Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Ca+2].N1C2C(=CC=CC=2)C=CC=1.[CH3:16][C:17]([OH:25])([C:19]#[C:20][C:21]([CH3:24])([OH:23])[CH3:22])[CH3:18].[H][H]>CO>[CH3:16][C:17]([OH:25])(/[CH:19]=[CH:20]\[C:21]([CH3:24])([OH:23])[CH3:22])[CH3:18]
Reactant: [H][H]
Reactant: CC(C)(O)C#CC(C)(C)O
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: c1ccc2ncccc2c1
Solvent: CO
Product: CC(C)(O)/C=C\C(C)(C)O
Yield: 99.4 %

Procedure:
1.6 g of 5% palladized calcium carbonate and 0.6 g of quinoline were added to a solution of 24 g of 2,5-dimethyl-hex-3-yne-2,5-diol [Ray et al, Am. Soc., Vol. 74 (1952), p. 1247] in 200 ml of methanol and the mixture was stirred with hydrogen until hydrogen absorption ceased. The catalyst was removed by filtration and the filtrate was evaporated to dryness under reduced pressure to obtain 24.2 g of cis 2,5-dimethyl-hex-3-ene-2,5-diol melting at 64° C. which was used as is for the next step.
Reaction SMILES: [C:1]([C:3]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH:17]([F:19])[F:18])=[C:12]([O:20][CH:21]([F:23])[F:22])[CH:11]=2)[CH2:8][CH2:7]C(=O)[CH2:5][CH2:4]1)#[N:2].[CH:24]([O:29][CH3:30])([O:27][CH3:28])OC.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:30][O:29][C:24]1([O:27][CH3:28])[CH2:5][CH2:4][C:3]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH:17]([F:18])[F:19])=[C:12]([O:20][CH:21]([F:22])[F:23])[CH:11]=2)([C:1]#[N:2])[CH2:8][CH2:7]1
Reactant: N#CC1(c2ccc(OC(F)F)c(OC(F)F)c2)CCC(=O)CC1
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC1(OC)CCC(C#N)(c2ccc(OC(F)F)c(OC(F)F)c2)CC1
Yield: 98.2 %

Procedure:
A mixture of 4-cyano-4-(3,4-bisdifluoromethoxyphenyl)cyclohexan-1-one (1.34 g, 4.05 mmol), trimethyl orthoformate (0.53 mL, 4.85 mmol) and a catalytic amount of p-toluenesulfonic acid in methanol (40 mL) was heated gently under an argon atmosphere for 2 h. The mixture was cooled and then concentrated. The residue was partitioned between 5% aqueous sodium carbonate and ethyl acetate, was extracted twice with ethyl acetate, the organic extract was dried (potassium carbonate) and the solvent was removed in vacuo to provide an oil (1.5 g, 98%).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:30](=[O:31])[N:13]3[C:14]([C:27]([OH:29])=[S:28])=[C:15]([C:18]4[S:19][CH:20]=[C:21]([CH2:23][C:24]([OH:26])=[O:25])[N:22]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+:33]>O.CO.CC(C)=O>[C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:30](=[O:31])[N:13]3[C:14]([C:27]([O-:29])=[S:28])=[C:15]([C:18]4[S:19][CH:20]=[C:21]([CH2:23][C:24]([OH:26])=[O:25])[N:22]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+:33].[Na+:33].[C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:30](=[O:31])[N:13]3[C:14]([C:27]([O-:29])=[S:28])=[C:15]([C:18]4[S:19][CH:20]=[C:21]([CH2:23][C:24]([OH:26])=[O:25])[N:22]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)Cc1csc(C2=C(C(O)=S)N3C(=O)[C@@H](NC(=O)Cc4ccccc4)[C@H]3SC2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Solvent: CO
Product: O=C(O)Cc1csc(C2=C(C([O-])=S)N3C(=O)[C@@H](NC(=O)Cc4ccccc4)[C@H]3SC2)n1
Temperature: 30 °C
Reaction time: 2 h

