Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:17])[C:5]2[S:10][C:9](=[O:11])[N:8]([CH2:12][CH:13]=[CH:14][CH2:15][CH3:16])[C:6]=2[N:7]=1.[H-].[Na+].I[CH3:21]>CN(C=O)C>[NH2:1][C:2]1[N:3]([CH3:21])[C:4](=[O:17])[C:5]2[S:10][C:9](=[O:11])[N:8]([CH2:12][CH:13]=[CH:14][CH2:15][CH3:16])[C:6]=2[N:7]=1
Reactant: CI
Reactant: CCC=CCn1c(=O)sc2c(=O)[nH]c(N)nc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC=CCn1c(=O)sc2c(=O)n(C)c(N)nc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 5-amino-3-(pent-2-ene-1-yl)thiazolo[4,5-d]pyrimidine-2,7(3H,6H)-dione (350 mg, 1.35 mmol), NaH (80% dispersion in mineral oil, 42 mg, 1.4 mmol) and anhydrous DMF (15 mL) was protected from moisture and stirred at ambient temperature for 0.25 h. Iodomethane (0.1 mL, 1.61 mmol) was added and the mixture was stirred for an additional 1 h. The mixture was evaporated in vacuum and then H2O (20 mL) was added. The mixture was stirred for 15 min and then the solid was collected by filtration. The solid was suspended in MeOH (25 mL) and silica gel (5 g) was added. The mixture was evaporated and the dry powder was placed on top of a silica gel column (5.5×20 cm). The column was flash eluted with progressively increasing concentrations of MeOH in CH2Cl2 (%MeOH, vol in L): (0, 1); (1, 1); (2, 1); (3, 1). Eluate containing the homogeneous product was evaporated and the solid was dried in vacuum at 80° C. for 16 h; 240 mg (0.901 mmol, 66%), mp 184-187° C. Ir (KBr): ν3420, 3330 and 3210 (NH2), 1715 (C=O), and 1675 (C=N) cm-1. Uv, λmax (nm), (ε×10-3): pH 1, 300 (9.37), 252 (8.02), 222 (30.9); MeOH, 302 (9.07), 252 (8.35), 222 (31.3); pH 11, 300 (9.41), 252 (8.08), 226 (21.0). 1H nmr (DMSO-d6): δ0.954 (t, 3H, CH3), 2.15-2.22 (m, 2H, CH3CH2), 3.29 (s, 3H, CH3), 4.38 (d, 2H, NCH2), 5.34-5.40 (m, 1H, CHCH) 5.53-5.59 (m, 1H, CHCH), and 7.51 (br s, 2H, NH2). Anal. Calc'd for C11H14N4O2S (266.32): C, 49.61; H, 5.30; N, 21.04. Found: C, 49.93; H, 5.17; N, 20.77.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:12]([O-])=O)[CH:5]=[C:6]([O:8][CH2:9][CH2:10][F:11])[CH:7]=1.[BH4-].[Na+].C(OCC)C.Cl>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([O:8][CH2:9][CH2:10][F:11])[CH:7]=1)[NH2:12]
Reactant: O=[N+]([O-])c1cc(Br)cc(OCCF)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Nc1cc(Br)cc(OCCF)c1
Temperature: 25 °C

Procedure:
A solution of 3-bromo-5-fluoroethoxynitrobenzene, as described above in Step D, (990 mg, 3.75 mmol) in tetrahydrofuran (22 mL) was added to a mixture of NaBH4/S3 (1.2 g) in tetrahydrofuran (15 mL) and the resulting mixture was placed in a 60° C. oil bath and heated overnight. The reaction was cooled to room temperature and concentrated using the rotary evaporator giving a yellow solid. Diethyl ether was added and 10% HCl until the pH was 1. The resulting mixture was filtered through celite and the layers were separated. The aqueous layer was washed with diethyl ether. The aqueous layer was made basic (pH>10) with diethyl ether present, the layers were separated and the aqueous layer was extracted with diethyl ether and ethyl acetate. The organic layers were combined and dried (MgSO4), filtered and concentrated in vacuo to give 3-bromo-5-fluoroethoxyaniline as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:8]([O-])=O)[CH:5]=[CH:6][CH:7]=1.[S:11]([O-:14])([O-:13])=[O:12].[Na+].[Na+].[OH-].[Na+].Cl>O>[Cl:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[CH:6][C:7]=1[S:11]([OH:14])(=[O:13])=[O:12]
