Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].Br[C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[CH:9][S:8][C:7]=2[CH:11]=1.[CH3:12][Si:13]([CH3:30])([CH3:29])[CH2:14][CH2:15][O:16][CH2:17][N:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[C:19]1[CH:27]=[O:28].Cl>O1CCCC1>[S:8]1[CH:9]=[CH:10][C:6]2[CH:5]=[CH:4][C:3]([CH:27]([C:19]3[N:18]([CH2:17][O:16][CH2:15][CH2:14][Si:13]([CH3:29])([CH3:30])[CH3:12])[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[N:20]=3)[OH:28])=[CH:11][C:7]1=2
Reactant: Brc1ccc2ccsc2c1
Reactant: C[Si](C)(C)CCOCn1c(C=O)nc2ccccc21
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1c(C(O)c2ccc3ccsc3c2)nc2ccccc21
Reaction time: 12 h

Procedure:
To a suspension of magnesium (86 mg) in tetrahydrofuran is added a solution of 6-bromobenzo[b]thiophene (which can be prepared according to WO2006/107784) (500 mg) in tetrahydrofuran. After reflux for 3 h, a solution of 1-(2-trimethylsilylethoxymethyl)-1H-benzimidazole-2-carbaldehyde (which can be prepared according to US2003/220341 or US6476041 for example) (635 mg) in tetrahydrofuran is added to the Grignard reagent at room temperature. After stirring for 12 h, the reaction mixture is treated with diluted hydrochloric acid and the organic phase is dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography over silica gel (gradient dichloromethane/methanol from 100/0 to 90/10) to afford benzo[b]thiophen-6-yl[1-(2-trimethylsilylethoxymethyl)-1H-benzimidazol-2-yl]methanol.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Li][CH2:15]CCC.CI.Cl>C1COCC1>[CH3:15][CH:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: [Li]CCCC
Agent: Cl
Solvent: CI
Solvent: C1CCOC1
Product: CC1c2ccccc2-c2ccccc21
Temperature: -70 °C
Yield: 67.6 %

Procedure:
A mixture of fluorene (78.3 g) and THF (700 mL) was cooled down to −70° C., and n-BuLi (300 mL, corresponding to 0.48 mol) was dropwise added thereto while maintaining −60° C. or lower. Then, methyl iodide (66.8 g) was added, and the temperature was allowed to slowly go back to a room temperature. The mixture was cooled again down to 0° C. to add 3M-hydrochloric acid (300 mL), and the reaction mixture was extracted with toluene. The organic layer obtained was washed well in order with saturated sodium hydrogencarbonate, saturated sodium hydrogensulfite and water, and then dried on anhydrous magnesium sulfate. The solvent was distilled off from this organic layer under reduced pressure, and the residue was purified by means of column chromatography (silica gel, eluting solvent: toluene/heptane [40/60]) and recrystallization (ethanol) to obtain 9-methylfluorene (57.4 g) of pale yellow crystal. Melting point: 47.3-48.8° C.
Reaction SMILES: [Br:1][C:2]1[C:7]2[O:8][CH2:9][C@@H:10]3[C@@H:15]([CH2:16][N:17]4C(=O)C5=CC=CC=C5C4=O)[CH2:14][N:13]([CH3:28])[CH2:12][C@H:11]3[C:6]=2[CH:5]=[C:4]([O:29][CH3:30])[CH:3]=1.O.NN.Cl>CO>[NH2:17][CH2:16][C@@H:15]1[CH2:14][N:13]([CH3:28])[CH2:12][C@H:11]2[C:6]3[CH:5]=[C:4]([O:29][CH3:30])[CH:3]=[C:2]([Br:1])[C:7]=3[O:8][CH2:9][C@H:10]12
Reactant: COc1cc(Br)c2c(c1)[C@@H]1CN(C)C[C@H](CN3C(=O)c4ccccc4C3=O)[C@H]1CO2
Agent: Cl
Agent: NN
Solvent: O
Solvent: CO
Product: COc1cc(Br)c2c(c1)[C@@H]1CN(C)C[C@@H](CN)[C@H]1CO2