Procedure:
To a solution of 7β-(2-phenylacetamido)-3-(4-carboxymethylthiazol-2-yl)thio-3-cephem-4-carboxylic acid (100 mg) in water (50 ml) was added 0.1 mol/l-sodium hydroxide solution (4.06 ml). The solution was lyophilized. The above obtained powder was dissolved in a mixture of methanol (0.5 ml) and acetone (1.3 ml) under stirring at 30° C. The stirring was continued for 2 hours at room temperature to give crystals, which were collected by filtration and dried to give disodium 7β-(2-phenylacetamido)-3-(4-carboxymethylthiazol-2-yl)thio-3-cephem-4-carboxylate (69.1 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][CH2:7][CH:8]([OH:22])[CH2:9][N:10]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>N1C=CC=CC=1>[C:25]([O:22][CH:8]([CH2:9][N:10]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:7][O:6][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:24][CH:23]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)CN(CC(O)COc1ccc(Cl)cc1)c1ccccc1
Solvent: c1ccncc1
Product: COC(=O)CN(CC(COc1ccc(Cl)cc1)OC(C)=O)c1ccccc1
Reaction time: 20 h
Yield: 82.9 %

Procedure:
After 5.5 g (0.0157 moles) of 1-(p-chlorophenoxy)-3-(N-carbomethoxymethyl-N-phenylamino)-2-propanol and 6.0 g (0.059 moles) of acetic anhydride were dissolved in 30 ml of pyridine and left to stand at the room temperature for 20 hr, the reaction mixture was concentrated. The resulting residue was poured into iced water to afford precipitates. The precipitates were collected by filtration, washed with water and dried. Recrystallization from isopropanol gave 5.1 g (83%) of the crystals, m.p. 82°-83°.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[O:5].IC.[C:15](=O)([O-])[O-].[Na+].[Na+].O>CN(C)C=O>[CH3:15][O:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1O
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])cc1C=O
Reaction time: 24 h

Procedure:
2-Hydroxy-5-nitrobenzaldehyde (2.40 g, 14.0 mmol) was dissolved in dimethylformamide (50 mL). To this was added iodomethane (4.48 ml, 72.0 mmol) and sodium carbonate (3.04 g, 28.0 mmol). This mixture was stirred for 24 hours and was poured into water. The solid was collected by filtration to give 2.38 g (93.0%). Mp 88-89° C.;1H NMR (CDCl3): d, 10.46 (s,1H), 8.69 (d,1H), 8.45 (dd,1H), 7.15 (d,1H), 4.10 (s,3H). MS (DCl): 182 (MH+). C8H7NO4.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([NH2:19])[CH:17]=2)[NH:12][N:11]=1.[S:20]1[CH:24]=[CH:23][N:22]=[C:21]1[CH:25]=O.N1C=CC=CC=1>CC(O)=O.CO.C(Cl)Cl>[NH:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=[C:2]1[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([NH:19][CH2:25][C:21]3[S:20][CH:24]=[CH:23][N:22]=3)[CH:17]=2)[NH:12][N:11]=1
Reactant: O=Cc1nccs1
Reactant: Nc1ccc2[nH]nc(-c3nc4ccccc4[nH]3)c2c1
Solvent: CC(=O)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: c1ccc2[nH]c(-c3n[nH]c4ccc(NCc5nccs5)cc34)nc2c1

