Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=O.[CH3:8][NH:9][CH3:10].[BH4-].[Na+].[CH3:13]O>>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]([N:9]([CH3:10])[CH3:8])[CH3:13]
Reactant: CNC
Reactant: CO
Reactant: O=Cc1ncc[nH]1
Agent: [BH4-]
Agent: [Na+]
Product: CC(c1ncc[nH]1)N(C)C
Temperature: 50 °C

Procedure:
To a two-necked round-bottomed flask equipped with a reflux condenser and a pressure-equalizing addition funnel, was added 2-imidazolecarboxaldehyde (6 g, 62.5 mmol) in MeOH (60 mL). To this suspension (ambient temperature) was added a solution of dimethylamine (40% aqueous, 60 mL) at a fast dropping rate (20 min). After the addition was complete, solid sodium borohydride (7 g, 186.8 mmol.) was CAUTIOUSLY added portionwise over 45 min. Foaming occurred after each portion, and the internal temperature was allowed to maintain ˜50° C. without external cooling. The reaction mixture was then heated to 65° C. for 3 h and allowed to cool to ambient temperature for overnight. The reaction contents were concentrated in vacuo and the resultant residue was taken up in EtOAc (2×30 mL) washed with brine and with CHCl3 (4×100 mL). The EtOAc extract was discarded. The CHCl3 extract was dried over (NaSO4), filtered, and concentrated in vacuo to give 3.7 g of the desired product as a waxy solid.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[C:4]([CH3:14])[CH:3]=1.Cl[C:16]1[N:17]=[N:18][C:19]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])=[CH:20][C:21]=1[CH3:22].C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[CH3:65][CH2:66][O:67][C:68](C)=[O:69]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCO.CN(C=O)C>[CH3:14][C:4]1[CH:3]=[C:2]([C:68]([O:67][CH2:66][CH3:65])=[O:69])[N:7]=[N:6][C:5]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[CH3:22][C:21]1[CH:20]=[C:19]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])[N:18]=[N:17][C:16]=1[C:68]([O:67][CH2:66][CH3:65])=[O:69]
Reactant: Cc1cc(OCC(F)(F)F)nnc1Cl
Reactant: Cc1cc(Cl)nnc1OCC(F)(F)F
Reactant: CCOC(C)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(C)c(OCC(F)(F)F)nn1
Product: CCOC(=O)c1nnc(OCC(F)(F)F)cc1C
Temperature: 80 °C
Reaction time: 20 h

Procedure:
A mixture of 6-chloro-4-methyl-3-(2,2,2-trifluoroethoxy)pyridazine and 3-chloro-4-methyl-6-(2,2,2-trifluoroethoxy)pyridazine (3.40 g, 15.0 mmol, Step-1), palladium(II) acetate (0.34 g, 1.50 mmol), 1,3-bis(diphenylphosphino)propane (1.24 g, 3.00 mmol), triethylamine (6.27 mL, 45.0 mmol), DMF (40 mL), and EtOH (20 mL) is stirred at 80° C. under carbon monoxide atmosphere (1 atm) for 20 hours. After cooling to rt, the mixture is diluted with EtOAc (200 mL). This is washed with water (200 mL×2), and the organic layer is dried over sodium sulfate. After removal of the organic solvent, the residue is purified by column chromatography on silica-gel eluting with n-hexane/EtOAc (8:1-5:1) to give 2.15 g of ethyl 5-methyl-6-(2,2,2-trifluoroethoxy)pyridazine-3-carboxylate (54% yield, more polar product) as an off-white solid and 0.63 g of ethyl 4-methyl-6-(2,2,2-trifluoroethoxy)pyridazine-3-carboxylate (16% yield, less polar product) as pale yellow oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7](Br)[S:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1)=[O:4].[CH3:18][NH:19][CH3:20]>>[CH3:18][N:19]([CH3:20])[C:7]1[S:8][C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)=[C:5]([C:3]([OH:2])=[O:4])[N:6]=1
Reactant: CNC
Reactant: COC(=O)c1nc(Br)sc1-c1cccc(F)c1
Product: CN(C)c1nc(C(=O)O)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of 2-bromo-5-(3-fluoro-phenyl)-thiazole-4-carboxylic acid methyl ester with dimethylamine. LC-MS: tR=0.87 min; [M+H]+=267.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([NH2:15])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([CH2:39]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]>CN(C=O)C>[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([CH2:39][N:11]([C@@H:12]([C:13](=[O:14])[NH2:15])[CH2:16][CH:17]([CH3:19])[CH3:18])[S:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)(=[O:9])=[O:10])[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: CC(C)C[C@@H](NS(=O)(=O)c1ccc(Cl)cc1)C(N)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)C[C@H](C(N)=O)N(CC1CCN(C(=O)OC(C)(C)C)CC1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 18 h
Yield: 42.7 %

