Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]([CH:14]([C:16]1[CH:20]=[CH:19][N:18]([C:21]2[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:28])[CH:17]=1)[CH3:15])[O:6]CC1C=CC=CC=1)=[O:4]>C(OCC)(=O)C>[CH3:1][NH:2][C:3]([N:5]([CH:14]([C:16]1[CH:20]=[CH:19][N:18]([C:21]2[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:28])[CH:17]=1)[CH3:15])[OH:6])=[O:4]
Reactant: CNC(=O)N(OCc1ccccc1)C(C)c1ccn(-c2c(C)cccc2C)c1
Solvent: CCOC(C)=O
Product: CNC(=O)N(O)C(C)c1ccn(-c2c(C)cccc2C)c1

Procedure:
A solution of 1.0 g of N-(N'-methylcarbamoyl)-N-benzyloxy-1-[1-(2,6-dimethylphenyl)-1H-pyrrol-3-yl]-ethylamine in 50 ml of ethyl acetate is hydrogenated at room temperature and 3 atmospheres pressure for 3 hours to yield N-(N'-methylcarbamoyl)-N-hydroxy-1-[1-(2,6-dimethylphenyl)-1H-pyrrol-3-yl]-ethylamine.
Reaction SMILES: [CH2:1]([N:3]([CH2:30][CH3:31])[CH2:4][CH2:5][N:6]([CH2:24][CH:25](OC)[O:26]C)[C:7](=[O:23])[CH2:8][CH2:9][O:10][CH2:11][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1)[CH3:2].C(=O)(O)[O-].[Na+]>Cl.O1CCOCC1>[CH2:30]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]([CH2:24][CH:25]=[O:26])[C:7](=[O:23])[CH2:8][CH2:9][O:10][CH2:11][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1)[CH3:31]
Reactant: CCN(CC)CCN(CC(OC)OC)C(=O)CCOCCc1ccc2ccccc2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CCN(CC)CCN(CC=O)C(=O)CCOCCc1ccc2ccccc2c1
Reaction time: 0.17 h
Yield: 102.6 %

Procedure:
N-[2-(Diethylamino)ethyl]-N-(2,2-dimethoxyethyl)-3-[2-(2-naphthyl)ethoxy]propanamide (Example 32c) (0.5 g) was dissolved in 4M HCl in dioxane (5.8 ml), and stirred for 10 mins. The reaction mixture was poured into saturated sodium bicarbonate solution (100 ml), which was then extracted with DCM (×4). The organic layers were combined, dried over sodium sulfate, filtered and evaporated to give the sub-titled compound (458 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:17][C:16]3[C:11](=[CH:12][C:13]([OH:18])=[CH:14][CH:15]=3)[CH:10]3[CH2:19][S:20][CH2:21][CH:9]23)=[CH:4][CH:3]=1.[OH:22]OS([O-])=O.[K+].[O-]S([O-])=O.[Na+].[Na+]>CO.O.CCOC(C)=O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[O:17][C:16]3[C:11](=[CH:12][C:13]([OH:18])=[CH:14][CH:15]=3)[C@@H:10]3[CH2:19][S@@:20](=[O:22])[CH2:21][C@H:9]23)=[CH:6][CH:7]=1
Reactant: Oc1ccc(C2Oc3ccc(O)cc3C3CSCC32)cc1
Reactant: O=S([O-])OO
Agent: O=S([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: O=[S@]1C[C@H]2[C@@H](C1)c1cc(O)ccc1O[C@H]2c1ccc(O)cc1
Yield: 81.8 %