Procedure:
3-Benzimidazol-2-yl-1H-indazole-5-ylamine (1 equivalent), 2-thiazolecarboxaldehyde(1.1 equivalent), BH3: pyridine (10 equivalents, 8 M in pyridine) in AcOH:MeOH:CH2Cl2 (1:2:2) were stirred for 18 hours at room temperature. The solvent was removed, and the residue was purified by preparatory HPLC. LC/MS (m/z) 347.1 (MH+), Rt 1.93 minutes.
Reaction SMILES: [Cl-].[Ce+3].[Cl-].[Cl-].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([C:15]2[N:16]([S:26]([N:29]([CH3:31])[CH3:30])(=[O:28])=[O:27])[CH:17]=[C:18]([CH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][CH3:23])[N:19]=2)=[O:14])=[CH:8][CH:7]=1.[CH3:32][Mg]Br>O1CCCC1>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([C:15]2[N:16]([S:26]([N:29]([CH3:31])[CH3:30])(=[O:27])=[O:28])[CH:17]=[C:18]([CH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][CH3:23])[N:19]=2)([OH:14])[CH3:32])=[CH:8][CH:7]=1
Reactant: C[Mg]Br
Reactant: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(C(=O)Cc2ccc(Br)cc2)n1
Agent: [Ce+3]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(C(C)(O)Cc2ccc(Br)cc2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Cerium Chloride (1.625 g, 6.59 mmol) was added to an ambient temperature solution of 2-[(4-bromophenyl)acetyl]-4-(2,2-dimethylbutyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (intermediate 8) (1 g, 2.2 mmol) in tetrahydrofuran (22 mL). After stirring at ambient temperature for 1 h, the reaction mixture was cooled to 0° C. and methylmagnesium bromide (3 M in diethyl ether) (2.2 mL, 6.59 mmol) was added. After stirring at 0° C. for a further 30 min, the reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with methylene chloride. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-50% ethyl acetate/hexane afforded the title compound.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[NH2:8][C:9]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:10]=1[CH2:11][NH:12][C:13]1[C:14]2[N:15]([C:19]([CH3:23])=[C:20]([CH3:22])[N:21]=2)[CH:16]=[CH:17][CH:18]=1.N1C=CC=CC=1.C(=O)([O-])O.[K+]>ClCCl.O>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([NH:8][C:9]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:10]=1[CH2:11][NH:12][C:13]1[C:14]2[N:15]([C:19]([CH3:23])=[C:20]([CH3:22])[N:21]=2)[CH:16]=[CH:17][CH:18]=1)=[O:6]
Reactant: Cc1cccc(N)c1CNc1cccn2c(C)c(C)nc12
Reactant: O=C(Cl)CCCCl
Agent: O=C([O-])O
Agent: [K+]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: Cc1cccc(NC(=O)CCCCl)c1CNc1cccn2c(C)c(C)nc12
Temperature: 10 °C
Reaction time: 2 h
Yield: 86.1 %

Procedure:
0.88 ml (7.85 mmol) of 4-chlorobutyryl chloride is added dropwise at 0-5° C. with stirring to a solution of 2.2 g (7.85 mmol) of 8-(2-amino-6-methylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridine and 0.63 ml (7.85 mmol) of pyridine in 30 ml of dichloromethane and the mixture is stirred for a further 2 h at 0-20° C. It is treated with water and potassium hydrogen carbonate to pH 7, the mixture is extracted with shaking, and the organic layer is dried with magnesium sulfate and concentrated in vacuo. The residue is recrystallized from toluene and petroleum ether (50/70° C.). 2.6 g (86%) of the title compound are obtained. M.p. 138-140° C.
Reaction SMILES: C1COCC1.[CH:6]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)=[CH2:7].C(=O)([O-])[O-].[K+].[K+].[F:21][C:22]([F:46])([F:45])[C:23]([F:44])([F:43])[C:24]([F:42])([F:41])[O:25][C:26]([F:40])([C:31]([F:39])([F:38])[O:32][C:33]([F:37])=[C:34]([F:36])[F:35])[C:27]([F:30])([F:29])[F:28]>C(O)C(O)C>[F:36][C:34]([F:35])([O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:6]=[CH2:7])=[CH:9][CH:10]=1)[CH:33]([F:37])[O:32][C:31]([F:38])([F:39])[C:26]([F:40])([O:25][C:24]([F:41])([F:42])[C:23]([F:43])([F:44])[C:22]([F:21])([F:45])[F:46])[C:27]([F:30])([F:29])[F:28]
Reactant: FC(F)=C(F)OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Reactant: C=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(O)CO
Solvent: C1CCOC1
Product: C=Cc1ccc(OC(F)(F)C(F)OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F)cc1
Temperature: 25 °C