Reactant: O=[N+]([O-])c1cccc(Cl)c1
Reactant: O=S([O-])[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1ccc(S(=O)(=O)O)c(Cl)c1
Reaction time: 1.5 h

Procedure:
A mixture of 31.5 grams of 3-chloronitrobenzene, 450 milliliters of 5N-sodium sulphite solution and 500 milliliters of 2N sodium hydroxide solution was refluxed with stirring for 90 minutes, acidified with concentrated hydrochloric acid, and refluxed for 1 hour. On cooling and diluting with water a solid crystallised out which was filtered and washed with water to give 9.9 grams of 2-chlorosulphanilic acid.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[Cl:36])[C:7]([CH2:10][C:11]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(C(OCC)=O)[C:12]([O:14]CC)=[O:13])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[OH-].[K+].O>C(O)C>[CH2:1]([C:5]1[N:6]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[Cl:36])[C:7]([CH2:10][CH:11]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:12]([OH:14])=[O:13])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(CC(Cc2ccccc2)(C(=O)OCC)C(=O)OCC)n1Cc1ccccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCc1ncc(CC(Cc2ccccc2)C(=O)O)n1Cc1ccccc1Cl
Yield: 91.3 %

Procedure:
A mixture of diethyl [2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]methyl-2-benzylmalonate (0.72 g, 1.36 mmol), potassium hydroxide (0.83 g, 14.7 mmol), water (15 mL) and ethanol (25 mL) was refluxed for 4 hours. The ethanol was evaporated, the residual aqueous layer was extracted with diethyl ether, and the basic solution was adjusted to pH 3.75 with concentrated hydrochloric acid. The precipitated product was extracted into methylene chloride, dried, and concentrated. This crude product was flash chromatographed on silica gel with 10% methanol in methylene chloride to give 0.51 g (86%) of 3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-benzylpropanoic acid; mp 118°-120° C. (from acetone/diethyl ether as the hydrochloride salt).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:13]2=[N:14][C:15]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[N:16][C:17](=[O:18])[C:12]2=[C:11]([CH3:25])[NH:10]1.[N+:26]([O-])([OH:28])=[O:27]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:26]([O-:28])=[O:27])=[CH:4][C:3]=1[CH2:8][N:9]1[C:13]2=[N:14][C:15]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[N:16][C:17](=[O:18])[C:12]2=[C:11]([CH3:25])[NH:10]1
Reactant: O=[N+]([O-])O
Reactant: Cc1[nH]n(Cc2ccccc2Cl)c2nc(-c3ccncc3)nc(=O)c1-2
Product: Cc1[nH]n(Cc2cc([N+](=O)[O-])ccc2Cl)c2nc(-c3ccncc3)nc(=O)c1-2
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a solution of 90% nitric acid (30 ml) at -10° C. was added in portions over 4 hours 1-(2-chlorophenylmethyl)-3-methyl-6-(4-pyridyl)pyrazolo[3,4-d]pyrimidin-4-one (4.9 g, 0.014 mol). The mixture was stirred at -10° C. for 30 minutes and poured into ice-water. The product was collected by filtration and washed with water. The solid residue was dissolved in methanol/DMF (3/1), treated with charcoal and the solvent was concentrated in vacuo. Ether was added to the residue and the product was collected by filtration and washed with ether to afford 5.5 g (99%) of 1-(2-chloro-5-nitrophenylmethyl)-3-methyl-6-(4-pyridyl)pyrazolo[3,4-d]pyrimidin-4-one as an off-white powder, m.p. 290°-1° C. when dried at 80° C. in high vacuum.
