Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([S:5][CH2:6][C:7](=O)[CH2:8][C:9]([CH3:15])([CH3:14])[C:10]([O:12][CH3:13])=[O:11])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.C([O-])(=O)C.[Na+].[Cl:26][C:27]1[CH:49]=[CH:48][C:30]([CH2:31][N:32]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=3)=[CH:36][CH:35]=2)N)=[CH:29][CH:28]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C.CCCCCC.O>[Cl:26][C:27]1[CH:49]=[CH:48][C:30]([CH2:31][N:32]2[C:34]3[C:39](=[CH:38][C:37]([O:40][CH2:41][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=4)=[CH:36][CH:35]=3)[C:6]([S:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[C:7]2[CH2:8][C:9]([CH3:15])([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:29][CH:28]=1
Reactant: COC(=O)C(C)(C)CC(=O)CSC(C)(C)C
Reactant: NN(Cc1ccc(Cl)cc1)c1ccc(OCc2ccccn2)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(OCc3ccccn3)ccc2n1Cc1ccc(Cl)cc1
Reaction time: 120 h

Procedure:
To a solution of methyl 5-t-butylthio-2,2-dimethyl-4-oxopentanoate (33.2 g; 135 mmol), prepared as in Example 1, step 4, in 300 mL toluene and 150 mL acetic acid was added sodium acetate (12.7 g; 155 mmol) followed by 1-(4-chlorobenzyl)-1-[4-(pyrid-2-ylmethoxy)phenyl] hydrazine (48.4 g; 143 mmol), prepared as in step 4. The reaction mixture was stirred in the dark for 5 days, then was poured into water and extracted with ethyl acetate. Solid sodium bicarbonate was added to the extracts and then filtered. The filtrate was washed with water, dried over magnesium sulfate, and the solvent was evaporated. The product was isolated by flash chromatography (40% diethyl ether in hexane) and then recystallized from ethyl acetate/hexane to yield methyl 3-[1-(4-chlorobenzyl)-3-(1,1-dimethylethylthio)-5-(pyrid-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropionate.
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH2:9][CH2:10][S:11][C:12]1[CH2:18][CH:17]2[N:14]([C:15](=[O:21])[CH:16]2[CH2:19][CH3:20])[C:13]=1[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1)=[O:23].[C:35](Cl)(=[O:37])[CH3:36]>ClCCl.C1C=CC=CC=1>[C:35]([O:8][CH2:9][CH2:10][S:11][C:12]1[CH2:18][CH:17]2[N:14]([C:15](=[O:21])[CH:16]2[CH2:19][CH3:20])[C:13]=1[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1)=[O:23])(=[O:37])[CH3:36]
Reactant: CCC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SCCO)CC12
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: c1ccccc1
Product: CCC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SCCOC(C)=O)CC12

Procedure:
Triethylamine (13.3 microliters) was added to a solution in 2 ml of dichloromethane of 3.75 mg of the p-nitrobenzyl 3-(2-hydroxyethylthio)-6-ethyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate obtained in Example 44. Then, 6.8 microliters of acetyl chloride was added dropwise to the resulting solution at -10° C. with stirring. At the same temperature, the mixture was stirred for 10 minutes. The reaction mixture was diluted with 10 ml of benzene, and washed three times with 5 ml of a 0.1 M phosphate buffer (pH6.8). The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to afford a yellow oily product.
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:10][C:9]2[C:4](=[CH:5][C:6]([O:22][CH3:23])=[C:7]([O:20][CH3:21])[CH:8]=2)[N:3]=1.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([CH2:37][CH2:38][CH2:39][NH2:40])[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.CCOC(C)=O>[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([CH2:37][CH2:38][CH2:39][NH:40][C:2]2[C:11]([CH:12]=[CH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:10][C:9]3[C:4](=[CH:5][C:6]([O:22][CH3:23])=[C:7]([O:20][CH3:21])[CH:8]=3)[N:3]=2)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]
Reactant: COc1cc2nc(Cl)c(C=Cc3ccccc3)nc2cc1OC
Reactant: CC(C)(C)OC(=O)N1CCC(CCCN)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1cc2nc(C=Cc3ccccc3)c(NCCCC3CCN(C(=O)OC(C)(C)C)CC3)nc2cc1OC
Temperature: 25 °C

