Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C@@H:6]([C@H:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[OH:9])[OH:7])([O:3][CH2:4][CH3:5])=[O:2].O=[CH:16][C:17]1[CH:26]=[CH:25][C:23]([OH:24])=[C:19]([O:20][CH2:21][CH3:22])[CH:18]=1.C1(C)C=CC=CC=1.O>C1(C)C=CC(S(O)(=O)=O)=CC=1.CO>[CH2:21]([O:20][C:19]1[CH:18]=[C:17]([CH:16]2[O:9][C@@H:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C@H:6]([C:1]([O:3][CH2:4][CH3:5])=[O:2])[O:7]2)[CH:26]=[CH:25][C:23]=1[OH:24])[CH3:22]
Reactant: CCOC(=O)[C@H](O)[C@@H](O)C(=O)OCC
Reactant: CCOc1cc(C=O)ccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CO
Solvent: O
Product: CCOC(=O)[C@@H]1OC(c2ccc(O)c(OCC)c2)O[C@H]1C(=O)OCC
Yield: 33.9 %

Procedure:
A mixture of diethyl L-tartrate (309 g, 1.5 mol), ethyl vanillin (166 g, 1 mol), toluene (2 L) and p-toluenesulfonic acid (5 g, 0.026 mol) was heated at 115°-116° C. for 24 hours under a nitrogen atmosphere. During the reaction, water was removed by azeotropic distillation via a Dean-Stark trap. The mixture was washed sequentially with saturated sodium bicarbonate solution (500 mL), brine (2×1 L) and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the solid obtained was recrystallized from isopropanol to provide 120 g (34% yield) of (4R,5R)-2-(3-ethoxy-4-hydroxy-phenyl)-4,5-dicarboethoxy-1,3-dioxolane, mp 78°-80° C., [α]D25 -38.0° (c,1.0; methanol). 1H-NMR (CDCl3) δ7.17 (1H, d,J=1.8 Hz), 7.06 (1H,dd,J=1.8 Hz and 8.10 Hz), 6.91 (1H,d,J =8.2 Hz), 6.07 (1H,s), 5.83 (1H,s), 4.91, (1H,d,J=4.0 Hz), 4.80 (1H,d,J=4.0 Hz), 4.37-4.25 (4H, 2q, overlapping, J=7.2 Hz), 4.15 (2H,q,J=7.0 Hz), 1.45 (3H,t,J=7.0 Hz), 1.38-1.29 (6H,2t, overlapping J=7.2 Hz). IR (KBr) 3390, 2980, 2930, 1735, 1600 cm-1. MS m/e (% abundance) 354 (55), 326 (3), 281 (40), 182 (85), 167 (85), 154 (100), 137 (70), 110 (30), 93 (10), 81 (10), 53 (5).
Reaction SMILES: [F:1][S:2]([F:13])([F:12])([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[Cl:14]Cl>C(O)(=O)C>[Cl:14][C:7]1[CH:8]=[C:3]([S:2]([F:10])([F:11])([F:12])([F:13])[F:1])[CH:4]=[CH:5][C:6]=1[OH:9]
Reactant: ClCl
Reactant: Oc1ccc(S(F)(F)(F)(F)F)cc1
Solvent: CC(=O)O
Product: Oc1ccc(S(F)(F)(F)(F)F)cc1Cl
Temperature: 30 °C
Reaction time: 1.5 h

Procedure:
5.00 g of 4-pentafluorosulfanylphenol (prepared in example 11a) were dissolved in 100 ml of acetic acid and a chlorine gas stream was passed through at 0° C. for 10 minutes. This warmed the solution to 30° C. which was subsequently stirred at RT for a further 90 minutes. Argon was used to drive the chlorine out of the solution and the solvent was subsequently removed under reduced pressure. 5.50 g of a pale yellow oil were obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([N:11]1[C:15]([C:16]2[N:25]=[C:24]3[N:18]([CH2:19][CH2:20][O:21][C:22]4[CH:29]=[C:28]([CH:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)[CH:27]=[CH:26][C:23]=43)[CH:17]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9].[CH:36]([S:38]([CH:41]=C)(=[O:40])=[O:39])=[CH2:37]>>[CH:8]([N:11]1[C:15]([C:16]2[N:25]=[C:24]3[C:23]4[CH:26]=[CH:27][C:28]([CH:30]5[CH2:35][CH2:34][N:33]([CH2:37][CH2:36][S:38]([CH3:41])(=[O:40])=[O:39])[CH2:32][CH2:31]5)=[CH:29][C:22]=4[O:21][CH2:20][CH2:19][N:18]3[CH:17]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CCNCC3)cc1OCC2
Reactant: C=CS(=O)(=O)C=C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CCN(CCS(C)(=O)=O)CC3)cc1OCC2