Procedure:
To a solution of (2R)-2-(4-chlorobenzenesulfonylamino)-4-methylpentanoic acid amide (4.2 grams, 14 mmol) in DMF (50 mL) was added cesium carbonate (13.6 grams, 417 mmol). To this reaction was added 4-(toluene-4-sulfonyloxymethyl)-piperidine 1-carboxylic acid tert-butyl ester (ref.: Gilissen, C. et al., J. Labeled Cmpd. Radiopharm., 42:1289 (1999); 10.4 g, 282 mmol). The reaction was stirred at 70° C. for 18 h. The reaction was then quenched with sat. aq. NaHCO3 and extracted with EtOAc. The organic layer was collected, washed with brine, dried over MgSO4, and concentrated to a clear oil. The oil was then purified on a BIOTAGE® 40S (eluted with 30% EtOAc in hexanes) to afford a white solid (3.0 g, 44%). MS (ESI), (M+H)+502.1; 1H NMR (DMSO-d6, 500 MHz) δ 7.86 (dd, 2H, J=2.0, 6.8), 7.65 (dd, 2H, J=2.0, 6.8) 7.37 (br s, 1H), 7.07 (br s, 1H), 4.19 (t, 1H, J=7.6), 3.92 (br s, 2H), 3.35 (dd, 1H, J=15, 6.8), 3.05 (dd, 1H, J=15, 8.1), 1.85 (br s, 1H), 1.50-1.70 (m, 4H), 1.38 (s, 9H), 1.10-1.20 (m, 1H), 0.80-1.00 (m, 3H), 0.82 (d, 6H, J=7.6).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[S:11])=[CH:5][CH:4]=1)#[N:2].[C:12]1([S:18]([NH2:21])(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH-].[Na+].[CH2:24](O)C.CI>CC(C)=O.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[N:21][S:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:20])=[O:19])[S:11][CH3:24])=[CH:7][CH:8]=1)#[N:2]
Reactant: CCO
Reactant: N#Cc1ccc(N=C=S)cc1
Reactant: NS(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CI
Solvent: O
Product: CSC(=NS(=O)(=O)c1ccccc1)Nc1ccc(C#N)cc1
Yield: 82.7 %

Procedure:
A mixture of 5 g (0.031 mol) of 4-cyanophenyl isothiocyanate, of 6.3 g (0.04 mol) of benzenesulfonamide in 50 cm3 of acetone and of 1.6 g (0.04 mol) of sodium hydroxide in 3 cm3 of water is maintained for two hours at room temperature. The precipitate obtained is filtered, washed with acetone and ethyl ether (2×20 cm3). The final solid (9 g; yield 94%) is then placed in 50 cm3 of 95% ethanol containing 2.75 cm3 (0.044 mol) of methyl iodide. After 24 hours at room temperature the solution is concentrated to dryness and the residue is washed with ethyl ether (3×20 cm3) and dried in vacuo. 8.5 g (yield 80%) of N-(4-cyanophenyl)-N'-phenylsulfonyl-S-methylisothiourea (melting point 150° C.) is obtained: ##STR23##
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH2:9][NH2:10])=[CH:4][CH:3]=1.[CH:17]1([C:22]([N:24]2[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]2)=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>ClCCCl>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH2:9][NH:10][CH:27]2[CH2:28][CH2:29][N:24]([C:22]([CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:23])[CH2:25][CH2:26]2)=[CH:4][CH:3]=1
Reactant: NCc1ccccc1Oc1ccc(Cl)cc1
Reactant: O=C1CCN(C(=O)C2CCCC2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: O=C(C1CCCC1)N1CCC(NCc2ccccc2Oc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Yield: 81.5 %