Procedure:
To a solution of enantiomer A of 4-(4-hydroxy-phenyl)-1,3a,4,9b-tetrahydro-3H-5-oxa-2-thia-cyclopenta[a]naphthalen-8-ol 11d (20 mg, 0.066 mmol) in MeOH/H2O (1:1, 3 mL) add oxone (40 mg, 0.066 mmol). Stir the reaction at room temperature for 30 minutes. Add 1.0 M Na2SO3 and stir the reaction for 5 minutes. Dilute with EtOAc and wash with saturated sodium bicarbonate. Extract aqueous layer with EtOAc (2×). Combine organic extracts, dry (Na2SO4), filter and concentrate to afford 4-(4-hydroxy-phenyl)-2-oxo-1,2,3,3a,4,9b-hexahydro-5-oxa-2λ4-thia-cyclopenta[a]naphthalen-8-ol 13 (17 mg, 0.054 mmol, 85%). 1H NMR (δ, 400 MHz, MeOD) 7.44 (d, 2H, J=8.8 Hz), 6.85 (d, 2H, J=8.8 Hz), 6.75 (d, 1H, J=8.8 Hz), 6.70 (d, 1H, J=2.8 Hz), 6.61 (dd, 1H, J=8.8, 2.8 Hz), 5.19 (s, 1H), 4.19 (dd, 1H, J=6.2, 6.2 Hz), 3.76 (d, 1H, J=7.9 Hz), 3.06-2.94 (m, 1H), 2.84 (dd, 1H, J=14.1, 5.3 Hz), 2.62 (dd, 1H, J=13.0, 5.5 Hz), 2.29 (dt, 1H, J=5.2, 14.0 Hz). HPLC (Zorbax C18 column; 10 to 100% CH3CN/H2O for 10 min then 100% CH3CN for 5 min; 1 mL/min; tr 7.17 min). LRMS calcd for C17H15O4S: 315.1; found (ES−, M−H): 315.2.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([CH3:21])[CH:20]=1)[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=O)[C:13]([NH:15][CH3:16])=[O:14].Cl.[O:23]([NH2:25])[CH3:24].O>CO>[CH3:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([CH3:21])[CH:20]=1)[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1/[C:12](=[N:25]\[O:23][CH3:24])/[C:13]([NH:15][CH3:16])=[O:14]
Reactant: CNC(=O)C(=O)c1ccccc1Oc1cc(C)cc(C)c1
Reactant: CON
Agent: Cl
Solvent: CO
Solvent: O
Product: CNC(=O)/C(=N/OC)c1ccccc1Oc1cc(C)cc(C)c1
Reaction time: 8 h
Yield: 68.9 %

Procedure:
2-[2-(3,5-dimethylphenoxy)phenyl]-2-oxo-N-methyl-acetamide (2.58 g) and methoxylamine hydrochloride (1.52 g) were dissolved in methanol (50 ml), and the mixture was heated under reflux with stirring overnight. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried, and then the solvent was evaporated. The resulting oil was purified by column chromatography on silica gel to give the title compound (1.96 g). mp. 90°-91° C.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([O:8][C:9]1[N:30]=[CH:29][C:12]2[C:13]3[N:17]([CH2:18][CH2:19][O:20][C:11]=2[CH:10]=1)[CH:16]=[C:15]([C:21]1[N:22]([CH:26]([CH3:28])[CH3:27])[N:23]=[CH:24][N:25]=1)[N:14]=3)[CH:5]([CH3:7])[CH3:6].O.[OH-].[Li+].C[N:36](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl-].[NH4+].C(N(CC)CC)C>CO.O.C(OCC)(=O)C>[CH:26]([N:22]1[C:21]([C:15]2[N:14]=[C:13]3[C:12]4[CH:29]=[N:30][C:9]([O:8][CH:4]([CH:5]([CH3:7])[CH3:6])[C:3]([NH2:36])=[O:2])=[CH:10][C:11]=4[O:20][CH2:19][CH2:18][N:17]3[CH:16]=2)=[N:25][CH:24]=[N:23]1)([CH3:28])[CH3:27]
Reactant: COC(=O)C(Oc1cc2c(cn1)-c1nc(-c3ncnn3C(C)C)cn1CCO2)C(C)C
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)C(Oc1cc2c(cn1)-c1nc(-c3ncnn3C(C)C)cn1CCO2)C(N)=O
Temperature: 50 °C
Reaction time: 2 h
Yield: 17.9 %