Procedure:
Following the procedure for 152, 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene trifluoroacetic acid salt was reacted with vinyl sulfone to give 225 as a white solid. 1H NMR δ (ppm) (DMSO-d): 8.27 (1H, d, J=8.29 Hz), 7.86-7.84 (2H, m), 7.00 (1H, dd, J=8.37, 1.76 Hz), 6.85 (1H, d, J=1.70 Hz), 5.88-5.78 (1H, m), 4.44 (4H, q, J=5.99 Hz), 3.26 (3H, m), 3.00 (3H, s), 2.95 (2 H, d, J=11.00 Hz), 2.68 (2H, t, J=6.79 Hz), 2.02 (2H, t, J=11.39 Hz), 1.72 (2H, d, J=12.62 Hz), 1.57 (2H, qd, J=12.27, 3.58 Hz), 1.42 (6H, d, J=6.60 Hz). LCMS: RT=2.68 min, M+H+=485
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[NH:11][C:12]([CH2:14][N:15]2[CH2:21][CH:20]3[N:22](C(OC(C)(C)C)=O)[CH:17]([CH2:18][CH2:19]3)[CH2:16]2)=[O:13])[NH:3]1.CO.[ClH:32]>O1CCOCC1>[ClH:32].[CH:20]12[NH:22][CH:17]([CH2:18][CH2:19]1)[CH2:16][N:15]([CH2:14][C:12]([NH:11][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=1[CH2:10][C:2](=[O:1])[NH:3]3)=[O:13])[CH2:21]2
Reactant: CC(C)(C)OC(=O)N1C2CCC1CN(CC(=O)Nc1cccc3c1CC(=O)N3)C2
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=C1Cc2c(cccc2NC(=O)CN2CC3CCC(C2)N3)N1

Procedure:
The product of step (ii) (0.8 g) was dissolved in 2M hydrogen chloride in 1,4-dioxane (10 ml), 1,4-dioxane (10 ml), methanol (10 ml) and the reaction mixture was stirred at ambient temperature for 2 hours. The solvents evaporated under reduced pressure to dryness. Yield: 0.8 g
Reaction SMILES: [CH2:1]1[CH:12]2[CH:4]([NH:5][C:6]3[C:7]([C:13]([NH:15][C@@H:16]([CH2:20][OH:21])[C:17](O)=[O:18])=[O:14])=[CH:8][CH:9]=[CH:10][C:11]=32)[CH2:3][CH2:2]1>C(O)(=O)C>[OH:18][CH2:17][C@@H:16]1[NH:15][C:13](=[O:14])[C:7]2=[C:6]3[C:11](=[CH:10][CH:9]=[CH:8]2)[CH:12]2[CH2:1][CH2:2][CH2:3][CH:4]2[N:5]3[C:20]1=[O:21]
Reactant: O=C(N[C@@H](CO)C(=O)O)c1cccc2c1NC1CCCC21
Solvent: CC(=O)O
Product: O=C1N[C@@H](CO)C(=O)N2c3c1cccc3C1CCCC12

