Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]([O:5][C:6]1[CH:10]=[C:9]([CH2:11][S:12][CH3:13])[O:8][N:7]=1)=[O:4].ClC1C=CC=C(C(OO)=[O:23])C=1>C(Cl)Cl>[CH3:1][N:2]([CH3:14])[C:3]([O:5][C:6]1[CH:10]=[C:9]([CH2:11][S:12]([CH3:13])=[O:23])[O:8][N:7]=1)=[O:4]
Reactant: CSCc1cc(OC(=O)N(C)C)no1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CN(C)C(=O)Oc1cc(CS(C)=O)on1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.1 %

Procedure:
A solution of 757 mg of 3-dimethylcarbamoyloxy-5-methylthiomethylisoxazole in 5 ml of methylene chloride was added dropwise over a period of 30 minutes, with stirring, to an ice-cooled solution of 711 mg of m-chloroperbenzoic acid in 15 ml of methylene chloride. The mixture was then stirred for a further 30 minutes, after which it was filtered and the precipitate was washed with 2 ml of methylene chloride. The filtrate and the washings were combined, and then the solvent was removed by distillation, leaving a colourless, crystalline residue, which was recrystallized from diethyl ether, to give 700 mg (yield 86.1%) of 3-dimethylcarbamoyloxy-5-methylsulphinylmethylisoxazole, in the form of colourless needles melting at 84°-85° C.
Reaction SMILES: [O:1]=[C:2]1[C:15]2[CH:14]=[C:13]([C:16]([OH:18])=[O:17])[CH:12]=[CH:11][C:10]=2[C:9](=[O:19])[C:8]2[C:3]1=[CH:4][C:5]([OH:20])=[CH:6][CH:7]=2.S(=O)(=O)(O)O.[C:26](OC(=O)C)(=[O:28])[CH3:27]>>[C:26]([O:20][C:5]1[CH:4]=[C:3]2[C:8]([C:9](=[O:19])[C:10]3[CH:11]=[CH:12][C:13]([C:16]([OH:18])=[O:17])=[CH:14][C:15]=3[C:2]2=[O:1])=[CH:7][CH:6]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1ccc2c(c1)C(=O)c1cc(O)ccc1C2=O
Agent: O=S(=O)(O)O
Product: CC(=O)Oc1ccc2c(c1)C(=O)c1cc(C(=O)O)ccc1C2=O
Reaction time: 6 h

Procedure:
9,10-Dihydro-9,10-dioxo-7-hydroxyanthracene-2-carboxylic acid (36.39 g) was suspended in glacial acetic anhydride (364 ml). Concentrated sulphuric acid (5 ml) was added and the mixture was stirred magnetically at 110°±5° C. for 6 hours in a heating mantle.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]O)=[CH:6][C:5]=1[N+:12]([O-:14])=[O:13].C(N(CC)CC)C.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[NH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>ClCCl>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)=[CH:6][C:5]=1[N+:12]([O-:14])=[O:13]
Reactant: C1CCNCC1
Reactant: COC(=O)c1ccc(CO)cc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(CN2CCCCC2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.5 %

Procedure:
To a solution of 4-hydroxymethyl-2-nitro-benzoic acid methyl ester (2.0 g, 9.47 mmol) in dry dichloromethane (80 mL) under argon, at room temperature, triethylamine (1.6 mL, 10.9 mmol, 1.15 eq.) and then p-toluenesulfonyl chloride (2.08 g, 10.9 mmol, 1.15 eq.) were added. The reaction mixture was stirred at room temperature for 1 h, then piperidine (1.6 mL, 18.94 mmol, 2 eq.) was added and the mixture stirred for additional 24 hours. The solvent was evaporated and the residue purified by flash chromatography on silica gel, using dichloromethane/ethanol 95:5 as eluant, affording 1.2 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][O:19][CH2:20][O:21][CH3:22])=[CH:13][CH:12]=2)=[C:7]([OH:9])[CH:8]=1.[C:23]([O:26][C@@H:27]1[C@@H:39]([O:40][C:41](=[O:43])[CH3:42])[C@H:38]([O:44][C:45](=[O:47])[CH3:46])[C@@H:37]([CH2:48][O:49][C:50](=[O:52])[CH3:51])[O:36][C@@H:28]1OC(=N)C(Cl)(Cl)Cl)(=[O:25])[CH3:24].C(=O)([O-])O.[Na+]>ClCCl>[C:23]([O:26][C@@H:27]1[C@@H:39]([O:40][C:41](=[O:43])[CH3:42])[C@H:38]([O:44][C:45](=[O:47])[CH3:46])[C@@H:37]([CH2:48][O:49][C:50](=[O:52])[CH3:51])[O:36][C@H:28]1[O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=1[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][O:19][CH2:20][O:21][CH3:22])=[CH:13][CH:12]=1)(=[O:25])[CH3:24]
Reactant: COCOCCc1ccc(Cc2ccc(OC)cc2O)cc1
Reactant: CC(=O)OC[C@H]1O[C@H](OC(=N)C(Cl)(Cl)Cl)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COCOCCc1ccc(Cc2ccc(OC)cc2O[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)cc1
Reaction time: 0.33 h
Yield: 83 %

