Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][C:27]=2[Cl:28])[NH:24][CH:23]=[C:22]3[CH:29]=[O:30])=[CH:15][CH:14]=1)([CH3:12])[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC(=CC)C.Cl([O-])=[O:37].[Na+].O.OP([O-])(O)=O.[Na+].[Cl-].[NH4+]>O1CCCC1.C(O)(C)(C)C.O>[Si:1]([O:8][CH2:9][C:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][C:27]=2[Cl:28])[NH:24][CH:23]=[C:22]3[C:29]([OH:37])=[O:30])=[CH:15][CH:14]=1)([CH3:12])[CH3:11])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: [O-][Cl+][O-]
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)c1ccc(-c2cc3c(C=O)c[nH]c3cc2Cl)cc1
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)c1ccc(-c2cc3c(C(=O)O)c[nH]c3cc2Cl)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of 5-[4-(1-{[tert-butyl(dimethyl)silyl]oxy}-2-methylpropan-2-yl)phenyl]-6-chloro-1H-indole-3-carbaldehyde (130 mg, 0.294 mmol) in tetrahydrofuran (2.5 mL) and tert-butanol (2.5 mL) was treated with 2-methyl-2-butene (2.19 mL, 20.6 mmol) followed by a solution of sodium chlorite (496 mg, 5.9 mmol) and sodium phosphate monobasic hydrate (811 mg, 5.9 mmol) in water (2.5 mL) via glass pipet at room temperature. The reaction mixture was stirred vigorously at room temperature for 15 hours, and was poured into saturated aqueous ammonium chloride solution (35 mL). The product was extracted with ethyl acetate (3×25 mL), and the combined organic layers were dried over sodium sulfate, filtered and evaporated to give the title compound as an amber oil. MS (ES−) 456.6 (M−H)−. 1H NMR (400 MHz, CD3OD) δ 8.01 (s, 1H), 7.99 (d, J=1.2 Hz, 1H), 7.57 (s, 1H), 7.43 (d, 2H), 7.37 (d, 2H), 3.63 (s, 2H), 1.36 (s, 6H), 0.86 (s, 9H), −0.05 (s, 6H).
Reaction SMILES: Cl.[C:2]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)=[N:11]1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[N:32]#CBr>C(Cl)(Cl)Cl>[C:2]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]#[N:32])[CH2:21][CH2:20]2)=[N:11]1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CN1CCC(c2nn(C(=O)c3ccccc3)c3ccccc23)CC1
Reactant: N#CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: N#CN1CCC(c2nn(C(=O)c3ccccc3)c3ccccc23)CC1
Yield: 28.2 %

Procedure:
A sample of 8.4 g of 1-benzoyl-3(1-methyl-4-piperidinyl)-1H-indazole hydrochloride was converted to its free base and the base was dissolved in 135 ml of chloroform. The solution was stirred and 4.0 g of potassium carbonate was added followed by 2.7 g of cyanogen bromide. The reaction mixture was stirred unde reflux for 16 hrs. The mixture was filtered, and the solvent was removed in vacuo. The mixture was chromatographed on a high-pressure column chromatography apparatus (silica gel), eluting with 0.3% methanol/dichloromethane. Evaporation of the appropriate fraction followed by recrystallization from toluene hexane yielded 2.2 g (28%) of the product, mp 144°-146° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][C@H:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][CH2:17][CH2:18]Br)=[CH:12][CH:13]=2)[CH2:8][CH2:7]1)[CH3:2].[CH2:21]([C:23]1[N:24]=[C:25]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([O:35][CH3:36])[CH:29]=2)[O:26][CH:27]=1)[CH3:22].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[CH2:21]([C:23]1[N:24]=[C:25]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:18][CH2:17][CH2:16][O:15][C:11]3[CH:10]=[C:9]4[C:14](=[CH:13][CH:12]=3)[C@H:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:20])[CH2:7][CH2:8]4)=[C:30]([O:35][CH3:36])[CH:29]=2)[O:26][CH:27]=1)[CH3:22]
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCBr)ccc21
Reactant: CCc1coc(-c2ccc(O)c(OC)c2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc(-c4nc(CC)co4)cc3OC)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.3 %

