Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:10][C:5]=2[C:4](=[O:17])[N:3]1[CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1.Cl[CH2:32][C:33]1[N:34]=[C:35]([CH3:38])[S:36][CH:37]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:38][C:35]1[S:36][CH:37]=[C:33]([CH2:32][N:7]2[C:6]3[CH:8]=[C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[S:10][C:5]=3[C:4](=[O:17])[N:3]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[C:2]2=[O:1])[N:34]=1
Reactant: Cc1nc(CCl)cs1
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3cc(-c4ccccc4)sc3c2=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)cs1

Procedure:
According to GP1 tert-butyl 4-(2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl)piperidine-1-carboxylate (855 mg; compound B50) is reacted with 4-(chloromethyl)-2-methyl-1,3-thiazole (295 mg; compound D10) in the presence of potassium carbonate (276 mg) in DMF (15 ml). Using WU1 the title compound is obtained as a solid.
Reaction SMILES: [C:1]([C:4](=[CH:10]OCC)[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=O)[CH3:2].[NH2:14][C:15]([S:17][CH3:18])=[NH:16].C(N(CC)CC)C>CCO>[CH2:8]([O:7][C:5]([C:4]1[C:1]([CH3:2])=[N:14][C:15]([S:17][CH3:18])=[N:16][CH:10]=1)=[O:6])[CH3:9]
Reactant: CSC(=N)N
Reactant: CCOC=C(C(C)=O)C(=O)OCC
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnc(SC)nc1C
Yield: 81 %

Procedure:
Equimolar quantities of ethyl 2-acetyl-3-ethoxy-2-propenoate 1 (20.0 g, 107 mmol), ((amino(imino)methyl)-sulfanyl)methane 2 (9.68 g, 107 mmol) and triethylamine (10.8 g, 107 mmol) in EtOH (100 mL) were stirred at reflux for 48 hours. Then reaction mixture was concentrated and diluted with water. The biphasic mixture was transferred into a separatory funnel and extracted with DCM. Organic extract was washed with water, dried, filtered, and concentrated. The product was purified by crystallization from ethanol/water to yield in a colorless solid (18.4 g, 86.7 mmol, 81%).
Reaction SMILES: FC1C(O[C:9](=[O:15])[CH2:10][S:11][C:12](=[O:14])[CH3:13])=C(F)C(F)=C(F)C=1F.[NH2:20][C@H:21]([C:30]([OH:32])=[O:31])[CH2:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26].C(N(CC)CC)C>ClCCl>[C:25]([O:24][C:23](=[O:29])[CH2:22][CH:21]([NH:20][C:9](=[O:15])[CH2:10][S:11][C:12](=[O:14])[CH3:13])[C:30]([OH:32])=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)C[C@H](N)C(=O)O
Reactant: CC(=O)SCC(=O)Oc1c(F)c(F)c(F)c(F)c1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)SCC(=O)NC(CC(=O)OC(C)(C)C)C(=O)O
Reaction time: 3.5 h
Yield: 121.7 %

Procedure:
Acetylsulfanyl-acetic acid pentafluorophenyl ester (1.6 g, 5.3 mmol) and H-Asp(OtBu)-OH (1 g, 5.3 mmol) were mixed in 20 ml of dry dichloromethane (DCM). Then 1.6 ml of triethylamine (11.5 mmol) was added, and the reaction was allowed to proceed at ambient temperature for 3.5 hours. The organic layer was then extracted with 3×15 ml of 1 M sodium carbonate, the combined aqueous fractions were acidified with 100 ml of 1 M sodium hydrogensulfate and extracted with 3×30 ml ethyl acetate. The combined organic fractions were then rinsed with 30 ml of 1 M sodium hydrogensulfate, 30 ml of 5 M NaCl, dried over sodium sulfate, filtered, and evaporated under reduced pressure to yield 1.97 g of 24 as a nearly colorless syrup which was used without further purification. MW=305 (found 306, M+1).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:8])[C@@H:5]([CH3:7])[NH2:6].CN1CCOCC1.[CH2:16]([O:23][C:24]([NH:26][C@H:27]([C:35](O)=[O:36])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1.C(O)(=O)C>[CH3:2][O:3][C:4](=[O:8])[C@@H:5]([CH3:7])[NH:6][C:35](=[O:36])[C@H:27]([CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[NH:26][C:24]([O:23][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:25]
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: COC(=O)[C@@H](C)N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COC(=O)[C@@H](C)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Reaction time: 0.25 h