Procedure:
In the dry box, THF (50 mL) and 4-vinylphenol (5.00 g of a 10% solution in propylene glycol) were added to an oven dry RB flask equipped with a stirrer, Potassium carbonate (0.35 g, 0.0025 mol) was then added. 1,1,1,2,2,3,3-Heptafluoro-3-(1,1,1,2,3,3-hexafluoro-3-(1,2,2-trifluorovinyloxy)propan-2-yloxy)propane (2.70 g, 0.00625 mol) was then added via the addition funnel and the reaction allowed to stir at room temperature. The reaction mixture was heated to a gentle reflux under nitrogen overnight. An aliquot was withdrawn and concentrated under vacuum and analyzed via proton NMR which showed the complete conversion to be 1-(1,1,2-trifluoro-2-(1,1,2,3,3,3-hexafluoro-2-(perfluoropropoxy)propoxy)ethoxy)-4-vinylbenzene. The cooled reaction mixture was then concentrated at reduced pressure taken up in methylene chloride washed with water (˜25 mL) separated, then dried over anhydrous sodium sulfate. The separated organic phase was then concentrated at reduced pressure and then column chromatograph on silica gel obtaining 1.15 g (about 50.0%) of the theoretical yield) of product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][N:3]=1.C(O)(=O)[CH2:11][C:12]([OH:14])=[O:13].N1CCCCC1>N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]=[CH:11][C:12]([OH:14])=[O:13])[CH:5]=[CH:4][N:3]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1ccnc(Br)c1
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1ccnc(Br)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 74.2 %

Procedure:
2-Bromo-pyridin-4-carbaldehyde (20.0 g, 107.5 mmol), malonic acid (25.2 g, 241.9 mmol), and piperidine (8.8 mL, 89.2 mmol) were added to pyridine (65.2 mL). The reaction mixture was stirred at 100° C. for 1 hour, concentrated under reduced pressure, and then distilled water was added thereto. The mixture was filtered and then the resulting solid dried under reduced pressure to give 18.2 g of the titled compound as a white solid.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:6]=2[N:25]=1.[NH2:26][C:27]1[CH:42]=[CH:41][C:30]([C:31]([NH:33][CH:34]2[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]2)=[O:32])=[CH:29][C:28]=1[O:43][CH3:44].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.C(O)(C)C>[F:14][C:9]1([F:15])[CH2:8][N:7]([CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:6]2[N:25]=[C:2]([NH:26][C:27]3[CH:42]=[CH:41][C:30]([C:31]([NH:33][CH:34]4[CH2:35][CH2:36][N:37]([CH3:40])[CH2:38][CH2:39]4)=[O:32])=[CH:29][C:28]=3[O:43][CH3:44])[N:3]=[CH:4][C:5]=2[N:11]([CH3:12])[C:10]1=[O:13]
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1N
Reactant: CN1C(=O)C(F)(F)CN(CCCc2ccccc2)c2nc(Cl)ncc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Solvent: ClCCl
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(CCCc1ccccc1)CC(F)(F)C(=O)N2C
Yield: 306.3 %

Procedure:
The mixture of 0.08 g (0.22 mmole) of 2-chloro-7,7-difluoro-5-methyl-9-(3-phenyl-propyl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-281), 0.069 g (0.26 mmole) of 4-amino-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide, 0.062 g (0.33 mmole) of p-toluenesulfonic acid monohydrate and 4 mL of isopropanol was heated in a pressure tube at 140 degrees overnight. After cooling, dichloromethane and saturated sodium carbonate were added. The mixture was extracted with dichloromethane twice. The combined organic layers were washed three times with sodium carbonate, three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-80:20) gave 0.40 g of 4-[7,7-difluoro-5-methyl-6-oxo-9-(3-phenyl-propyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino]-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (I-282) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[Li][CH2:12]CCC.C(O)(C)(C)C.IC>O.C(OCC)C>[CH2:1]([C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH3:12]
Reactant: Cc1cc2ccccc2[nH]1
Reactant: [Li]CCCC
Solvent: CI
Solvent: CC(C)(C)O
Solvent: CCOCC
Product: CCc1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
In an ice water bath, 2-methylindole (5 g, 38.1 mmol), 300 mL anhydrous diethyl ether, 2.4 M n-BuLi 47.5 mL (114 mmol), tert-butanol (8.5 g, 75.8 mmol) were added into a reaction vessel. Upon completion of addition, under protection of nitrogen, the reaction was stirred at room temperature for 0.5 h. Then the system was cooled to −70° C., and iodomethane (10.245 g, 72.2 mmol) was added dropwise. Upon completion of addition, it was reacted for 2 h maintaining this temperature. Then it was warmed up to −40° C. 2 mL water was added, and then warmed up to room temperature. The system was poured into water, adjusted to pH=6, extracted with diethyl ether, dried and rotate evaporated to dryness to obtain the product 3.74 g, at a yield of 67.7%.
Reaction SMILES: CS([C:5]1[S:9][C:8]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15](C([O-])=O)[CH:14]=[CH:13]3)=[N:7][N:6]=1)(=O)=O.[CH3:22][NH2:23].CCOC(C)=O>CS(C)=O>[NH:15]1[C:16]2[C:12](=[CH:11][C:10]([C:8]3[S:9][C:5]([NH:23][CH3:22])=[N:6][N:7]=3)=[CH:18][CH:17]=2)[CH:13]=[CH:14]1
Reactant: CS(=O)(=O)c1nnc(-c2ccc3c(ccn3C(=O)[O-])c2)s1
Reactant: CN
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CNc1nnc(-c2ccc3[nH]ccc3c2)s1
Temperature: 110 °C
Yield: 78 %

