Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:8]([NH2:10])=[O:9])[N:5]([CH3:7])[CH:6]=1.[C:11]([C:15]1[CH:16]=[C:17]2[C:22](=[C:23]([F:25])[CH:24]=1)[C:21](=[O:26])[N:20]([C:27]1[CH:37]=[CH:36][CH:35]=[C:34](B3OC(C)(C)C(C)(C)O3)[C:28]=1[CH2:29][O:30]C(=O)C)[N:19]=[CH:18]2)([CH3:14])([CH3:13])[CH3:12]>>[C:11]([C:15]1[CH:16]=[C:17]2[C:22](=[C:23]([F:25])[CH:24]=1)[C:21](=[O:26])[N:20]([C:27]1[C:28]([CH2:29][OH:30])=[C:34]([C:2]3[N:3]=[C:4]([C:8]([NH2:10])=[O:9])[N:5]([CH3:7])[CH:6]=3)[CH:35]=[CH:36][CH:37]=1)[N:19]=[CH:18]2)([CH3:14])([CH3:12])[CH3:13]
Reactant: Cn1cc(Br)nc1C(N)=O
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Product: Cn1cc(-c2cccc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)nc1C(N)=O
Yield: 12 %

Procedure:
This compound was prepared with the same method as described in Example 1 by using 4-bromo-1-methyl-1H-imidazole-2-carboxylic acid amide (intermediate-1) and acetic acid 2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl ester (intermediate 5). The desired compound was prepared in two steps (12% yield). 1H NMR (300 MHz, DMSO-d6) δ 8.50 (d, J=2.7 Hz, 1H), 7.87-7.71 (m, 5H), 7.50-7.44 (m, 2H), 7.30 (dd, J=1.2, 7.8 Hz, 1H), 4.38-4.33 (m, 2H), 4.00 (s, 3H), 1.39 (s, 9H). LC-MS calcd for C24H24FN5O3 (m/e) 449.19, obsd 450 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][N:16]([CH3:29])[C:17]([C:19]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]([CH3:28])[CH:20]=3)=[O:18])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[OH:8].Br[CH2:31][C:32]#[N:33].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][N:16]([CH3:29])[C:17]([C:19]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]([CH3:28])[CH:20]=3)=[O:18])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:31][C:32]#[N:33]
Reactant: CN(Cc1ccc(-c2ccc(O)c(Br)c2)cc1)C(=O)c1cn(C)c2ccccc12
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(Cc1ccc(-c2ccc(OCC#N)c(Br)c2)cc1)C(=O)c1cn(C)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.3 %

Procedure:
A mixture of N-[(3′-bromo-4′-hydroxy-1,1′-biphenyl-4-yl)methyl]-N,1-dimethyl-1H-indole-3-carboxamide (4.6 g, 10.2 mmol), prepared in the previous step, bromoacetonitrile (856 μL, 12.3 mmol) and potassium carbonate (7.0 g, 50 mmol) in 75 mL of DMF was stirred under nitrogen at room temperature for 23 h (overnight). The reaction was partitioned between ethyl acetate and water. The organic layer was separated, extracted multiple times with water, dried (MgSO4) and the solvent removed under reduced pressure to give N-{[3′-bromo-4′-(cyanomethoxy)-1,1′-biphenyl-4-yl]methyl}-N,1-dimethyl-1H-indole-3-carboxamide (3.4 g, 68%) as an off-white solid, mp 202-206° C. Elemental Analysis for C26H22BrN3O2. Calc'd: C, 63.94; H, 4.54; N, 8.60. Found: C, 50.59; H, 3.30; N, 8.00
Reaction SMILES: [O:1]1[CH2:16][CH:2]1[CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:15])[NH:10]2.[C:17]1([SH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[OH:1][CH:2]([CH2:16][S:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:15])[NH:10]2
Reactant: O=C1CCc2c(cccc2OCC2CO2)N1
Reactant: Sc1ccccc1
Product: O=C1CCc2c(cccc2OCC(O)CSc2ccccc2)N1

Procedure:
Prepared analogous to Example 59 from 5-(2,3-epoxy-propoxy)-3,4-dihydro-carbostyril and thiophenol.
Reaction SMILES: CN(C)C=O.O=[CH:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:11]([O:12][CH3:13])[C:9]=1[OH:10].Cl[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+]>O>[CH3:13][O:12][C:11]1[C:9]2[O:10][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:7][C:8]=2[CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)CCl
Reactant: COc1cccc(C=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cccc(OC)c2o1
Temperature: 120 °C
Reaction time: 14 h
Yield: 48 %