Procedure:
First benzyloxycarbonyl-L-phenylalanyl-D-alanine methyl ester was prepared, as follows. A solution of 0.56 g of D-alanine methyl ester hydrochloride in 6 ml tetrahydrofuran was cooled to 0° C. and then treated with 0.53 ml of N-methylmorpholine. After 15 min of stirring, 1.20 g of benzyloxycarbonyl-L-phenylalanine and 1.08 g of 1-hydroxybenzotriazole were added. A cold solution of 0.99 g of N, N'-dicyclohexylcarbodiimide in 2 ml tetrahydrofuran was then added and the mixture stirred for 1 hour at 0° C., then overnight at room temperature. After adding 0.3 ml of glacial acetic acid, the mixture was stirred 5 min., filtered, and the filtrate concentrated in vacuo to dryness. The residue was dissolved in CHCl3, washed 3 times with 5% aqueous NaHCO3, dried over anhydrous Na2SO4, and the solvent removed in vacuo. The residue was purified by silica gel column chromatography (silica 60 g) using CHCl3 followed by CHCl3 -acetone 10:1 as eluant. Appropriate fractions were pooled and the solvent removed in vacuo to obtain 0.74 g of white solid, m.p. 134-136 C. TLC on silica gel using an eluant of 10 acetone gave Rf =0.37.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14](Cl)[C:15]([OH:17])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4].[CH2:21](Br)[CH:22]=[CH2:23].C1CCN2C(=NCCC2)CC1.[Cl:36]CCl>CCOC(C)=O>[F:1][C:2]([F:20])([F:19])[C:3]([N:5]1[CH2:11][C:10]([Cl:36])([CH3:12])[C:9]2[CH:13]=[CH:14][C:15]([O:17][CH2:21][CH:22]=[CH2:23])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: C=CCBr
Reactant: CC1CN(C(=O)C(F)(F)F)CCc2cc(O)c(Cl)cc21
Reactant: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: C=CCOc1ccc2c(c1)CCN(C(=O)C(F)(F)F)CC2(C)Cl
Reaction time: 2 h

Procedure:
A solution of N-trifluoroacetyl-8-chloro-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (24 mg, 0.078 mmol) in dichloromethane (2 mL) was treated with allyl bromide (18 mg, 0.15 mmol), DBU (23 mg, 0.15 mmol) and stirred 2 hours at 20 C. The product mixture was diluted with EtOAc (10 mL), washed with 5% aqueous HCl (5 mL), brine (5 mL), dried with Na2SO4 and concentrated. Flash chromatography (15% EtOAc in hexane, silica) resulted in 23 mg of a white solid. MS calculated for C16H17ClF3NO2+H: 348, observed: 348.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]3[O:18][CH2:17][CH2:16][C:15]([C:19]([O:21]CC)=[O:20])=[CH:14][C:13]=3[CH:24]=2)=[CH:5][CH:4]=1.[OH-].[Na+]>C(O)C.O1CCCC1>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]3[O:18][CH2:17][CH2:16][C:15]([C:19]([OH:21])=[O:20])=[CH:14][C:13]=3[CH:24]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)C1=Cc2cc(-c3ccc(SC)cc3)ccc2OCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CSc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCO3)cc1
Reaction time: 20 h
Yield: 93.3 %

Procedure:
To a solution of ethyl 7-(4-methylthiophenyl)-2,3-dihydro-1-benzoxepine-4-carboxylate (132 mg) in ethanol-tetrahydrofuran (5 ml-5 ml) was added 1N sodium hydroxide (1.0 ml) at room temperature, and the mixture was stirred for 20 hours and concentrated under reduced pressure. To the residue was added 1N hydrochloric acid (2 ml) and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The resulting crystal was collected by filtration to give 7-(4-methylthiophenyl)-2,3-dihydro-1-benzoxepine-4-carboxylic acid (113 mg) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16](I)[S:17][C:13]=2[N:12]2[C:19]([CH3:22])=[N:20][N:21]=[C:11]2[CH2:10][N:9]=1.[CH2:23]([N:26]1[C:38]2[CH2:37][CH2:36][CH2:35][CH2:34][C:33]=2[C:32]2[C:27]1=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:24]#[CH:25].C(O)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:25]#[C:24][CH2:23][N:26]3[C:38]4[CH2:37][CH2:36][CH2:35][CH2:34][C:33]=4[C:32]4[C:27]3=[CH:28][CH:29]=[CH:30][CH:31]=4)[S:17][C:13]=2[N:12]2[C:19]([CH3:22])=[N:20][N:21]=[C:11]2[CH2:10][N:9]=1
Reactant: Cc1nnc2n1-c1sc(I)cc1C(c1ccccc1Cl)=NC2
Reactant: C#CCn1c2c(c3ccccc31)CCCC2
Solvent: ClCCl
Solvent: CCO
Product: Cc1nnc2n1-c1sc(C#CCn3c4c(c5ccccc53)CCCC4)cc1C(c1ccccc1Cl)=NC2