Procedure:
Following the procedure of method 7E, (2S)-2-[(1,2,3,3a,4,8b-hexahydrocyclopenta[b]indol-5-ylcarbonyl)amino]-3-hydroxypropanoic acid (1.5 mmol, 430 mg) was cyclized by refluxing in acetic acid (40 mL). Purification by flash chromatography through silica gel (elution with 5% methanol-chloroform) provided each diastereomer: less polar product (0.55 mmol, 0.15 g, 37%) arbitrarily assigned as the R,R configuration and more polar product (0.26 mmol, 0.070 g, 17%) assigned as the S,S configuration.
Reaction SMILES: C([Li])CCC.[Br-].[F:7][C:8]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:9]=1[CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[F:35][C:36]1[CH:41]=[CH:40][C:39]([S:42]([C:45]2[CH:52]=[CH:51][C:48]([CH:49]=O)=[CH:47][CH:46]=2)(=[O:44])=[O:43])=[CH:38][CH:37]=1.FC1C=CC(S)=CC=1>O1CCCC1.C(OCC)(=O)C.O>[F:7][C:8]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:9]=1/[CH:10]=[CH:49]/[C:48]1[CH:47]=[CH:46][C:45]([S:42]([C:39]2[CH:40]=[CH:41][C:36]([F:35])=[CH:37][CH:38]=2)(=[O:44])=[O:43])=[CH:52][CH:51]=1
Reactant: O=Cc1ccc(S(=O)(=O)c2ccc(F)cc2)cc1
Reactant: Fc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(F)c1
Agent: Fc1ccc(S)cc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(F)cc1)c1ccc(/C=C/c2ccc(F)cc2F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22 %

Procedure:
Butyllithium (1.6M in hexanes, 0.35 mL, 0.57 mmol) was added dropwise to a cooled (0° C.) suspension of (2,4-difluorobenzyl)triphenylphosphonium bromide (266 mg, 0.57 mmol) in tetrahydrofuran (2.5 mL). The orange suspension was allowed to warm to room temperature for 1 hour. A solution of 4-[(4-fluorophenyl)sulfonyl]benzaldehyde (prepared according to the method of Example 46 Steps 1–4 using 4-fluorobenzenethiol in Step 1, 150 mg, 0.57 mmol) in tetrahydrofuran (0.5 mL) was added and the reaction was stirred overnight at room temperature. Water and ethyl acetate were added and the organic layer was dried over MgSO4 and evaporated in vacuo. The residue was purified by flash column chromatography on silica, eluting with 30% ethyl acetate/isohexane, followed by preparative HPLC to give the title compound (46 mg, 22%). 1H NMR δ (ppm)(DMSO): 8.01–7.99 (2H, m), 7.83 (2H, d, J=8.5 Hz), 7.47–7.42 (2H, m), 7.37 (2H, d, J=8.4 Hz), 7.27–7.17 (2H, m), 6.99 (1H, td, J=2.2, 8.6 Hz), 6.82 (1H, d, J=12.3 Hz), 6.70 (1H, d, J=12.0 Hz).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([NH:10]C(=O)OC(C)(C)C)[CH2:6][CH2:5]1.Cl>C(O)C>[NH2:10][CH:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][OH:1])[CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCO)CC1
Agent: Cl
Solvent: CCO
Product: NC1CCN(CCO)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.4 %

Procedure:
To a solution of 0.58 g of tert-butyl 1-(2-hydroxyethyl)piperidin-4-ylcarbamate obtained in step 1 in 10 ml of ethanol was added 1 ml of conc. HCl, followed by stirring for 2 hrs under reflux. The reaction mixture was cooled to room temperature, and concentrated in a reduced pressure to remove solvent. The residue was added with 10 ml of distilled water, neutralized with saturated sodium hydrogen carbonate aqueous solution, and extracted twice with 10 ml of methylene chloride. After being dried over a desiccant, the fraction was concentrated in a reduced pressure to afford 0.33 g of the title compound (Yield: 95%). 1H NMR (CDCl3) δ 3.68 (s, 2H), 3.60 (t, 2H), 2.86 (d, 2H), 2.69 (m, 1H), 2.53 (t, 2H), 2.11 (t, 2H), 1.82 (d, 2H), 1.42 (t, 2H) ppm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[OH:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[CH:22]1[CH2:27][CH2:26][CH2:25][N:24]([C:28](=[O:30])[CH3:29])[CH2:23]1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH:22]2[CH2:27][CH2:26][CH2:25][N:24]([C:28](=[O:30])[CH3:29])[CH2:23]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2O)CC1
Reactant: CC(=O)N1CCCC(O)C1
Product: CC(=O)N1CCCC(Oc2ccccc2N2CCN(C(=O)OC(C)(C)C)CC2)C1