Procedure:
To N,N-dimethylformamide (300 ml), o-vanillin (25.2 g), ethyl chloroacetate (23.5 ml) and potassium carbonate (45 mg) were added and the resulting mixture was stirred at 120° C. for 14 hours. The reaction mixture was filtered to remove insoluble inorganic salts, and 1N hydrochloric acid (50 ml) was added to the mixture to stop the reaction. Distilled water (250 ml) was added and the resulting mixture was extracted 4 times with totally 150 ml of ethyl acetate containing 15% of n-hexane. The organic layers were washed with distilled water (100 ml) and with saturated brine (100 ml), and dried over anhydrous sodium sulfate. The sodium sulfate was removed by filtration and the solvent was concentrated to dryness under reduced pressure. The residue was purified by column chromatography (solvent: n-hexane/ethyl acetate=10/1 to 5/1) using silica gel to obtain the desired compound (17.4 g, yield: 48%) in the form of colorless needle-shaped crystals.
Reaction SMILES: [Br:1][C:2]1[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:3]=1[CH2:4][C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH2:12][CH2:11][N:10](C(=O)C(F)(F)F)[C:9]=2[CH:20]=1.[BH4-].[Na+]>CO.C1COCC1>[Br:1][C:2]1[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:3]=1[CH2:4][C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH2:12][CH2:11][NH:10][C:9]=2[CH:20]=1
Reactant: O=C(N1CCOc2ccc(Cc3cc(I)ccc3Br)cc21)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Brc1ccc(I)cc1Cc1ccc2c(c1)NCCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.3 %

Procedure:
To a stirred solution of 1-[6-(2-bromo-5-iodo-benzyl)-2,3-dihydro-benzo[1,4]oxazin-4-yl]-2,2,2-trifluoro-ethanone (12.0 g, 22.81 mmol) in methanol (100 mL) and THF (20 mL) was added sodium borohydride (1.73 g, 45.62 mmol) portion wise and the reaction mixture was stirred at room temperature for 1 h. The excess of sodium borohydride was quenched by adding 1N HCl. Methanol was evaporated and the residue was partitioned between dichloromethane and water. The organic layer was washed with water, and brine, then concentrated to furnish the crude product which was purified by silica gel column chromatography to provide 6-(2-bromo-5-iodo-benzyl)-3,4-dihydro-2H-benzo[1,4]oxazine (9.45 g).
Reaction SMILES: [C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:11](=[O:12])[CH:10]=[CH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].C([Al+]CC(C)C)C(C)C.C(OCC)(=O)C.Cl>C1(C)C=CC=CC=1>[C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:11]([OH:12])[CH:10]=[CH:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1C=CCC1(c1ccccc1)c1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: OC1C=CCC1(c1ccccc1)c1ccccc1
Reaction time: 0.5 h
Yield: 48.8 %

Procedure:
To a suspension of 5,5-diphenyl-2-cyclopenten-1-one (5.0 g) in toluene (25 ml) was added dropwise diisobutylaluminum hydride (15 ml, 1.5M solution in toluene) for 10 minutes at -78° C. to -50° C. After 30 minutes, ethyl acetate (5 ml) was added to the resultant yellow solution. The solution was acidified to pH 1 with 6N hydrochloric acid (20 ml) and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel with methylene chloride as an eluent and further purified by bulb to bulb distillation to give 5,5-diphenyl-2-cyclopenten-1-ol (2.46 g).
Reaction SMILES: [NH2:1][C@@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20]([OH:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1>C(O)C>[C:14]1([CH3:24])[CH:15]=[CH:16][C:17]([S:20]([OH:23])(=[O:21])=[O:22])=[CH:18][CH:19]=1.[CH2:14]([O:11][C:10](=[O:12])[C@@H:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[NH2:1])[CH3:15]
Reactant: N[C@H](Cc1ccccc1)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: CCOC(=O)[C@H](N)Cc1ccccc1
Temperature: 25 °C
Yield: 88.5 %