Procedure:
The title compound was obtained by coupling 4-(2-chlorophenyl)-2-iodo-9-methyl-6H-thieno-[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine with 1,2,3,4-tetrahydro-9(2-propynyl)-9H-carbazole under the conditions used in Example 37. The product was isolated by chromatography over the 50-fold amount of silica gel using 8 % (v/v) of ethanol in methylene chloride for elution. The residue obtained after evaporation of the combined clean fractions containing product was crystallized from ethanol to give colorless crystals of 4-(2-chlorophenyl)-2-[3-(1,2,3,4-tetrahydro 9H-carbazol-9-yl)-1-propynyl]-9-methyl-6H-thieno-[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine with m.p. 164°-166°. These crystals contained 0.66 molar amounts of ethanol according to analytical and spectral data.
Reaction SMILES: [K].[N+:2]([C:5]1[CH:6]=[C:7]([OH:13])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1)([O-:4])=[O:3].BrC[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].[CH3:23]N(C=O)C>>[CH3:23][O:13][C:7]1[CH:6]=[C:5]([N+:2]([O-:4])=[O:3])[CH:10]=[CH:9][C:8]=1[O:11][CH2:12][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COc1ccc([N+](=O)[O-])cc1O
Agent: [K]
Product: COc1cc([N+](=O)[O-])ccc1OCC(=O)OC(C)(C)C
Yield: 88 %

Procedure:
A solution of 4-nitroguaiacol potassium salt (613 mg; 2.96 mmol) and t-butyl bromoacetate (0.65 mL; 4.43 mmol) in DMF (7 mL) was stirred at rt for 0.5 h prior to dilution with H2O and extraction with EtOAc. The organic layer was washed with H2O, dried over MgSO4, filtered and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, Hexanes/EtOAc, 100:0 to 1:1 gradient) to afford the title compound (738 mg; 88%) as a beige solid. 1H NMR (CDCl3) δ 1.46 (s, 9H), 3.96 (s, 3H), 4.67 (s, 2H), 6.77 (d, J=8.79 Hz, 1H), 7.76 (d, J=2.74 Hz, 1H), 7.85 (dd, J=8.80 Hz, 2.75 Hz, 1H); 13C NMR (CDCl3) δ 27.98, 56.37, 66.18, 83.09, 107.07, 111.52, 117.28, 142.17, 149.19, 152.69, 166.66; HPLC (Method #1): 3.13 min retention time, (97%); MS (ES): m/z 306 [M+Na]+.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:12]O)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Br)(Br)[Br:15]>ClCCl>[Br:15][CH2:12][C:9]1[S:10][CH:11]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=1
Reactant: BrP(Br)Br
Reactant: OCc1nc(-c2ccccc2)cs1
Solvent: ClCCl
Product: BrCc1nc(-c2ccccc2)cs1
Temperature: 22 °C
Reaction time: 0.17 h
Yield: 177 %

Procedure:
A solution of (4-phenylthiazol-2-yl)methanol (Example 4C, 0.530 g, 2.77 mmol) in dichloromethane (10 mL) was cooled to 0° C. (ice bath) and treated with PBr3 (0.118 mL, 1.247 mmol) added dropwise over 2 min. A heavy white gum was immediately formed. After 10 min, the bath was removed and the solution was stirred at 22° C. for 4 h. The reaction mixture was quenched with ice (˜10 g) and poured into a mixture of ethyl acetate (150 mL) and saturated sodium bicarbonate (50 mL). The organic phase was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The solid residue was chromatographed on silica gel (2.5×6 cm, elution toluene) to give the title material (0.561 g, 80%) as a light yellow oil which solidified in the fridge to a pale yellow solid. LC (Method C): 2.062 min. HRMS (ESI) calcd for C10H9BrNS [M+H]+ m/z 253.9634, found 253.9655. 1H NMR (CDCl3, 400 MHz) δ ppm: 4.81 (s, 2H), 7.34-7.39 (m, 1H), 7.41-7.47 (m, 2H), 7.52 (s, 1H), 7.86-7.92 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[C:13]([S:16][CH3:17])[N:14]=[CH:15][C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([C:18]([O:20][CH3:21])=[O:19])=[CH:5][C:4]=2[N:3]=1.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>CN1C(=O)CCC1>[CH3:17][S:16][C:13]1[N:14]=[CH:15][C:10]2[C:9]3[CH:8]=[CH:7][C:6]([C:18]([O:20][CH3:21])=[O:19])=[CH:5][C:4]=3[N:3]=[C:2]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:11]=2[N:12]=1
Reactant: Nc1ccccc1
Reactant: COC(=O)c1ccc2c(c1)nc(Cl)c1nc(SC)ncc12
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)c1ccc2c(c1)nc(Nc1ccccc1)c1nc(SC)ncc12
Temperature: 120 °C