Procedure:
To a solution of [(1S-5-(3-bromopropoxy)-2,3-dihydro-1H-inden-1-yl]acetate (Example 45) (93.4mg, 0.274 mmol) and 4-(4-ethyl-1,3-oxazol-2-yl)-2-methoxyphenol (40.0 mg, 0.182 mmol) (Example 172) in DMF (4 mL) was added Cs2CO3 (118.9 mg, 0.365 mmol) and water (4 drops). The reaction mixture was stirred at rt for 16 h, then filtered, and the filtrate concentrated under reduced pressure. Purification by preparative HPLC (acetonitrile/water (v/v)=1:1 to 9:1 gradient) gave 73.6 mg (84%) of the title compound as an off-white solid. 1H NMR (400 MHz, CD2Cl2) δ 7.57 (d, 2H), 7.41 (s, 1H), 7.05 (d, 1H), 6.98 (d, 1H), 6.80 (s, 1H), 6.72 (d, 1H), 4.25 (t, 2H), 4.17 (m, 4H), 3.93 (s, 3H), 3.51 (m, 1H), 2.85 (m, 2H), 2.71 (dd, 1H), 2.62 (q, 2H), 2.40 (m, 2H), 2.31 (t, 2H), 1.76 (m, 1H), 1.29 (m, 6H).
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]1[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[C:16]([NH2:22])[N:15]=1)[N:7]=3.C(=O)([O-])[O-].[K+].[K+].C(#N)C.O.CC1(C)C(C)(C)OB([C:43]2[CH:44]=[N:45][N:46]([CH2:48][CH2:49][O:50]C(=O)C)[CH:47]=2)O1>C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:22][C:16]1[N:15]=[C:14]([C:8]2[N:7]=[C:6]3[C:5]4[CH:23]=[CH:24][C:2]([C:43]5[CH:44]=[N:45][N:46]([CH2:48][CH2:49][OH:50])[CH:47]=5)=[CH:3][C:4]=4[O:13][CH2:12][CH2:11][N:10]3[CH:9]=2)[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=1
Reactant: CC(=O)OCCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)n1nc(N)nc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CC#N
Product: CC(C)n1nc(N)nc1-c1cn2c(n1)-c1ccc(-c3cnn(CCO)c3)cc1OCC2
Temperature: 140 °C
Yield: 17.8 %

Procedure:
To a microwave vial was added 5-(8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-2-yl)-1-isopropyl-1H-[1,2,4]triazol-3-ylamine (0.180 g, 0.000462 mol) and potassium carbonate (0.1917 g, 0.001387 mol) in acetonitrile (2.0 mL, 0.038 mol) and water (2.0 mL, 0.11 mol). The reaction was thoroughly degassed and purged with N2 for 5 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.05344 g, 4.624E-5 mol) and Acetic acid 2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-ethyl ester (0.1554 g, 0.0005549 mol) were added and the vial was sealed immediately. The reaction was heated to 140° C. for 20 minutes in the microwave. The mixture was diluted with methylene chloride and filtered through celite. Saturated NH4Cl was added and the mixture was extracted 3 times with methylene chloride. The organic layers were combined, dried with MgSO4 and concentrated. The crude was purified by reverse-phase HPLC to give 211 (34.6 mg) as a colorless solid. MS (ESI+) 421.1. 1H NMR (400 MHz, DMSO) δ 8.35 (d, J=8.4, 1H), 8.22 (s, 1H), 7.95 (s, 1H), 7.73 (s, 1H), 7.38 (dd, J=8.4, 1.8, 1H), 7.27 (d, J=1.7, 1H), 5.84-5.69 (m, 1H), 5.19 (s, 2H), 4.93 (t, J=5.3, 1H), 4.50 (s, 4H), 4.16 (t, J=5.6, 2H), 3.77 (q, J=5.6, 2H), 1.42 (d, J=6.6, 6H)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](Cl)=[O:23]>>[Cl:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:23]
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: O=C(Cl)c1cccc(Cl)c1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4cccc(Cl)c4)nc23)CC1
Yield: 80.1 %

