and purification by prep. RP-HPLC gave the title compound 5 (3.5 mg, 10% for two steps) as a white solid. 1H NMR (400 MHz, CDCl3) δ: 7.85 (s, 1H), 7.77 (d, J=7.6 Hz, 1H), 7.54-7.41 (m, 5H), 7.35 (d, J=8.4 Hz, 1H), 6.90 (s, 1H), 6.75 (d, J=8.4 Hz, 1H), 4.83 (s, 2H), 4.77 (s, broad, 2H), 3.20 (t, J=10.4 Hz, 2H), 3.04 (m, 1H), 2.58 (t, J=10.6 Hz, 2H), 2.17 (m, 1H), 1.31-1.30 (m, 2H), 1.20-1.16 (m, 2H). MS (ESI−) m/z: 617 [M−1]−.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:12]2[C:16]([CH3:17])=[CH:15][CH:14]=[C:13]2[CH3:18])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C([Li])CCC.[CH3:24][C:25]([CH3:27])=[O:26].[NH4+].[Cl-]>C1COCC1.CCCCCC>[CH3:18][C:13]1[N:12]([C:4]2[CH:3]=[C:2]([C:25]([OH:26])([CH3:27])[CH3:24])[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=2)[C:16]([CH3:17])=[CH:15][CH:14]=1
Reactant: CC(C)=O
Reactant: Cc1ccc(C)n1-c1cc(Br)cc(C(F)(F)F)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1ccc(C)n1-c1cc(C(C)(C)O)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.4 %

Procedure:
To a solution of 1-[3-bromo-5-(trifluoromethyl)phenyl]-2,5-dimethyl-1H-pyrrole (4.98 g, 15.6 mmol) in THF (75 mL) at −78° C., was added a solution of 2.50M n-butyllithium in hexane dropwise. The reaction mixture was allowed to stir for 30 min and then acetone (1.49 mL, 20.4 mmol) was added dropwise. The reaction mixture was allowed to stir at −78° C. for 30 min, and then allowed to warm to rt. Saturated aq. NH4Cl was added and the mixture was extracted with EtOAc (3×). The organic solutions were combined, washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give 2-[3-(2,5-dimethyl-1H-pyrrol-1-yl)-5-(trifluoromethyl)phenyl]propan-2-ol (2.29 g, 49.2%). LCMS: (FA) ES+ 298.2.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[C:4]([O:12][C:13]([F:16])([F:15])[F:14])[CH:3]=1.CC(C)=[O:19].OS(O)(=O)=O.O=[Cr](=O)=O.O>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:19])=[O:11])=[C:4]([O:12][C:13]([F:14])([F:15])[F:16])[CH:3]=1
Reactant: OCCCc1ccc(Br)cc1OC(F)(F)F
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)CCc1ccc(Br)cc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
To a solution of 3-(4-bromo-2-trifluoromethoxy-phenyl)-propan-1-ol obtained in step B of example 62 (1 g, 3.34 mmol) in acetone (15 mL) was added Jones reagent (4 mL) at 4° C. The mixture was stirred at ambient temperature for 2 hr. The solution was poured into water (50 mL), and the aqueous layer was extracted with Et2O (three times). The combined organic layer was dried over MgSO4, filtered, concentrated, and purified by flash chromatography (silica gel, 25% EtOAc in hexane) to give 3-(4-Bromo-2-trifluoromethoxy-phenyl)-propionic acid (930 mg, 89%) as a colorless oil.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:13][CH3:14])[CH:9]=2)[CH2:4]1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>O.C(Cl)Cl.[OH-].[Na+]>[C:15]([NH:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:13][CH3:14])[CH:9]=2)[CH2:4]1)(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc2c(c1)CCC(N)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: COc1ccc2c(c1)CCC(NC(C)=O)C2
Temperature: 15 °C

Procedure:
2-Amino-6-methoxy-1,2,3,4-tetrahydronaphthalene hydrochloride is dissolved in a mixture of water and methylene chloride, and 10 N sodium hydroxide solution is added thereto until the pH is 12. 1.5 equivalents of acetic anhydride are then added, the pH being kept between 10 and 12 with 10 N sodium hydroxide solution, and the mixture being cooled to about 15° C. The pH is then brought to between 7 and 8 and the organic phase is separated off, dried and evaporated. When recrystallised from petroleum ether, the residue melts at 175° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH:13]([C:15]2[N:16]=[CH:17][NH:18][CH:19]=2)O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>CS(O)(=O)=O>[C:1]([C:5]1[CH:10]=[C:9]2[C:8]([CH2:11][CH2:12][CH:13]2[C:15]2[N:16]=[CH:17][NH:18][CH:19]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(CCC(O)c2c[nH]cn2)cc1
Agent: CS(=O)(=O)O
Product: CC(C)(C)c1ccc2c(c1)C(c1c[nH]cn1)CC2
Temperature: 60 °C

Procedure:
A mixture of 3-(4-tert-butylphenyl)-1-(1H-imidazol-4-yl)-propan-1-ol (2.0 g) and methanesulfonic acid (30 ml) is heated at 60° C. for 5 minutes. The reaction is then quenched by pouring it into ice-water solution. The acidic solution is made basic with ammmonium hydroxide solution, and extracted with ethyl acetate. The combined organic layers are washed with water, dried with sodium sulfate, and evaporated to dryness under reduced pressure. The crude product is purified by flash chromatography by eluting with methylene chloride-methanol as eluent. The product is crystallized from ethyl acetate. The yield is 220 mg.
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:12])[CH3:11].C(OP([C:21](Br)([F:23])[F:22])(=O)OCC)C>C(#N)C.O>[F:22][CH:21]([F:23])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:12])[CH3:11]
Reactant: CCOP(=O)(OCC)C(F)(F)Br
Reactant: CC(=O)c1ccccc1O
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: CC(=O)c1ccccc1OC(F)F
Temperature: -20 °C
Yield: 91.7 %