Procedure:
A mixture 2-chloro-6,7-dimethoxy-3-styryl-quinoxaline (see Kadin, S. B., Ger Offen., DE 2357186; 255 mg, 0.78 mmol), 4-(3-amino-propyl)-piperidine-1-carboxylic acid tert-butyl ester (see Egbertson, M, U.S. Pat. No. 5494921; 392 mg, 1.6 mmol) and potassium carbonate (220 mg, 1.6 mmol) was heated at 120° C. in DMSO (2 mL) for 17 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc and washed with sat'd aq NaHCO3, sat'd aq NaCl, dried and concentrated under vacuum. The crude residue was chromatographed on SiO2-gel to give 150 mg of a yellow oil. API-MS: 533 (M+1). 1H NMR (300 MHz, CDCl3): d 7.75 (d, 1 H), 7.58 (d, 1 H), 7.35 (m), 7.15 (d, 1 H), 4.05 (m), 3.99 (s, 3 H), 3.97 (s, 3 H), 3.54 (bs, 1 H), 2.68 (t, 2 H),1.75 (m), 1.42 (s, 9 H), 1.1 (m).
Reaction SMILES: [CH2:1]1[CH2:29][O:28][C:3]2([CH:8]=[CH:7][C@H:6]3[C@H:9]4[C@H:18]([CH2:19][CH2:20][C@:4]23[CH3:5])[C:17]2[CH:16]=[CH:15][C:14]([OH:21])=[CH:13][C:12]=2[CH2:11][C@H:10]4[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27])[O:2]1.[OH-].[Li+].[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C)C=O.C(OCC)(=O)C>[CH2:32]([O:21][C:14]1[CH:15]=[CH:16][C:17]2[C@@H:18]3[C@H:9]([C@H:6]4[C@@:4]([CH2:20][CH2:19]3)([CH3:5])[C:3]3([O:2][CH2:1][CH2:29][O:28]3)[CH:8]=[CH:7]4)[C@H:10]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27])[CH2:11][C:12]=2[CH:13]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: BrCc1ccccc1
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCO)[C@H]3[C@@H]1C=CC21OCCO1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@]12CC[C@@H]3c4ccc(OCc5ccccc5)cc4C[C@@H](CCCCCO)[C@H]3[C@@H]1C=CC21OCCO1

Procedure:
A solution of 32.7 g of 17,17-ethylenedioxy-7α-(5-hydroxypentyl)-estra-1,3,5(10),15-tetraen-3-ol (see Example 1h) in 327 ml of dimethylformamide is mixed at room temperature with 5.73 g of lithium hydroxide and stirred with 15.1 ml of benzyl bromide for 2 hours at 60° C. Then, it is diluted with ethyl acetate, washed with water, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with dichloromethanenimethanol. 32.8 g of 3-benzyloxy-17,17-ethylenedioxy-7α-(5-hydroxypentyl)-estra-1,3,5(10),15-tetraene is obtained.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=2)[N:7]=1.[F:15][C:16]([F:28])([F:27])[O:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>C(OCC)(=O)C.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>[F:15][C:16]([F:27])([F:28])[O:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=3)[N:7]=2)=[CH:20][CH:19]=1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
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: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: FC(F)(F)Oc1ccc(-c2ccc3nnc(C(F)(F)F)n3n2)cc1