Procedure:
Beginning with 0.085 gm (0.369 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.099 mL (0.776 mMol) 3-chlorobenzoyl chloride, 0.109 gm (80.1%) of the title compound was recovered as a crystalline solid by the procedure described in Example 16.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([NH2:12])[C:8]([NH2:11])=[CH:9][CH:10]=1)=[O:4].N1C=CC=CC=1.[C:19]([C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20]>C(#N)C>[C:19]([C:23]1[CH:24]=[CH:25][C:26]([C:27]([NH:12][C:7]2[C:8]([NH2:11])=[CH:9][CH:10]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=2)=[O:28])=[CH:30][CH:31]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: COC(=O)c1ccc(N)c(N)c1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Solvent: CC#N
Solvent: c1ccncc1
Product: COC(=O)c1ccc(N)c(NC(=O)c2ccc(C(C)(C)C)cc2)c1
Reaction time: 3 h

Procedure:
To a stirring solution of 4-methoxycarbonyl-1,2-benzenediamine (8.5 g, 51 mmol) and pyridine (4.1 mL, 51 mmol) in acetonitrile (225 mL) at 0° C. was added via an addition funnel a solution of 4-t-butylbenzoyl chloride (10 g, 51 mmol) in acetonitrile (25 mL). After 3 h, the mixture was concentrated to a volume of about 20 mL in vacuo and then diluted with ethyl acetate (300 mL) and water (100 mL). The phases were separated and the organic phase was washed twice with 1 M citric acid, once with brine, twice with satd aq NaHCO3 and once again with brine. The organic phase was then dried with MgSO4, filtered and partially concentrated in vacuo. After standing for 48 h, the resulting precipitate was filtered, washed with ethyl acetate and dried in vacuo to give 8.2 g (48%) of off white solid. By a similar procedure, a second crop of 2.6 g (16%) was isolated from the mother liquor.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][OH:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Br:15][C:16]1[C:17]([F:23])=[N:18][CH:19]=[C:20](O)[CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Br:15][C:16]1[CH:21]=[C:20]([O:14][CH2:13][C@@H:9]2[CH2:10][CH2:11][CH2:12][N:8]2[C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH:19]=[N:18][C:17]=1[F:23]
Reactant: Oc1cnc(F)c(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cnc(F)c(Br)c1

Procedure:
A sample of 1-BOC-2-(S)-pyrrolidinemethanol, prepared as described above, and of 3-bromo-2-fluoro-5-hydroxypyridine, prepared as in step b above, are reacted with triphenylphosphine and DEAD in THF at room temperature for 16 hours, to give the title compound.
Reaction SMILES: C([O:5][C:6](=[O:39])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([F:17])=[CH:14][CH:15]=2)[C:10]([C:18]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[S:21](=[O:29])(=[O:28])[N:20]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[Cl:37])[N:19]=2)=[C:9]1[CH3:38])(C)(C)C.C(O)(C(F)(F)F)=O>>[Cl:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[CH2:30][N:20]1[N:19]=[C:18]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=3)[N:8]([CH2:7][C:6]([OH:39])=[O:5])[C:9]=2[CH3:38])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[S:21]1(=[O:29])=[O:28]
Reactant: Cc1c(C2=NN(Cc3ccccc3Cl)S(=O)(=O)c3ccccc32)c2cc(F)ccc2n1CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(C2=NN(Cc3ccccc3Cl)S(=O)(=O)c3ccccc32)c2cc(F)ccc2n1CC(=O)O