Procedure:
To a solution of 5-methoxy-2-{4-[2-(methoxymethyl-oxy)ethyl]benzyl}phenol (0.19 g) and 2,3,4,6-tetra-O-acetyl-1-O-trichloroacetoimidoyl-α-D-glucopyranose (0.40 g) in dichloromethane (15 mL) was added boron trifluoride-diethyl ether complex (0.088 mL) at 0° C., and the mixture was stirred 20 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the organic layer was separated. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=1/1) to give 5-methoxy-2-{4-[2-(methoxymethyloxy)ethyl]benzyl}phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (0.33 g).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[C:18]([C:19]2[N:20]=[C:21]3[C:27]4[CH:28]=[C:29]([C:32](O)=[O:33])[CH:30]=[CH:31][C:26]=4[O:25][CH2:24][CH2:23][N:22]3[CH:35]=2)=[N:17][CH:16]=[N:15]1.C[N:37](C)C=O.CN(C)C(=O)C>C(Cl)Cl.N>[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[C:18]([C:19]2[N:20]=[C:21]3[C:27]4[CH:28]=[C:29]([C:32]([NH2:37])=[O:33])[CH:30]=[CH:31][C:26]=4[O:25][CH2:24][CH2:23][N:22]3[CH:35]=2)=[N:17][CH:16]=[N:15]1
Reactant: O=C(O)c1ccc2c(c1)-c1nc(-c3ncnn3-c3ccccc3Cl)cn1CCO2
Reactant: CN(C)C=O
Agent: N
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: NC(=O)c1ccc2c(c1)-c1nc(-c3ncnn3-c3ccccc3Cl)cn1CCO2
Reaction time: 2 h
Yield: 349.8 %