Procedure:
To suspension of 0.305 g (±)-[4R*,4aS*,10bR*]-7-bromo-1,3,4,4a,5,10b-hexahydro-9-methoxy-2-methyl-4-(phthalimidomethyl)-2H-[1]benzopyrano[4,3-c]pyridine in 40 ml MeOH, is added 0.102 ml hydrazine hydrate. The mixture is refluxed 12 hours, cooled, acidified to pH 1 with 12N HCl, and concentrated to a 3 ml volume under reduced pressure. The residue is partitioned between 10 ml 2N NaOH and CH2Cl2 (40 ml). The organic phase is dried over MgSO4, filtered, and evaporated to dryness in vacuo to yield the title compound; m.p. HCl salt 277°-279° dec.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:6]([N+:10]([O-:12])=[O:11])=[CH:5][C:3]=1[NH2:4].[N:13]([O-])=O.[Na+]>C(O)(=O)C.O>[CH3:9][C:7]1[CH:8]=[C:2]2[C:3](=[CH:5][C:6]=1[N+:10]([O-:12])=[O:11])[NH:4][N:13]=[CH:1]2
Reactant: O=N[O-]
Reactant: Cc1cc(C)c([N+](=O)[O-])cc1N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc2cn[nH]c2cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 3 h
Yield: 58.1 %

Procedure:
2,4-Dimethyl-5-nitroaniline (1.662 g, 10.00 mmol) was dissolved in glacial acetic acid (100 ml) and the mixture was cooled to 0° C. A solution of sodium nitrite (1 eq, 690 mg) in water (2 ml) was added while maintaining a temperature below 25° C. Stirring was continued for three hours and the mixture was filtered. The filtrate was allowed to stand for three days at room temperature, then was concentrate under reduced pressure. The residue was diluted with water and the resulting mixture was stirred vigorously. The solid product was collected by filtration, washed thoroughly with cold water, and dried. The product was purified by flash chromatography (99:1 dichloromethane/methanol) to give 1.030 g (58.1%) of 5-methyl-6-nitro-1H-indazole as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[N:11][N:10]=[C:9]1[C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:17][CH:18]=1.C1C(=O)N([Br:32])C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(O)(=O)C>[Br:32][C:12]1[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Br:1])[C:9]([C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:17][CH:18]=2)=[N:10][N:11]=1
Reactant: Brc1ccccc1-n1cnnc1-c1ccc(-c2ccccc2)nc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC(=O)O
Product: Brc1ccccc1-n1c(Br)nnc1-c1ccc(-c2ccccc2)nc1
Temperature: 25 °C
Yield: 69 %

Procedure:
5-[4-(2-Bromophenyl)-4H-1,2,4-triazol-3-yl]-2-phenylpyridine prepared in the Production Example 2 was dissolved in a mixture solvent of carbon tetrachloride (100 ml) and acetic acid (100 ml), followed by addition of n-bromosuccinimide (5.90 g), and refluxed under heating for 3 hours. After the reaction solution was cooled to ambient temperature, the solution was concentrated under reduced pressure. Saturated aqueous sodium hydrogen carbonate solution was added to the resulting residue, and extracted with chloroform. Subsequently, the organic layer was dried over anhydrous magnesium sulfate. After the solvent was evaporated under reduced pressure, the resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=3/1), to afford the entitled compound as yellow solid (6.96 g, 69%). The physico-chemical values are as follows.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12][O:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:8][C:7]([C:18]3[CH:19]=[CH:20][C:21]4[O:25][CH2:24][CH2:23][C:22]=4[CH:26]=3)=[N:6]2)[CH2:3][CH2:2]1.[F:27][C:28]1C=CC(CN2C(=O)C(CO)=CC(C3C=CC4OCCC=4C=3)=N2)=[CH:30][CH:29]=1>>[F:27][C:28]1[CH:3]=[CH:2][C:1]([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12][O:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:8][C:7]([C:18]3[CH:19]=[CH:20][C:21]4[O:25][CH2:24][CH2:23][C:22]=4[CH:26]=3)=[N:6]2)=[CH:30][CH:29]=1
Reactant: O=c1c(CO)cc(-c2ccc3c(c2)CCO3)nn1Cc1ccc(F)cc1
Reactant: CS(=O)(=O)OCc1cc(-c2ccc3c(c2)CCO3)nn(CC2CC2)c1=O
Product: CS(=O)(=O)OCc1cc(-c2ccc3c(c2)CCO3)nn(Cc2ccc(F)cc2)c1=O
Yield: 78.6 %