Procedure:
The title compound was prepared by using mitsonobu condition from 4-(2-hydroxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester and 1-(3-Hydroxy-piperidin-1-yl)-ethanone.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[CH:26]3[CH2:27][N:28](C(OCC)=O)[CH2:29][CH2:30][CH:25]3[N:13]3[CH2:14][CH:15]([CH3:24])[N:16](C(OCC)=O)[C:17]([CH:18]=1)=[C:12]23.[OH-].[K+]>CCCCO.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[CH:26]3[CH2:27][NH:28][CH2:29][CH2:30][CH:25]3[N:13]3[CH2:14][CH:15]([CH3:24])[NH:16][C:17]([CH:18]=1)=[C:12]23
Reactant: CCOC(=O)N1CCC2C(C1)c1cc(-c3ccc(Cl)cc3Cl)cc3c1N2CC(C)N3C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCCCO
Product: CC1CN2c3c(cc(-c4ccc(Cl)cc4Cl)cc3C3CNCCC32)N1
Temperature: 120 °C
Reaction time: 16 h
Yield: 44.5 %

Procedure:
To a solution of diethyl 5-(2,4-dichlorophenyl)-2-methyl-6b,9,10,10a-tetrahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-3,8(2H,7H)-dicarboxylate (30 mg, 0.06 mmol) in 10 mL of n-BuOH was added KOH (33 mg, 0.6 mmol) and stirred at 120° C. for 16 h. The reaction was allowed to cool to ambient temperature and was diluted with ethyl acetate, washed with water (10 mL). The organic layer was collected and washed with 1N HCl (10 mL) and water (10 mL). This time the aqueous layer was collected and neutralized with saturated aqueous sodium bicarbonate and extracted with EtOAc (2×20 mL). The combined extracts were dried over magnesium sulfate, concentrated to afford 5-(2,4-dichlorophenyl)-2-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline (10 mg, 45%) as a solid. MS [M+H]+ 374.
Reaction SMILES: COC[N:4]1[C:9]2[CH:10]=[C:11]([CH2:14][N:15]3[C:23]4[C:18](=[N:19][CH:20]=[N:21][C:22]=4[S:24][CH2:25][CH2:26][CH2:27][C:28]([O:30]CC)=[O:29])[N:17]=[CH:16]3)[CH:12]=[CH:13][C:8]=2[S:7][C:6]2[N:33]=[CH:34][CH:35]=[N:36][C:5]1=2.B(Br)(Br)Br.O>ClCCl>[N:36]1[C:5]2[NH:4][C:9]3[CH:10]=[C:11]([CH2:14][N:15]4[C:23]5[C:18](=[N:19][CH:20]=[N:21][C:22]=5[S:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])[N:17]=[CH:16]4)[CH:12]=[CH:13][C:8]=3[S:7][C:6]=2[N:33]=[CH:34][CH:35]=1
Reactant: CCOC(=O)CCCSc1ncnc2ncn(Cc3ccc4c(c3)N(COC)c3nccnc3S4)c12
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: O=C(O)CCCSc1ncnc2ncn(Cc3ccc4c(c3)Nc3nccnc3S4)c12
Yield: 42.6 %

Procedure:
To 15 ml of a solution of 0.109 g of ethyl 4-[7-(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)purin-6-ylthio]butanoate in dichloromethane was added in a nitrogen atmosphere 0.84 ml of a 1 M solution of boron tribromide in dichloromethane and the resulting mixture was heated under reflux for 2 hours. Then the reaction mixture was distributed into dichloromethane and water. The organic layer was extracted and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (eluted with dichloromethane/methanol) and recrystallized from diethyl ether to thereby give 40 mg of the title compound as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]3[CH2:15][CH2:16][S:17](=[O:24])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[C:10]3=[N:9]2)=[CH:4][CH:3]=1.[OH:25]O.O>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]3[CH2:15][CH2:16][S:17](=[O:25])(=[O:24])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[C:10]3=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=c1cc2c(nn1-c1ccc(Cl)cc1)-c1ccccc1S(=O)CC2
Reactant: OO
Solvent: O
Solvent: CC(=O)O
Product: O=c1cc2c(nn1-c1ccc(Cl)cc1)-c1ccccc1S(=O)(=O)CC2
Temperature: 25 °C

