Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([Cl:17])[CH:16]=1)[O:5][CH:6]1[CH2:10][CH2:9][N:8]([C:11](Cl)=[O:12])[CH2:7]1.[CH2:18]([N:20]([CH2:26][CH3:27])[CH2:21][CH2:22][NH:23][CH2:24][CH3:25])[CH3:19].C(O)(=O)C(O)=O>O1CCCC1.CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([Cl:17])[CH:16]=1)[O:5][CH:6]1[CH2:10][CH2:9][N:8]([C:11]([N:23]([CH2:22][CH2:21][N:20]([CH2:26][CH3:27])[CH2:18][CH3:19])[CH2:24][CH3:25])=[O:12])[CH2:7]1
Reactant: O=C(Cl)N1CCC(Oc2cc(Cl)cc(Cl)c2)C1
Reactant: CCNCCN(CC)CC
Agent: O=C(O)C(=O)O
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CCN(CC)CCN(CC)C(=O)N1CCC(Oc2cc(Cl)cc(Cl)c2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.7 %

Procedure:
A stirred solution of 7 g (0.024 mole) of 3-(3,5-dichlorophenoxy)-1-pyrrolidinecarbonyl chloride in 70 ml of tetrahydrofuran was treated with 7 g (0.05 mole) of N,N,N'-triethylethylenediamine (slight exothermic) and stirred at ambient temperature overnight. The mixture filtered to remove a small amount of precipitate. The filtrate was diluted with 200 ml of ice water, extracted with 3×100 ml of benzene and the combined extracts washed with water, dried over magnesium sulfate and concentrated in vacuo to give a pale brown oil, 8.24 g. The oil was dissolved in acetone, treated with 1.9 g of oxalic acid and heated until dissolved. A fine amorphous gel was removed by filtration and the filtrate diluted with isopropyl ether until cloudy. The salt was allowed to precipitate overnight. After 2 weeks the oil which separated from the acetone/isopropyl ether failed to crystallize. The solvents were removed by decantation and the residual oil converted back to the free base. The free base in methylene chloride was treated with 200 g of florisil and diluted with enough methylene chloride to give a stirrable slurry. After 30 minutes the slurry was filtered and the florisil washed with 2 volumes of methylene chloride. The florisil was suspended in 500 ml of methanol and transferred to a column. The column was washed with an additional 500 ml of methanol. Concentration in vacuo of the combined methanol effluents gave 7.6 g of dark oil which was chromatographed on a 100 g alumina column by eluting with a 0-5% methanol/acetonitrile gradient. The first 2 fractions were discarded and the remainder combined and concentrated to an oil (5.2 g). The oil was dissolved in ethyl ether, filtered to remove traces of alumina, concentrated in vacuo and excess solvent removed by pumping under high vacuum at 55° C. for 18 hours.
Reaction SMILES: I[CH2:2][C@@H:3]([CH3:17])[CH2:4][N:5]1[C:10]2[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:16].[CH2:18]([O:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[CH2:19][CH3:20].CCN(CC)CC>C(Cl)Cl.CC(C)=O.CO>[CH3:15][C:12]1[CH:13]=[CH:14][C:9]2[O:8][CH2:7][C:6](=[O:16])[N:5]([CH2:4][C@H:3]([CH3:17])[CH2:2][N:25]3[CH2:26][CH2:27][CH:22]([O:21][CH2:18][CH2:19][CH3:20])[CH2:23][CH2:24]3)[C:10]=2[CH:11]=1
Reactant: CCCOC1CCNCC1
Reactant: Cc1ccc2c(c1)N(C[C@H](C)CI)C(=O)CO2
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: CO
Product: CCCOC1CCN(C[C@@H](C)CN2C(=O)COc3ccc(C)cc32)CC1
Yield: 83.3 %