Procedure:
The general procedure of Example 1 (5) was carried out by use of 2-(4-fluorobenzyl)-6-(2,3-dihydro-1-benzofuran-5-yl)-4-hydroxymethyl-2H-pyridazin-3-one, to thereby yield the title compound as a yellow oil (yield: 78.6%).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:14][CH2:15][O:16][CH3:17])=[C:4]([CH2:12][OH:13])[CH:5]=[C:6]([O:8][CH2:9][O:10][CH3:11])[CH:7]=1.N1C=CN=C1.[C:23]([Si:27](Cl)([CH3:29])[CH3:28])([CH3:26])([CH3:25])[CH3:24].O>CN(C=O)C>[Br:1][C:2]1[C:3]([O:14][CH2:15][O:16][CH3:17])=[C:4]([CH:5]=[C:6]([O:8][CH2:9][O:10][CH3:11])[CH:7]=1)[CH2:12][O:13][Si:27]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:29])[CH3:28]
Reactant: COCOc1cc(Br)c(OCOC)c(CO)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1cc(Br)c(OCOC)c(CO[Si](C)(C)C(C)(C)C)c1
Yield: 97.2 %

Procedure:
Prepare a solution of (3-bromo-2,5-bis-methoxymethoxy-phenyl)-methanol (1.46 g, 4.76 mmol) and imidazole (0.357 g, 5.24 mmol) in DMF (50 mL). Add tertbutyldimethylsilyl chloride (TBSCl) (0.790 g, 5.24 mmol). Stir the reaction for 3 hours and pour into cold H2O (150 mL). Extract the H2O with EtOAc (3×50 mL), combine the extracts, and wash with H2O (2×50 mL) and brine (20 mL). Dry (MgSO4), filter and concentrate to afford the subtitled product (1.95 g, >95%) as an oil that may be used without purification. 1NMR (CDCl3) δ 0.11 (s, 6H), 0.95 (s, 9H),3.47 (s, 3H), 3.51 (s, 3H), 4.84 (s, 2H), 5.02 (s, 2H), 5.12 (s, 2H), 7.15 (d, J=2.9 Hz, 1H), 7.17 (d, J=3.0 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([NH:14][C:15]3[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=3)[N:12]=2)[N:7]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:6]=1)=[O:4].[O:33]=[C:34]([N:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1)[CH2:35][C:36]#[N:37].N1CCCCC1>CO>[CH3:1][C:2]([CH3:32])([CH3:31])[C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([NH:14][C:15]3[CH:22]=[CH:21][C:18]([CH:19]=[C:35]([C:34]([N:38]4[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]4)=[O:33])[C:36]#[N:37])=[CH:17][CH:16]=3)[N:12]=2)[N:7]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:28])[CH3:29])[CH:6]=1)=[O:4]
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccc(C=O)cc3)nc12
Reactant: N#CCC(=O)N1CCCCC1
Solvent: C1CCNCC1
Solvent: CO
Product: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccc(C=C(C#N)C(=O)N4CCCCC4)cc3)nc12
Reaction time: 5 h
Yield: 59.6 %