Procedure:
Oxalyl chloride in methylene chloride (2.00 M, 3.0 mL) was added to a suspension of 2-(1-(2-chlorophenyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylic acid (112 mg, 0.178 mmol) in 30 ml of methylene chloride. Catalytic amount of N,N-Dimethylformamide (1.0 uL, 0.013 mmol) was added and the mixture was stirred for 2 hours. The mixture was filtered, the filtrate was concentrated in vacuum and the residue dried in high vacuum for 1 hour. The above residue was dissolved in N,N-dimethylacetamide (3.0 mL, 32 mmol) and saturated with gaseous ammonia. The mixture was stirred for 20 min, concentrated in vacuum, dissolved in aqueous methanol and subjected to RP HPLC purification to yield 18.5 mg of 102 (26%), MS: 407.1. 1H NMR (400 MHz, DMSO) δ 8.26 (d, J=2.2, 1H), 8.20 (s, 1H), 7.80 (s, 1H), 7.72-7.51 (m, 6H), 7.29 (s, 1H), 7.00 (d, J=8.5, 1H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:32]=[CH:31][C:9]3[N:10]=[C:11]([N:13]4[CH2:18][CH2:17][CH:16]([O:19][CH2:20][C@@H:21]([NH:23][C:24](=[O:30])OC(C)(C)C)[CH3:22])[CH2:15][CH2:14]4)[O:12][C:8]=3[CH:7]=2)[CH2:3][CH2:2]1.Cl.[C:34](OCC)(=O)C>>[CH:1]1([CH2:4][O:5][C:6]2[CH:32]=[CH:31][C:9]3[N:10]=[C:11]([N:13]4[CH2:18][CH2:17][CH:16]([O:19][CH2:20][C@@H:21]([NH:23][C:24](=[O:30])[CH3:34])[CH3:22])[CH2:15][CH2:14]4)[O:12][C:8]=3[CH:7]=2)[CH2:2][CH2:3]1
Reactant: C[C@@H](COC1CCN(c2nc3ccc(OCC4CC4)cc3o2)CC1)NC(=O)OC(C)(C)C
Reactant: CCOC(C)=O
Agent: Cl
Product: CC(=O)N[C@@H](C)COC1CCN(c2nc3ccc(OCC4CC4)cc3o2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To tert-butyl [(1S)-2-({1-[6-(cyclopropylmethoxy)-1,3-benzoxazol-2-yl]piperidin-4-yl}oxy)-1-methylethyl]carbamate (438 mg) was added 4M hydrogen chloride/ethyl acetate (5 mL), and the mixture was stirred at room temperature for 30 min and concentrated. Pyridine (2.5 mL) and acetic anhydride (0.186 mL) were added to the residue, and the mixture was stirred at room temperature for 2 hr. After concentration, the residue was dissolved in ethyl acetate, and the solution was washed successively with 10% aqueous potassium carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The extract was applied to silica gel chromatography (NH, ethyl acetate) and concentrated under reduced pressure, and the obtained solid was washed with diisopropyl ether to give the title compound (295 mg).
Reaction SMILES: [CH3:1][C:2]([S@@:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[Si:8]([O:15][CH2:16][CH:17]=O)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]>>[Si:8]([O:15][CH2:16][CH:17]=[N:7][S@:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[O:6])([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Reactant: CC(C)(C)[S@@](N)=O
Product: CC(C)(C)[S@](=O)N=CCO[Si](C)(C)C(C)(C)C

Procedure:
(S)-N-(2-{[tert-butyl(dimethyl)silyl]oxy}ethylidene)-2-methylpropane-2-sulfinamide was prepared from (S)-(−)-2-methyl-2-propanesulfinamide and (tert-butyldimethylsilyloxy)acetaldehyde essentially according to the procedure of Barrow, J. C.; Ngo, P. L. Tetrahedron Lett. 2000, PAGES.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:37]=[C:38]([F:40])[CH:39]=1)[CH2:5][C@H:6]([NH:20]C(C1C=C(C)N=C(N(CCC)CCC)N=1)=O)[C@H:7]([OH:19])[CH2:8][NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH3:18])[CH:12]=1.[CH2:41]([N:45]([CH3:56])[C:46]1[CH:47]=[C:48]([CH:52]=[C:53]([Cl:55])[N:54]=1)[C:49]([OH:51])=O)[CH2:42][CH2:43][CH3:44]>>[CH2:41]([N:45]([CH3:56])[C:46]1[CH:47]=[C:48]([CH:52]=[C:53]([Cl:55])[N:54]=1)[C:49]([NH:20][C@@H:6]([CH2:5][C:4]1[CH:37]=[C:38]([F:40])[CH:39]=[C:2]([F:1])[CH:3]=1)[C@H:7]([OH:19])[CH2:8][NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH3:18])[CH:12]=1)=[O:51])[CH2:42][CH2:43][CH3:44]
Reactant: CCCN(CCC)c1nc(C)cc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CNCc2cccc(CC)c2)n1
Reactant: CCCCN(C)c1cc(C(=O)O)cc(Cl)n1
Product: CCCCN(C)c1cc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CNCc2cccc(CC)c2)cc(Cl)n1

Procedure:
In the same manner as for N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-2-(dipropylamino)-6-methylpyrimidine-4-carboxamide {Example S-2435}, Step 3, 2-[butyl(methyl)amino]-6-chloroisonicotinic acid (0.15 g) was converted to 0.13 g of the title compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH:16]([CH2:18][CH:19]=[CH2:20])O)=[N:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(P([N:66]=[N+:67]=[N-:68])(C2C=CC=CC=2)=O)C=CC=CC=1>C1C=CC=CC=1>[N:66]([CH:16]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:1][N:2]=1)[CH2:18][C:19]#[CH:20])=[N+:67]=[N-:68]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: C=CCC(O)c1ccccc1-c1noc2ccccc12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: C#CCC(N=[N+]=[N-])c1ccccc1-c1noc2ccccc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 34.5 %