Procedure:
A mixture of D-phenylalanine (5.0 g, 30 mmol) and p-toluenesulfonic acid monohydrate (12.7 g, 67 mmol) in 150 mL of anhydrous ethanol was refluxed for 24 hours. After cooling to room temperature, the solvent was removed by rotary evaporator, the residue triturated with diethyl ether, filtered and dried in vacuo over P2O5 to give the p-toluenesulfonate salt of the title compound (9.7 g) as a white solid and the structure verified by NMR.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:14][C:15](=[O:19])OCC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2.[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:22]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH3:1][O:2][C:3]1[C:4]([NH:14][C:15]([N:31]2[CH2:32][CH2:33][N:28]([C:22]3[C:23]([CH3:27])=[CH:24][CH:25]=[CH:26][C:21]=3[CH3:20])[CH2:29][CH2:30]2)=[O:19])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2
Reactant: CCOC(=O)Nc1nc2ccc(C)cc2nc1OC
Reactant: Cc1cccc(C)c1N1CCNCC1
Product: COc1nc2cc(C)ccc2nc1NC(=O)N1CCN(c2c(C)cccc2C)CC1
Yield: 83 %

Procedure:
Ethyl N-(3-methoxy-6-methylquinoxalin-2-yl)carbamate and 1-(2,6-dimethylphenyl)piperazine were reacted by the same way with the example 127 to obtain the titled compound (yield, 83%). 1H NMR (300 MHz, CDCl3): δ 2.33-2.50 (m, 9H), 3.14-2.20 (m, 4H), 3.70-3.75 (m, 4H), 4.14 (s, 3H), 7.00 (s, 3H), 7.09-7.78 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:12])[N:4]([CH:9]([CH3:11])[CH3:10])[N:5]=[CH:6][C:7]=1[NH2:8].[H-].[Na+].[CH2:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>CN(C)C=O.C1C=CC=CC=1>[Cl:1][C:2]1[C:3](=[O:12])[N:4]([CH:9]([CH3:10])[CH3:11])[N:5]=[CH:6][C:7]=1[NH:8][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: ClCc1ccccc1
Reactant: CC(C)n1ncc(N)c(Cl)c1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CC(C)n1ncc(NCc2ccccc2)c(Cl)c1=O
Reaction time: 0.5 h

Procedure:
In 6 ml of dry dimethylformamide, 1.875 g of 4-chloro-5-amino-2-i-propyl-3(2H)pyridazinone was dissolved. 0.48 g of sodium hydride (50% mineral oil suspension) was added thereto at a temperature of from 5° to 10° C., and the mixture was stirred for about 30 minutes. Then, 1.4 g of benzyl chloride was dropwise added thereto at the same temperature. After the dropwise addition, the mixture was stirred at room temperature for 2 hours. To the reaction solution, 50 ml of benzene and 30 ml of a 10% hydrochloric acid aqueous solution were added, and the mixture was vigorously shaken. The organic layer was washed with water, and dried, and then the solvent was distilled off. The crude crystals thereby obtained were recrystallized from ethyl ether to obtain 2.3 g of the above identified compound having a melting point of from 131° to 132° C.
Reaction SMILES: [N+]([O-])(O)=[O:2].[CH3:5][C:6]1([CH3:15])[CH2:11][CH2:10][CH2:9][C@H:8]([CH3:12])[C@H:7]1[CH:13]=[O:14]>>[CH3:15][C:6]1([CH3:5])[CH2:11][CH2:10][CH2:9][C@H:8]([CH3:12])[C@H:7]1[C:13]([OH:2])=[O:14]
Reactant: C[C@H]1CCCC(C)(C)[C@@H]1C=O
Reactant: O=[N+]([O-])O
Product: C[C@H]1CCCC(C)(C)[C@@H]1C(=O)O
Temperature: 55 °C
Reaction time: 2 h
Yield: 98.5 %

Procedure:
In a 300-ml 4-necked flask equipped with a condenser, a thermometer, a dropping funnel, and a stirrer was placed 42 g of nitric acid (aqueous 60% solution), and the temperature was raised to 55° C. by heating. To the solution was added dropwise 100 g (0.65 mole) of (1R,6S)-2,2,6-trimethylcyclohexanecarbaldehyde (10) [composition: 90% of the (1R,6S)-form, 10% of the (1S,6S)-form] synthesized in Synthetic Example 4-A) with stirring over a period of 2 hours. After carrying out the reaction for 3 hours at the same temperature, the reaction mixture was washed with water with 100 g of toluene and 100 g of water at room temperature, followed by separating an organic layer from an aqueous layer. The organic layer was washed thrice with 100 g of a saturated aqueous sodium chloride solution, followed by separating the organic layer from an aqueous layer. The toluene was distilled off from the organic layer by an evaporator under reduced pressure to provide 109 g of crude (1R,6S)-2,2,6-trimethylcyclohexanecarboxylic acid (11) [composition: 91% of the (1R,6S)-form, 9% of the (1S,6S)-form; melting point: 44° C. to 54° C⟧
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26]([OH:28])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O[N:30]=[C:31]([C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1)[NH2:32]>>[N:36]1[CH:37]=[CH:38][C:33]([C:31]2[N:32]=[C:26]([CH:11]3[CH2:12][CH:13]([C:15]4[CH:16]=[CH:17][C:18]([O:21][C:22]([F:23])([F:24])[F:25])=[CH:19][CH:20]=4)[CH2:14][N:9]([C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[O:8])[CH2:10]3)[O:28][N:30]=2)=[CH:34][CH:35]=1
Reactant: NC(=NO)c1ccncc1
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Product: O=C(N1CCOCC1)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(-c3ccncc3)no2)C1

