Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[C:9]([O:13][C:14]([CH:16]1[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].[CH3:19][Si:20]([C:23]#[C:24][CH2:25]Br)([CH3:22])[CH3:21].CN1C(=O)N(C)CCC1>C1COCC1>[C:9]([O:13][C:14]([C:16]1([CH2:25][C:24]#[C:23][Si:20]([CH3:22])([CH3:21])[CH3:19])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: C[Si](C)(C)C#CCBr
Reactant: CC(C)(C)OC(=O)C1CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: CC(C)(C)OC(=O)C1(CC#C[Si](C)(C)C)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 14.0 ml (2.0 M in THF/n-heptane/ethylbenzene, 28 mmol) LDA in 100 ml THF was treated during 15 min at −78° C. with 2.84 g (20 mmol) cyclopropanecarboxylic acid tert-butyl ester in 20 ml THF. After 6 h at −78° C., a solution of 3-(trimethylsilyl) propargyl bromide and 29 ml DMPU in 40 ml THF was added during 20 min. Over night, the solution was naturally warmed to room temperature, poured on ice/aqueous saturated NH4Cl solution and extracted with ether (three times). The organic phases were washed with aqueous 10% KHSO4, water (5×), aqueous 10% NaCl and dried (Na2SO4) to give 5.59 g of the title compound as volatile dark brown liquid.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[C:10](Cl)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:28]3[C:23](=[N:24][CH:25]=[N:26][C:27]=3[NH2:29])[N:22]([CH:30]3[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]3)[N:21]=2)=[CH:16][C:15]=1[O:37][CH3:38]>ClCCl.N1C=CC=CC=1>[NH2:29][C:27]1[N:26]=[CH:25][N:24]=[C:23]2[N:22]([CH:30]3[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]3)[N:21]=[C:20]([C:17]3[CH:18]=[CH:19][C:14]([NH:13][C:10]([C@@H:8]4[CH2:9][C@H:7]4[C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[O:11])=[C:15]([O:37][CH3:38])[CH:16]=3)[C:28]=12
Reactant: COc1cc(-c2nn(C3CCN(C)CC3)c3ncnc(N)c23)ccc1N
Reactant: O=C(Cl)[C@@H]1C[C@H]1c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(-c2nn(C3CCN(C)CC3)c3ncnc(N)c23)ccc1NC(=O)[C@@H]1C[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 88.7 %

Procedure:
trans-2-Phenyl-1-cyclopropanecarbonyl chloride (31 mg, 0.170 mmol) in dichloromethane (0.3 mL) was added to a solution of 3-(4-amino-3-methoxyphenyl)-1-(1-methyl-4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (60 mg, 0.17 mmol) in pyridine (1.2 mL) at 0° C. After 5 minutes, the ice-water bath was removed and the reaction mixture was stirred at room temperature for 1 hours then, more trans-2-Phenyl-1-cyclopropanecarbonyl chloride (15 mg, 0.083 mmol) was added. After 2 hours, the solvent was evaporated and the residue was purified by flash column chromatography using dichloromethane/methanol (95:5 to 70:30) as mobile phase to give N1-{4-[4-Amino-1-(1-methyl-4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-trans-2-phenyl-1-cyclopropanecarboxamide (75 mg, 89%). 1H NMR (CDCl3) δ 1.42 (m, 1H), 1.77 (m, 1H), 1.85 (m, 1H), 2.03 (m, 1H), 2.24 (m, 2H), 2.37 (s, 3H), 2.46 (m, 2H), 2.62 (m, 1H), 3.05 (m, 2H), 3.96 (s, 3H), 4.77 (m, 1H), 5.69 (s, 2H), 7.24 (m, 7H), 8.11 (s, 1H), 8.35 (m, 1H), 8.45 (d, J=8.38 Hz, 1H). LCMS (Thermoquest AQA single Quad MS, Finnigan HPLC-Column: Genesis, C18, 3 um, 33×4.6 mm. Eluents: 30% B/A to 95% B/A in 4.5 min. (B: acetonitrile, A: 50 mM ammonia acetate buffer, pH 4.5), 0.8 mL/min.): MH+=498.3, Rt=1.84 min.
Reaction SMILES: [NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:15]([Cl:19])=[CH:14][C:3]=1[C:4]([N:6]=[S:7]([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])=[O:5].C(=O)([O-])[O-].[K+].[K+].[Cl:26][C:27]1[C:28]([N:33]2[C:37]([C:38](Cl)=[O:39])=[CH:36][C:35]([C:41]([F:44])([F:43])[F:42])=[N:34]2)=[N:29][CH:30]=[CH:31][CH:32]=1.C(O)C>C1(C)C=CC=CC=1>[Cl:26][C:27]1[C:28]([N:33]2[C:37]([C:38]([NH:1][C:2]3[C:3]([C:4](=[O:5])[N:6]=[S:7]([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:9])[CH3:10])=[CH:14][C:15]([Cl:19])=[CH:16][C:17]=3[Cl:18])=[O:39])=[CH:36][C:35]([C:41]([F:44])([F:42])[F:43])=[N:34]2)=[N:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)S(=NC(=O)c1cc(Cl)cc(Cl)c1N)C(C)C
Reactant: O=C(Cl)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(C)S(=NC(=O)c1cc(Cl)cc(Cl)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl)C(C)C
Reaction time: 6 h
Yield: 60.2 %