Procedure:
Crude (S)-4-(3-iodo-2-methylpropyl)-6-methyl-4H-benzo[1,4]oxazin-3-one (0.23 g), 4-propyloxypiperidine (0.12 g, .81 mmol) and Et3N (0.5 mL) were reacted according to GP17. Flash CC (SiO2; CH2Cl2/acetone/MeOH 90:5:5) gave the title compound (0.20 g, 83%). 1H NMR (CD3OD) δ 6.97 (brs, 1H), 6.79 (d, J=8.0 Hz, 1H), 6.75 (dm, J=8.0 Hz, 1H), 4.47 (brs, 2H), 3.97 (dd, J=6.4, 14.4 Hz, 1H), 8.82 (dd, J=7.2, 14.4 Hz, 1H), 3.44 (brs, 1H), 3.33 (t, J=6.8 Hz, 2H), 3.10-2.90 (m, 2H), 2.90-2.6 (m, 3H), 2.29 (m, 1H), 2.24 (s, 3H), 1.98-1.86 (m, 2H), 1.78-1.64 (m, 2H), 1.47 (tq, J=14.4, 7.2 Hz, 2H), 0.92 (d, J=6.4 Hz), 0.83 (t, J=7.2 Hz); 13C NMR (CD3OD) δ 166.4, 143.8, 132.8, 128.3, 124.7, 116.7, 116.1, 69.9, 67.4, 61.5, 50.7, 50.5, 44.1, 28.9, 28.6, 23.0, 20.0 15.6, 9.8.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[C@@H:10]([N:14]=[N+]=[N-])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>O=[Pt]=O.CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[C@@H:10]([NH2:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@H](N=[N+]=[N-])[C@@H](O)C1
Agent: O=[Pt]=O
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@H](N)[C@@H](O)C1
Yield: 84.6 %

Procedure:
22.3 A solution of 2.0 g (3S,4S)-3-azido-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester in 25 MeOH was treated under an argon atmosphere with 100 mg PtO2. The reaction mixture was stirred over night under a hydrogen atmosphere. The catalyst was filtered off and washed with methanol. The filtrate was concentrated. The crude product was purified by chromatography (silica gel; gradient: CH2Cl2->CH2Cl2/MeOH 4:1) to give 1.5 g (3S,4S)-3-amino-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester as off-white solid. MS 202.9 ([M+H]+)
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[O:13]=[C:14]1[CH2:18][CH2:17][C:16]2([CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[O:15]1.[F:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36]Br)=[CH:34][CH:33]=1>C1COCC1>[O:13]=[C:14]1[CH:18]([CH2:36][C:35]2[CH:38]=[CH:39][C:32]([F:31])=[CH:33][CH:34]=2)[CH2:17][C:16]2([CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[O:15]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(=O)O2)CC1
Reactant: Fc1ccc(CBr)cc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(Cc1ccc(F)cc1)C(=O)O2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.2 %

Procedure:
A solution of diisopropyl amine (0.36 mL, 2.6 mmol) in 7.5 mL dry THF was cooled to −78° C. and n-butyllithium (1.5 mL, 1.6 M in hexane, 2.4 mmol) was added. The mixture was warmed to 0° C. for 15 min then recooled to −78° C. A solution of 2-oxo-8-(t-Butoxycarbonyl)-8-aza-1-oxaspiro[4.5]decane (510 mg, 2.0 mmol, from Step B) in 2 mL THF was added dropwise. After 30 min at −78° C. 4-fluorobenzyl bromide (0.32 mL, 2.6 mmol) was added and after 30 min the mixture was warmed to room temperature and quenched with sat'd ammonium chloride. The mixture was extracted with ethyl acetate and the organic portion was dried over sodium sulfate and concentrated. Flash chromatography (3/1 hexane/EtOAc) afforded 510 mg (70%) of the desired product. 1H NMR (400 MHz, CDCl3). δ 1.44 (s, 9H), 1.51-1.81 (5H), 2.03-2.19 (m, 1H), 2.76-2.81 (dd, 1H), 2.99-3.04 (m, 1H), 3.18-3.3 (m, 3H), 3.72-3.81 (m, 2H), 6.97-7.03 (m, 2H), 7.11-7.18 (m, 2H). The lactone was separated into its enantiomers by semiprep chiral HPLC (chiralpak AD, 9/1 hexane/IPA→8/1 hexane/IPA) to afford the two enantiomers (enantiomer A, 92% ee and enantiomer B, 73% ee). The two enantiomers were converted to the spiro tetrahydrofuran derivatives as described below for enantiomer B.
Reaction SMILES: CC([O:4][CH2:5][C:6]1[C@H:10]2[C@H:11]([O:18][C@@H:19]3[O:24][C@H:23]([CH2:25][OH:26])[C@@H:22]([OH:27])[C@H:21]([OH:28])[C@H:20]3[OH:29])[O:12][CH:13]=[C:14]3[C:15]([O:17][C@H:8]([C@@H:9]23)[CH:7]=1)=[O:16])=O.[CH3:30][OH:31]>O>[CH3:30][O:31][C:15]([C:14]1[C@H:9]2[C@@H:8]([OH:17])[CH:7]=[C:6]([CH2:5][OH:4])[C@H:10]2[C@H:11]([O:18][C@@H:19]2[O:24][C@H:23]([CH2:25][OH:26])[C@@H:22]([OH:27])[C@H:21]([OH:28])[C@H:20]2[OH:29])[O:12][CH:13]=1)=[O:16]
Reactant: CC(=O)OCC1=C[C@@H]2OC(=O)C3=CO[C@@H](O[C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)[C@H]1[C@@H]32
Reactant: CO
Solvent: O
Product: COC(=O)C1=CO[C@@H](O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H]2C(CO)=C[C@H](O)[C@H]12