Procedure:
To a round bottom flask was added 6-chloro-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (0.982 mmole), 4-(trifluoromethoxy)phenylboronic acid (1.18 mmole), tetrakis(triphenylphosphine)palladium (0.0491 mmole), 2M Na2CO3 (2 mL), and 1,2-dimethoxyethane (3 mL). The resulting reaction mixture was heated at 85 C for 2 hours. The reaction mixture was diluted with ethyl acetate and filtered through celite. The filtrate was washed with water. The organic extract was dried over Na2SO4 and evaporated in vacuo. The crude residue was purified by preparative HPLC to yield 6-(4-(trifluoromethoxy)phenyl)-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: CCN(CC)CC.[F:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][NH2:16])=[CH:11][CH:10]=1.Cl.FC1C=CC(N2[C:29]3[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:28]=3[C:27]([CH2:35][OH:36])=N2)=CC=1>CCO>[F:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:27]([CH2:35][OH:36])=[C:28]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][C:29]3=[N:16]2)=[CH:11][CH:10]=1
Reactant: NNc1ccc(F)cc1
Reactant: OCc1nn(-c2ccc(F)cc2)c2c1CCCCC2
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: OCc1c2c(nn1-c1ccc(F)cc1)CCCCC2
Reaction time: 8 h

Procedure:
The crude diketone was dissolved in 60 mL of absolute EtOH and combined with 3.07 mL (22 mmol, 2.23 g) of Et3N and 3.45 g (21.1 mmol) of 4-fluorophenylhydrazine.HCl. The resulting solution was stirred under N2 overnight and refluxed for 4 h. A 30 mL portion of 1N aqueous HCl was added and the mixture was refluxed for an additional hour. The mixture was cooled and extracted with 200 mL of Et2O. The organic phase was washed with water, saturated aqueous NaHCO3, and brine and dried over Na2SO4. The solution was concentrated to give 5.50 g of a 1.2:1 mixture of 1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydrocycloheptapyrazole-3-methanol and the title compound as a brown oil. The crude product was crystallized from EtOAc:Et2O to afford 0.97 g (18%) of the title compound as an off-white solid, m.p. 177°-178° C.; 1H NMR (CDCl3, 300 MHz) 1.72 (m, 4), 1.85 (m, 2), 2.60 (m, 2), 2.80 (m, 2), 4.51 (d, 2, J=5 Hz), 7.15 (m, 2), 7.60 (m, 2); IR (KBr) 3240 (broad), 1513, 1223 cm-1 ; MS (DCI) m/z 261 (base). Anal. Calcd. for C15H17FN2O: C, 69.21; H, 6.58; N, 1076. Found C, 69.15; H, 6.77; N, 10.63.
Reaction SMILES: ClC1C=C(Cl)C(OC)=CC=1N[C:12]1[C:21]2[C:16](=[CH:17][C:18](F)=[CH:19][CH:20]=2)[N:15]=[CH:14][C:13]=1[C:23]#[N:24]>COCCO>[N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=[C:13]([C:23]#[N:24])[CH:14]=1
Reactant: COc1cc(Nc2c(C#N)cnc3cc(F)ccc23)c(Cl)cc1Cl
Solvent: COCCO
Product: N#Cc1cnc2ccccc2c1

Procedure:
Following the procedure used to prepare Example 15, 4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-fluoro-3-quinolinecarbonitrile (300 mg, 0.83 mmol) and 2-(methoxy)ethanol provides 194 mg of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-(2-methoxy)ethoxy]-3-quinolinecarbonitrile, mp 182-183° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH2:14][CH2:13][NH:12][C:11]3=[O:15])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.Br[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1.N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH2:14][CH2:13][N:12]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)[C:11]3=[O:15])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: Brc1ccccn1
Reactant: O=C1NCCN1c1ccc2ncsc2c1
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: O=C1N(c2ccc3ncsc3c2)CCN1c1ccccn1
Yield: 18.1 %