Procedure:
To a solution of 14 g of 2-(4-chlorophenyl)-5,6-dihydro-[1]benzothiepino[5,4-c]pyridazin-3(2H)-one 7-oxide prepared in Example 14 in 200 ml of acetic acid is added 15 ml of hydrogen peroxide with stirring at room temperature. The mixture is stirred at 50°-55° C. for 2 hours, poured into 1 liter of water and the precipitated crystals are collected by filtration. The crude products obtained are purified by column chromatography on silica gel and recrystallized from chloroform-methanol to give 9.8 g of 2-(4-chlorophenyl-5,6-dihydro-[1]benzothiepino[5,4-c]pyridazin-3(2H)-one 7,7-dioxide, melting at above 310° C.
Reaction SMILES: [F:1][C:2]1[C:11]([CH3:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([N+:13]([O-])=O)[CH:3]=1>CO.[Pd]>[NH2:13][C:4]1[CH:3]=[C:2]([F:1])[C:11]([CH3:12])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cc(C)c(F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(C)c(F)cc1N
Yield: 51.4 %

Procedure:
The solution of crude methyl 4-fluoro-5-methyl-2-nitrobenzoate (5 g) in MeOH (50 mL) was hydrogenated using 10% Pd/C (0.5 g) as catalyst at atmospheric pressure overnight. The catalyst was removed by filtration, and the solvent was evaporated at reduced pressure. The residue was purified by column chromatography on silica gel eluted with PE-EA (8:1) to give methyl 2-amino-4-fluoro-5-methylbenzoate (2.21 g, yield 50% over three steps) as a white solid. 1H NMR (500 MHz, CDCl3) δ 7.715 (d, J=9.0 Hz, 1H), 6.339 (d, J=11.5 Hz, 1H), 3.873 (s, 3H), 2.154 (s, 3H) ppm.
Reaction SMILES: COC1C=CC(C2C=NN(COCC[Si](C)(C)C)C=2C)=CC=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[C:32]([CH3:44])=[N:33][N:34]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[CH:35]=2)=[CH:27][CH:26]=1.[Li]CCCC.C([O:53][B:54](OC(C)C)[O:55]C(C)C)(C)C>C1COCC1>[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[C:32]([CH3:44])=[N:33][N:34]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:42])([CH3:41])[CH3:43])[C:35]=2[B:54]([OH:55])[OH:53])=[CH:27][CH:26]=1
Reactant: COc1ccc(-c2cn(COCC[Si](C)(C)C)nc2C)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: COc1ccc(-c2cnn(COCC[Si](C)(C)C)c2C)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(-c2c(C)nn(COCC[Si](C)(C)C)c2B(O)O)cc1
Reaction time: 0.5 h

Procedure:
A mixture of 4-(4-methoxy-phenyl)-5-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazole and 4-(4-methoxy-phenyl)-3-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazole (1 eq) was taken up in THF and cooled under nitrogen to −78° C. nBuLi (1.2 eq) was added dropwise and all was stirred for 30 minutes. Triisopropylborate (2.5 eq) was added and the reaction was stirred to room temperature. After 45 minutes, the reaction mixture was quenched with water and extracted with EtOAc. The organic phase was dried over MgSO4, filtered and concentrated in vacuo to give a gum. This was purified by flash chromatography (9:1 hexane: EtOAc) to give 4-(4-methoxy-phenyl)-3-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazole-5-boronic acid as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[CH:14][CH:15]=3)[O:10][CH:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:27]([CH:29]1[O:31][CH2:30]1)Cl.C(#N)C>O>[CH3:20][O:19][C:13]1[CH:12]=[C:11]2[C:16]([C:17](=[O:18])[C:8]([C:5]3[CH:4]=[CH:3][C:2]([O:1][CH2:27][CH:29]4[CH2:30][O:31]4)=[CH:7][CH:6]=3)=[CH:9][O:10]2)=[CH:15][CH:14]=1
Reactant: COc1ccc2c(=O)c(-c3ccc(O)cc3)coc2c1
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1ccc2c(=O)c(-c3ccc(OCC4CO4)cc3)coc2c1
Reaction time: 4 h
Yield: 43.2 %