Procedure:
Potassium hydroxide (105 g, 1872 mmol) was suspended in a mixture of acetonitrile (200 mL) and water (200 mL) and cooled to approximately −20° C. 1-(2-Hydroxyphenyl)ethanone (11.28 mL, 93.7 mmol) was added dropwise, followed by diethyl[bromo(difluoro)methyl]phosphonate (33.27 mL, 187.3 mmol) over 15 minutes. The mixture was then allowed to warm to room temperature over 1 h. The mixture was extracted with ethyl acetate (3×200 mL), then the combined organic layers were washed with brine (50 mL), dried over magnesium sulfate and concentrated under vacuum. The mixture was purified by flash chromatography to afford the title compound (16.0 g, 92%) as a colourless oil. Method B HPLC-MS: MH+ m/z 187, RT 1.77 minutes.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]([OH:8])=[O:7].O.[Na].[CH2:11]([O:18][C:19](Cl)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>O>[CH2:11]([O:18][C:19]([N:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]([OH:8])=[O:7])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)C1CCCN1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na]
Solvent: O
Product: O=C(O)C1CCCN1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To the solution of pyrrolidine-2-carboxylic acid (1.15 g, 10 mmol) of water (20 ml) was added sodium hydrate (1.6 g, 40 mmol). Then benzyloxycarbonyl chloride (2.02 g, 12 mmol) was added drop wise at 0° C. The mixture was stirred at 0° C. for 2 h. The resulting mixture was treated with 5N hydrochloric acid to pH=6 and extracted with ethyl acetate, the solvent was removed under reduced pressure and dried in vacuum. 2.0 g of 1-(benzyloxycarbonyl)pyrrolidine-2-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[CH2:10][CH2:9][C:8](=[O:13])[NH:7][C:6]=2[CH:14]=1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([N:7]1[C:8](=[O:13])[CH2:9][CH2:10][C:11](=[O:12])[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:14][C:6]1=2)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1CCC(=O)c2ccc(Cl)cc2N1
Reactant: BrCc1ccccc1
Product: O=C1CCC(=O)N(Cc2ccccc2)c2cc(Cl)ccc21
Yield: 38 %

Procedure:
In a manner similar to that described for Method W, 8-chloro-3,4-dihydro-1H-benzo[b]azepine-2,5-dione and benzyl bromide were converted to the title compound (38%): MS m/z=300 (M+H).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH:12]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.[ClH:27]>C(OCC)(=O)C>[ClH:27].[ClH:27].[C:1]1([C:7]2[N:8]=[C:9]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccccc3)cs2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: c1ccc(-c2csc(C3CCNCC3)n2)cc1
Yield: 98.2 %

Procedure:
A solution of tert-butyl 4-(4-phenyl-1,3-thiazol-2-yl)piperidine-1-carboxylate (1.35 g, 3.92 mmol), 2N hydrogen chloride methanol (100 ml) and ethyl acetate (10 ml) was stirred at room temperature for 12 hours and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solution of methanol and ether to obtain the desired product (1.08 g, 98.2%) as a solid.
Reaction SMILES: [NH2:1][C:2]1([CH2:19][CH2:20][OH:21])[C:15]2[CH:14]=[C:13]([Cl:16])[N:12]=[C:11]([F:17])[C:10]=2[O:9][C:8]2[C:3]1=[CH:4][C:5]([Br:18])=[CH:6][CH:7]=2.C([O-])(=O)C.[Na+].[N:27]#[C:28]Br>CCO>[Br:18][C:5]1[CH:4]=[C:3]2[C:2]3([CH2:19][CH2:20][O:21][C:28]([NH2:27])=[N:1]3)[C:15]3[CH:14]=[C:13]([Cl:16])[N:12]=[C:11]([F:17])[C:10]=3[O:9][C:8]2=[CH:7][CH:6]=1
Reactant: N#CBr
Reactant: NC1(CCO)c2cc(Br)ccc2Oc2c1cc(Cl)nc2F
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: NC1=NC2(CCO1)c1cc(Br)ccc1Oc1c2cc(Cl)nc1F
Temperature: 25 °C
Reaction time: 120 h
Yield: 44.7 %

Procedure:
To a solution of 2-(5-amino-7-bromo-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-yl)ethanol (13 g, 34.8 mmol) in EtOH (50 mL) was added sodium acetate (5.71 g, 69.6 mmol) followed by the dropwise addition of cyanogen bromide (3.0M solution in DCM; 13.92 ml, 41.8 mmol). The resulting mixture was stirred at RT for 5 days. The reaction mixture was concentrated under reduced pressure, washed with water and extracted with DCM. The combined organic layers were dried over Na2SO4, concentrated under reduced pressure and azeotropically dried with toluene. The obtained residue was dissolved in DCM and TFA (40 mL) was added to the solution. The resulting mixture was stirred at RT for 30 min. The mixture was carefully quenched with aqueous, saturated NaHCO3 solution and extracted with DCM. The combined organics were dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by chromatography (0-3% MeOH/DCM) to afford 7-bromo-3-chloro-1-fluoro-5′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazin]-2′-amine (6.2 g, 15.55 mmol, 44.7% yield) as a light yellow solid.