Procedure:
A mixture containing 4.0 g of 2-(1,2-benzisoxazol-3-yl)-α-2-propenyl-benzenemethanol, 4.32 g of triphenylphosphine, 2.61 g of diethyl azodicarboxylate and 4.12 g of diphenylphosphoryl azide in 50 ml of benzene was stirred at room temperature for 24 h. Evaporation of the solvent under reduced pressure afforded a solid which was purified by chromatography on silica gel, eluting with 5% ethanol in toluene, to afford 1.5 g of 3-[2-(1-azido-3-butynyl)phenyl]-1,2-benzisoxazole as an oil, M.S. (C.I:)-(M/Z): 289 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N:15]=[N:14][CH:13]=[C:12]([CH3:18])[C:11]=2[C:10](=O)[CH2:9]1.Cl.[NH2:21][NH:22][C:23]([NH:25][OH:26])=[NH:24].Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N:15]=[N:14][CH:13]=[C:12]([CH3:18])[C:11]=2[C:10](=[N:21][NH:22][C:23](=[NH:24])[NH:25][OH:26])[CH2:9]1
Reactant: N=C(NN)NO
Reactant: Cc1cnnc2c1C(=O)CC(c1ccccc1Cl)C2
Agent: Cl
Solvent: CCO
Product: Cc1cnnc2c1C(=NNC(=N)NO)CC(c1ccccc1Cl)C2
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 155.8 %

Procedure:
To a mixture of 7-(2-chlorophenyl)-4-methyl-5,6,7,8-tetrahydrocinnolin-5-one (101 mg) and 1-amino-3-hydroxyguanidine hydrochloride (48 mg) were added ethanol (2 ml) and concentrated hydrochloric acid (0.05 ml), and the mixture was stirred at 90° C. for 1.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was washed with ethanol and dried to give 7-(2-chlorophenyl)-5-(1-hydroxyguanidin-3-yl)imino-4-methyl-5,6,7,8-tetrahydrocinnoline hydrochloride (Compound 156) (110 mg) as gray white crystals.
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]([NH2:7])=[NH:6])=[NH:3].C(=O)=O.[Br:11][C:12]1[CH:17]=[C:16]([Br:18])[CH:15]=[C:14]([Br:19])[C:13]=1[NH:20][CH2:21][C:22](OCC)=O>CO>[NH2:6][C:5]1[N:4]=[C:2]([NH2:1])[N:3]=[C:22]([CH2:21][NH:20][C:13]2[C:14]([Br:19])=[CH:15][C:16]([Br:18])=[CH:17][C:12]=2[Br:11])[N:7]=1
Reactant: CCOC(=O)CNc1c(Br)cc(Br)cc1Br
Reactant: N=C(N)NC(=N)N
Agent: O=C=O
Solvent: CO
Product: Nc1nc(N)nc(CNc2c(Br)cc(Br)cc2Br)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 57 %

Procedure:
Freshly prepared biguanide (6.1 g, 0.06 mole) in methanol (700 ml) was placed in a flask equipped with a stirrer and a soda lime trap to exclude CO2. IV (25.0 g, 0.06 mole) was added all at once through a powder funnel. After the solution was stirred for 10 min at room temperature, a white precipitate began to form. After being stirred for 7.5 h, the mixture was allowed to stand overnight. The crystals were filtered and washed with fresh methanol. They were then slurried with water (250 ml), filtered again, and washed with methanol. A crude yield of 21.9 g (81%) was obtained. It was recrystallized by dissolving 21.8 g in 80 ml of hot DMF (125° C.) and then adding 9 ml of water dropwise. When the solution cooled, white crystals separated. A second crop of crystals was obtained from the filtrate. The total recovery was 15.5 g, a yield of 57% based on the theoretical yield of 27.2 g. An analytical sample with mp of 250°-51° C. was obtained by recrystallizing again from hot DMF and finally washing with cold methanol. Anal. calcd. for C10H9Br3N6 : C, 26.52; H, 2.00; Br, 52.93; N, 18.55. Found: C, 26.52; H, 2.02; Br, 52.71; N, 18.59.
Reaction SMILES: [O:1]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10](Cl)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][NH:18][CH3:19]>C(Cl)Cl>[CH3:17][N:18]([CH3:19])[C:10](=[O:11])[C:9]1[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=1[O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1Oc1ccccc1
Reactant: CNC
Solvent: ClCCl
Product: CN(C)C(=O)c1ccccc1Oc1ccccc1