Procedure:
80 mg (0.20 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethoxy)phenyl]piperidine-3-carboxylic acid (Example 44A) and 30 mg (0.22 mmol, 1.1 eq.) of N′-hydroxypyridine-4-carboximidamide were reacted according to the General Method 1. Yield: 52 mg (52% of theory)
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11]C(=O)OC(C)(C)C)[N:4]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][CH3:26])[CH:20]=2)[N:3]=1.[C:27](Cl)(=[O:30])[CH:28]=[CH2:29].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([C:19]3[CH:20]=[C:21]([N:25]([CH3:26])[C:27](=[O:30])[CH:28]=[CH2:29])[CH:22]=[CH:23][CH:24]=3)[N:3]=[C:2]([I:1])[C:10]=12
Reactant: C=CC(=O)Cl
Reactant: CNc1cccc(-n2nc(I)c3c(NC(=O)OC(C)(C)C)ncnc32)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CC(=O)N(C)c1cccc(-n2nc(I)c3c(N)ncnc32)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
To a stirred solution of tert-butyl 3-iodo-1-(3-(methylamino)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylcarbamate (46) (440 mg, 0.99 mmol) in DCM (8 mL) at 0° C. was added acryloyl chloride (103 mg, 1.13 mmol) dropwise. The resulting mixture was stirred at RT overnight before introducing TFA (8 mL). Stirring was continued for an additional 2 h. Solvents were removed and the residue was dissolved in sat. aquous NaHCO3. The product was extracted with 85% DCM/IPA (50 mL×3). The combined organic extracts were dried over Na2SO4, filtered and concentrated to provide N-(3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)phenyl)-N-methylacrylamide (50) (375 mg, 95%) as a white solid. LC-MS (ESI): m/z (M+1) 421.0.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[C:3]([C:5]1[CH:16]=[C:15]([O:17]CC2C=CC=CC=2)[C:8]2[N:9]=[C:10]([CH2:13][CH3:14])[N:11]([CH3:12])[C:7]=2[CH:6]=1)=[O:4].C(O)(=O)C>C(O)C.[Pd]>[CH3:25][N:2]([CH3:1])[C:3]([C:5]1[CH:16]=[C:15]([OH:17])[C:8]2[N:9]=[C:10]([CH2:13][CH3:14])[N:11]([CH3:12])[C:7]=2[CH:6]=1)=[O:4]
Reactant: CCc1nc2c(OCc3ccccc3)cc(C(=O)N(C)C)cc2n1C
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CCc1nc2c(O)cc(C(=O)N(C)C)cc2n1C
Yield: 106.4 %

Procedure:
A solution of 10.9 g (26.6 mmol) 7-benzyloxy-2-ethyl-3-methyl-3H-benzimidazole-5-carboxylic acid dimethylamide and 1.8 ml acetic acid in 160 ml ethanol was hydrogenated over 1.7 g 10% Pd/C in autoclave (5 bar H2) at 50° C. for 18 h. The catalyst was filtered off and the filtrate was concentrated in vacuo. The residue was crystallized from acetone to afford 7 g (91%) of the title compound as a white solid. m.p. 193°-199° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.C[S-:27].[Na+]>CN(C)C=O>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([SH:27])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(S)c2c1
Temperature: 130 °C
Reaction time: 16 h