Procedure:
A solution of 2-(4-chlorophenoxy)benzylamine (AMR01076, 100 mg, 0.428 mmol) and 1-cyclopentanecarbonylpiperidin-4-one (83.5 mg, 0.428 mmol) in DCE (5 mL) was treated with NaBH(OAc)3 (127 mg, 0.60 mmol) and acetic acid (26 mg, 0.428 mmol). The mixture was stirred at room temperature under a N2 atmosphere until TLC showed that the reactants were consumed (30 min). Then it was quenched with saturated NaHCO3 solution, the aqueous layer was washed with DCM (2×20 mL), and the combined organic layers were dried (MgSO4), filtered and evaporated to dryness. Column chromatography on silica gel of the crude product using DCM to DCM/MeOH 95:5 gradient as eluent gave {4-[2-(4-chlorophenoxy)benzylamino]piperidin-1-yl}cyclopentylmethanone (144 mg, 81%) as a colorless oil. Rf: 0.4 (DCM/MeOH 9:1) LC/MS (APCI) tr=5.42 min, m/z 415.36 (36), 413.40 (M++H, 100). HPLC tr=6.82 min (98.32%) 1H NMR (270 MHz, CDCl3) δ 1.23 (2H, m, CH2), 1.52 (2H, m, CH2), 1.60-1.90 (9H, m, 4CH2+NH), 2.66 (2H, m, CH2), 2.85 (1H, quin, J=7.9 Hz, CHCO), 3.00 (1H, m, CHNH), 3.79 (2H, m, CH2), 3.85 (1H, m, ½CH2), 4.40 (1H, m, ½CH2), 6.83 (2H, AA′BB′, ArH), 6.87 (1H, m, ArH), 7.12 (1H, td, ArH), 7.23 (1H, m, ArH), 7.24 (2H, AA′BB′, ArH) and 7.38 (1H, dd, J=7.4, 1.7 Hz, ArH). 13C NMR (270 MHz, CDCl3) δ 26.12, 30.09, 32.29, 32.24, 40.55 (CH2), 41.19 (CH), 44.04, 45.65 (CH2), 54.00 (CH), 118.93, 119.62, 124.54, 127.95, 128.70, 129.84, 130.58, 131.83, 154.34, 156.38 (ArC), and 174.37 (C═O).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)=[O:3].[OH:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]([C@@H:26]2[CH2:30][C@H:29]([S:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=3)[CH2:28][N:27]2[C:41]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][C:48]([N+:51]([O-:53])=[O:52])=[CH:47][CH:46]=2)=[O:42])=[O:25])[CH2:20][CH2:19]1>CN(C)C1C=CN=CC=1.C(Cl)Cl.C(OCC)(=O)C>[N+:12]([C:9]1[CH:10]=[CH:11][C:6]([CH2:5][O:4][C:2]([O:15][CH2:16][CH2:17][N:18]2[CH2:19][CH2:20][N:21]([C:24]([C@@H:26]3[CH2:30][C@H:29]([S:31][CH2:32][C:33]4[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=4)[CH2:28][N:27]3[C:41]([O:43][CH2:44][C:45]3[CH:50]=[CH:49][C:48]([N+:51]([O-:53])=[O:52])=[CH:47][CH:46]=3)=[O:42])=[O:25])[CH2:22][CH2:23]2)=[O:3])=[CH:7][CH:8]=1)([O-:14])=[O:13]
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCN(CCO)CC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCN(CCOC(=O)OCc4ccc([N+](=O)[O-])cc4)CC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.3 %