Procedure:
Asperuloside (1.0 g) was dissolved in distilled water (10 ml) and adjusted to pH=10 by adding a small amount of a saturated solution of BaO in methanol. This solution was allowed to stand for a few minutes to become cloudy white, which, after neutralization and concentration, was treated by silica gel column chromatography (Waco Gel C-300, 50 g, solvent: chloroform-methanol system). Silica gel column chromatography gave deacetyl asperulosidic acid methyl ester having Rf value=0.79 (chloroform-methanol-water=6:6:1, visualized with 50(%)-sulfuric acid) on TLC, as white needles (1.80 mg).
Reaction SMILES: Cl[C:2]12[O:8][CH:7]1[CH2:6][CH2:5][C:4](F)([F:9])[CH:3]2[CH3:11].Cl>CN(C=O)C.CN(C1C=CN=CC=1)C>[F:9][C:4]1[C:3]([CH3:11])=[C:2]([OH:8])[CH:7]=[CH:6][CH:5]=1
Reactant: CC1C(F)(F)CCC2OC21Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1c(O)cccc1F
Reaction time: 0.12 h
Yield: 21.5 %

Procedure:
0.65 g (3.69 mmol) of epoxide 2l (a mixture of 2l, 2l', 2l" above) in solution in 3 cm3 of anhydrous DMF were heated to reflux for 3 h; 91% of transposition ketone 6b was then detected by macrobore GC (verification by mass/GC coupling). 0.86 g (2 eq.) of DMAP were then added and the mixture was again heated to reflux for 3 h. It was acidified (pH=1) with 3N HCl, extracted with ether, concentrated, and a 3N sodium hydroxide solution was added to the ether phase (while the mixture was kept stirred for 5 to 10 min), the ether phase was removed and the material was washed once with ether. The aqueous phase was acidified using a solution with 3N HCl (pH=1) and was extracted with ether (4×15 cm3), dried over MgSO4, filtered and evaporated down. The crude product obtained was purified by flash chromatography on silica (eluent: ether/petroleum ether=5/95). 0.10 g of phenol 4h were obtained (macrobore GC purity>97%). The yield of compound 4h was 22%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][C:34]([CH2:44][CH3:45])([CH2:42][CH3:43])[C:35]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])=[O:36])=[C:6]([CH:8]2[CH2:13][C:12](=O)[NH:11][CH:10]([C:15]3[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=3[CH3:22])[C:9]32[C:30]2[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=2)[NH:24][C:23]3=[O:32])[CH:7]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:47]>C1(C)C=CC=CC=1>[Cl:31][C:27]1[CH:26]=[C:25]2[NH:24][C:23](=[O:32])[C:9]3([CH:8]([C:6]4[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[O:33][C:34]([CH2:42][CH3:43])([CH2:44][CH3:45])[C:35]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])=[O:36])[CH2:13][C:12](=[S:47])[NH:11][CH:10]3[C:15]3[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=3[CH3:22])[C:30]2=[CH:29][CH:28]=1
Reactant: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12)C(=O)NS(C)(=O)=O
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: Cc1ccccc1
Product: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=S)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12)C(=O)NS(C)(=O)=O
Temperature: 60 °C
Yield: 58.2 %