Procedure:
{3-[2-(2-Chloro-benzyl)-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2,3]thiadiazin-4-yl]-5-fluoro-2-methyl-indol-1-yl}-acetic acid tert-butyl ester (61 mmol) was treated with TFA (2 mL) for 2 hours, concentrated, and purified by preparative LCMS to give the title compound. 1H NMR (d6-DMSO) δ 8.18 (d, 1H), 7.94 (t, 1H), 7.83 (t, 1H), 7.45 (m, 6H), 6.88 (dt, 1H), 6.51 (dd, 1H), 5.19 (bs, 2H), 4.43 (s, 2H), 2.02 (s, 3H) ppm. MS calculated for C25H19FClN3O4S—H: 510, observed: 510.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:11][O:12][C:13](=[O:23])[CH2:14][CH2:15][C:16]1[C:17](=[O:22])[NH:18][CH2:19][CH2:20][CH:21]=1.[CH3:24]Br>C1COCC1>[CH3:11][O:12][C:13](=[O:23])[CH2:14][CH2:15][C:16]1[C:17](=[O:22])[N:18]([CH3:24])[CH2:19][CH2:20][CH:21]=1
Reactant: CBr
Reactant: COC(=O)CCC1=CCCNC1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)CCC1=CCCN(C)C1=O
Reaction time: 0.5 h
Yield: 72 %

Procedure:
0.22 ml of 1.0 M NaHMDS solution in THF (0.22 mmol) was added to 0.5 ml of THF solution containing 80 mg 3-(2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-propionic acid methyl ester (f) prepared from the step 1 in Example 3 (0.44 mmol) in a dropwise manner at −79° C. and then stirred for 30 min. After 0.48 ml of methyl bromide (0.48 mmol) was added to the reaction mixture, the solution was stirred at 0° C. for 3 hrs. The reaction mixture was quenched by 2 ml of sat. NH4Cl solution and then the organic layer was extracted with ethyl acetate (7 ml). The combined organic layer was washed with 2 ml of sat. NH4Cl solution (2 ml) and 2 ml of sat. NaCl solution subsequently. Then the organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resulting compound was purified by column chromatography on Silica gel with EtOAc solvent as an eluant to give 62 mg (yield: 72%) of the title compound (i2).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:7]=1[CH3:13].[C:17]([NH2:20])(=[S:19])[CH3:18]>>[CH3:1][O:2][C:3]([C:4]1[N:20]=[C:17]([CH3:18])[S:19][C:5]=1[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:7]=1[CH3:13])=[O:16]
Reactant: COC(=O)C(=O)C(Cl)c1cccc(C)c1C
Reactant: CC(N)=S
Product: COC(=O)c1nc(C)sc1-c1cccc(C)c1C

Procedure:
prepared by reaction of 3-chloro-3-(2,3-dimethyl-phenyl)-2-oxo-propionic acid methyl ester with thioacetamide. LC-MS: tR=0.95 min; [M+H]+=262.3.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH3:22])=[C:10]([C:23]([F:26])([F:25])[F:24])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.OC1CCNC1.[OH:33][CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[CH3:22][O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:37]3[CH2:38][CH2:39][CH:34]([OH:33])[CH2:35][CH2:36]3)[CH:7]=2)=[CH:9][C:10]=1[C:23]([F:26])([F:25])[F:24]
Reactant: OC1CCNCC1
Reactant: COc1ccccc1Sc1ccc(-c2ccnc(Cl)c2)cc1C(F)(F)F
Agent: OC1CCNC1
Product: COc1ccccc1Sc1ccc(-c2ccnc(N3CCC(O)CC3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared according to the procedures of Example 38E, substituting compound 76 with compound 96 (0.039 g, 0.0985 mmol) and 3-hydroxypyrrolidine with 4-hydroxypiperidine. A yellow solid 98 was obtained (0.0299 g, 66%). 1H-NMR (CDCl3, 400 MHz) δ 1.76-1.84 (m, 2H), 2.02-2.10 (m, 2H), 3.69-3.76 (m, 2H), 3.83 (s, 3H), 4.01-4.07 (m, 2H), 4.12-4.17 (m, 1H), 6.95 (d, J=6.6 Hz, 1H), 6.99 (s, 1H), 7.01-7.07 (m, 3H), 7.46-7.52 (m, 3H), 7.85 (s, 1H), 8.23 (d, J=6.6 Hz, 1H), MS (APCI) m/z 461 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[CH:25]([OH:26])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18]3=[O:27])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.N.[C:34]([OH:39])(=[O:38])[C:35]([OH:37])=[O:36]>CO.C(Cl)Cl.C(#N)C>[C:34]([OH:39])(=[O:38])[C:35]([OH:37])=[O:36].[CH3:34][O:27][CH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:25](=[O:26])[N:17]1[CH2:16][CH2:15][CH2:14][N:11]1[CH2:10][CH2:9][N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:13][CH2:12]1
Reactant: O=C1c2ccccc2C(O)N1CCCN1CCN(c2ccc(Cl)cc2)CC1
Agent: N
Agent: O=C(O)C(=O)O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CC#N
Solvent: CO
Product: COC1c2ccccc2C(=O)N1CCCN1CCN(c2ccc(Cl)cc2)CC1
Reaction time: 5 h
Yield: 169.2 %