Procedure:
To a solution of 2-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-yloxy]-3-methyl-butyric acid methyl ester (160 mg, 0.38 mmol) in methanol (5 mL) and water (1 mL) was added lithium hydroxide monohydrate (18 mg, 0.45 mmol) and the reaction mixture stirred at 50° C. for 2 h. The reaction mixture was concentrated in vacuo and the resultant residue azeotroped with acetonitrile (3×20 mL). The residue was dissolved in DMF (3 mL), HATU (286 mg, 0.75 mmol), ammonium chloride (60 mg, 1.12 mmol) and triethylamine (157 μL, 1.12 mmol) added and the reaction mixture stirred at RT for 1 h. The reaction mixture was diluted with ethyl acetate, washed with water, extracting with ethyl acetate (3×15 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was subjected to reverse phase preparative HPLC (C-18, 10-90% MeCN in water 0.1% formic acid, 25 min gradient) to yield 452 as a white solid (28 mg, 43%). LCMS: RT=3.61 min, [M+H]+=412; 1H NMR (400 MHz, d6-DMSO) 9.04 (1H, s), 7.87 (1H s), 7.86 (1H, s), 7.31 (1H, br s), 7.08 (1H, br s), 6.43 (1H, s), 5.86 (1H, sept, J=6.56 Hz), 4.97 (1H, d, J=4.91 Hz), 4.61-4.43 (4H, m), 2.21-2.08 (1H, m), 1.43 (6H, dd, J=6.6, 3.6 Hz), 0.94 (6H, dd, J=6.6 Hz, 1.5 Hz)
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=2)=[CH:5][CH:4]=1.[F:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[NH:33][CH3:34]>>[F:29][C:30]1[CH:31]=[C:32]([N:33]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[C:10]([NH:15][S:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=3)=[CH:5][CH:4]=2)[CH3:34])[CH:35]=[CH:36][CH:37]=1
Reactant: CNc1cccc(F)c1
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1ccccc1C(F)(F)F
Product: CN(Cc1ccc(-c2nccnc2NS(=O)(=O)c2ccccc2C(F)(F)F)cc1)c1cccc(F)c1
Yield: 69 %

Procedure:
Following the general method as outlined in Example 1 (Method B), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzenesulfonamide (Intermediate 9), and 3-Fluoro-N-methylaniline, the title compound was isolated as a yellow solid in 69% yield (92% purity by HPLC).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8](OC)=[O:9])=[C:6]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[N:5]2[N:19]=[CH:20][CH:21]=[C:4]2[N:3]=1.CC(C[AlH]CC(C)C)C.C1COCC1>C(Cl)Cl>[CH3:1][C:2]1[C:7]([CH2:8][OH:9])=[C:6]([C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[N:5]2[N:19]=[CH:20][CH:21]=[C:4]2[N:3]=1
Reactant: COC(=O)c1c(C)nc2ccnn2c1-c1ccc(C)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1ccc(-c2c(CO)c(C)nc3ccnn23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.3 %