Procedure:
1-Benzothiazol-6-yl-imidazolidin-2-one (I-84b: 150 mg, 0.6904 mmol) was reacted with 2-bromo-pyridine (99 mL, 1.0356 mmol), 1,4-dioxane (10 mL), copper iodide (16 mg), trans-1,2-diamino cyclohexane (32 mg) and potassium phosphate (440 mg, 2.0713 mmol) to afford the crude product. Purification by column chromatography on silica gel (10% ethylacetate in hexane), followed by preparative HPLC afforded 37 mg of the product (18.13% yield).
Reaction SMILES: [NH2:1][NH:2][C:3]([NH:5][NH2:6])=[O:4].[C:7]([N:11]=[N:12][C:13]1([N:19]=[C:20]=[S:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)([CH3:10])([CH3:9])[CH3:8].O>CO>[C:7]([N:11]=[N:12][C:13]1([NH:19][C:20]([NH:1][NH:2][C:3]([NH:5][NH:6][C:20]([NH:19][C:13]2([N:12]=[N:11][C:7]([CH3:10])([CH3:9])[CH3:8])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[S:21])=[O:4])=[S:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)N=NC1(N=C=S)CCCCC1
Reactant: NNC(=O)NN
Solvent: CO
Solvent: O
Product: CC(C)(C)N=NC1(NC(=S)NNC(=O)NNC(=S)NC2(N=NC(C)(C)C)CCCCC2)CCCCC1
Reaction time: 8 h

Procedure:
To a slurry of 2.25 grams (.025 moles) of carbohydrazide in 30 ml of methanol stirred by a magnetic stirrer in a 50 ml erlenmeyer flask was added 11.3 grams (.05 moles) of 1-t-butylazo-1-isothiocyanatocyclohexane (from Example I). The reaction was stirred overnight, during which time complete solution was obtained. The next morning the solution was poured into 200 ml water and the product extracted with methylene chloride. The methylene chloride extract was washed with water, dried over anhydrous Na2SO4, filtered and the methylene chloride evaporated under reduced pressure to leave 11.9 grams (87.5% crude yield) of a yellow viscous liquid that slowly crystallized.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:16][CH2:15][C:14]4([O:20][CH2:19][CH2:18][O:17]4)[CH2:13][CH2:12]3)[C:8]2=O)=[CH:4][CH:3]=1.[CH3:21][C:22]([S:25]([NH2:27])=[O:26])([CH3:24])[CH3:23].CCOC(C)=O>[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC.O>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:16][CH2:15][C:14]4([O:20][CH2:19][CH2:18][O:17]4)[CH2:13][CH2:12]3)[C:8]2=[N:27][S:25]([C:22]([CH3:24])([CH3:23])[CH3:21])=[O:26])=[CH:4][CH:3]=1
Reactant: O=C1c2cc(Br)ccc2CC12CCC1(CC2)OCCO1
Reactant: CC(C)(C)S(N)=O
Agent: [Ti+4]
Agent: CC[O-]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)S(=O)N=C1c2cc(Br)ccc2CC12CCC1(CC2)OCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.3 %