Reaction SMILES: C[O-].[Na+].[CH3:4][O:5][C:6]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:7]=1[C:8]([CH2:10][O:11][C:12]1[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=1[C:14]([O:16]C)=O)=[O:9]>CO>[CH3:4][O:5][C:6]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:7]=1[C:8]([C:10]1[O:11][C:12]2[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=2[C:14]=1[OH:16])=[O:9]
Reactant: COC(=O)c1ccccc1OCC(=O)c1cc(OC)ccc1OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(OC)c(C(=O)c2oc3ccccc3c2O)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of sodium methoxide (0.04 g, 0.67 mmol) in methanol was added to a solution of methyl 2-(2,5-dimethoxybenzoylmethoxy)-benzoate (0.20 g, 0.60 mmol) in dry methanol (20 ml) at 0° C. The reaction mixture was stirred at room temperature for 5 h. The reaction mixture was concentrated under reduced pressure and water was added, then extracted with ethyl acetate (three timer 30 ml). The organic layer was wahed with water, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography eluting with a gradient from 12% to 20% ethyl acetate in hexane to get the title product, m.p. 158° C. 1H-NMR (CDCl3, 400 MHz): 3.81 (s 3H), 3.83 (s, 3H), 6.99 (d, 1H), 7.07 (dd, 1H), 7.19 (d, 1H), 7.28 (d, 1H) 7.37 (d, 1H), 7.50 (t, 1H), 7.80 (d 1H).
Reaction SMILES: [C:1]([O:9]CC)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[CH2:12]([CH2:14][NH2:15])[OH:13]>>[OH:13][CH2:12][CH2:14][NH:15][C:1]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)=[O:9]
Reactant: CCOC(=O)c1cccnc1
Reactant: NCCO
Product: O=C(NCCO)c1cccnc1
Reaction time: 48 h
Yield: 85.1 %

Procedure:
A solution of 49.2 g (0.32525 mol) ethyl nicotinate and 72 g (1.17 mol) ethanolamine was heated at 70° C. for 60 hours. The excess ethanolamine was removed under reduced pressure and the resulting viscous cream oil was stirred with ether for 48 hours. The resulting white solid was removed by filtration, affording 46 g (85.1%) of the title compound melting at 75°-78° C.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][NH:18][CH2:19][C:20]3[CH:31]=[CH:30][C:23]([O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[C:34]([C:38]1[CH:43]=[CH:42][C:41]([N:44]=[C:45]=[O:46])=[CH:40][CH:39]=1)([CH3:37])([CH3:36])[CH3:35].N1CCOCC1.C(O)C(N)(CO)CO>C(Cl)Cl>[C:34]([C:38]1[CH:43]=[CH:42][C:41]([NH:44][C:45]([N:18]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:30][CH:31]=2)[CH2:17][C:16]2[CH:15]=[CH:14][C:13]([C:12]#[C:11][C:8]3[CH:7]=[CH:6][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[CH:10][CH:9]=3)=[CH:33][CH:32]=2)=[O:46])=[CH:40][CH:39]=1)([CH3:37])([CH3:35])[CH3:36]
Reactant: CCCCc1ccc(C#Cc2ccc(CNCc3ccc(OCC(=O)OC)cc3)cc2)cc1
Reactant: CC(C)(C)c1ccc(N=C=O)cc1
Agent: NC(CO)(CO)CO
Solvent: C1COCCN1
Solvent: ClCCl
Product: CCCCc1ccc(C#Cc2ccc(CN(Cc3ccc(OCC(=O)OC)cc3)C(=O)Nc3ccc(C(C)(C)C)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of methyl {4-[({4-[(4-butylphenyl)ethynyl]benzyl}amino)methyl]phenoxy}acetate (45 mg, 0.10 mmol) and 4-tert-butylphenylisocyanate (Aldrich, 27 mg, 0.15 mmol) in DCM (2 mL) was stirred at rt overnight in presence of a morpholine resin (1.5 eq., Novabiochem HL, 3.8 mmol/g). Trisamine resin (1.2 eq, Novabiochem, 3.5 mmol/g) was then added and the mixture was stirred at rt for an additional 2 hrs. The reaction mixture was then filtrated and the solvent was removed under reduced pressure to give quantitatively the title compound. HPLC, Rt: 5.97 min purity: 96.3%). M+(ESI): 619.6, M−(ESI): 616.9.