Procedure:
To a stirred solution of methyl 5-methyl-7-p-tolylpyrazolo[1,5-a]pyrimidine-6-carboxylate (950 mg, 3.38 mmol) in CH2Cl2 (50 mL) was added DIBAL-H, 1M in THF (16.9 mL, 16.9 mmol) dropwise. The reaction mixture was stirred at room temperature for 1 h before being quenched with saturated NH4Cl solution. The aqueous layer was extracted with CH2Cl2 and the combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography to give the title compound (482 mg, 56.3%). 1H-NMR (500 MHz, CDCl3) δ ppm 1.64 (1H, t, J=4.9 Hz), 2.45 (3H, s), 2.78 (3H, s), 4.58 (2H, d, J=4.9 Hz), 6.60 (1H, d, J=2.4 Hz), 7.34-7.40 (2H, m), 7.42-7.49 (2H, m), 8.00 (1H, d, J=2.4 Hz).
Reaction SMILES: C([Li])CCC.CC1(C)CCCC(C)(C)N1.[Cl:16][C:17]1[N:18]=[N:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=1.[CH:25](=[O:27])[CH3:26].Cl.C(=O)(O)[O-].[Na+]>CCCCCC.O1CCCC1.C(O)C>[Cl:16][C:17]1[N:18]=[N:19][C:20]([O:23][CH3:24])=[C:21]([CH:25]([OH:27])[CH3:26])[CH:22]=1
Reactant: CC=O
Reactant: COc1ccc(Cl)nn1
Agent: CC1(C)CCCC(C)(C)N1
Agent: Cl
Agent: O=C([O-])O
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCO
Product: COc1nnc(Cl)cc1C(C)O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
47.7 ml of a 1.6M solution of n-Butyl lithium in hexane is added dropwise at −75° C. to 100 ml tetrahydrofuran followed by 12.9 ml 2,2,6,6-tetramethylpiperidine and the resulting solution is allowed to warm to 0° C. and stirred for 30 min. The solution is cooled to −75° C. and a solution of 5 g 3-chloro-6-methoxypyridazine in 100 ml tetrahydrofuran is added at the same temperature. The reaction is stirred for 30 min at −75° C. A solution of 23.5 ml acetaldehyde in 50 ml tetrahydrofuran is cooled to −75° C. and added to the reaction. The solution is stirred at −75° C. for 90 min, then a mixture of 25 ml concentrated aqueous HCl, 100 ml ethanol and 125 ml tetrahydrofuran is added and the mixture is allowed to warm to room temperature. 60 ml of saturated aqueous sodium bicarbonate is slowly added, and the tetrahydrofuran is removed under reduced pressure. The resulting aqueous phase is extracted 3 times with dichloromethane. The organic phase is dried (MgSO4), filtered and evaporated under reduced pressure. The product is purified by silica gel chromatography, eluting with a gradient of ethyl acetate in heptane. Yield 3.85 g. LC-MS (ES+) 189 (M+H)+. NMR analysis indicates that the product contained approximately 15% of 1-(3-Chloro-6-methoxy-pyridazin-4-yl)-ethanol.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([OH:17])=O)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[O:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][NH2:29])[CH2:23][CH2:22]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([NH:29][CH2:28][CH2:27][N:24]3[CH2:25][CH2:26][O:21][CH2:22][CH2:23]3)=[O:17])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2ccc(-c3cccc(C(=O)O)c3)nc12
Reactant: NCCN1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncnc2ccc(-c3cccc(C(=O)NCCN4CCOCC4)c3)nc12

Procedure:
Following the same reaction and purification procedure, the acid 14 (80 mg, 0.3 mmol) was reacted with 2-morpholinoethanamine (CAS 2038-03-1) (78 mg, 0.6 mmol), HATU (129 mg, 0.33 mmol) and DIPEA (0.26 mL, 1.5 mmol) in DMF (1 mL) at room temperature to provide 3-(4-aminopyrido[3,2-d]pyrimidin-6-yl)-N-(2-morpholinoethyl)benzamide 21. LC/MS (ESI+): m/z 379 (M+H). 1H NMR (400 MHz, DMSO) δ 8.73 (s, 1H), 8.60 (d, J=7.5 Hz, 2H), 8.50 (d, J=8.9 Hz, 1H), 8.43 (d, J=4.9 Hz, 1H), 8.19 (d, J=8.8 Hz, 1H), 8.06 (d, J=13.7 Hz, 2H), 7.96 (d, J=7.8 Hz, 1H), 7.64 (t, J=7.8 Hz, 1H), 3.67-3.53 (m, 4H), 3.47 (dd, J=13.2, 6.6 Hz, 2H), 2.53 (d, J=7.1 Hz, 2H), 2.48-2.40 (m, 4H).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][C:6]2=[CH:9][CH:10]=[C:11]([CH:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[OH:13])[N:5]2[N:4]=1.C(Cl)Cl.ClC1C=CC=C(C(OO)=[O:31])C=1>>[CH3:1][S:2]([C:3]1[N:8]=[CH:7][C:6]2=[CH:9][CH:10]=[C:11]([CH:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[OH:13])[N:5]2[N:4]=1)=[O:31]
Reactant: CSc1ncc2ccc(C(O)c3ccccc3)n2n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1ncc2ccc(C(O)c3ccccc3)n2n1
Yield: 48.2 %