Procedure:
A solution of 7.7 parts of 2-phenoxybenzoyl chloride in 50 parts of methylene chloride was added slowly to a cold (0°) vigorously stirred mixture of 50 parts of methylene chloride and 40 parts of 25% aqueous dimethyl amine. After 8 hours the methylene chloride layer was separated. The organic layer was washed with water and dried over magnesium sulfate. Removal of the magnesium sulfate by filtration and the methylene chloride under vacuum gave 5.1 parts of N,N dimethyl-2-phenoxybenzamide as a viscous oil. NMR (CDCl3) 2.9δ(S,3H,N--CH3), 3δ(S,3H,N--CH3), 7.2δ(m,9H,Aromatic H).
Reaction SMILES: [C:1]1([CH2:7][O:8][N:9]([CH2:18][C@@H:19]2[O:23][CH2:22][C@@H:21]([S:24][C:25](=[O:27])[CH3:26])[CH2:20]2)[C:10](OCC(Cl)(Cl)Cl)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:28](OC(=O)C)(=O)C>C(O)(=O)C.C(OCC)(=O)C.[Zn]>[C:10]([N:9]([CH2:18][C@@H:19]1[O:23][CH2:22][C@@H:21]([S:24][C:25](=[O:27])[CH3:26])[CH2:20]1)[O:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:11])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)S[C@@H]1CO[C@@H](CN(OCc2ccccc2)C(=O)OCC(Cl)(Cl)Cl)C1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(=O)S[C@@H]1CO[C@@H](CN(OCc2ccccc2)C(C)=O)C1
Reaction time: 0.17 h

Procedure:
To a room temperature solution, under argon, of 0.188 g of product from Example 71 in 2.3 ml of glacial acetic acid is added 0.269 g of zinc dust. The reaction is stirred 10 minutes and 155 microliter of acetic anhydride is added. The reaction is stirred at room temperature overnight, diluted with ethyl acetate and filtered. The filtrate is concentrated in vacuo to give 0.110 g of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[CH2:5][C:6]1[C:7]([CH2:13][CH3:14])=[N:8][NH:9][C:10]=1[CH2:11][CH3:12].Cl.Cl[CH2:21][CH2:22][NH2:23]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[CH2:5][C:6]1[C:10]([CH2:11][CH3:12])=[N:9][N:8]([CH2:21][CH2:22][NH2:23])[C:7]=1[CH2:13][CH3:14]
Reactant: NCCCl
Reactant: CCc1n[nH]c(CC)c1Cc1cc(Cl)cc(Cl)c1
Agent: Cl
Product: CCc1nn(CCN)c(CC)c1Cc1cc(Cl)cc(Cl)c1
Temperature: 150 °C
Yield: 53.5 %