Procedure:
The same procedure is followed as in Example 2, but starting from an agitated solution of 2-[3-(4-(4-chlorophenyl)-1-piperazinyl)propyl-3-hydroxy-1-isoindolinone (4.8 g) in methanol (115 cc) to which 22.6 cc of concentrated sulphuric acid is added at a temperature close to 20° C. and in the course of 10 minutes. Agitation is continued for 5 hours at a temperature close to 65° C. After cooling the solution to a temperature close to 0° C., 55 cc of a 33% aqueous solution of ammonia is added in the course of 1 hour. The precipitate formed is filtered and washed with methanol (50 cc). The filtrate is diluted with distilled water (200 cc) and 33% aqueous solution of ammonia (50cc), and extracted with methylene chloride (3×200 cc). The organic extracts are combined, dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. The residue obtained is dissolved in methylene chloride (20 cc) and the solution is poured onto silica (500 g) contained in a column of 8 cm diameter. Elution is carried out with a mixture of methylene chloride and methanol (98.5-1.5 by volume). The first 100 cc are eliminated and the next 630 cc are evaporated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 50° C. The residue obtained is dissolved in acetonitrile (30 cc). A solution of oxalic acid (0.63 g) in acetonitrile (15 cc) is added and agitation is continued for 1 hour at a temperature close to 20° C. The precipitate formed is separated by filtration. 2.9 g of 3-methoxy-2-[3-(4-(4-chlorophenyl)-1-piperazinyl)propyl]-1-isoindolinone oxalate are thus obtained, melting at 200° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7]2.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7]2
Reactant: COc1ccccc1B(O)O
Reactant: CCOC(=O)c1cnc2c(Br)cccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cnc2c(-c3ccccc3OC)cccc2c1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
A solution of ethyl 8-bromoquinoline-3-carboxylate (2.01 g, 10 mmol), prepared as described in Patent WO 2001047891, 2-methoxyphenylboronic acid (2.79 g, 10 mmol), Pd(PPh3)4 (5% mol), K2CO3 (5 g) in DMF/water (3/1) is stirred at 50° C. for 12 hours. The reaction mixture is then pored on water (150 mL). The aqueous phase is extracted with ethyl acetate (3×100 mL). The combined organic layers are washed with water (3×200 mL). The organic phase is dried over magnesium sulfate and evaporated under vacuum to afford the title compound.
Reaction SMILES: C1(C[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[NH:19][C:18]3=[O:26])[CH2:10][CH2:9]2)C=CC=CC=1.[H][H]>[Pd].CO>[N:11]1([CH2:14][CH2:15][CH2:16][N:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[NH:19][C:18]2=[O:26])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: O=c1[nH]c2ccccc2n1CCCN1CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=c1[nH]c2ccccc2n1CCCN1CCNCC1