Procedure:
(2-Methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl-methanol (0.340 g, 1.25 mmol) was dissolved in Methylene chloride (6 mL, 90 mmol) and the solution was treated with m-Chloroperbenzoic acid (0.379 g, 1.69 mmol) at room temperature. The reaction was allowed to stir until HPLC showed consumption of starting materials. The mixture was poured over saturated sodium bicarbonate and organics were extracted with dichloromethane. Combined extracts were then dried over sodium sulfate, filtered and reduced. The crude reaction mixture was then purified by Isco flash column chromatography (hexanes/ethyl acetate eluent) and combined fractions were reduced and dried under vacuum to afford 173 mg of (2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl-methanol. 1H NMR (400 MHz, CDCl3) δ 8.91 (s, 1H), 7.48 (m, 2H), 7.33 (m, 3H), 6.92 (m, 1H), 6.84 (m, 1H), 6.50 (m, 1H).
Reaction SMILES: [N:1]1([CH2:7]CCC2CCNCC2)[CH2:6]CCC[CH2:2]1.ICC(N)=O.N1(CCC[CH:30]2[CH2:35][CH2:34][N:33]([CH2:36][C:37]([NH2:39])=[O:38])[CH2:32][CH2:31]2)CCCCC1>>[CH3:2][N:1]([CH2:7][CH:32]1[CH2:31][CH2:30][CH2:35][CH2:34][N:33]1[CH2:36][C:37]([NH2:39])=[O:38])[CH3:6]
Reactant: C1CCN(CCCC2CCNCC2)CC1
Reactant: NC(=O)CN1CCC(CCCN2CCCCC2)CC1
Agent: NC(=O)CI
Product: CN(C)CC1CCCCN1CC(N)=O

Procedure:
from 4-[3-(piperidin-1-yl)propyl]piperidine and iodoacetamide in a yield of 96% of theory, 2-[4-[3-(piperidin-1-yl)propyl]-piperidin-1-yl]acetamide, m.p. 94°-97° C.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([SH:20])[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:24]1[C:33]2[C:28](=[CH:29][C:30]([O:36][CH2:37][CH2:38][Cl:39])=[C:31]([O:34][CH3:35])[CH:32]=2)[N:27]=[CH:26][N:25]=1>C1COCC1.CN(C=O)C.C(OCC)(=O)C>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:24]3[C:33]4[C:28](=[CH:29][C:30]([O:36][CH2:37][CH2:38][Cl:39])=[C:31]([O:34][CH3:35])[CH:32]=4)[N:27]=[CH:26][N:25]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCl
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(S)c2)no1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc2c(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCl
Temperature: 25 °C
Reaction time: 0.12 h
Yield: 94.9 %

Procedure:
To a solution of 1-(5-tert-butyl-isoxazol-3-yl)-3-(3-mercapto-phenyl)-urea (319 mg, 1.098 mmol) described in Example 44A in THF: DMF (2:1, 6 mL) was added NaH (95%, 30.5 mg, 1.207 mmol), stirred for 5-10 min at ambient temperature. Then 4-chloro-7-(2-chloro-ethoxy)-6-methoxy-quinazoline from Example 35A (300 mg, 1.098 mmol) was added as a solution in DMF:THF (2:1). The reaction mixture was then stirred overnight. Completion of the reaction was monitored by LCMS. The reaction mixture was diluted with ethyl acetate and washed the ethyl acetate layer with water and brine successively. The organic layer was dried (Na2SO4) concentrated to dryness to get the pure compound 1-(5-tert-Butyl-isoxazol-3-yl)-3-{3-[7-(2-chloro-ethoxy)-6-methoxy-quinazolin-4-ylsulfanyl]-phenyl}-urea (550 mg, 95%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.60 (s, 1H), 9.05 (s, 1H), 8.68 (s, 1H), 7.85 (s, 1H), 7.55-7.25 (m, 5H), 6.45 (s, 1H), 4.50 (m, 2H), 4.05 (m, 5H), 1.25 (s, 9H); LC-MS (ESI) m/z 528 (M+H)+.
Reaction SMILES: [C:1]1([S:7](Cl)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH3:10]>CCOCC>[C:1]1([S:7]([NH2:10])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N
Reactant: O=S(Cl)c1ccccc1
Solvent: CCOCC
Product: NS(=O)c1ccccc1
Yield: 17 %