Procedure:
To a solution of the above obtained solution of 2-amino-3,5-dichloro-N-(bis-2-propyl-λ4-sulfanylidene)benzamide (6.7 mL; ˜3.6 mmol) was added potassium carbonate (0.60 g, 4.3 mmol, 1.20 equiv) and a solution of 2-(3-chloro-2-pyridyl)-5-(trifluoromethyl)pyrazole-3-carbonyl chloride (1.34 g, 4.31 mmol, 1.20 equiv.) in toluene (10 mL) at room temperature. After 6 h at this temperature, the mixture poured onto water and treated with a small amount of ethanol under sonification. The resulting precipitate was collected by filtration, washed with water and diisopropyl ether and dried to obtain the title compound (1.29 g, 60%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[S:6][C:7]=1[C:8]([O:10]CC)=[O:9].[OH-].[Na+]>CO>[CH3:1][O:2][C:3]1[N:4]=[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[S:6][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: CCOC(=O)c1sc(-c2ccccc2)nc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1nc(-c2ccccc2)sc1C(=O)O
Temperature: 50 °C
Reaction time: 4 h
Yield: 102.1 %

Procedure:
To a solution (10 mL) of ethyl 4-methoxy-2-phenyl-1,3-thiazole-5-carboxylate (1.37 g) synthesized by a known method (WO2007/089031) in methanol was added 2N aqueous sodium hydroxide solution (3 mL) at room temperature, and the mixture was stirred at 50° C. for 4 hr. The reaction was quenched with 6N hydrochloric acid (1 mL), and the obtained crystals were collected by filtration. The obtained crystals were recrystallized from methanol and diisopropyl ether to give 4-methoxy-2-phenyl-1,3-thiazole-5-carboxylic acid (1.25 g, 100%) as white crystals.
Reaction SMILES: [C:1]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[Br:14])[C:6]1=[O:15])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].Cl>CO.O1CCCC1>[C:1]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[Br:14])[CH:6]1[OH:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C1Cc2c(Br)cccc2C1=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)C1Cc2c(Br)cccc2C1O

Procedure:
To a solution of 2-tert-butyl-4-bromo-1-indanone in a mixture of methanol (100 ml) and tetrahydrofuran (200 ml) was added sodium borohydride (1.58 g) at room temperature. After stirring at the same temperature, the reaction mixture was poured into dilute hydrochloric acid, and the aqueous layer was saturated with saline and extracted with ether. The organic layer was saturated with a saturated aqueous saline solution, dried over magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residual concentrate (7.49 g) thus obtained was used for the next reaction without further purification.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11](/[CH:15]=[C:16]3/[C:17](=[O:22])[NH:18][C:19](=[O:21])[S:20]/3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[C@@H:33]1([CH2:43]O)[C@@H:42]2[N:37]([CH2:38][CH2:39][CH2:40][CH2:41]2)[CH2:36][CH2:35][CH2:34]1>>[F:32][C:2]([F:31])([F:1])[C:3]1[CH:26]=[C:25]([C:27]([F:29])([F:28])[F:30])[CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11](/[CH:15]=[C:16]3/[C:17](=[O:22])[N:18]([CH2:43][C@H:33]4[C@@H:42]5[N:37]([CH2:38][CH2:39][CH2:40][CH2:41]5)[CH2:36][CH2:35][CH2:34]4)[C:19](=[O:21])[S:20]/3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Reactant: OC[C@H]1CCCN2CCCC[C@H]12
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)C(=O)N1C[C@@H]1CCCN2CCCC[C@H]12