Procedure:
To a mixture of 5-(5-(methylsulfonyl)-1,3,4-thiadiazol-2-yl)-1H-indole-1-carboxylate (8 g, 21.11 mmol) in a sealed tube was added methylamine in DMSO (80 mL). The reaction was heated at 110° C. for 1 h and ice-cold water and EtOAc was added. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried, filtered and concentrated. The residue was purified with silica gel chromatography (eluting with 40% EtOAc in Hex) to give 5-(1H-indol-5-yl)-N-methyl-1,3,4-thiadiazol-2-amine (3.8 g, 78%). MS (ESI, pos. ion) m/z: 231 (M+1); 1H-NMR (DMSO-d6, 300 MHz): δ ppm 2.9 (s, 3H), 6.5 (d, 1H) 7.4 (d, 3H) 7.8 (m, 1H), 7.9 (s, 1H), 11.4 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=1.[Br:12][C:13]1[CH:14]=[CH:15][C:16]([Cl:21])=[C:17]([CH:20]=1)[CH:18]=O>>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([Cl:21])=[C:17]([CH2:18][C:7]2[S:6][C:5]3[C:9]([CH3:11])=[CH:10][C:2]([CH3:1])=[CH:3][C:4]=3[CH:8]=2)[CH:20]=1
Reactant: Cc1cc(C)c2sccc2c1
Reactant: O=Cc1cc(Br)ccc1Cl
Product: Cc1cc(C)c2sc(Cc3cc(Br)ccc3Cl)cc2c1

Procedure:
5,7-Dimethylbenzo[b]thiophene (see Yoshimura, Y. et al., J. Med. Chem. 43 (2000) 2929-2937) and 5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16-(1) were treated in a manner similar to Reference Example 7 to give the target compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[Si:10](Cl)([CH3:13])([CH3:12])[CH3:11].[Li]CCCC.O>C1COCC1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([Si:10]([CH3:13])([CH3:12])[CH3:11])=[CH:3][CH:4]=1
Reactant: COc1ccc(Br)cc1
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc([Si](C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
4-Bromoanisole (9.35 g, 50.0 mmol, 1.0 eq) was dissolved in anhydrous THF (200 mL). Me3SiCl (12.7 mL, 100.0 mmol, 2.0 eq) was added at 0° C. followed by n-BuLi (2.5 M in hexanes, 40 mL, 100.0 mmol, 2.0 eq). The reaction mixture was stirred at room temperature for 1 h. Water (150 mL) was then added, the organic layer was separated and the aqueous layer was extracted with Et2O (150 mL×2). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give (4-methoxyphenyl)trimethylsilane as a light yellow oil (8.1 g, 90% yield). 1H NMR (300 MHz, CDCl3) δ: 7.48 (d, J=11.2 Hz, 2H), 6.95 (d, J=11.2 Hz, 2H), 3.84 (s, 3H), 0.27 (s, 9H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[NH2:18][C:19]1[CH:28]=[CH:27][C:22]2[NH:23][C:24](=[O:26])[S:25][C:21]=2[CH:20]=1.Cl.N1C=CC=CC=1.C(OC(O)C)C.C(=O)([O-])[O-].[Na+].[Na+].Cl>O>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][C:3]([C:16]#[N:17])=[C:2]2[NH:18][C:19]1[CH:28]=[CH:27][C:22]2[NH:23][C:24](=[O:26])[S:25][C:21]=2[CH:20]=1
Reactant: Nc1ccc2[nH]c(=O)sc2c1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Agent: CCOC(C)O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: c1ccncc1
Product: COc1cc2ncc(C#N)c(Nc3ccc4[nH]c(=O)sc4c3)c2cc1OC
Yield: 86.3 %