Procedure:
Benzenesulphinamide was prepared by reacting benzenesulphinyl chloride with ammonia in ether initially at -78° C. and finally at ambient temperature and was isolated in 17% yield as a solid, m.p. 112°-115° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:18]3[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:17]=3[O:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N-]C(C)C)(C)C.[Li+].C[O:33]B(OC)OC.OO>O1CCCC1.C(O)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:18]3[CH:19]=[CH:20][C:21]([F:23])=[C:22]([OH:33])[C:17]=3[O:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2noc3cc(F)ccc23)CC1
Reactant: COB(OC)OC
Agent: CC(C)[N-]C(C)C
Agent: OO
Agent: [Li+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2noc3c(O)c(F)ccc23)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 58.8 %

Procedure:
To a stirred solution of 4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-carboxylic acid tert-butyl ester (1.00 g, 3.13 mmol) in dry tetrahydrofuran (31.3 mL) cooled to −78° C. was added lithium diisopropylamide (1.72 mL, 3.35 mmoles). The resulting solution was stirred at −78° C. for 2 hours when trimethylborate (0.44 mL, 3.84 mmoles) was added. The resulting solution was stirred at −78° C. for 1 hour then was allowed to warm to room temperature over 3 hours when hydrogen peroxide (2.00 mL) and acetic acid (1.00 mL) were added. The resulting mixture was stirred at room temperature overnight when the mixture was quenched with saturated NH4Claq (20 mL) and 10% HClaq (20 mL). The resulting mixture was extracted with CH2Cl2 (4×50 mL). The combined extracts were washed with brine (50 mL), dried (MgSO4), filtered and evaporated. The residue was separated via column chromatography (1:1; Et2O/Pet. ether) yielding 0.619 g (59%) of the phenol as a white, crystalline solid, mp 169-170° C. Analysis calculated for C17H21N2FO4; 60.70% C, 6.29% H, 8.33% N. Found: 60.72% C, 6.15% H, 8.22% N.
Reaction SMILES: [S:1]1(=[O:12])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1C=C(C=CC=1)C(OO)=[O:18].[O-]S([O-])=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[S:1]1(=[O:18])(=[O:12])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S1CCCCc2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=S1(=O)CCCCc2ccccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 213.2 %

Procedure:
To a stirred solution of 13.44 g (31.07 mmol) of enantiomerically-enriched tetrahydrobenzothiepine-1-oxide (obtained from Step 7) in 150 mL of methylene chloride was added 9.46 g of 68% m-chloroperoxybenzoic acid (37.28 mmol, Sigma) at 0° C. After stirring at 0° C. for 2 hours, the mixture was allowed to warm up to room temperature and stirred for 4 hours. 50 mL of saturated Na2SO3 was added into the mixture and stirred for 30 minutes. The solution was then neutralized with 50 mL of saturated NaHCO3 solution. The methylene chloride layer was separated, dried over MgSO4, and concentrated in vacuo to give 13.00 g (97.5%) of the enantiomerically-enriched tetrahydrobenzothiepine-1,1-dioxide (4R,5R) as a light yellow solid: 1H NMR (CDCl3) δ 0.89-0.95 (m, 6H), 1.09-1.42 (m, 12H), 2.16-2.26 (m, 1H), 3.14 (q, J=15.6 Hz, 1H), 3.87 (s, 3H), 4.18 (s, 1H), 5.48 (s, 1H), 6.54 (dd, J=10.2 Hz, 2.4 Hz, 1H), 6.96-7.07 (m, 3H), 7.40 (d, J=8.1 Hz, 2H), 8.11 (dd, J=8.6 Hz, 5.9 Hz, 11H).
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][O:4][C:3]=1[CH:7]=[O:8].[CH:9]#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>ClCCl>[C:9]([C:2]1[CH:6]=[CH:5][O:4][C:3]=1[CH:7]=[O:8])#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: C#CCCCCCCCCCCC
Reactant: O=Cc1occc1Br
Solvent: ClCCl
Product: CCCCCCCCCCCC#Cc1ccoc1C=O
Yield: 39 %