Procedure:
(5Z)-5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(1S,9aR)-octahydro-2H-quinolizin-1-yl methyl]-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[2,4-bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 6) and [(1S,9aR)-octahydro-2H-quinolizin-1-yl]methanol following General Procedure J.
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[CH2:22][N:21]3[C:29]([C:32]([NH:34][CH2:35][C:36]4[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=4)=[O:33])=[CH:30][CH:31]=[C:20]3[CH2:19]2)=[O:17])=[CH:12][CH:11]=1)[CH3:3].C(=O)([O-])[OH:43].[Na+].ClC1C=C(C=CC=1)C(OO)=O>ClCCl>[OH:1][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:11]=[CH:12][C:13]([C:16]([N:18]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[CH2:22][N:21]3[C:29]([C:32]([NH:34][CH2:35][C:36]4[CH:37]=[N+:38]([O-:43])[CH:39]=[CH:40][CH:41]=4)=[O:33])=[CH:30][CH:31]=[C:20]3[CH2:19]2)=[O:17])=[CH:14][CH:15]=1)[CH3:3]
Reactant: O=C([O-])O
Reactant: CC(O)c1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: CC(O)c1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4ccc[n+]([O-])c4)n3Cc3ccccc32)cc1
Reaction time: 1 h
Yield: 6 %

Procedure:
To a solution of 10-{[2′-(1-hydroxyethyl)-1,1′-biphenyl-4-yl]carbonyl}-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Example 52 (0.500 g, 0.92 mmol) in dichloromethane (20 mL) was added saturated aqueous sodium hydrogencarbonate solution (20 mL) followed by 70% 3-chloroperoxybenzoic acid (909 mg, 3.69 mmol) and the biphasic mixture was stirred vigorously for 1 hour. The reaction was quenched by the addition of 5% aqueous sodium metabisulfite solution (20 mL), the mixture stirred vigorously for 5 minutes, then partitioned between ethyl acetate (100 mL) and 2 M sodium hydroxide (100 mL). The organic layer was separated, washed with 2 M sodium hydroxide (2×100 mL), water (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford a white solid. Purification by flash chromatography using a solvent gradient of 3 to 10% methanol in dichloromethane gave the title compound (31.1 mg, 6%) as a white solid, m.p. 213-215° C.
Reaction SMILES: C[Al](C)C.[CH3:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.[Si:13]([O:30][CH2:31][CH2:32][O:33][CH2:34][C@H:35]([O:40][C:41]1[N:46]=[CH:45][N:44]=[C:43]2[N:47]([C:50]3[CH:55]=[CH:54][CH:53]=[C:52]([Cl:56])[C:51]=3[CH3:57])[N:48]=[CH:49][C:42]=12)[C:36](OC)=[O:37])([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1C=CC=CC=1)[C:14]1C=CC=CC=1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[Si:13]([O:30][CH2:31][CH2:32][O:33][CH2:34][C@H:35]([O:40][C:41]1[C:42]2[CH:49]=[N:48][N:47]([C:50]3[CH:55]=[CH:54][CH:53]=[C:52]([Cl:56])[C:51]=3[CH3:57])[C:43]=2[N:44]=[CH:45][N:46]=1)[C:36]([NH:12][C:9]1[CH:8]=[CH:7][C:6]([CH3:5])=[CH:11][N:10]=1)=[O:37])([C:26]([CH3:27])([CH3:28])[CH3:29])([CH3:20])[CH3:14]
Reactant: COC(=O)[C@H](COCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)Oc1ncnc2c1cnn2-c1cccc(Cl)c1C
Reactant: Cc1ccc(N)nc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1ccc(NC(=O)[C@H](COCCO[Si](C)(C)C(C)(C)C)Oc2ncnc3c2cnn3-c2cccc(Cl)c2C)nc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 113 %