Procedure:
5.86 g of 4-dimethylaminopyridine and a solution of 10.35 g of p-nitrobenzyl chloroformate in 40 ml of anhydrous methylene chloride were added to a solution of 22.35 g of (2S,4S)-2-[4-(2-hydroxyethyl)-1-piperazinylcarbonyl]-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (prepared as described in Preparation 7) in 160 ml of anhydrous methylene chloride, and the resulting mixture was stirred at room temperature for 1 hour. At the end of this time, the reaction mixture was diluted with 300 ml of ethyl acetate and washed with 100 ml of water, with 100 ml of a saturated aqueous solution of sodium hydrogencarbonate and with 100 ml of a saturated aqueous solution of sodium chloride, in that order. The solvents were removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel. Those fractions eluted with ethyl acetate were collected and concentrated by evaporation under reduced pressure, to give 26.35 g of the title compound as a colorless powder.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:32])[C@@H:10]([C@@H:15]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:16]/[CH:17]=C/C1C=CC=CC=1)[CH2:11][CH:12]([CH3:14])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].C[OH:36]>ClCCl>[CH2:1]([O:8][C:9](=[O:32])[C@@H:10]([C@@H:15]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:16][CH2:17][OH:36])[CH2:11][CH:12]([CH3:13])[CH3:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C[C@@H](C(=O)OCc1ccccc1)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)C[C@@H](C(=O)OCc1ccccc1)[C@H](CCO)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 32.12 g of (E)-benzyl-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-4-methylvalerate in 300 ml of dichloromethane was cooled to −78° C. and ozone was then bubbled through the mixture for 2.5 hours. 35 ml of dimethyl sulfide was then addded to the mixture and stirring continued overnight at room temperature. The solvent was evaporated to give an orange oil. This was dissolved in 300 ml of methanol, cooled to 0° C. under nitrogen and then treated portionwise with 5.6 g of sodium borohydride. The mixture was then quenched with glacial acetic acid and evaporated. The residue was dissolved in ethyl acetate and washed sequentially with 2M aqueous hydrogen chloride, water, 5% aqueous sodium hydrogen carbonate and brine and then dried over anhydrous magnesium sulfate. Filtration and evaporation gave a residue which was purified by flash column chromatography on silica gel, using ethyl acetate/hexane (2:8 increasing to 4:6) for the elution, to give 15.3 g of benzyl-2(R)-[1(S)-(tert-butoxycarbonyl)-3-hydroxypropyl]-4-methylvalerate in the form of a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([CH3:12])=[CH:5]2.OO.[O-:15]S([O-])=O.[Na+].[Na+].[I-].[Na+]>C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N+:8]([O-:15])=[CH:7][C:6]([CH3:12])=[CH:5]2
Reactant: O=S([O-])[O-]
Reactant: Cc1cnc2ccc(F)cc2c1
Agent: OO
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc2cc(F)ccc2[n+]([O-])c1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
6-Fluoro-3-methyl-quinoline (Intermediate 28) (48.0 mg, 0.298 mmol) was dissolved in acetic acid (1 mL) and 30% aqueous H2O2 (0.040 mL, 0.396 mmol) was added. This was stirred at 80° C. for 16 h before cooling. A few mLs of a 10% aq. solution of Na2SO3 was added followed by a spatula tip of sodium iodide. This was stirred for 10 min before partitioning between ethyl acetate and sat. NaHCO3. The separated aqueous layer was extracted with ethyl acetate and the combined organics dried over MgSO4. Purification by silica gel flash chromatography (methanol/ethyl acetate) gave 6-fluoro-3-methyl-quinoline 1-oxide (29.4 mg) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.72 (dd, J=9.4, 5.3 Hz, 1 H) 8.38 (s, 1 H) 7.36-7.50 (m, 3 H) 2.46 (s, 3 H); MS (M+1): 178.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](I)=[N:6][CH:7]=1.[O:9]1[CH2:14][CH:13]=[C:12](B2OC(C)(C)C(C)(C)O2)[CH2:11][CH2:10]1>O1CCOCC1.O>[Br:1][C:2]1[CH:3]=[N:4][C:5]([C:12]2[CH2:13][CH2:14][O:9][CH2:10][CH:11]=2)=[N:6][CH:7]=1
Reactant: Brc1cnc(I)nc1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Solvent: C1COCCO1
Solvent: O
Product: Brc1cnc(C2=CCOCC2)nc1
Temperature: 80 °C

Procedure:
5-bromo-2-iodo-pyrimidine (250 mg; 0.88 mmol) and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (196 mg, 0.92 mmol) were dissolved in 1,4-dioxane-H2O (10:1; 10 mL) and degassed with a stream of N2 for 10 min. Pd(Ph3)2Cl2 (30 mg, 0.04 mmol) was introduced and the reaction sealed and heated in a microwave reactor for 30 min at 80° C. The reaction was concentrated in vacuo, re-dissolved in DCM, filtered and purified over silica (gradient elution, 0-50% EtOAc-n-heptane) yielding i (105 mg, 50%). MS: 241.1 & 243.0; 1:1 [M+H]+.
Reaction SMILES: [CH2:1](Cl)[CH:2]=[CH2:3].[C:5]([O-:11])(=[O:10])[CH2:6][C:7]([O-:9])=[O:8].[Na+].[Na+].Cl[C:15]1[CH:20]=CC=C[CH:16]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[C:5]([O:11][CH2:20][CH:15]=[CH2:16])(=[O:10])[CH2:6][C:7]([O:9][CH2:1][CH:2]=[CH2:3])=[O:8]
Reactant: O=C([O-])CC(=O)[O-]
Reactant: Clc1ccccc1
Reactant: C=CCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Product: C=CCOC(=O)CC(=O)OCC=C
Temperature: 100 °C
Yield: 16 %