Procedure:
A mixture of 63 parts of 1,3-dihydro-1-{3-[4-(phenylmethyl)-1-piperazinyl]propyl}-2H-benzimidazol-2-one in 400 parts of methanol is hydrogenated at normal pressure and at room temperature with 10 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off over hyflo and the filtrate is evaporated. The residue is crystallized from a mixture of 4-methyl-2-pentanone and 2-propanol. The product is filtered off and dried, yielding 1,3-dihydro-1-[3-(1-piperazinyl)propyl]-2H-benzimidazol-2-one; mp. 157.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:14][CH2:15][CH:16]=[C:17]([Cl:19])[Cl:18])[CH:5]=[C:6]([Cl:13])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11]Br.[C:20]([OH:28])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:1][C:2]1[CH:3]=[C:4]([O:14][CH2:15][CH:16]=[C:17]([Cl:19])[Cl:18])[CH:5]=[C:6]([Cl:13])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][O:28][C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: ClC(Cl)=CCOc1cc(Cl)c(OCCCBr)c(Cl)c1
Reactant: O=C(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(OCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 95.1 %

Procedure:
A reaction vessel was charged with 11.1 g of 3,5-dichloro-4-(3-bromopropoxy)-1-(3,3-dichloro-2-propenyloxy)benzene, 3.31 g of benzoic acid, 3.90 g of potassium carbonate and 50 ml of N,N-dimethylformamide. After stirring at room temperature for 24 hours, the reaction mixture was poured into water and extracted twice with 150 ml of diethyl ether. The ether layers were combined, and washed with water, dried over anhydrous magnesium chloride, and then concentrated to give a crude product. The crude product was subjected to silica gel chromatography, which afforded 11.6 g of 3,5-dichloro-4-(3-benzoyloxypropyloxy)-1-(3,3-dichloro-2-propenyloxy)benzene (95% yield).
Reaction SMILES: [O:1]1[C:5]([C:6]([O:8]CC)=O)=[CH:4][N:3]=[CH:2]1.Cl.[Cl:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[C:16]2[CH2:22][CH2:23][NH2:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>O1CCCC1.[OH-].[Na+].O.CN(C=O)C.C(OCC)(=O)C>[Cl:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[C:16]2[CH2:22][CH2:23][NH:24][C:6]([C:5]1[O:1][CH:2]=[N:3][CH:4]=1)=[O:8]
Reactant: CCOC(=O)c1cnco1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cnco1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.2 %

Procedure:
A mixture of ethyl oxazole-5-carboxylate (0.167 g; 1.19 mmol) in tetrahydrofurane (5 mL) and sodium hydroxide in water (2M, 2.7 mL) was stirred at room temperature for 1 hour and diluted in water, extracted with dichloromethane and the waters acidified with HCl 6N in water to pH 2 extracted with ethyl acetate, the organic layer was dried and concentrated under reduced pressure. The residue was added to a mixture of 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.25 g; 1.08 mmol), HATU (0.411 g; 1.08 mmol), N,N diisopropylethylamine (0.466 mL; 2.70 mmol), in DMF (6 mL) and was stirred at room temperature overnight. The reaction mixture was diluted in ethyl acetate, washed with sodium disulphate, sodium carbonate and brine, dried and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.182 g (32%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)oxazole-5-carboxamide as a yellow solid.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[CH2:9][OH:10].C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)(Cl)Cl>[CH3:18][S:19]([O:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[CH2:9][O:10][S:19]([CH3:18])(=[O:21])=[O:20])(=[O:21])=[O:20]
Reactant: OC[C@@H]1CCCC[C@H]1CO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)OC[C@@H]1CCCC[C@H]1COS(C)(=O)=O
Yield: 59.1 %

Procedure:
To a solution of the compound (2) (71.86 g; 0.499 mol) and triethylamine (151.21 g; 1.497 mol) in chloroform (1 liter), methanesulfonyl chloride (114.27 g; 0.998 mol) is dropwise added under ice-cooling, and the resultant mixture is stirred at room temperature for 6 hours. The reaction mixture is washed with water, dried and concentrated under reduced pressure. Diethyl ether is added to the residue for crystallization, and the precipitated crystals are collected to give trans-1,2-bis(methanesulfonyloxymethyl)cyclohexane (3) (88.57 g).