Procedure:
A solution of 2M trimethyl aluminium in toluene (1.790 mL, 3.58 mmol) in toluene (15 mL) was added dropwise to a stirred suspension of 5-methylpyridin-2-amine (0.387 g, 3.58 mmol) in toluene (15 mL) cooled to 0° C., over a period of 2 minutes under nitrogen and the resulting suspension was stirred at 0° C. for 20 minutes. A solution of (2S)-methyl 3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-(1-(3-chloro-2-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanoate (Intermediate AE2) (1.05 g, 1.63 mmol) in toluene (10 mL) was added dropwise over 2 minutes, the mixture allowed to warm to ambient temperature and then heated to 60° C. for 20hrs. The reaction was cooled to ˜5° C. and a 10% solution of Rochelles salt (25 mL) added followed by ethyl acetate (30 mL). The organic phase was separated, washed with water (20 mL) and brine (20 mL), dried (MgSO4), filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 20 to 50% EtOAc in iso-hexane to afford the product (1.1 g, 94%). 1H NMR (400 MHz, DMSO) δ 0.89 (9H, s), 2.03 (3H, s), 2.24 (3H, s), 3.70-3.79 (4H, m), 4.03-4.07 (1H, m), 4.12-4.16 (1H, m), 5.99-6.00 (1H, m), 7.33-7.47 (8H, m), 7.55-7.62 (5H, m), 7.67-7.69 (1H, m), 7.86-7.89 (1H, m), 8.17-8.18 (1H, m), 8.50 (1H, s), 8.53 (1H, s), 10.87 (1H, s); m/z (ESI+) (M+H)+=721; HPLC tR=3.63 min.
Reaction SMILES: O(CC(C)CCCC(C)=CC[Br:27])[Si](C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:30]([O:37][CH2:38][CH:39]([CH3:48])[CH2:40][CH2:41][CH2:42][C:43]([CH3:47])(O)[CH:44]=[CH2:45])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:30]([O:37][CH2:38][CH:39]([CH3:48])[CH2:40][CH2:41][CH2:42][C:43]([CH3:47])=[CH:44][CH2:45][Br:27])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: C=CC(C)(O)CCCC(C)COCc1ccccc1
Reactant: CC(=CCBr)CCCC(C)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Product: CC(=CCBr)CCCC(C)COCc1ccccc1
Yield: 90 %

Procedure:
Following the procedure for the synthesis of 8-t-butyldiphenylsiloxy-1-bromo-3,7-dimethyl-oct-2-ene, treatment of 8-benzyloxy-3,7-dimethyl-1-octen-3-ol (0.605 g) gives 8-benzyloxy-1-bromo-3,7-dimethyl-oct-2-ene (0.675 mg, 90% yield, 7:3 E:Z).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[CH3:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](O)=[O:28]>>[CH3:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27]([O:23][C@@:9]1([C:14]#[C:15][C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)[CH2:10][CH2:11][CH2:12][C@@H:13]2[C@H:8]1[CH2:7][CH2:6][N:5]2[C:3]([O:2][CH3:1])=[O:4])=[O:28]
Reactant: Cc1ccccc1C(=O)O
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC(=O)c1ccccc1C