Procedure:
In an autoclave, 7.65 g (0.1 mol) of allyl chloride were added to a solution of 2.96 g (20 mmol) of disodium malonate and 0.64 g (2 mmol) of tetrabutylammonium bromide in 5 ml of water and 10 ml of chlorobenzene. The mixture was heated to 100° C. over a period of 30 minutes, with the pressure in the autoclave rising to 2.5 bar. After a reaction time of 3½ hours at 100° C., the mixture was cooled to room temperature and depressurized. The aqueous phase was extracted with tert-butyl methyl ether (2×5 ml). The combined organic phases were dried over sodium sulfate and analyzed by gas chromatography (internal standard: dimethyl succinate). The product yield was 16 percent.
Reaction SMILES: [CH:1]([CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8])=O.[NH3:11].[H][H].[Si]([O-])([O-])([O-])[O-].[Mg+2].[Mg+2]>[Ni]>[NH2:11][CH2:1][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8]
Reactant: N
Reactant: COC(=O)CCCCC=O
Reactant: [H][H]
Agent: [Ni]
Agent: [Mg+2]
Agent: [O-][Si]([O-])([O-])[O-]
Product: COC(=O)CCCCCN

Procedure:
U.S. Pat. Nos. 4,730,041 and 4,731,445 use methyl 5-formylvalerate as a starting material and an alkanol as a solvent to produce caprolactam. First, methyl 5-formylvalerate is reacted with excess ammonia and hydrogen in the presence of an alkanol as a solvent and in the presence of a magnesium silicate-supported nickel catalyst at 40° to 130° C. under superatmospheric pressure to form methyl 6-aminocaproate. After the unreacted ammonia and hydrogen gas are removed, methyl 6-aminocaproate is converted into 6-aminocaproic acid and then formed to caprolactam by dehydrolyzation and cyclization or by direct de-alcoholization and cyclization. Although the process does not involve the hydrolyzation procedure of 5-formylvalerate, it suffers from the disadvantage that the starting material has a very low concentration (only 10%) and a great amount of alkanol should be separated and recycled.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.Br[CH2:14][C:15]#[C:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[CH2:14]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1)[C:15]#[C:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: O=c1ccc2ccc(O)cc2o1
Reactant: CCCCCC#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCCCCC#CCOc1ccc2ccc(=O)oc2c1

Procedure:
A solution of 7-hydroxycoumarin (0.324 g, 1.99 mmol) and 1-bromo-2-octyne (0.378 g, 1.99 mmol) in 200 ml of acetone was heated under reflux in the presence of anhydrous potassium carbonate (3 grams) for 24 hours. After the reflux period, the reaction mixture was cooled, filtered and the collected solid was washed with fresh acetone. The acetone washings and the filtrate were combined and the solvent evaporated under reduced pressure to yield a pale yellow viscous liquid. The crude product was dissolved in a minimum amount of ethyl acetate and petroleum ether added until the solution became cloudy. The cloudy solution was concentrated under reduced pressure and a white precipitate formed. This precipitate was collected by vacuum filtration and recrystallized from aqueous methanol to yield the title compound as shiny, colorless plates, m.p. 74°-75° C., 0.245 g, 50%. 1H-NMR: 0.8-2.2 (m, 11H, (CH2)4CH3), 4.7 (t, 2H, OCH2C C), 6.2 (d, 1H, C3 --H J=9.3 Hz), 6.8 (dd, 1H, C6 --H), 6.9 (d, 1H, C8 --H, J=2.1 Hz), 7.4 (dd, 1H, C5 --H, J=8.1 Hz), 7.6 (d, 1H, C4 --H, J=9.3 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](OS(C(F)(F)F)(=O)=O)=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([SH:26])=[CH:22][CH:21]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:26][C:23]2[CH:24]=[CH:25][C:20]([CH3:19])=[CH:21][CH:22]=2)=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1
Reactant: Cc1ccc(S)cc1
Reactant: Cc1ccc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c1
Product: Cc1ccc(Sc2ccc(C)cc2[N+](=O)[O-])cc1