Procedure:
A mixture of 7-methoxy-4′-hydroxyisoflavone (1, 0.27 g, 1 mmol), K2CO3 (0.41 g, 3 mmol), epichlorohydrin (0.3 g, 3 mmol) and acetonitrile (30 mL) was refluxed with stirring for 4 hrs (TLC monitoring). The mixture was evaporated in vacuo to give a residue which was treated with H2O (50 mL). The precipitate thus formed was collected, purified by column chromatography (MeOH/CH2Cl2=1:50), and crystallized from EtOH to give the title compound 3 (0.14 g, 43% yield). M.p.: 153-154° C.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.C(O)(=O)C.S(=O)(=O)(O)O>O>[F:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([I:1])[CH:11]=1
Reactant: Oc1ccc(F)cc1
Reactant: O=C1CCC(=O)N1I
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: Oc1ccc(F)cc1I
Temperature: 25 °C
Reaction time: 18 h
Yield: 40 %

Procedure:
N-Iodosuccinimide (10 g, 45.0 mmol) and 4-fluoro-phenol (5.00 g, 40.0 mmol) were suspended in acetic acid (39 ml, 649.0 mmol) and stirred for 5 minutes before addition of concentrated sulphuric acid (0.79 ml, 13.4 mmol). The reaction mixture was stirred for 18 hours at room temperature before diluting with water (100 ml). The aqueous layer was extracted with dichloromethane (2×30 ml). The combined organic extracts were washed with sodium thiosulphate solution (20% aqueous, wt:v), water, dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by column chromatography (silica gel) eluting with toluene to afford the title compound as an off white solid, 4.5 g, 40% yield.
Reaction SMILES: [N+:1]([CH:3]([CH3:11])[C:4]([O:6][CH2:7][CH2:8][CH2:9][CH3:10])=[O:5])#[C-:2].C(N(CCCC)CCCC)CCC>ClC1C=CC=CC=1>[CH3:11][C:3]1[N:1]=[CH:2][O:5][C:4]=1[O:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: [C-]#[N+]C(C)C(=O)OCCCC
Solvent: CCCCN(CCCC)CCCC
Solvent: Clc1ccccc1
Product: CCCCOc1ocnc1C

Procedure:
A continuously operated dividing wall column (4.8 m×64 mm) packed with 3×3 mm V2A Raschig rings and a dividing wall of height 2.4 m having 60 theoretical plates was charged with a mixture of 13.1% by weight of n-butyl α-isocyanopropionate (R1 =n-butyl, R2=methyl), 32.2% by weight of monochlorobenzene and 50.1% by weight of tri-n-butylamine.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[CH3:19][N:20]1[CH2:25][CH2:24][CH:23]([NH:26][CH3:27])[CH2:22][CH2:21]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:26]([CH3:27])[CH:23]3[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]3)=[CH:8][C:6]=2[N:7]=1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CNC1CCN(C)CC1
Product: CN1CCC(N(C)Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1