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and 2-methyl-benzoic acid to yield (3aR,4S,7aR)-methyl 4-(2-methylbenzoyloxy)-4-(m-tolylethynyl)octahydro-1H-indole-1-carboxylate. MS [M+H]=296 (ester eliminated ion); RT=4.217 min; HPLC Method III
Reaction SMILES: [CH2:1]([C:3]1[S:29][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:27]#[N:28])=[CH:22][CH:23]=[C:24]([CH3:26])[CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[NH:9][C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Br[CH2:31][C:32]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)=[O:33].CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[CH2:1]([C:3]1[S:29][C:6]2[N:7]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([C:20]4[C:21]([C:27]#[N:28])=[CH:22][CH:23]=[C:24]([CH3:26])[CH:25]=4)=[CH:18][CH:19]=3)[C:8](=[O:12])[N:9]([CH2:31][C:32]([C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)=[O:33])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4cc(C)ccc4C#N)cc3)c2s1
Reactant: COc1ccc(C(=O)CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1cc2c(=O)n(CC(=O)c3ccc(OC)cc3)c(=O)n(Cc3ccc(-c4cc(C)ccc4C#N)cc3)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.8 %

Procedure:
To a mixture of 4′-[(6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)methyl]-5-methylbiphenyl-2-carbonitrile (2 g), 2-bromo-1-(4-methoxyphenyl)ethanone (1.4 g) and N,N-dimethylformamide (19 mL) was added 60% sodium hydride (0.3 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% potassium hydrogensulfate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (1.2 g, 80%).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[N:9][N:10]([CH:12]3[CH2:29][CH:28]4[N:14]([C:15](=[O:35])[N:16]([CH3:34])[CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[CH:22][CH:23]5[C:25]([C:31](O)=[O:32])([NH:26][C:27]4=[O:30])[CH2:24]5)[CH2:13]3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:48]1([S:51]([NH2:54])(=[O:53])=[O:52])[CH2:50][CH2:49]1.C1CCN2C(=NCCC2)CC1>C1COCC1>[C:1]1([C:7]2[N:8]=[N:9][N:10]([CH:12]3[CH2:29][CH:28]4[N:14]([C:15](=[O:35])[N:16]([CH3:34])[CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[CH:22][CH:23]5[C:25]([C:31]([NH:54][S:51]([CH:48]6[CH2:50][CH2:49]6)(=[O:53])=[O:52])=[O:32])([NH:26][C:27]4=[O:30])[CH2:24]5)[CH2:13]3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN1CCCCC=CC2CC2(C(=O)O)NC(=O)C2CC(n3nnc(-c4ccccc4)n3)CN2C1=O
Reactant: NS(=O)(=O)C1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CN1CCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(n3nnc(-c4ccccc4)n3)CN2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 9 (50 mg, 0.104 mmol) and CDI (68 mg, 0.418 mmol) in dry THF (5 mL) is heated at reflux for 2 h under nitrogen. The reaction mixture is cooled to room temperature and cyclopropylsulfonamide (101 mg, 0.836 mmol) is added. Then, DBU (73 mg, 0.481 mmol) is added and the reaction mixture is stirred at room temperature for 1 h, and then heated at 55° C. for 24 h. Solvent is evaporated, and the residue partitioned between AcOEt and acidic water (pH=3). The crude material is purified by column chromatography (AcOEt/CH2Cl2/Petroleum ether, 1:1:1). The residue is crystallized in Et2O, filtered to give the target compound contaminated with the cyclopropylsulfonamide. This material is triturated in 1.5 mL of water, filtered, washed with water and dried overnight in the high vacuum pump to give the target compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]([NH:11][NH2:12])=O)[CH2:4][CH2:3]1.[F:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=1)[CH2:17][N:18]=[C:19]=[S:20]>C(O)C>[SH:20][C:19]1[N:18]([CH2:17][C:16]2[CH:21]=[CH:22][CH:23]=[C:14]([F:13])[CH:15]=2)[C:9]([CH2:8][N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[N:11][N:12]=1
Reactant: Fc1cccc(CN=C=S)c1
Reactant: CN1CCN(CC(=O)NN)CC1
Solvent: CCO
Product: CN1CCN(Cc2nnc(S)n2Cc2cccc(F)c2)CC1