Procedure:
methyl 5-chloro-3-(methylthio)pyrimido[4,5-c]quinoline-8-carboxylate (1.0 eq, 182 mg, 0.57 mmol) was mixed with aniline (0.5 ml) in NMP (1 ml). The mixture was heated under microwave for 10 minutes at 120° C. Water was added and the resulting solid was filtered and dried. The compound was triturated in EtOAc and hexanes and filtered to afford methyl 3-(methylthio)-5-(phenylamino)pyrimido[4,5-c]quinoline-8-carboxylate as a yellow solid. LCMS (ES): >95% pure, m/z 377 [M+1]+. This material was suspended in CH2Cl2 (4 ml) and meta-chloroperbenzoic acid (77% pure, 2.5 eq, 165 mg, 0.737 mmol) was added in small portions. After one hour, an additional amount (100 mg) of mcpba was added and the mixture stirred for 1.5 hours. After addition of more CH2Cl2, the organic phase was washed with water (4×), dried over Na2SO4 and the solution was filtered through a pad of silica gel, eluting with a MeOH/CH2Cl2 mixture. After evaporation of the solvents, methyl 3-(methylsulfonyl)-5-(phenylamino)pyrimido[4,5-c]quinoline-8-carboxylate was isolated as a yellow solid (166 mg, 72% yield). LCMS (ES): >95% pure, m/z 409 [M+1]+, 1H NMR (DMSO-d6, 400 MHz) δ 3.77 (s, 3H), 3.93 (s, 3H), 7.15 (t, J=7.2, 1H), 7.45 (t, J=7.6, 2H), 7.99 (dd, J=2.0, J=8.4, 1H), 8.16 (d, J=7.6, 2H), 8.28 (d, J=2.0, 1H), 8.89 (d, J=8.8, 1H), 9.76 (s, 1H), 10.61 (s, 1H) ppm.
Reaction SMILES: [C:1]([C:3]1[CH:7]=[N:6][NH:5][C:4]=1[NH2:8])#[N:2].CN(C)[CH:11]=[CH:12][C:13]([C:15]1[CH:16]=[C:17]([N:21]([CH3:31])[S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH:18]=[CH:19][CH:20]=1)=O.C(OCC)(=O)C>C(O)(=O)C>[C:1]([C:3]1[CH:7]=[N:6][N:5]2[C:13]([C:15]3[CH:16]=[C:17]([N:21]([CH3:31])[S:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)(=[O:24])=[O:23])[CH:18]=[CH:19][CH:20]=3)=[CH:12][CH:11]=[N:8][C:4]=12)#[N:2]
Reactant: N#Cc1cn[nH]c1N
Reactant: CN(C)C=CC(=O)c1cccc(N(C)S(=O)(=O)c2ccccc2)c1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CN(c1cccc(-c2ccnc3c(C#N)cnn23)c1)S(=O)(=O)c1ccccc1
Yield: 42.5 %