Procedure:
To a solution of 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (1.5 g, 4 mmol, prepared in analogy to the one in Example 17-1) in dry N,N-dimethylformamide (100 mL) was added sodium methanethiolate (1.4 g, 20 mmol) under argon protection. The reaction was stirred at 130° C. for 16 hours. The reaction mixture was cooled to 50° C. and concentrated in vacuo. The residue was dissolved in cooled water (150 mL) and carefully acidified with 20% of hydrochloric acid to pH 4˜5 under argon atmosphere. The resultant solution was extracted with cooled dichloromethane (150 mL×3). The combined organic layer was washed with cooled brine (100 mL×2) and concentrated in vacuo at room temperature to afford the crude product, which was used for next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#N)=[N:6][CH:7]=1.Cl.[CH2:11]([OH:13])[CH3:12].C([OH:16])C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:13][CH2:11][CH3:12])=[O:16])=[N:6][CH:7]=1
Reactant: N#Cc1ccc(Cl)cn1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)c1ccc(Cl)cn1
Yield: 97 %

Procedure:
To a solution of the compound (3.16 g) obtained in (2) above in ethanol (5 ml) was added a 2.7N hydrochloric acid-ethanol solution (10 ml) and the mixture was stirred with refluxing for 2 hours. Ethanol was distilled away under reduced pressure, and the mixture was neutralized with a saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The extract was dried over magnesium sulfate and the solvent was distilled away under reduced pressure to give 4.10 g of a pale-brown solid (yield 97%).
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[CH:5]=[CH:6][C:7]([CH3:10])=[N:8][CH:9]=1.[CH3:11]I.O>CS(C)=O>[CH3:11][O:3][C:4]1[CH:5]=[CH:6][C:7]([CH3:10])=[N:8][CH:9]=1
Reactant: CI
Reactant: Cc1ccc(O)cn1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(C)nc1
Reaction time: 1 h

Procedure:
To a suspension of potassium hydroxide (113 g, 2 mol) in DMSO (800 ml) was added 53.9 g, (0.49 mmol) 5-hydroxy-2-methylpyridine and the mixture stirred for 1 h. To this was added CH3I (34 ml, 0.55 mol) and the reaction mixture was stirred for one hour, then poured into water (2400 ml) and extracted with ether (1000 ml×5). The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated in vacuo to provide 5-methoxy-2-methylpyridine as a yellow oil. 1H NMR: (400 MHz, CDCl3) δ 8.19 (d, J=2.8 Hz, 1H), 7.14 (dd, J=8.8, 3.8 Hz, 1H), 7.08 (d, J=8.4 Hz, 1H), 3.83 (s, 3H), 2.65 (s, 3H). (5-methoxypyridin-2-yl)methanol: To a 0° C. solution of 10 g (72 mmol) 5-methoxy-2-methylpyridine in CHCl3 (50 ml) was slowly added 20 g (93.9 mmol) mCPBA and the mixture was stirred at room temperature for 16 h. The mixture was neutralized with excess sat. NaHSO3 solution. The aqueous layer was extracted with CHCl3 three times. The combined organic layers were dried over MgSO4 and evaporated to give 7 g of 5-methoxy-2-methyl-1-oxopyridine as a yellow solid. This was added slowly to hot (1000° C.)acetic anhydride (25 mL, 26 mmol) over 30 minutes and the mixture heated an additional 30 minutes, whereupon ethanol was added until the excess acetic anhydride was consumed. The mixture was cooled, concentrated, and neutralized with aqueous KHCO3 solution. The aqueous layer was extracted with CH2Cl2, dried over MgSO4, and concentrated in vacuo to afford 7.5 of (5-methoxypyridin-2-yl)methyl acetate as a dark oil. To this oil was added 25 mL of concentrated HCl and the mixture heated to reflux for 1 hour then concentrated in vacuo. The residue was treated with aqueous KHCO3 and extracted with CH2Cl2. The CH2Cl2 extract was dried over MgSO4, filtered, and concentrated in vacuo to give (5-methoxypyridin-2-yl)methanol as an oil. 1H NMR (400 MHz, DMSO-d6) δ 7.65 (m, 2H), 6.45 (m, 1H), 4.75 (s, 2H), 3.25 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]3[CH:16]=[CH:15][C:14]([I:17])=[CH:13][CH:12]=3)[CH2:10][O:9]2)=[CH:4][CH:3]=1.[CH2:18]([CH2:20][NH2:21])[OH:19].C(N(CC)CC)C>C(O)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([I:17])=[CH:13][CH:12]=2)([OH:9])[CH2:10][NH:21][CH2:20][CH2:18][OH:19])=[CH:4][CH:3]=1
Reactant: NCCO
Reactant: Clc1ccc(C2(c3ccc(I)cc3)CO2)cc1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: OCCNCC(O)(c1ccc(Cl)cc1)c1ccc(I)cc1
Yield: 99.9 %