Procedure:
6″-Bromodispiro[1,3-dioxolane-2,1′-cyclohexane-4′,2″-inden]-1″(3″H)-one (Intermediate 71, 320 mg, 0.95 mmol), 2-methylpropane-2-sulfinamide (173 mg, 1.42 mmol) and titanium ethoxide (0.391 mL, 1.90 mmol) were dissolved in 2-Me THF (5 mL) and heated to reflux overnight. The reaction was stopped and was left to cool down to r.t. EtOAc and water were added under stirring. The mixture was left to stand still for 2 h. The organic phase was collected by filtration, dried using a phase separator and concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-30% EtOAc in heptane to give the title compound (290 mg, 69% yield): 1H NMR (500 MHz, CDCl3) δ ppm 1.35 (s, 9H) 1.48-1.54 (m, 1H) 1.61 (dd, 1H) 1.67-1.77 (m, 2H) 1.81-1.90 (m, 2H) 2.10 (br. s., 2H) 2.95-3.05 (m, 2H) 3.95-4.02 (m, 4H) 7.25 (s, 1H) 7.60 (dd, 1H) 8.62 (br. s., 1H); MS (ES+) m/z 440.0 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][N:14]3[CH2:19][CH2:18][NH:17][CH2:16][C:15]3=[O:20])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.C(=O)(O)[O-].[Na+].C(OCC)(=O)C.[I:32][C:33]1[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1>C1COCC1>[I:32][C:33]1[CH:38]=[CH:37][C:36]([S:39]([N:17]2[CH2:18][CH2:19][N:14]([CH2:13][CH:10]3[CH2:11][CH2:12][N:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)[CH2:8][CH2:9]3)[C:15](=[O:20])[CH2:16]2)(=[O:41])=[O:40])=[CH:35][CH:34]=1
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Reactant: O=C1CNCCN1CC1CCN(c2ccncc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1CN(S(=O)(=O)c2ccc(I)cc2)CCN1CC1CCN(c2ccncc2)CC1
Yield: 14.3 %

Procedure:
To a mixture of 1-[1-(4-pyridyl)-4-piperidylmethyl]-2-piperazinone (549 mg), sodium bicarbonate solution (5 ml), ethyl acetate (10 ml) and THF (5 ml) was added dropwise, under ice-cooling, a solution of 4-iodobenzenesulfonyl chloride (1.21 g) in THF (10 ml), and the mixture was stirred at 0° C. for 1 hour. The separated organic layer was washed with saturated brine, dried (MgSO4) andconcentrated, and the residuewas purifiedwith silica gel column chromatography (acetone:methanol=9:1→1:1) and washed with water to give colorless crystals of 4-(4-iodobenzenesulfonyl)-1-[1-(4-pyridyl)-4-piperidylmethyl]-2-piperazinone (155 mg). A part of the crystals were treated with hydrochloric acid to give colorless crystals of the title compound as hydrochloride.
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:9]=[CH:8][C:7](Br)=[C:6]([CH3:11])[CH:5]=1)[CH3:2].[Mg].BrC(Br)C.[Br-].C[O:19][B:20](OC)[O:21]C>C1COCC1>[CH2:1]([S:3][C:4]1[CH:9]=[CH:8][C:7]([B:20]([OH:21])[OH:19])=[C:6]([CH3:11])[CH:5]=1)[CH3:2]
Reactant: COB(OC)OC
Reactant: CCSc1ccc(Br)c(C)c1
Agent: CC(Br)Br
Agent: [Br-]
Agent: [Mg]
Solvent: C1CCOC1
Product: CCSc1ccc(B(O)O)c(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 100 ml portion of a solution of the product from example 10 step (i) (120.7 g) in THF (500 ml) was added to a stirred mixture of magnesium turnings (13.4 g) in THF (100 ml). Dibromoethane (0.2 ml) was added, and the mixture gently refluxed on initiation. The remaining bromide solution was added dropwise maintaining the reaction at reflux. After addition the mixture was allowed to cool to RT then transferred via cannula into a stirred solution of trimethylborate (112 ml) in TIE (200 ml) at 0° C. The mixture was warmed to RT, stirred for 2 h then quenched with 2M hydrochloric acid (300 ml). After stirring at RT for 18 h the THF was removed under reduced pressure and the mixture extracted with diethylether. The organics were separated, washed with water, dried and evaporated under reduced pressure. The residue was triturated with diethylether/isohexane and filtered. Yield 53.02 g
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[C:5]([Br:12])[C:3]=1N.N([O-])=O.[Na+].[BrH:17]>C(O)(=O)C.S(=O)(=O)(O)O.O.[Cu]Br>[Br:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[C:5]([Br:12])[C:3]=1[Br:17]
Reactant: Nc1c(Br)cc([N+](=O)[O-])cc1Br
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1cc(Br)c(Br)c(Br)c1
Temperature: 20 °C