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:32][CH2:31][CH2:30][C@@:7]2([CH2:11][C@H:10]([O:12][Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:9][CH2:8]2)[C:6]1=[O:33])=[O:4].FC(F)(F)C(O)=O.C([SiH](CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O>[CH3:1][O:2][C:3]([CH:5]1[CH2:32][CH2:31][CH2:30][C@@:7]2([CH2:11][C@H:10]([O:12][Si:13]([C:26]([CH3:29])([CH3:27])[CH3:28])([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:9][CH2:8]2)[CH:6]1[OH:33])=[O:4]
Reactant: COC(=O)C1CCC[C@]2(CC[C@@H](O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)C1=O
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)C1CCC[C@]2(CC[C@@H](O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)C1O
Yield: 106.2 %

Procedure:
To a solution of the crude (2R,5R)-2-(tert-butyldiphenylsilanyloxy)-6-oxo-spiro[4.5]de cane-7-carboxylic acid methyl ester (1.65 g) obtained in Step 4 in toluene (1.6 mL) were added trifluoroacetic acid (5 mL) and triethylsilane (0.52 mL) under ice-cooling, followed by stirring the mixture under ice-cooling for 3 hours. Then, to the reaction mixture was added dropwise a solution of potassium carbonate (4.95 g) in water (20 mL), and the mixture was stirred under ice-cooling for 10 minutes, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated to give (2R,5R)-2-(tert-butyldiphenylsilanyloxy)-6-hydroxy-spiro[4.5]decane-7-carboxylic acid methyl ester (1.76 g) as a crude product.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]([CH2:27][C:28]([O:30][CH3:31])=[O:29])[C@H:8]([CH2:18][O:19][Si](C(C)(C)C)(C)C)[CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:6])[CH:2]=[CH2:3].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>CO>[CH2:1]([O:4][C:5]([N:7]([CH2:27][C:28]([O:30][CH3:31])=[O:29])[C@H:8]([CH2:18][OH:19])[CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N(CC(=O)OC)[C@@H](CCC(=O)OC(C)(C)C)CO[Si](C)(C)C(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: C=CCOC(=O)N(CC(=O)OC)[C@H](CO)CCC(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 892.7 %

Procedure:
To a solution of tert-butyl (4S)-4-[[(allyloxy)carbonyl](2-methoxy-2-oxoethyl)amino]-5-{[tert-butyl(dimethyl)silyl]oxy}pentanoate (5.29 g, 1.2 mmol) in methanol (106 ml) was added p-toluenesulfonic acid monohydrate (0.22 g, 1.2 mmol) and the mixture was stirred for 30 minutes. To the mixture was further added p-toluenesulfonic acid monohydrate (0.22 g, 1.2 mmol) and the mixture was stirred for 1 hour. The reaction mixture was poured into water and extracted three times with ethyl acetate. The organic layer was washed with water and then a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and the solvent was removed. The residue was purified with silica gel chromatography to give tert-butyl (4S)-4-[[(allyloxy)carbonyl](2-methoxy-2-oxoethyl)amino]-5-hydroxypentanoate (3.7 g, 93%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[N:10]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:5]=[C:6]([F:8])[CH:7]=1.CCN(C(C)C)C(C)C.[CH3:32][S-:33].[Na+].CCOC(C)=O>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[F:8][C:6]1[CH:5]=[C:4]([C@H:9]2[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[N:10]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:3]=[C:2]([S:33][CH3:32])[CH:7]=1