Procedure:
A mixture of 0.134 g (1.24 mmol) of 4-cyano-2H-pyrazol-3-ylamine and 0.43 g (1.24 mmol) of N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-methyl-benzenesulfonamide in 10 ml of glacial acetic acid was refluxed for 8 hours and then the solvent was removed by reduced pressure distillation. To the resulting residue were added 10 ml of dichloromethane and 10 ml of saturated sodium bicarbonate solution. The two layers were separated, and the aqueous layer was washed with 10 ml of dichloromethane. The organic layers were washed with 10 ml of water and dried over magnesium sulfate. The dichloromethane layer was evaporated to dryness to yield an oil which, in the presence of ethyl acetate, gave 205 mg of N-[3-(3-cyano-pyrazolo[1,5-a]pyrimidin-7-yl)-phenyl]-N-methyl-benzenesulfonamide as a yellow solid (yield 42%).
Reaction SMILES: [OH-].[Na+:2].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([OH:13])(=[O:12])=[O:11])=[CH:6][C:5]=1[I:14].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O.S(=O)(=O)(O)O>C(O)(C)C>[CH2:15]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([O-:13])(=[O:11])=[O:12])=[CH:6][C:5]=1[I:14])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Na+:2]
Reactant: O=S(=O)(O)c1ccc(O)c(I)c1
Reactant: BrCc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: O=S(=O)([O-])c1ccc(OCc2ccccc2)c(I)c1
Temperature: 84 °C
Reaction time: 0.21 h

Procedure:
Sodium hydroxide (pellets, 110 g, 2.75 mol, 3.00 eq) was added portionwise to the vigorously stirring aqueous solution of the 4-hydroxy-3-iodo-benzenesulfonic acid. After addition was complete, 10-15 min., isopropyl alcohol (150 mL) was added to the resulting white suspension. The dropping-funnel was charged with benzyl bromide (Aldrich; 164.9 g, 0.964 mol, 1.05 eq.) and added to the reaction mixture over a period of approx. 5 mins. and the reaction mixture was heated to 80°≦Tint≦84° C. After approx. 25 min. it was determined that the reaction was not proceeding further and therefore additional sodium hydroxide (3.67 g, 91.8 mmol, 0.1 eq.) and then benzyl bromide (15.7 g, 91.8 mmol, 0.1 eq.) were added to the reaction mixture to give a homogenous solution. After 70 min. from the original benzyl bromide addition, the heating was stopped and the reaction was allowed to cool slowly in the oil-bath with stirring. At 7.5 h, the reaction mixture appeared as a suspension of fine-reflective precipitate in brown liquid. The reaction mixture was acidified with 3:1 water-sulfuric acid from about pH 13 to between pH 7.5 and 8 (approx. 70 mL is required). The reaction mixture was then cooled gradually to about 5° C. and stirred at that temperature for ˜1 h. The waxy white plaques were collected by filtration, washed with dichloromethane and dried under high vacuum (lyophilizer, 100-200 mTorr) for ˜24 h to give sodium 4-benzyloxy-3-iodo-benzenesulfonate as a brilliant white, crystalline solid, (267.7 g, 71%).
Reaction SMILES: Br[C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].[N:17]1[NH:18][N:19]=[CH:20][CH:21]=1>CN(C=O)C>[CH3:8][C:6]1[CH:7]=[C:2]([N:18]2[N:19]=[CH:20][CH:21]=[N:17]2)[C:3]([C:9]#[N:10])=[N:4][CH:5]=1.[CH3:8][C:6]1[CH:7]=[C:2]([N:17]2[CH:21]=[CH:20][N:19]=[N:18]2)[C:3]([C:9]#[N:10])=[N:4][CH:5]=1
Reactant: Cc1cnc(C#N)c(Br)c1
Reactant: c1cn[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cnc(C#N)c(-n2ccnn2)c1
Product: Cc1cnc(C#N)c(-n2nccn2)c1
Temperature: 100 °C
Yield: 27 %
Yield: 35 %

Procedure:
To 3-bromo-5-methylpicolinonitrile (1.5 g, 7.6 mmol) in DMF (19 mL) was added K2CO3 (1.2 g, 8.4 mmol) and 2H-1,2,3-triazole (440 μL, 7.6 mmol). The mixture was heated to 100° C. for 16 h, cooled to rt and extracted with EtOAc (2×). The combined organics were dried (Na2SO4) and concentrated. Purification via silica gel chromatography (5-60% EtOAc in hexanes) gave the title compound (490 mg, 35%) 1H NMR (500 MHz, CDCl3) 8.58-8.53 (m, 1H), 8.29-8.24 (m, 1H), 7.98 (s, 2H), 2.54 (s, 3H) and 5-methyl-3-(1H-1,2,3-triazol-1-yl)picolinonitrile (387 mg, 27%).
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:7]=2[CH:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[NH:5][CH2:4][C:3]1=[O:20].[O-2].[Mg+2].[CH3:23][N:24]1[C:30]2[CH:31]=[CH:32][C:33]([Cl:35])=[CH:34][C:29]=2[CH:28]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:27]([C:42](Cl)=[O:43])[CH2:26][C:25]1=[O:45]>C(Cl)(Cl)Cl>[CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:7]=2[CH:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:5]([C:42]([N:27]2[CH:28]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:29]3[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:30]=3[N:24]([CH3:23])[C:25](=[O:45])[CH2:26]2)=[O:43])[CH2:4][C:3]1=[O:20]
Reactant: CN1C(=O)CN(C(=O)Cl)C(c2ccccc2)c2cc(Cl)ccc21
Reactant: CN1C(=O)CNC(c2ccccc2)c2cc(Cl)ccc21
Agent: [Mg+2]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CN1C(=O)CN(C(=O)N2CC(=O)N(C)c3ccc(Cl)cc3C2c2ccccc2)C(c2ccccc2)c2cc(Cl)ccc21
Yield: 66.2 %