Procedure:
At 20° C., with stirring and cooling with ice, a solution of 2,6-dibromo-4-nitro-aniline (47.2 g) in acetic acid (1.6 liters) is slowly poured into a solution of sodium nitrite (12 g) in concentrated sulphuric acid (85 ml). Then, the mixture is stirred for 20 minutes at ambient temperature. The solution thus prepared is then slowly added with stirring and cooling with ice to a solution of copper (I) bromide (12.8 g) in 63% hydrobromic acid (40 ml). After it has all been added the mixture is stirred for a further 30 minutes. It is diluted with water, the precipitate is filtered off and washed with water. This crude product is recrystallized from methanol.
Reaction SMILES: C(C1CCNCC1)(=O)C1C=CC=CC=1.C(N(CC)CC)C.BrCC[C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27][CH:26]=1.O>CN(C)C=O>[NH:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:25]=[CH:26]1
Reactant: BrCCc1c[nH]c2ccccc12
Agent: O=C(c1ccccc1)C1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: c1ccc2[nH]ccc2c1

Procedure:
A solution of 10.4 g of 4-(benzoyl)piperidine, 6.1 g of triethylamine and 11.2 g of 3-(2-bromoethyl)indole in 350 ml of dimethylformamide is stirred at ambient temperature for 16 hours. Water is added dropwise, precipitating an off-white solid. The solid is collected, washed with water and low boiling petroleum ether, and dried. The solid is recrystallized from 95% ethanol to give white flakes, mp [145°-147° C., of 3-]2-(4-benzoylpiperidyl)ethyl]indole.
Reaction SMILES: [CH2:1]([C:8]1[CH:29]=[C:28]([O:30][CH3:31])[C:11]2[N:12]([CH2:24][CH2:25][O:26][CH3:27])[C:13]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=3)=[N:14][C:10]=2[C:9]=1[CH:32]=[CH2:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Ni]>[CH2:1]([C:8]1[CH:29]=[C:28]([O:30][CH3:31])[C:11]2[N:12]([CH2:24][CH2:25][O:26][CH3:27])[C:13]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=3)=[N:14][C:10]=2[C:9]=1[CH2:32][CH3:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=Cc1c(Cc2ccccc2)cc(OC)c2c1nc(-c1ccc(C(C)C)cc1)n2CCOC
Agent: [Ni]
Solvent: CO
Product: CCc1c(Cc2ccccc2)cc(OC)c2c1nc(-c1ccc(C(C)C)cc1)n2CCOC
Yield: 45.2 %

Procedure:
A solution of 58 mg (0.13 mmol) 5-benzyl-2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-4-vinyl-1H-benzoimidazole in 5 ml methanol is hydrogenated in the presence of 10 mg Raney-Nickel (B113W Degussa) at normal pressure for 25 h. The catalyst is filtered off and the filtrate is concentrated in vacuo. The residue is purified by flash-chromatography on silica gel (hexane:EtOAc=6:1) to afford 26 mg of the title compound as a white crystalline solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:11])([CH3:10])[C@:4]([C:13]2[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[N:23][C:22]=1[C:27](=O)[CH3:28].[B][B][B][B][B][B][B][B][B][B]>>[NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:10])([CH3:11])[C@:4]([C:13]2[CH:18]=[C:17]([NH:19][CH:27]([C:22]3[N:23]=[CH:24][CH:25]=[CH:26][N:21]=3)[CH3:28])[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1
Reactant: CC(=O)c1ncccn1
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1N
Agent: [B][B][B][B][B][B][B][B][B][B]
Product: CC(Nc1ccc(F)c([C@@]2(C)N=C(N)N(C)C(=O)C2(C)C)c1)c1ncccn1