Reactant: C[S-]
Reactant: CC(C)(C)OC(=O)N1[C@@H](c2cc(F)cc(Br)c2)COC1(C)C
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CSc1cc(F)cc([C@H]2COC(C)(C)N2C(=O)OC(C)(C)C)c1
Temperature: 110 °C
Yield: 101.5 %

Procedure:
A mixture of Xantphos (13.91 mg, 0.024 mmol), Pd2(dba)3 (22.02 mg, 0.024 mmol), (5)-tert-butyl 4-(3-bromo-5-fluorophenyl)-2,2-dimethyloxazolidine-3-carboxylate (300 mg, 0.802 mmol), DIEA (700 μl, 4.01 mmol) and sodium methanethiolate (112 mg, 1.603 mmol) in toluene (2.6 mL) was microwave heated at 110° C. for 18 min. EtOAc was added, and washed with sat NaHCO3, water, and brine. The mixture was filtered off, concentrated and purified with flash chromatography eluting with 0-60% of EtOAc/heptane to provide (S)-tert-butyl 4-(3-fluoro-5-(methylthio)phenyl)-2,2-dimethyloxazolidine-3-carboxylate (278 mg, 102%) as an oil. LCMS (m/z): 286.1 (MH+-56), 1.14 min.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([OH:26])[CH:13]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)[CH:10]=2)[N:5]=[C:4]([O:27][CH3:28])[C:3]=1[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=1.C(O)(C(F)(F)F)=O.[OH-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[OH:26])[CH:10]=2)[N:5]=[C:4]([O:27][CH3:28])[C:3]=1[CH2:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]([F:38])([F:37])[F:39])=[CH:34][CH:35]=1
Reactant: COc1nc2ccc(C(O)C3CCN(C(=O)OC(C)(C)C)CC3)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1nc2ccc(C(O)C3CCNCC3)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-((4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(hydroxy)methyl)piperidine-1-carboxylate (110 mg, 0.19 mmol, Intermediate 11: step a) in DCM (5 mL) was added TFA (75 μL, 0.97 mmol). The resulting solution was stirred at room temperature for 2 hours. TFA (75 μL, 0.97 mmol) was added and the mixture stirred at room temperature overnight. Then the reaction was diluted with DCM, cooled to 0° C., and the pH adjusted to ˜pH 8 by the addition of 3 N aqueous NaOH dropwise. The layers were separated and the organics dried (MgSO4), filtered and concentrated to dryness to afford the title compound which was used without further purification.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:8][C:9](=[O:16])[N:10]2[CH:13]([CH3:15])[CH3:14])=[CH:5][CH:4]=1.C(=O)([O-])[O-:24].[Na+].[Na+].CO.[OH-].[Na+]>C(Cl)(Cl)Cl.C1C=CC=CC=1.O>[OH:24][CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:8][C:9](=[O:16])[N:10]2[CH:13]([CH3:15])[CH3:14])=[CH:5][CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)n1c(=O)nc(-c2ccccc2)c2ccc(CBr)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: c1ccccc1
Product: CC(C)n1c(=O)nc(-c2ccccc2)c2ccc(CO)cc21

Procedure:
A mixture of 69.3 of crude 7-bromomethyl-1-isopropyl-4-phenyl-2(1H)-quinazolinone (obtained by repeating Step A, above), 500 ml of a 10% aqueous sodium carbonate solution and 500 ml of methanol is refluxed for 8 hours, cooled, diluted by addition of 200 ml of distilled water containing 6 ml of 10N sodium hydroxide solution, and the resulting mixture extracted 3 times each with 400 ml of chloroform. Each extract is then washed twice with 200 ml portions of distilled water. The organic extracts are combined and evaporated to dryness to obtain a residue. The residue, thus obtained, is taken up in 100 ml of a mixture of chloroform: benzene (1:1), which solution is then placed on a chromatographic column of 480 g of silica gel in the same solvent. The column is eluted and fractions of from about 600 to 750 ml taken, in turn with 3 liters of chloroform: benzene (1:1) (fractions 1 to 4); 2 liters of 100% chloroform (fractions 5 to 7); 5 liters of ethyl acetate: chloroform (1:3) (fractions 8 to 14); and lastly 3 liters of ethyl acetate: Chloroform (1:1) (fractions 15 to 18). Fractions 9 to 14 are combined and evaporated to dryness to obtain a residue which yields refined title compound on repeated crystallization from ethyl acetate, m.p. 223° -225°.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:5]([NH2:11])=[N:6][C:7]([CH3:10])=[N:8][CH:9]=1.C(N(CC)CC)C.[C:19]1([C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[CH2:31][NH:30][CH2:29][CH2:28]3)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[CH3:10][C:7]1[N:6]=[C:5]([NH2:11])[C:4]([CH2:3][N:30]2[CH2:29][CH2:28][C:27]3[C:32](=[CH:33][CH:34]=[C:25]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:26]=3)[CH2:31]2)=[CH:9][N:8]=1
Reactant: Cc1ncc(CCl)c(N)n1
Reactant: c1ccc(-c2ccc3c(c2)CCNC3)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ncc(CN2CCc3cc(-c4ccccc4)ccc3C2)c(N)n1
Temperature: 25 °C
Reaction time: 60 h
Yield: 60.5 %

Procedure:
A suspension of 0.20 g (0.00080 mol) of 5-chloromethyl-2-methyl-pyrimidin-4-ylamine hydrochloride in 10 ml of dimethylformamide was treated with 0.34 ml (0.0024 mol) of triethylamine and 0.19 g (0.00097 mol) of 6-phenyl-1,2,3,4-tetrahydro-isoquinoline and the mixture was stirred at room temperature under argon for 60 hours The mixture was completely freed from the solvents. The residue was partitioned between dichloromethane and water, extracted, chromatographed over silica gel with acetonitrile/methanol 5:1 as the eluent and digested in diethyl ether. 0.16 g (61%) of 2-methyl-5-(6-phenyl-3,4-dihydro-1H-isoquinolin-2-ylmethyl)-pyrimidin-4-ylamine was obtained as white crystals; m.p. 186°-188°. A further 0.03 g of pale yellow crystals was recovered from the mother liquor.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(C)=O.[SH2]=N.[C:14]1([NH:20][C:21](C2C=CC=CC=2C(O)=O)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O>[C:1]1([NH:7][C:21]([NH:20][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC1CCCCC1
Reactant: O=C(O)c1ccccc1C(=O)Nc1ccccc1
Agent: N=[SH2]
Solvent: O
Solvent: CC(C)=O
Product: O=C(Nc1ccccc1)NC1CCCCC1
Yield: 88.7 %

Procedure:
A mixture of 1.0 g cyclohexylamine and 5 ml aceton was added dropwise to a suspension of 1.5 g phenylcarbamoyl-benzoic acid sulfimide with 20 ml aceton, under stirring. The reaction mixture was stirred for 80 minutes at room temperature, then diluted with 150 ml water. The precipitated solid product was cooled, filtered, washed with water and dried. 1.0 g 1-phenyl-3-cyclohexylurea was obtained with a melting point of from 182° to 184° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[NH:7][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[O:3]1.[Cl:14][C:15]([Cl:21])([S:19]Cl)[CH:16]([Cl:18])[Cl:17].C(N(CC)CC)C>ClCCl>[CH3:1][C:2]1([CH3:13])[N:7]([S:19][C:15]([Cl:21])([Cl:14])[CH:16]([Cl:18])[Cl:17])[C:6](=[O:8])[C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[O:3]1