Procedure:
A mixture of chiral (2′R, 3R, 4′S)-4′-[5-chloro-2-(2-methanesulfonylamino-1,1-diethyl-2-oxo-ethoxy)-phenyl]-6-chloro-2′-(5-fluoro-2-methyl-phenyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (200 mg, 0.3 mmol) and P2S5 (130 mg, 0.6 mmol) was heated at 60° C. for 1 h, and then diluted with toluene (20 mL). The mixture was concentrated in vacuo and the residue was washed with DCM for 2 times. The DCM solution was collected and purified by flash column to give the title compound as white solid (121 mg).
Reaction SMILES: Cl.[Br:2][CH2:3][CH2:4][NH:5][C:6](=[O:21])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH2:14][CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH:8]=1.[N+](C1C=CC([O:29][C:30]([O:32][C:33]2[CH:34]=[N:35][CH:36]=[C:37]([CH:42]=2)[C:38]([O:40][CH3:41])=[O:39])=O)=CC=1)([O-])=O>C(#N)C>[Br:2][CH2:3][CH2:4][NH:5][C:6]([C:7]1[CH:8]=[C:9]([CH2:13][CH2:14][CH:15]2[CH2:20][CH2:19][N:18]([C:30]([O:32][C:33]3[CH:34]=[N:35][CH:36]=[C:37]([CH:42]=3)[C:38]([O:40][CH3:41])=[O:39])=[O:29])[CH2:17][CH2:16]2)[CH:10]=[CH:11][CH:12]=1)=[O:21]
Reactant: COC(=O)c1cncc(OC(=O)Oc2ccc([N+](=O)[O-])cc2)c1
Reactant: O=C(NCCBr)c1cccc(CCC2CCNCC2)c1
Agent: Cl
Solvent: CC#N
Product: COC(=O)c1cncc(OC(=O)N2CCC(CCc3cccc(C(=O)NCCBr)c3)CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
TEA (0.90 ml) was dropwise added to an acetonitrile (30 ml) suspension of N-(2-bromoethyl)-3-(2-piperidin-4-ylethyl)benzamide hydrochloride (1.20 g) and methyl 5-{[(4-nitrophenoxy)carbonyl]oxy}nicotinate (1.02 g), followed by stirring overnight at room temperature. The reaction solvent was evaporated under reduced pressure, then aqueous saturated sodium hydrogencarbonate solution was added thereto, extracted with EtOAc, and dried over anhydrous magnesium sulfate. This was filtered, the solvent was evaporated, and the residue was purified two times through silica gel column chromatography (basic silica with eluent: hexane:EtOAc=1:2 (v/v), next neutral silica with eluent: chloroform:methanol=19:1 (v/v)) to obtain methyl 5-[{(4-[2-(3-{[(2-bromoethyl)amino]carbonyl}phenyl)ethyl]piperidin-1-yl}carbonyl)oxy]nicotinate (762 mg) as a white powder.
Reaction SMILES: [CH:1]([CH2:3][N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([C:15](=[O:38])[C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:37])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=3)=[CH:18][CH:17]=2)[CH2:7][CH2:6][C:5]1=[O:39])=O.[CH3:40][N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1.C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>CO.C(O)(=O)C.C(Cl)(Cl)Cl>[CH3:36][C:33]1[CH:32]=[CH:31][C:30]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[C:23]([NH:22][C:19]2[CH:20]=[CH:21][C:16]([C:15]([N:8]3[C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[N:4]([CH2:3][CH2:1][N:44]4[CH2:45][CH2:46][N:41]([CH3:40])[CH2:42][CH2:43]4)[C:5](=[O:39])[CH2:6][CH2:7]3)=[O:38])=[CH:17][CH:18]=2)=[O:37])=[CH:35][CH:34]=1
Reactant: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N3CCC(=O)N(CC=O)c4ccccc43)cc2)cc1
Reactant: CN1CCNCC1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N3CCC(=O)N(CCN4CCN(C)CC4)c4ccccc43)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 26.1 %