Procedure:
Reaction between 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde 10 (Example 3) and 1-methyl-4-(methylamino)piperidine using General Procedure B-3 yielded (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methyl-(1-methyl-piperidin-4-yl)-amine.
Reaction SMILES: II.[Mg].[CH2:4](Br)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Br:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=[O:17].[Cl-].[NH4+]>O1CCCC1>[Br:12][C:13]1[CH:14]=[C:15]([CH:16]([OH:17])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH:18]=[CH:19][CH:20]=1
Reactant: CCCCCCCBr
Reactant: O=Cc1cccc(Br)c1
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCCCCC(O)c1cccc(Br)c1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
A small amount of iodine was added to a solution (100 ml) of magnesium (9.8 g) in anhydrous tetrahydrofuran and the mixture was stirred at 50° C. until the color of the iodine disappeared. A solution of heptyl bromide in anhydrous tetrahydrofuran (200 ml) was dropwise added thereto over 1 hour. The mixture was stirred at 65° C. for 1 hour and a solution of m-bromobenzaldehyde in anhydrous tetrahydrofuran (200 ml) was dropwise added thereto under ice-cooling. The mixture was stirred at room temperature for 30 minutes. Under ice-cooling, a saturated aqueous ammonium chloride solution (7.3 ml) was added thereto and the mixture was stirred for 1 hour. The insoluble matters were filtered off and the filtrate was concentrated. The concentrate was dissolved in ethyl acetate and the mixture was washed with water. The mixture was dried over magnesium sulfate and the solvent was distilled away. The residue obtained was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=10:1) to give 50.9 g of the subject compound as an oily substance.
Reaction SMILES: [CH:1]([C:4]([C:25]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[C:27]([O:35][CH3:36])[CH:26]=1)([CH2:7][CH2:8][CH2:9][N:10]([CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-])=O)[CH3:11])[C:5]#[N:6])([CH3:3])[CH3:2]>CO.[Pt]=O>[CH:1]([C:4]([C:25]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[C:27]([O:35][CH3:36])[CH:26]=1)([CH2:7][CH2:8][CH2:9][N:10]([CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH2:22])[CH3:11])[C:5]#[N:6])([CH3:3])[CH3:2]
Reactant: COc1cc(C(C#N)(CCCN(C)CCCOc2ccccc2[N+](=O)[O-])C(C)C)cc(OC)c1OC
Agent: O=[Pt]
Solvent: CO
Product: COc1cc(C(C#N)(CCCN(C)CCCOc2ccccc2N)C(C)C)cc(OC)c1OC
Yield: 105.2 %

Procedure:
0.92 g of alpha-isopropyl-alpha-[3-[N-[3-(2-nitrophenoxy)propyl]-N-methylamino]propyl]-3,4,5-trimethoxyphenylacetonitrile was hydrogenated in 20 ml of methanol over 10 mg of platinum oxide at atmospheric pressure and room temperature. The catalyst was filtered off and filtrate was evaporated to give 0.91 g of the desired compound as a yellow oil. The oxalate of this compound was obtained in the usual manner.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH2:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:14]1[O:22][CH:15]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][CH2:14][CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[OH:22])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCN)cc1OC
Reactant: c1ccc(C2CO2)cc1
Solvent: C1CCOC1
Product: COc1ccc(CCNCC(O)c2ccccc2)cc1OC

Procedure:
A mixture of 100 g (0.55 mol) of 3,4-dimethoxyphenylethylamine and 66.2 g (0.55 mol) of styrene oxide in 200 ml of tetrahydrofuran was refluxed overnight. The solvent was removed in vacuo. About 500 ml of n-butyl chloride was added to the residue and the mixture cooled slightly. Filtration furnished N-[2-(3,4-dimethoxyphenyl)ethyl]-2-phenyl-2-hydroxyethylamine, m.p. 92°-93°.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([N:29]4[CH2:33][C@@H:32]([CH2:34][NH:35][C:36](=[O:38])[CH3:37])[O:31][C:30]4=[O:39])=[CH:25][C:24]=3[F:40])[CH2:19][CH2:18]2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>CO.[Pd]>[F:40][C:24]1[CH:25]=[C:26]([N:29]2[CH2:33][C@H:32]([CH2:34][NH:35][C:36](=[O:38])[CH3:37])[O:31][C:30]2=[O:39])[CH:27]=[CH:28][C:23]=1[N:20]1[CH2:21][CH2:22][N:17]([CH:14]2[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]2)[CH2:18][CH2:19]1
Reactant: CC(=O)NC[C@@H]1CN(c2ccc(N3CCN(C4CCN(C(=O)OCc5ccccc5)CC4)CC3)c(F)c2)C(=O)O1
Agent: [Pd]
Solvent: CO
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCN(C4CCNCC4)CC3)c(F)c2)C(=O)O1

Procedure:
A suspension of 500 mg of 10% Pd/C and 2.5 g 4-(4-{4-[(5R)-5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}-piperazin-1-yl)-piperidin-1-carboxylic acid benzyl ester(, 5.51 mmol) in 50 ml methanol was stirred under hydrogen. The reaction was monitored by TLC. The Pd/C was filtered off, the filtrate evaporated to dryness and the residue digested in an ethyl acetate/hexane mixture. The glassy solid was filtered, washed with hexane and dried.