Reactant: CC1(C)NC(=O)c2ccccc2O1
Reactant: ClSC(Cl)(Cl)C(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)Oc2ccccc2C(=O)N1SC(Cl)(Cl)C(Cl)Cl
Temperature: 0 °C
Yield: 15.9 %

Procedure:
A 250-ml flask equipped with condenser, stirrer and thermometer and immersed in an ice bath was charged with 150 ml of dichloromethane, 8.3 g (0.047 mol) of 2,2-dimethyl-1,3-benzoxazin-4-one and 10.9 g (0.047 mol) of 1,1,2,2-tetrachloroethylsulfenyl chloride. Then 4.75 g (0.047 mol) of triethylamine dissolved in 10 ml of dichloromethane was added dropwise over a period of 15 minutes. The resulting solution was stirred at 0° C. for 45 more minutes. The crude reaction mixture was washed three times with equal quantities of water. The organic phase was dried and then stripped of solvent. The resulting residue was washed with 200 ml of hexane and filtered. The dried filter cake, 5.1 g, was unreacted 2,2-dimethyl-1,3-benzoxazin-4-one. The filtrate was stripped of hexane and the resulting residue was chromatographed through 300 g of silica gel using 1 liter of hexane, 1 liter of 3% ether-hexane and 3 liters of 5% ether-hexane to give 2.8 g of 2,2-dimethyl-3-(1',1',2',2'-tetrachloroethylthio)-1,3-benzoxazin-4-one. Analysis, calculated for C12H11Cl4NO2S: %C, 37.81; %S, 8.55. Found: %Cl, 40.0; %S, 8.8. NMR spectra confirmed the assigned structure. The infrared spectra had strong adsorption at 1785, 1600, 1460, 1300, 1240 and 740 cm-1. These spectra also had many distinct, medium-strength adsorption bands in the 800-1700 cm-1 region.
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[N:20]=[CH:19][C:18](B4OC(C)(C)C(C)(C)O4)=[CH:17][N:16]=3)[CH:10]=2)[N:6]=[C:5]([C:30]2[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=2)[C:33]#[N:34])[CH:4]=[CH:3]1.B1([O-])O[O:39]1.O.O.O.O.[Na+].[Cl-].[NH4+]>C1COCC1.O.ClCCl>[OH:39][C:18]1[CH:17]=[N:16][C:15]([C:11]2[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=2)[CH2:8][N:7]2[C:2](=[O:1])[CH:3]=[CH:4][C:5]([C:30]3[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=3)[C:33]#[N:34])=[N:6]2)=[N:20][CH:19]=1
Reactant: CC1(C)OB(c2cnc(-c3cccc(Cn4nc(-c5cccc(C#N)c5)ccc4=O)c3)nc2)OC1(C)C
Reactant: [O-]B1OO1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: N#Cc1cccc(-c2ccc(=O)n(Cc3cccc(-c4ncc(O)cn4)c3)n2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
50.46 g of 3-(6-oxo-1-{3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]benzyl}-1,6-dihydropyridazin-3-yl)benzonitrile (102.7 mmol) and 33.81 g of sodium perborate tetrahydrate (339 mmol) are mixed in a mixture of 220 ml of THF and 220 ml of water in a 1000 ml one-necked flask and stirred at room temperature for 2 h, during which a pale precipitate deposits. The reaction mixture is diluted with 800 ml of dichloromethane, shaken with 500 ml of saturated aqueous ammonium chloride solution, dried over sodium sulfate and evaporated to dryness in a rotary evaporator. The residue is slurried in methanol, filtered off with suction and washed with diethyl ether, m.p. 245-8° C.