Procedure:
To a mixture of 1-formylmethyl-5-{4-[2-(4-methylphenyl)benzoylamino]benzoyl}-1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one (380 mg) and 4-methylpiperazine (73.4 mg) in a mixture of methanol (10 ml) and acetic acid (0.5 ml) was added sodium cyanoborohydride (46.1 mg) and the mixture was stirred at ambient temperature for 5 hours. The mixture was poured into a mixture of chloroform and saturated aqueous sodium hydrogen carbonate and the mixture was stirred at ambient temperature for 30 minutes. The solution was extracted with chloroform and washed with brine, and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was subjected to a silica gel column (20g, 5% methanol in chloroform). The solvent was evaporated in vacuo and the residue was solidified with diethyl ether to give 5-{4-[2-(4-methylphenyl)benzoylamino]benzoyl}-1-[2-(4-methyl-1-piperazinyl)ethyl]-1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one (115 mg).
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[CH:11]=[CH:10][C:9]([Cl:13])=[CH:8][C:7]=2[C:6]2[CH2:14][N:15]([CH3:18])[CH2:16][CH2:17][C:5]1=2)[CH:2]=[CH2:3].Br[C:20]1[CH:21]=[CH:22][C:23]([CH3:26])=[N:24][CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:13][C:9]1[CH:10]=[CH:11][C:12]2[N:4]([CH2:1]/[CH:2]=[CH:3]/[C:20]3[CH:25]=[N:24][C:23]([CH3:26])=[CH:22][CH:21]=3)[C:5]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][C:6]=3[C:7]=2[CH:8]=1
Reactant: Cc1ccc(Br)cn1
Reactant: C=CCn1c2c(c3cc(Cl)ccc31)CN(C)CC2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(/C=C/Cn2c3c(c4cc(Cl)ccc42)CN(C)CC3)cn1
Temperature: 25 °C

Procedure:
5-Allyl-8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (300 mg, 1.15 mmol, 1 equiv.) and 5-bromo-2-methylpyridine (198 mg, 1.15 mmol, 1 equiv.) were heated to 100° C. with palladium acetate (7.8 mg, 0.034 mmol), triphenyl phosphine (18 mg, 0.069 mmol) and triethyl amine (0.35 mL, 2 equiv.) in THF (6 mL) for 14 h. The reaction mixture was cooled to RT and diluted with THF (10 mL), filtered over a Celite bed and concentrated. The concentrate was dissolved in EtOAc (20 mL) and washed with water (5 mL) followed by brine. The organic layer was dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain crude product that was purified by HPLC. 1H NMR (CD3OD) δ (ppm): 8.57 (s, 1H), 8.39-8.37 (d, 1H), 7.74-7.72 (d, 1H), 7.51 (s, 1H), 7.41 (d, 1H), 7.17 (d, 1H), 6.78-6.72 (m, 1H), 6.28-6.24 (d, 1H), 5.02(m, 2H), 4.7 (bs, 1H), 4.36 (bs, 1H), 3.87 (bs, 1H), 3.6 (bs, 1H), 3.29-3.24 (m, 2H), 3.12-3.10 (s, 3H), 2.7 (s, 3H).
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].[C:6]1([CH3:16])[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=1.Cl>C(Cl)Cl.[OH-].[Na+]>[CH2:1]([NH:5][S:12]([C:9]1[CH:10]=[CH:11][C:6]([CH3:16])=[CH:7][CH:8]=1)(=[O:14])=[O:13])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCCCNS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Dissolve butylamine (10 mmol) in methylene chloride (50 mL) and 10% sodium hydroxide (50 mL). Cool to 0° C. Add excess p-toluenesulfonyl chloride with stirring. After 1 hour allow the reaction to warm to room temperature and stir for 2 days. Neutralize the reaction with 0.5N hydrochloric acid and extract the aqueous with methylene chloride (2×100 mL). Rinse the combined organic extracts with water (100 mL), brine (100 mL), dry over anhydrous sodium sulfate, filter and concentrate under vacuum to provide N-butyl-4-methyl-benzenesulfonamide.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[S:6]([N:16]1CC2=C[S:22][CH:23]=[C:18]2[CH2:17]1)([C:9]1[CH:15]=[CH:14][C:12]([CH3:13])=[CH:11][CH:10]=1)(=[O:8])=[O:7].IC.O>CCCCCC.O1CCCC1>[CH3:4][C:3]1[S:22][CH:23]=[C:18]2[CH2:17][N:16]([S:6]([C:9]3[CH:10]=[CH:11][C:12]([CH3:13])=[CH:14][CH:15]=3)(=[O:7])=[O:8])[CH2:1][C:2]=12
Reactant: Cc1ccc(S(=O)(=O)N2Cc3cscc3C2)cc1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: Cc1ccc(S(=O)(=O)N2Cc3csc(C)c3C2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 86 %