Procedure:
A solution of 2-(4-chloro-phenyl)-2-(4-iodo-phenyl)-oxirane (0.60 g, 1.68 mmol), ethanolamine (0.5 mL, 8.3 mmol) and triethylamine (0.5 mL, 3.6 mmol) in, iso-propanol (5 mL) was maintained at 50° C. for 72 hours then concentrated in vacuo. The residue was taken up in ethyl acetate and washed with saturated potassium carbonate solution/water (1:9). The aqueous phase was extracted a second time with ethyl acetate, then the combined extracts were washed with brine, dried (MgSO4), filtered and concentrated to give the title compound (701 mg, quantitative); LCMS (PS-A2) Rt 2.29 min [M+H]30 418, [M−H2O+H]+ 400.
Reaction SMILES: [NH3:1].Cl.[CH:3]([N:6]([CH:27]([CH3:29])[CH3:28])[CH2:7][CH2:8][N:9]([C:19]1[N:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[N:20]=1)[C:10](=O)[O:11]C1C=CC=CC=1)([CH3:5])[CH3:4]>O1CCCC1>[CH:3]([N:6]([CH:27]([CH3:29])[CH3:28])[CH2:7][CH2:8][N:9]([C:19]1[N:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[N:20]=1)[C:10]([NH2:1])=[O:11])([CH3:5])[CH3:4]
Reactant: Cc1cc(C)nc(N(CCN(C(C)C)C(C)C)C(=O)Oc2ccccc2)n1
Reactant: N
Agent: Cl
Solvent: C1CCOC1
Product: Cc1cc(C)nc(N(CCN(C(C)C)C(C)C)C(N)=O)n1

Procedure:
Concentrated ammonia (10 ml) is added to a solution of phenyl N-(2-diisopropylaminoethyl)-N-(4,6-dimethyl-2-pyrimidinyl)carbamate hydrochloride (7.33 g., 0.018 mole) in 50 ml of tetrahydrofuran and the mixture is allowed to stand for twenty-four hours. It is concentrated, water and chloroform are added to the residue, the chloroform is separated and concentrated. Crystallization of the residue from hexane yields N-(2-diisopropylaminoethyl)-N-(4,6-dimethyl-2-pyrimidinyl)urea melting at 134°-136° C.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[NH:5]([CH:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[S:9](=[O:17])(=[O:16])[NH:8]1)[NH2:6]>O1CCOCC1>[CH3:1][NH:2][C:3]([NH:6][NH:5][C:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[S:9](=[O:17])(=[O:16])[N:8]=1)=[O:4]
Reactant: CN=C=O
Reactant: NNC1NS(=O)(=O)c2ccccc21
Solvent: C1COCCO1
Product: CNC(=O)NNC1=NS(=O)(=O)c2ccccc21
Reaction time: 1 h
Yield: 92.8 %

Procedure:
A solution of 3.7 g (0.55 mol) of methyl isocyanate in 30 ml of dioxane is added dropwise to 9.8 g (0.05 mol) of 3-hydrazino-2H,3H-1,2-benzisothiazole 1,1-dioxide in 100 ml of dioxane at room temperature. Stirring is continued for 1 hour, after which the product is filtered off under suction. 11.8 g (89% of theory) of 3-methylaminocarbonylhydrazino-1,2-benzisothiazole 1,1-dioxide of melting point 183° C. are obtained. The product can be recrystallized from ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:13]([OH:16])(=O)[CH3:14]>>[CH3:7][O:6][C:4]([C:3]1[CH:8]=[C:9]([N:12]2[C:13](=[O:16])[C:14]3[CH2:9][CH2:10][CH2:11][CH2:2][C:3]=3[C:4]2=[O:5])[CH:10]=[CH:11][C:2]=1[Cl:1])=[O:5]
Reactant: COC(=O)c1cc(N)ccc1Cl
Reactant: CC(=O)O
Product: COC(=O)c1cc(N2C(=O)C3=C(CCCC3)C2=O)ccc1Cl
Temperature: 25 °C

Procedure:
A solution of 9.1 g (0.06 mole) of 3,4,5,6-tetrahydrophilic anhydride and 11.1 g (0.06 mole) of methyl 2-chloro-5-aminobenzoate dissolved in glacial acetic acid (30 ml.) is vigorously refluxed for one hour. The reaction mixture is cooled to room temperature and the crude product is collected by filtration, washed with water and then dried to afford 14.9 g of N-[3-methoxycarbonyl-4-chlorophenyl]-3,4,5,6-tetrahydrophthalimide m.p. 113°-115° C.