Procedure:
A solution of 2-(4-methyl-1-piperazinyl)acetic acid, hydrazide (2.58 g., 0.015 mole) and 3-fluorobenzylisothiocyanate (2.51 g., 0.015 mole) in ethanol (30 ml.) was refluxed for 17 hours and the solvent was removed under vacuum. The residue was triturated with ether and the resulting solid was filtered and recrystallized from ethyl acetate to give 3-mercapto-4-(3-fluorobenzyl)-5-[(4-methyl-1-piperazinyl)methyl]-1,2,4-triazole as a solid melting at 179.5°-180.5° C. (2.30 g., 48%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])#[N:2].Br[CH2:11][CH2:12][CH2:13][Cl:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(Cl)(Cl)Cl>[Cl:14][CH2:13][CH2:12][CH2:11][O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: N#Cc1ccccc1O
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Product: N#Cc1ccccc1OCCCCl
Yield: 97.5 %

Procedure:
A mixture of 2-cyanophenol (50.0 g, 0.42 mole), 1-bromo-3-chloropropane (67.7 g, 0.43 mole), and potassium carbonate (58.0 g, 0.42 mole) was heated overnight at gentle reflux in 500 ml of acetone. The reaction mixture was stripped to dryness and the residue was dissolved in chloroform. The chloroform layer was extracted several times with 5% sodium hydroxide. The chloroform layer was dried (anhydrous sodium sulfate), filtered, and the solvent was removed, to give a brown oil (80.09 g). A ten gram portion of this oil was subjected to flash chromatography on silica gel with 10% ethyl acetate-hexanes and 20% ethyl acetate-hexanes used for elution. Fractions were combined and solvent removed in vacuo. The clear oil obtained was dried 18 hrs in vacuo at room temperature and 8 hrs at 80° C. in vacuo. This furnished 5.24 g (50.0% yield--based on aliquot taken) of clear oil. 1H HMR (CDCl3); δ 2.1-2.5 (q, 2, --CH2), 3.8 (t, 2, --ClCH2), 4.2 (t, 2, --OCH2), 6.9 (m, 2, aromatic protons ortho and para to ether), 7.5 (m, 2, aromatic protons ortho and para to CN group).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:7]([CH3:18])([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[CH3:8])=[N:5][N:6]=1>CCOC(C)=O.[Pd]>[CH3:1][C:2]1[O:3][C:4]([C:7]([CH3:18])([C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=2)[CH3:8])=[N:5][N:6]=1
Reactant: Cc1nnc(C(C)(C)c2ccc([N+](=O)[O-])cc2)o1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1nnc(C(C)(C)c2ccc(N)cc2)o1
Reaction time: 16 h

Procedure:
A mixture of 2-methyl-5-[1-methyl-1-(4-nitro-phenyl)-ethyl]-[1,3,4]oxadiazole (1.36 g, 5.5 mmol.) and Pd/C (68 mg) in EtOAc (50 mL), was stirred under 1 atm of H2 for 16 h. The resultant was filtered over Celite®, and the filtrate was concentrated to give the titled compound as a pale yellow crystalline. MS: 218 (M+1) calc'd for C12H16N3O—218.12.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][OH:7])[CH2:2]1.C(N(CC)CC)C.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>ClCCl>[CH3:25][C:15]1[CH:20]=[CH:19][C:18]([S:21]([O:7][CH2:6][CH:3]2[CH2:4][CH2:5][O:1][CH2:2]2)(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2CCOC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.8 %

Procedure:
To a solution of (tetrahydrofuran-3-yl)methanol (5.15 g, 50.4 mmol) in dichloromethane (200 mL) were added triethylamine (21.08 mL, 151 mmol) and p-toluenesulfonyl chloride (9.61 g, 50.4 mmol) and the mixture was stirred at room temperature overnight. The reaction mixture was washed with water (100 mL) and brine (100 mL). The organic layer was dried with sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-40% ethyl acetate in hexane) to provide the title compound (12.5 g, 97%) as colorless viscous liquid. 1H NMR (300 MHz, DMSO-D6) δ ppm 1.40-1.51 (m, 1H) 1.83-1.95 (m, 1H) 2.43 (s, 3H) 3.28-3.31 (m, 1H) 3.31-3.37 (m, 1H) 3.51-3.67 (m, 3H) 3.90-4.00 (m, 2H) 7.48-7.51 (m, 2H) 7.78-7.82 (m, 2H); MS (DCI/NH3) m/z 274 (M+NH4)+.