Procedure:
9.4 ml (15 mmol) of a 1.6M solution of butyllithium in hexane are added, at -70° C., to a solution of 3.5 g (12.5 mmol) of 5-tosyl-5,6-dihydro-4H-thieno[3,4-c]pyrrole in 40 ml of dry tetrahydrofuran; after 15 min, 1 ml (16 mmol) of iodomethane is added, the mixture is then stirred at room temperature for 30 min and poured into 200 ml of water. The precipitate formed is filtered and washed with hexane; after purification on silica gel using the 1/9 ethyl acetate/hexane eluent mixture, there are obtained 3.16 g of a white solid. Yield 86%. Melting point: 158°-160° C.
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH3:13][CH:14]1[CH2:18][S:17](=[O:20])(=[O:19])[NH:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].CNCCNC>[Cu]I.O.C1(C)C=CC=CC=1>[CH3:13][CH:14]1[CH2:18][S:17](=[O:20])(=[O:19])[N:16]([C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=2)[CH2:15]1
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: CC1CNS(=O)(=O)C1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(N2CC(C)CS2(=O)=O)cc1

Procedure:
To a mixture of ethyl 4-iodobenzoate (571 mg), 4-methylisothiazolidine 1,1-dioxide (280 mg) described in Preparation Example 9, potassium carbonate (572 mg) and copper(I) iodide (197 mg) were added toluene (6 mL) and N,N′-dimethylethylenediamine (230 μL), and the mixture was stirred with heating under reflux for 9 hr. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give ethyl 4-(4-methyl-1,1-dioxo-1λ6-isothiazolidin-2-yl)benzoate. The obtained ethyl 4-(4-methyl-1,1-dioxo-1λ6-isothiazolidin-2-yl)benzoate was dissolved in tetrahydrofuran (5 mL), 1N aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated from the reaction mixture, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. To the obtained residue was added diethyl ether, and the precipitate was collected by filtration to give the title compound (210 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3([C@@H:15]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([Cl:22])[C:17]=4[F:23])[C@H:14]([C:24]([OH:26])=O)[NH:13][C:12]43[CH2:31][CH2:30][C:29]([CH3:33])([CH3:32])[CH2:28][CH2:27]4)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH3:34][N:35]1[C:39]([CH2:40][NH2:41])=[CH:38][N:37]=[CH:36]1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C@@:6]3([C@@H:15]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([Cl:22])[C:17]=4[F:23])[C@H:14]([C:24]([NH:41][CH2:40][C:39]4[N:35]([CH3:34])[CH:36]=[N:37][CH:38]=4)=[O:26])[NH:13][C:12]43[CH2:31][CH2:30][C:29]([CH3:32])([CH3:33])[CH2:28][CH2:27]4)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: CC1(C)CCC2(CC1)N[C@@H](C(=O)O)[C@H](c1ccnc(Cl)c1F)C21C(=O)Nc2cc(Cl)ccc21
Reactant: Cn1cncc1CN
Product: Cn1cncc1CNC(=O)[C@@H]1NC2(CCC(C)(C)CC2)[C@@]2(C(=O)Nc3cc(Cl)ccc32)[C@H]1c1ccnc(Cl)c1F
Yield: 39.6 %