Procedure:
To a 20 ml vial 4-[[7-(2,2-dimethylpropanoyl)-5-(2-trimethylsilylethoxymethyl)-pyrrolo[2,3-b]pyrazin-2-yl]amino]benzaldehyde (35 mg, 0.0800 mmol), 3-oxo-3-(1-piperidyl)propanenitrile (18.01 mg, 0.1200 mmol), piperdine (0.02 ml, 0.15 mmol) and 3-oxo-3-(1-piperidyl)propanenitrile (18.01 mg, 0.12 mmol), were taken in methanol (5 ml). To this reaction mixture, piperdine (0.02 ml, 0.15 mmol) was added drop wise at RT. After completion of the addition, the reaction mixture was stirred for 5 hrs. Ethanol was evaporated, the residue was loaded on silica gel column and elution with CH2Cl2 to MeOH 0-2, 3% yielded 28 mg of 3-[4-[[7-(2,2-dimethylpropanoyl)-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazin-2-yl]amino]phenyl]-2-(piperidine-1-carbonyl)prop-2-enenitrile.
Reaction SMILES: C(S[C:5]1[C:10]([F:11])=[CH:9][N:8]([C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)[C:7](=[O:17])[N:6]=1)C=C.[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][NH2:26]>CO>[F:11][C:10]1[C:5]([NH:26][CH2:25][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[F:18])=[N:6][C:7](=[O:17])[N:8]([C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)[CH:9]=1
Reactant: C=CCSc1nc(=O)n(-c2ccsc2)cc1F
Reactant: NCc1ccccc1F
Solvent: CO
Product: O=c1nc(NCc2ccccc2F)c(F)cn1-c1ccsc1
Temperature: 100 °C
Yield: 69 %

Procedure:
To a solution of 4-(allylthio)-5-fluoro-1-(thiophen-3-yl)pyrimidin-2(1H)-one (140 mg, 0.66 mmol) in MeOH (1 mL) was added (2-fluorophenyl)methanamine (50 mg, 0.186 mmol). The reaction mixture was heated at 100° C. for 30 min in a microwave. After cooling, the mixture was purified by preparative thin layer chromatography to give 5-fluoro-4-(2-fluorobenzylamino)-1-(thiophen-3-yl)pyrimidin-2(1H)-one (41 mg, 20%) as a white solid: mp 75-78° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.16 (d, J=7.0 Hz, 1H), 7.66 (dd, J=3.2, 1.4 Hz, 1H), 7.57 (dd, J=5.2, 3.2 Hz, 1H), 7.43-7.13 (m, 5H), 4.63 (d, J=5.5 Hz, 2H); ESIMS m/z 320 ([M+H]+).
Reaction SMILES: [CH3:1][N:2]1[CH2:10][O:9][CH2:8][CH:7]2[CH:3]1[CH2:4][N:5](C(OCC)=O)[CH2:6]2>O>[CH3:1][N:2]1[CH2:10][O:9][CH2:8][CH:7]2[CH:3]1[CH2:4][NH:5][CH2:6]2
Reactant: CCOC(=O)N1CC2COCN(C)C2C1
Solvent: O
Product: CN1COCC2CNCC21

Procedure:
9 g (42 mmol) of ethyl 2-methyl-4-oxa-2,8-diazabicyclo[4.3.0]nonane-8-carboxylate are heated under reflux with 28 g of Ba(OH)2 ·8H2O in 280 ml of water overnight. The BaCO3 is filtered off with suction, the filtrate is concentrated and the residue is boiled up with dioxane. The dioxane solution is concentrated and the residue is distilled.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].O=P(Cl)(Cl)Cl.CN([CH:23]=[O:24])C>>[CH2:13]([O:12][C:10]([C:2]1[NH:1][C:9]2[C:4]([C:3]=1[CH:23]=[O:24])=[CH:5][CH:6]=[CH:7][CH:8]=2)=[O:11])[CH3:14]
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1[nH]c2ccccc2c1C=O

Procedure:
Ethyl indole-2-carboxylate (10 g, 52.8 mmol) was formylated using POCl3 (1.3 equiv.) and DMF (1.3 equiv.) as above to give 3-formyl-1H-indole-2-carboxylic acid ethyl ester as a white solid.
Reaction SMILES: Br[C:2]1[C:3]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:4][C:5]2[N:10]([CH2:11][CH:12]3[CH2:14][CH2:13]3)[C:9](=[O:15])[CH2:8][O:7][C:6]=2[N:16]=1.CC1(C)C(C)(C)OB([C:31]2[CH:45]=[CH:44][C:34]([CH2:35][NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[CH:33][CH:32]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[CH:12]1([CH2:11][N:10]2[C:9](=[O:15])[CH2:8][O:7][C:6]3[N:16]=[C:2]([C:31]4[CH:45]=[CH:44][C:34]([CH2:35][NH:36][C:37](=[O:43])[O:38][C:39]([CH3:40])([CH3:41])[CH3:42])=[CH:33][CH:32]=4)[C:3]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][C:5]2=3)[CH2:14][CH2:13]1
Reactant: O=C1COc2nc(Br)c(-c3ccccc3)cc2N1CC1CC1
Reactant: CC(C)(C)OC(=O)NCc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)NCc1ccc(-c2nc3c(cc2-c2ccccc2)N(CC2CC2)C(=O)CO3)cc1
Temperature: 50 °C
Yield: 73.9 %