Procedure:
The pyrazole of Example 11 (5.47 g, 19.3 mmol) was mixed with 2-chloroethylamine hydrochloride (2.46 g, 21.3 mmol) and heated neat at 150° C. for 20 hours. After cooling, the solid was partitioned between dichloromethane and 10% aqueous potassium carbonate solution. The organic extract was concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel eluting with a solvent gradient of dichloromethane:methanol:ammonia (95:5:0, by volume) gradually changing to dichloromethane:methanol:ammonia (90:10:1, by volume) to afford the title compound (3.37 g) as a colourless oil.
Reaction SMILES: [CH3:1][N:2]1[C:9](=[O:10])[CH:8]([C:11]([O:13]CC)=O)[C:6](=[O:7])[N:5]([CH3:16])[C:3]1=[S:4].[Cl:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[C:20]([O:25][C:26]2[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:33])[CH:19]=1.C(O)C>CN(C)C=O>[CH3:16][N:5]1[C:6](=[O:7])[CH:8]([C:11](=[O:13])[NH:22][C:21]2[CH:23]=[CH:24][C:18]([Cl:17])=[CH:19][C:20]=2[O:25][C:26]2[C:27]([Cl:33])=[CH:28][CH:29]=[CH:30][C:31]=2[Cl:32])[C:9](=[O:10])[N:2]([CH3:1])[C:3]1=[S:4]
Reactant: CCOC(=O)C1C(=O)N(C)C(=S)N(C)C1=O
Reactant: Nc1ccc(Cl)cc1Oc1c(Cl)cccc1Cl
Solvent: CN(C)C=O
Solvent: CCO
Product: CN1C(=O)C(C(=O)Nc2ccc(Cl)cc2Oc2c(Cl)cccc2Cl)C(=O)N(C)C1=S
Reaction time: 6 h

Procedure:
2.5 g (10 mmol) of 1,3-dimethyl-5-ethoxycarbonyl-2-thiobarbituric acid, 2.9 g (10 mmol) of 4-chloro-2-(2,6-dichlorophenoxy)aniline, 40 ml of ethanol and 3 ml of dimethylformamide are mixed and then boiled under reflux with stirring for 6 hours. The reaction mixture is then cooled and the resultant crystalline precipitate is isolated by filtration. If necessary, the crystalline precipitate can be recrystallised from a mixture of dioxane and ethanol. Melting point 254°-257° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[C:22]([CH3:35])=[C:23]([CH3:34])[C:24]4[O:28][C:27]([CH3:30])([CH3:29])[CH:26](O)[C:25]=4[C:32]=3[CH3:33])[CH2:17][CH2:16]2)=[CH:11][CH:10]=1>>[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[C:22]([CH3:35])=[C:23]([CH3:34])[C:24]4[O:28][C:27]([CH3:29])([CH3:30])[CH:26]([N:1]5[CH2:6][CH2:5][O:4][CH2:3][CH2:2]5)[C:25]=4[C:32]=3[CH3:33])[CH2:17][CH2:16]2)=[CH:13][CH:14]=1
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(O)C(C)(C)O4)CC2)cc1
Reactant: C1COCCN1
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(N3CCOCC3)C(C)(C)O4)CC2)cc1
Yield: 80 %

Procedure:
Using morpholine and 5-(4-(4-methoxyphenyl)piperazin-1-yl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-ol obtained in Reference Example 18, the title compound was synthesized in the same manner as in Example 57. Yield 80%.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:10][CH2:9][N:8]([C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]1[C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:47])[CH2:27][C:28]2[CH:33]=[CH:32][C:31]([NH:34][C:35]([NH:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[CH3:44])=[O:36])=[C:30]([O:45][CH3:46])[CH:29]=2)=[CH:21][CH:20]=1)=[O:5])C.[OH-].[Na+]>C(O)C.C(#N)C>[C:11]([N:8]1[CH2:9][CH2:10][CH:6]([C:4]([OH:5])=[O:3])[CH:7]1[C:19]1[CH:20]=[CH:21][C:22]([NH:25][C:26](=[O:47])[CH2:27][C:28]2[CH:33]=[CH:32][C:31]([NH:34][C:35]([NH:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[CH3:44])=[O:36])=[C:30]([O:45][CH3:46])[CH:29]=2)=[CH:23][CH:24]=1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)C1CCN(C(=O)c2ccccc2)C1c1ccc(NC(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC#N
Product: COc1cc(CC(=O)Nc2ccc(C3C(C(=O)O)CCN3C(=O)c3ccccc3)cc2)ccc1NC(=O)Nc1ccccc1C
Temperature: 5 °C
Reaction time: 144 h
Yield: 42.5 %