Procedure:
The compound (400 mg, 0.81 mmol) obtained in Step 1 of Example 17 and 1-(1-methyl-1H-imidazole-5-yl)methanamine (95 mg, 0.98 mmol) were used as starting materials and treated in the same way as in Step 2 of Example 12 to give 188 mg (41%) of the title compound as a solid.
Reaction SMILES: O.[NH2:2]N.[N:4]1([C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[S:10])C=CN=C1>C(O)C>[CH3:17][N:14]1[CH2:15][CH2:16][N:11]([C:9](=[S:10])[NH:4][NH2:2])[CH2:12][CH2:13]1
Reactant: CN1CCN(C(=S)n2ccnc2)CC1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CN1CCN(C(=S)NN)CC1
Yield: 61.4 %

Procedure:
4-methylpiperazine-1-carbothiohydrazide (intermediate 6) can be formed according to the following scheme. Hydrazine hydrate (MW 50.06, 0.26 ml, 5.44 mmol, 1.1 eq) was added to a solution of imidazol-1-yl-(4-methyl-piperazin-1-yl)-methanethione (3; MW 210.30, 1.040 g, 4.95 mmol, 1 eq) in 30 ml ethanol at room temperature. The reaction mixture was stirred under reflux for 2 hours. This organic solution was concentrated. The solid thus obtained was triturated with diethyl ether and filtered to yield 4-methylpiperazine-1-carbothiohydrazide (6; MW 174.27, 0.53 g, 3.04 mmol, 61% yield) as a white solid which was used without further purification. TLC (CH2Cl2/MeOH: 90/10): Rf=0.15, Product UV and Ninhydrin stain active. 1H-NMR (400 MHz, DMSO-d6), δ ppm: 2.17 (s, 3H), 2.28 (t, 4H, J=5 Hz), 3.69 (t, 4H, J=5 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([C:13]3[CH:14]=[C:15]([CH3:23])[C:16]4[N:17]([C:19]([CH3:22])=[N:20][N:21]=4)[CH:18]=3)[C:11](=[O:24])[C:10](O)=[C:9]2[C:26]([CH:28]2[CH2:30][CH2:29]2)=O)=[CH:4][CH:3]=1.O.[NH2:32][NH2:33]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:9]3[C:26]([CH:28]4[CH2:30][CH2:29]4)=[N:33][NH:32][C:10]=3[C:11](=[O:24])[N:12]2[C:13]2[CH:14]=[C:15]([CH3:23])[C:16]3[N:17]([C:19]([CH3:22])=[N:20][N:21]=3)[CH:18]=2)=[CH:6][CH:7]=1
Reactant: NN
Reactant: Cc1cc(N2C(=O)C(O)=C(C(=O)C3CC3)C2c2ccc(Cl)cc2)cn2c(C)nnc12
Solvent: O
Product: Cc1cc(N2C(=O)c3[nH]nc(C4CC4)c3C2c2ccc(Cl)cc2)cn2c(C)nnc12

Procedure:
The title compound was prepared in analogy to the procedure described in Example 57 using 5-(4-chlorophenyl)-4-(cyclopropanecarbonyl)-1-(3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-3-hydroxy-1H-pyrrol-2(5H)-one (Step 117.1) and hydrazine hydrate. The crude product was purified by silica gel column chromatography (7.5% MeOH/CH2Cl2). tR: 0.83 min (LC-MS 2); ESI-MS: 419 [M+H]+ (LC-MS 2); 1H NMR (400 MHz, DMSO-d6) δ ppm 0.00-0.11 (m, 1H) 0.44-0.65 (m, 1H) 0.65-0.78 (m, 1H) 0.80-0.90 (m, 1H) 1.68-1.88 (m, 1H) 2.42 (s, 3H) 2.61 (s, 3H) 6.44 (s, 1H) 7.16-7.45 (m, 5H) 8.38 (d, J=0.8 Hz, 1H) 13.55 (br. s., 1H).