Procedure:
In a 15 mL reaction tube was added 6-bromo-1-(cyclopropylmethyl)-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (80 mg, 0.223 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (89 mg, 0.267 mmol) and CESIUM CARBONATE (363 mg, 1.114 mmol) in a mixture of 1,4-Dioxane (3341 NI) and water (1114 μl) to give a colourless solution. This was degassed by bubbling nitrogen for 15 minutes, followed by the addition of PdC12(dppf)-CH2Cl2Adduct (36.4 mg, 0.045 mmol) and degassing for a further 5 minutes. The reaction mixture was heated to 50° C. under a nitrogen atmosphere for one hour. LC-MS analysis showed reaction completion. The reaction mixture was allowed to cool to room temperature, diluted with water (5 mL) and extracted into ethyl acetate (3×5 mL). The combined organic phases were dried over Na2SO4, filtered and concentrated to dryness under reduced pressure to give an off-white solid. The resulting residue was purified via Biotage (15-85% cyclohexane:EtOAc; 10 g column) to give the title compound (80 mg, 74%). 1H NMR (500 MHz, CDCl3): 7.39 (1H, s), 7.32-7.26 (5H, m), 7.20-7.18 (2H, dd), 7.12-7.10 (2H, d), 4.89 (2H, s), 4.80 (1H, br), 4.27 (2H, s), 3.87-3.86 (2H, d), 1.48-1.45 (9H, br), 1.18-1.15 (1H, m), 0.60-0.56 (2H, m), 0.48-0.45 (2H, m).
Reaction SMILES: [ClH:1].[C:2]1([CH:8]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:9]2[CH2:12][CH:11]([O:13][C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=[CH:16][C:15]=3COC)[CH2:10]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrC1C2C(=CC=CC=2)C=CC=1[CH2:44][O:45]C>>[ClH:1].[C:27]1([CH:8]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[N:9]2[CH2:10][CH:11]([O:13][C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=[CH:16][C:15]=3[O:45][CH3:44])[CH2:12]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COCc1ccc2ccccc2c1Br
Reactant: COCc1ccc2ccccc2c1OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: Cl
Product: COc1ccc2ccccc2c1OC1CN(C(c2ccccc2)c2ccccc2)C1

Procedure:
1-(Diphenylmethyl)-3-[(2-(methoxymethyl)-1-naphthalenyl)oxy]-azetidine hydrochloride, M.S. (C.I.) (M/Z): 410 [M+H]+, starting from 1-bromo-2-(methoxymethyl)-naphthalene.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([CH2:15]O)[CH:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1.C([N:22](C(C)C)CC)(C)C.CS(Cl)(=O)=O>C(Cl)Cl>[F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([CH2:15][NH2:22])[CH:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1
Reactant: OCc1ccnc(-c2ccc(C(F)(F)F)cc2)n1
Reactant: CCN(C(C)C)C(C)C
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: NCc1ccnc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a solution of [2-(4-trifluoromethyl-phenyl)-pyrimidin-4-yl]-methanol (110 mg, 0.43 mmol), diisopropylethylamine (0.10 mL, 0.52 mmol), and CH2Cl2 (5 mL) was added methanesulfonyl chloride (37 μL, 0.47 mmol). After 1 h, the resulting solution was concentrated. The residue was re-dissolved in 7N NH3 in MeOH (10 mL) and heated to 70° C. in a sealed tube. After 1 h, the resulting solution was cooled, concentrated, and the residue was used crude (110 mg, 100%). MS (ESI): mass calcd. for C12H10F3N3, 253.0; m/z found, 254.1 [M+H]+.
Reaction SMILES: COCN[C:5]([C:7]1[C:8]([NH2:16])=[N:9][C:10]([S:13][CH2:14][CH3:15])=[N:11][CH:12]=1)=[O:6].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Li]>O1CCCC1>[NH2:16][C:8]1[C:7]([C:5]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[O:18][CH3:17])=[O:6])=[CH:12][N:11]=[C:10]([S:13][CH2:14][CH3:15])[N:9]=1
Reactant: CCSc1ncc(C(=O)NCOC)c(N)n1
Reactant: [Li]c1ccccc1OC
Solvent: C1CCOC1
Product: CCSc1ncc(C(=O)c2ccccc2OC)c(N)n1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 94 %