Procedure:
A stirred solution of 1-benzoyl-2-(4-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-phenyl)-pyrrolidine-3-carboxylic acid ethyl ester (0.33 g, Reference Example 13) in a mixture of ethanol (4 ml) and acetonitrile (40 ml), at 20° C., was treated dropwise with aqueous sodium hydroxide solution (0. 15 ml, 10 N). After stirring for 6 days the mixture was filtered and the insoluble light brown solid was triturated twice with acetonitrile (5 ml), then twice with dichloromethane (2.5 ml) and then dried. The solid was dissolved in water (30 ml) and filtered. The filtrate was cooled to 5° C. and the pH of the mixture adjusted to 2 by dropwise addition of hydrochloric acid (1.2 ml, 1N). The resulting white precipitate was filtered then washed three times with water (5 ml), then twice with diisopropyl ether (10 ml) and then dried under reduced pressure (40° C. and 2.7 kPa) to afford the title compound (0.134 g) as an off-white powder, m.p. 155° C. (with decomposition). 1H-NMR [500 MHz, (CD3)2SO at 383° K.]: δ 2.15 (m, 2H); 2.27 (s, 3H); 2.96 (m, 1H); 3.59 (s, 2H); 3.75 (m, 2H); 3.89 (s, 3H); 5.32 (m, 1H); 6.87 (bd, J=8 Hz, 1H); 6.98 (t, J=7.5 Hz, 1H); 7.02 (d, J=1.5 Hz, 1H); 7.10 to 7.25 (m, 4H); 7.30 to 7.45 (m, 5H); 7.52 (d, J=8.5 Hz, 2H); 7.67 (d, J=8 Hz, 1H); 7.99 (d, J=8 Hz, 1H); 8.15 (bs, 1H); 8.21 (bs, 1H); 9.55 (bs, 1H). MS(ES): 629 [M+Na]+.
Reaction SMILES: C[O:2][C:3]1[C:15]2[CH2:14][CH2:13][C@H:12]3[C@H:8]([CH2:9][CH2:10][N:11]3[CH2:16][CH2:17][CH3:18])[C:7]=2[CH:6]=[CH:5][CH:4]=1.[ClH:19]>Br>[ClH:19].[CH2:16]([N:11]1[C@@H:12]2[C@@H:8]([C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([OH:2])[C:15]=3[CH2:14][CH2:13]2)[CH2:9][CH2:10]1)[CH2:17][CH3:18]
Reactant: CCCN1CC[C@@H]2c3cccc(OC)c3CC[C@@H]21
Agent: Br
Agent: Cl
Product: CCCN1CC[C@@H]2c3cccc(O)c3CC[C@@H]21
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
2.65 g (0.0108 mol) of rac-cis-2,3,3a,4,5,9b-hexahydro-6-methoxy-3-propyl-1H-benzo[e]indole were dissolved in 0.151 of 48% aqueous HBr and boiled under reflux for 1 hour. The mixture was concentrated and the residue was taken up in CH2Cl2 and extracted with a mixture of saturated NaHCO3 solution (100 ml) and a 2N NaOH solution (20 ml). The extracts were dried with MgSO4, filtered and concentrated. The pale rose oil (2.5 g) was dissolved in 40 ml of methanol. 2.05 ml (11.89 mmol) of 5.8N ethanolic HCl solution were added dropwise thereto and the mixture was stirred at room temperature for 1 hour and at 0° for 1 hour. The separated crystals were filtered off under suction and washed with ethyl acetate. After working-up the mother liquors there were obtained a total of 2.4 g (83%) of rac-cis-2,3,3a,4,5,9b-hexahydro-3-propyl-1H-benzo[e] indol-6-ol hydrochloride as white crystals with m.p. 242°-244°.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:7][C:8]1[S:9][C:10](Cl)=[N:11][N:12]=1>C(O)C>[NH2:7][C:8]1[S:9][C:10]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[N:11][N:12]=1
Reactant: C1COCCN1
Reactant: Nc1nnc(Cl)s1
Solvent: CCO
Product: Nc1nnc(N2CCOCC2)s1
Temperature: 40 °C

Procedure:
Morpholine (200 μl) was added to a solution of 2-amino-5-chloro-1,3,4-thiadiazole (60 mg) in ethanol (2 ml) and the mixture heated in a sealed vial at 40° C. for 6 hours. The ethanol was evaporated from the cooled reaction under vacuum, the residue diluted with water and filtered. The filtrate was extracted with ethyl acetate (x2), the extracts dried (MgSO4) and the solvent removed under vacuum to give 2-amino-5-morpholinyl-1,3,4-thiadiazole.