Procedure:
Reaction of 3-bromofuran-2-carboxaldehyde (3.86 g, 21.5 mmole, from Example 5) with 1-tridecyne (6.7 g) as described in Example 1 afforded 2.28 g (39% of the title compound after chromatography with dichloromethane on silica. Recrystallisation from petroleum ether [bp 40°-60° C.] afforded material of mp 56°-57° C., νmax 3170, 3120, 2230, 1660, 1420, 1355, 1280 cm-1 ; δ(CDCl3) 0.84 (3H, distorted t, terminal CH3), 1.11-1.67 (18H, m, alkylene chain), 2.40 (2H, t, J 6.3 Hz, CH2C≡C), 6.47 (1H, d, J ca 2 Hz, C-4H), 7.51 (1H, d, J ca 2 Hz, C-5H), 9.71 (1H, s CHO).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([C@H:15]3[CH2:17][C@H:16]3[CH2:18][CH2:19][OH:20])[CH2:11][CH2:10]2)[O:6][N:5]=1.[F:21][C:22]1[CH:27]=[C:26](O)[CH:25]=[CH:24][C:23]=1[CH2:29][C:30]([O:32][CH3:33])=[O:31].N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>ClCCl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:21][C:22]1[CH:27]=[C:26]([O:20][CH2:19][CH2:18][C@@H:16]2[CH2:17][C@@H:15]2[CH:12]2[CH2:11][CH2:10][N:9]([C:7]3[O:6][N:5]=[C:4]([CH2:3][O:2][CH3:1])[N:8]=3)[CH2:14][CH2:13]2)[CH:25]=[CH:24][C:23]=1[CH2:29][C:30]([O:32][CH3:33])=[O:31]
Reactant: COC(=O)Cc1ccc(O)cc1F
Reactant: COCc1noc(N2CCC([C@H]3C[C@H]3CCO)CC2)n1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COCc1noc(N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)OC)c(F)c3)CC2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-[(1S,2R)-2-{1-[3-(methoxymethyl)-1,2,4-oxadiazol-5-yl]piperidin-4-yl}cyclopropyl]ethanol (0.900 g, 3.20 mmol) in 5 ml anhydrous dichloromethane at RT was added a solution of methyl (2-fluoro-4-hydroxyphenyl)acetate (Intermediate 1, 0.707 g, 3.84 mmol) in 10 ml anhydrous dichloromethane, triphenylphosphine, polymer-bound (2.52 g, 12.6 mmol), and di-tert-butyl azodicarboxylate (1.47 g, 6.40 mmol). The reaction mixture was stirred at RT for 3 hours. It was filtered by Celite and concentrated. The residue was purified on Biotage column (100 g silica gel) using a gradient eluent of 0-50% ethyl acetate in hexanes (700 ml) to afford the title compound. LC/MS (m/z) 448.2 (M+H)+.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:15])[C:6]1[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][C:7]=1[I:14]>O.CO>[I:14][C:7]1[CH:8]=[CH:9][C:10]([C:12]#[N:13])=[CH:11][C:6]=1[C:5]([OH:15])=[O:4]
Reactant: COC(=O)c1cc(C#N)ccc1I
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: N#Cc1ccc(I)c(C(=O)O)c1
Reaction time: 20 h
Yield: 66.2 %

Procedure:
A solution of sodium hydroxide (0.44 g, 11 mmol) in water (10 ml) was added to 2-iodo-5-cyanobenzoic acid methyl ester (2.7 g, 9.4 mmol) in methanol. The mixture was stirred for 20 h, then most of the solvent was evaporated and the residue acidified with 2N hydrochloric acid. The resulting precipitate was filtered off and dried to give a white solid (1.7 g). MS (-CI) m /z 272 [M-H]+.