Procedure:
4-Amino-2-ethylsulfanylpyrimidine-5-carboxylic acid methoxymethylamide (200 mg, 0.830 mmol, Example 1) was dissolved in anhydrous tetrahydrofuran (3 mL) and cooled to −78° C. A solution of 2-methoxyphenyl lithium (˜3 equiv, freshly prepared following the same procedure as Step A of Example 2) was added. The reaction was stirred at −78° C. for 1.5 hours and quenched with aqueous ammonium chloride solution. The resulting mixture was extracted with ethyl acetate (3×20 mL), washed with brine (2×10 mL), dried over sodium sulfate and evaporated in vacuo. The residue was purified on silica gel with 60:40 of hexane/ethyl acetate to give (4-amino-2-ethylsulfanylpyrimidin-5-yl)-(2-methoxy-phenyl)-methanone as a white solid (224.1 mg, 94% yield). HRMS, observed: 290.0961; Calcd for (M+H)+: 290.0958.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[I:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=1>CCOCC>[I:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:13])=[CH:10][CH:9]=1
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: C1COCCN1
Solvent: CCOCC
Product: O=C(c1ccc(I)cc1)N1CCOCC1

Procedure:
A solution of 15 ml of morpholine in 20 ml of ether was reacted with a solution of 5.4 g p-iodobenzoyl chloride in 20 ml ether. The excess organic solvent was removed and the crude product recovered as described in Example 3. After recrystallization there was obtained 3.1 g of N-p-iodobenzoyl-morpholine as translucent crystals, m.p. 116°-117°, Rf 0.72.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:10])=[O:9])=[C:6]([O:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])[CH:5]=1.O.[OH-].[Li+].Cl>CO.O>[Cl:23][C:17]1[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:16]=1[CH2:15][CH2:14][O:13][C:6]1[CH:5]=[C:4]([CH:12]=[CH:11][C:7]=1[C:8]([NH2:10])=[O:9])[C:3]([OH:24])=[O:2]
Reactant: COC(=O)c1ccc(C(N)=O)c(OCCc2ccc(Cl)cc2Cl)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: NC(=O)c1ccc(C(=O)O)cc1OCCc1ccc(Cl)cc1Cl
Temperature: 50 °C
Reaction time: 2 h