Procedure:
The reductive amination of (S)-2-amino-6-(5-amino-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate J) and 1-pyrimidin-2-yl-ethanone using decaborane yielded a mixture of epimers of the title compound as a yellow waxy solid. MS (ESI): m/z=385.2 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[OH-].[Na+].[C:8](Cl)(=[O:12])[C:9]([CH3:11])=[CH2:10].Cl>C(Cl)(Cl)Cl>[C:8]([NH:1][CH2:2][C:3]([OH:5])=[O:4])(=[O:12])[C:9]([CH3:11])=[CH2:10]
Reactant: NCC(=O)O
Reactant: C=C(C)C(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: C=C(C)C(=O)NCC(=O)O
Reaction time: 1 h

Procedure:
Glycine (7.5 g, 0.1 moles) is dissolved in 30 ml of aqueous sodium hydroxide solution (8 g, 0.2 moles) and cooled in ice and methacryloyl chloride (10.45 g, 0.1 moles), dissolved in 10 ml of chloroform, is added dropwise with stirring. After that, the reaction is allowed to continue for one hour at room temperature. The solution, cooled in ice, is acidified to a pH of 2 with 5N aqueous hydrochloric acid and exhaustively extracted with ethyl acetate. The organic solution is dried over sodium sulfate and evaporated under vacuum, 10 g (70%) of a crystalline product of N-methyacryloyl glycine with a melting point of 104° C. to 105° C. being obtained.
Reaction SMILES: [C:1]([NH:6][C:7]1[S:8][C:9]2[CH:15]=[C:14]([O:16][S:17]([C:20]3[CH:25]=[CH:24][C:23](F)=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH:13]=[CH:12][C:10]=2[N:11]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].[CH:27]([N:30]([CH:34]([CH3:36])[CH3:35])[CH2:31][CH2:32][NH2:33])([CH3:29])[CH3:28].[ClH:37]>CN1CCCC1=O.C(OCC)(=O)C.O1CCOCC1>[ClH:37].[C:1]([NH:6][C:7]1[S:8][C:9]2[CH:15]=[C:14]([O:16][S:17]([C:20]3[CH:25]=[CH:24][C:23]([NH:33][CH2:32][CH2:31][N:30]([CH:34]([CH3:36])[CH3:35])[CH:27]([CH3:29])[CH3:28])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH:13]=[CH:12][C:10]=2[N:11]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)N(CCN)C(C)C
Reactant: CCCC(=O)Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2s1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCCC(=O)Nc1nc2ccc(OS(=O)(=O)c3ccc(NCCN(C(C)C)C(C)C)cc3)cc2s1
Temperature: 150 °C
Yield: 28 %

Procedure:
A solution of 4-fluorobenzenesulfonic acid 2-butyrylaminobenzothiazol-6-yl ester (intermediate 78) (100 mg, 0.2 mmol) and N,N-diisopropylethylene-diamine (185 μl, 1.01 mmol) in 3 ml of N-methylpyrrolidone in a 5 ml microwave vial, equipped with a magnetic bar, is heated for 10 minutes at 150° C. by microwave. The reaction medium is extracted with ethyl acetate and washed with water. The organic phase is dried over magnesium sulfate, filtered and then evaporated to dryness. The residue obtained is purified by chromatography on Merck silica (40-63 μm). After evaporating off the solvent, 41 mg of a colorless oil (crystallizes when dry) are obtained. The product is dissolved in a minimum amount of ethyl acetate, and 4 N hydrochloric acid as a solution in dioxane is then added. The medium precipitates, and is concentrated, taken up in water and then filtered through a Milex 45 μm filter. The solution precipitates, and 31 mg (28% yield) of 4-(2-diisopropylamino-ethylamino)benzenesulfonic acid 2-butyrylaminobenzothiazol-6-yl ester hydrochloride are obtained after vacuum filtration and then drying under vacuum at 40° C.