Procedure:
The product from Example 4a (5.00 g, 17.53 mmol) was reacted with 4-methylthiophenol (2.17 g, 17.53 mmol) in place of thiophenol following the procedure from Example 1e for 18 h giving the crude title compound which was purified by silica gel column chromatography eluting with 5% EtOAc /hexane providing a solid (3.53 g, 78%).
Reaction SMILES: P(Cl)(Cl)Cl.[N:5]1[CH:6]=[CH:7][N:8]2[CH2:14][CH2:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[C:10](=[C:19]3[CH2:24][CH2:23][N+:22]([O-])([C:25]([C:27]4[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=4)=[O:26])[CH2:21][CH2:20]3)[C:9]=12.O.N>ClCCl>[N:5]1[CH:6]=[CH:7][N:8]2[CH2:14][CH2:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[C:10](=[C:19]3[CH2:24][CH2:23][N:22]([C:25]([C:27]4[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=4)=[O:26])[CH2:21][CH2:20]3)[C:9]=12
Reactant: O=C(c1ccncc1)[N+]1([O-])CCC(=C2c3ccccc3CCn3ccnc32)CC1
Agent: N
Solvent: ClCCl
Solvent: ClP(Cl)Cl
Solvent: O
Product: O=C(c1ccncc1)N1CCC(=C2c3ccccc3CCn3ccnc32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of phosphorous trichloride (0.25 ml)in dichloromethane (3 ml) was added to a solution of 4-(5,6-dihydro-11H-imidazo[2,1-b][3]benzazepin-11-ylidene)-1-(4-pyridinylcarbonyl)-piperidine N1 -oxide (B, 0.4 g) and dichloromethane (5 ml). The reaction mixture was allowed to stir overnight at 25° C. in an atmosphere of nitrogen, and was then poured onto a mixture of ice and water. The resulting mixture was basified with concentrated aqueous ammonia, and the aqueous layer was extracted with dichloromethane. The dried (magnesium sulfate), filtered extracts were concentrated to give 4-(5,6-dihydro-11H-imidazo[2,1-b][3]benzazepin-11-ylidene )-1-(4-pyridinylcarbonyl)piperidine (A, 0.34 g), m.p. 207°-209° C. from carbon tetrachloride. ##STR25##
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10][CH:11]([C:15]2[N:16]=[CH:17][N:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:19]=2)[C:12]([OH:14])=[O:13])=[CH:6][CH:5]=1.[CH2:26](O)[CH2:27][OH:28]>>[NH2:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10][CH:11]([C:15]2[N:16]=[CH:17][N:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:19]=2)[C:12]([O:14][CH2:26][CH2:27][OH:28])=[O:13])=[CH:6][CH:5]=1
Reactant: Nc1ccc(CC(C(=O)O)c2cn(C3CCCCC3)cn2)cn1
Reactant: OCCO
Agent: Cl
Product: Nc1ccc(CC(C(=O)OCCO)c2cn(C3CCCCC3)cn2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.4 ml of an HCl-saturated ether solution was added to a solution of 50.0 mg (0.16 mmol) of the compound from example 1i in 1 ml of ethylene glycol and stirred at RT for 1 h. The solution was then concentrated to dryness, and the residue was taken up in sat. NaHCO3 solution and extracted with EA several times. The combined EA extracts were dried, filtered and concentrated. The resulting residue was dried under high vacuum, resulting in 33 mg of the title compound in the form of a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH3:15].[C:17]1([S:23]([C:26]2[N:27]=[CH:28][S:29][C:30]=2[CH:31]=O)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(=O)([O-])O.[Na+].ClCCCl>[CH3:1][O:2][C:3](=[O:16])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[C:7]([CH2:31][C:30]2[S:29][CH:28]=[N:27][C:26]=2[S:23]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)(=[O:24])=[O:25])=[C:6]1[CH3:15]
Reactant: O=Cc1scnc1S(=O)(=O)c1ccccc1
Reactant: COC(=O)Cn1c(C)cc2cc(F)ccc21
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: COC(=O)Cn1c(C)c(Cc2scnc2S(=O)(=O)c2ccccc2)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.2 %

Procedure:
A mixture of (5-fluoro-2-methylindol-1-yl)acetic acid methyl ester (0.2 g), 4-benzenesulfonylthiazole-5-carbaldehyde (0.23 g) and 1,2-dichloroethane (7.0 mL) at 0° C. was treated dropwise with a mixture of triethylsilane (2.2 mL), trifluoroacetic acid (0.6 mL) and 1,2-dichloroethane (2.0 mL), and the resulting mixture was stirred at room temperature overnight. The mixture was cooled to 0° C. and diluted with saturated aqueous sodium hydrogen carbonate solution. The phases were separated and the organic phase was dried over magnesium sulfate and concentrated under reduced pressure. The residue purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and dichloromethane (0:1 to 1:4 by volume) to afford the title compound as a white foam (0.20 g).