Procedure:
103 mg of 3-[2-(2,4-Dichloro-phenyl)-ethoxy]-terephthalamic acid methyl ester were dissolved in 1.2 ml of MeOH/water 3:1. 14 mg of lithium hydroxide monohydrate were added to the added to the solution, and the reaction was stirred at RT for 16 h and 2 h at 50° C. The solution was cooled to RT, then acidified with half-concentrated hydrochloric acid. The suspension was concentrated under reduced pressure and then extracted with ethyl acetate. The organic layer was dried over Na2SO4 and the solvent was removed under reduced pressure to yield a white solid.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:9]=[C:10]([C:14]3[CH2:20][C:19](=[O:21])[NH:18][C:17]4[CH:22]=[C:23]([N:26]5[CH:30]=[CH:29][CH:28]=[CH:27]5)[CH:24]=[CH:25][C:16]=4[N:15]=3)[CH:11]=[CH:12][CH:13]=2)[O:6][CH:7]=1.[CH3:31][NH:32][CH3:33].O>CCO>[CH3:31][N:32]([CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:9]=[C:10]([C:14]3[CH2:20][C:19](=[O:21])[NH:18][C:17]4[CH:22]=[C:23]([N:26]5[CH:30]=[CH:29][CH:28]=[CH:27]5)[CH:24]=[CH:25][C:16]=4[N:15]=3)[CH:11]=[CH:12][CH:13]=2)[O:6][CH:7]=1)[CH3:33]
Reactant: O=C1CC(c2cccc(-c3nc(CCl)co3)c2)=Nc2ccc(-n3cccc3)cc2N1
Reactant: CNC
Solvent: CCO
Solvent: O
Product: CN(C)Cc1coc(-c2cccc(C3=Nc4ccc(-n5cccc5)cc4NC(=O)C3)c2)n1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A mixture of 4-[3-(4-chloromethyl-oxazol-2-yl)-phenyl]-8-pyrrol-1-yl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 78a) (125 mg) and KI (5 mg) in a 5.6M solution of dimethylamine in EtOH (1.5 mL) was stirred at 20° C. for 16 h. H2O (20 mL) was added and the precipitate was collected by filtration and purified by chromatography on silica gel using MeOH as eluent. The product was stirred with 20% aqueous MeOH (10 mL) the pH of the mixture being set to 11 by addition of 1N NaOH solution, and the solid was isolated by filtration to give the title compound (50 mg) as yellow solid.
Reaction SMILES: [C@@H:1]1([C:7]([OH:9])=[O:8])[O:3][C@@H:2]1[C:4]([OH:6])=[O:5].[OH-:10].[Na+:11]>>[C:7]([C@@H:1]([C@H:2]([C:4]([O-:6])=[O:5])[OH:10])[OH:3])([O-:9])=[O:8].[Na+:11].[Na+:11]
Reactant: O=C(O)[C@H]1O[C@H]1C(=O)O
Reactant: [OH-]
Agent: [Na+]
Product: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Temperature: 35 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
Clean microbic cells obtained similarly to Example 3 were placed in 100 ml of an aqueous solution containing as the substrate 1.0 g of cis-epoxysuccinic acid and having the pH value thereof adjusted to 8.0 with an aqueous sodium hydroxide solution and agitated at 35° C for four hours. The substrate was wholly used up to produce 1.40 g of sodium L(+)-tartrate. The yield was 95 percent. The reaction mixture was treated by following the procedure of Example 2. The L(+)-tartaric acid consequently obtained was found to have an optical purity of 100 percent.
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][C:5]([NH:14][C:15]([CH:17]2[CH2:19][CH2:18]2)=[O:16])=[N:6][C:7]=1[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1.C1C=C(Cl)C=C(C(OO)=[O:28])C=1>C(Cl)Cl>[Br:1][C:2]1[N:3]=[CH:4][C:5]([NH:14][C:15]([CH:17]2[CH2:18][CH2:19]2)=[O:16])=[N:6][C:7]=1[C:8]1[CH:9]=[N+:10]([O-:28])[CH:11]=[CH:12][CH:13]=1
Reactant: O=C(Nc1cnc(Br)c(-c2cccnc2)n1)C1CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C(Nc1cnc(Br)c(-c2ccc[n+]([O-])c2)n1)C1CC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 71.8 %

Procedure:
To a suspension of N-(5-bromo-6-pyridin-3-ylpyrazin-2-yl)cyclopropanecarboxamide (4.02 g, 12.6 mmol) in CH2Cl2 (45 mL), cooled at 0° C., was added mCPBA (3.11 g, 12.6 mmol) in small portions. Upon addition completion the ice bath was removed and the reaction continued at room temperature for 4 h. The mixture was diluted with CH2Cl2 (30 mL) and washed with saturated NaHCO3 (1×25 mL) and saturated NaCl (1×25 mL). The organic layer was concentrated in vaccuo up to 25 mL volume, and the precipitated product was filtered and washed with Et2O (4×5 mL), giving the title compound as a white powder (3.03 g, 72% yield).