Procedure:
1 g. of 1-methyl-5-phenyl-7-chloro-1,3,4,5-tetrahydro-2H-1,4-benzodiazepine-2-one and 1 g. of magnesium oxide are added to a solution of 0.8 g. (2.29 mmoles) of 1-methyl-4-chlorocarbonyl-5-phenyl-7-chloro-1,3,4,5-tetrahydro-2H-1,4-benzodiazepine-2-one in 10 ml. of chloroform, and the mixture is stirred at 40° C. overnight. Thereafter the inorganic salts are filtered off, washed with 10 ml. of chloroform, and the chloroform solution is stirred with 10 ml. of 2n hydrochloric acid. The hydrochloride of the non-reacted base separates. The salt is filtered off, and the filtrate is washed with 5 ml. of 2.5 % aqueous sodium hydrocarbonate solution and with water. The chloroform solution is dried and evaporated. The obtained dry residue is recrystallized from ethanol. 0.91 g. (66.2 %) of di-(1-methyl-2-oxo-5-phenyl-7-chloro-1,3,4,5-tetrahydro-2H-1,4-benzodiazepine-4-yl)-ketone are obtained; m.p.: 263°-266° C., Rf2 = 0.71.
Reaction SMILES: [CH2:1]([C:3]1[S:4][C:5]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH2:21])[CH:16]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)[N:7]=1)[CH3:2].[C:22]1([CH2:28][C:29](Cl)=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>O1CCCC1>[CH2:1]([C:3]1[S:4][C:5]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:29](=[O:30])[CH2:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:16]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)[N:7]=1)[CH3:2]
Reactant: CCc1nc(-c2cccc(C)c2)c(-c2ccnc(N)c2)s1
Reactant: O=C(Cl)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCc1nc(-c2cccc(C)c2)c(-c2ccnc(NC(=O)Cc3ccccc3)c2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.2 %

Procedure:
To a solution of 4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine (0.80 g, 2.7 mmol) in tetrahydrofuran (8 mL) was added phenylacetyl chloride (0.47 mL, 3.0 mmol), and triethylamine (0.41 mL, 3.0 mmol) was added to the obtained mixture. The reaction mixture was stirred at room temperature for 2 hrs. Saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried and concentrated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate 20:1–4:1) and crystallized from isopropyl ether to give the title compound (0.75 g, yield 67%).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:15](SC)=[CH:16][N+:17]([O-:19])=[O:18])[N:9]=1)[CH3:3].[CH3:22][O:23][CH2:24][CH2:25][NH2:26]>C(O)C>[CH3:3][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:15]([NH:26][CH2:25][CH2:24][O:23][CH3:22])=[CH:16][N+:17]([O-:19])=[O:18])[N:9]=1)[CH3:1]
Reactant: CSC(=C[N+](=O)[O-])NCCSCc1csc(CN(C)C)n1
Reactant: COCCN
Solvent: CCO
Product: COCCNC(=C[N+](=O)[O-])NCCSCc1csc(CN(C)C)n1

Procedure:
A reaction mixture, prepared from 1.25 g of 1-[2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl]amino-1-methylthio-2-nitroethylene, 0.27 g of 2-methoxyethylamine and 20 ml of ethanol, was heated to refluxing temperature for about three hours. The solvent was then removed by evaporation and the resulting residue was chromatographed over silica using a gradient elution technique. The desired compound was eluted with a 5:95 methanol:ethyl acetate solvent mixture. Removal of the solvent yielded N-2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl-N'-(2-methoxy)ethyl 2-nitro-1,1-ethenediamine as an oil.