Procedure:
A mixture of 0.249 g of 4-chloro-6,7-dimethoxy-quinolin-3-carbonitrile, 0.166 g of 6-amino-2-benzothiazolinone, 0.020 g of pyridine hydrochloride, and 10 ml of ethoxyethanol was stirred under nitrogen, at reflux temperature for 20 minutes. The mixture was cooled and added to 40 ml of water. To this mixture was added sodium carbonate and concentrated hydrochloric acid to adjust pH to 7. The product was collected, washed with water, and dried to give 0.326 g of 6,7-dimethoxy-4-(2-oxo-2,3-dihydro-benzothiazol-6-ylamino)-quinoline-3-carbonitrile as a solid, mp 285-287° C.; mass spectrum (electrospray, m/e): M+H 379.0858.
Reaction SMILES: CS(Cl)(=O)=O.[F:6][C:7]1[CH:8]=[C:9]2[C:20](=[CH:21][CH:22]=1)[C:12]1[N:13]([CH2:16][C@H:17](O)[CH3:18])[CH:14]=[CH:15][C:11]=1[CH2:10]2.C(N(CC)CC)C.[N-:30]=[N+:31]=[N-:32].[Na+]>ClCCl.CN(C)C=O.O>[N:30]([C@@H:17]([CH3:18])[CH2:16][N:13]1[CH:14]=[CH:15][C:11]2[CH2:10][C:9]3[C:20]([C:12]1=2)=[CH:21][CH:22]=[C:7]([F:6])[CH:8]=3)=[N+:31]=[N-:32]
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@@H](O)Cn1ccc2c1-c1ccc(F)cc1C2
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: C[C@@H](Cn1ccc2c1-c1ccc(F)cc1C2)N=[N+]=[N-]
Yield: 40.4 %

Procedure:
1.8 ml of methanesulfonyl chloride were added dropwise while stirring to a solution, cooled to 0°, of 2.75 g of (R)-1-(6-fluoro-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol and 6.7 ml of triethyl-amine in 70 ml of dichloromethane and the mixture was stirred at this temperature for an additional 1.5 hours. The reaction mixture was subsequently diluted with 100 ml of dichloromethane, washed twice with 90 ml of saturated sodium hydrogen carbonate solution each time and the combined aqueous phases were extracted once with 90 ml of dichloromethane. The combined organic phases were washed with 100 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated in a vacuum. The brown oil obtained was dissolved in 60 ml of anhydrous dimethylformamide, treated with 1.55 g of sodium azide and the reaction mixture was heated to 60° for 17 hours while stirring. After cooling the solution was poured into 80 ml of water and extracted three times with 100 ml of ethyl acetate each time. The combined organic phases were washed once with 70 ml of water and once with 70 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. The brown oil obtained was purified by column chromatography on silica gel (toluene). 1.23 g (40%) of (S)-1-(2-azido-propyl)-6-fluoro-1,4-dihydro-indeno[1,2-b]pyrrole were obtained as a light yellow oil.
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([SH:12])=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:14][C:15](=[O:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17].N1C=CN=C1>CO.CC(C)=O>[CH2:19]([O:18][C:16](=[O:17])[C:15](=[O:21])[CH2:14][S:12][C:10]1[O:11][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][N:9]=1)[CH3:20]
Reactant: CCOC(=O)C(=O)CBr
Reactant: Sc1nnc(-c2ccccc2)o1
Agent: c1c[nH]cn1
Solvent: CO
Solvent: CC(C)=O
Product: CCOC(=O)C(=O)CSc1nnc(-c2ccccc2)o1
Temperature: 20 °C
Reaction time: 4 h

Procedure:
To a solution of 5-phenyl-1,3,4-oxadiazole-2-thiol (178 mg, 1.0 mmol) and ethyl 3-bromopyruvate (0.150 mL, 1.19 mmol) in methanol (2 mL) and acetone (2 mL) was added imidazole (68 mg, 1.0 mmol). The resulted solution was shaken at 20° C. for 4 hour. After the removal of solvents under vacuum, the residue was triturated with ethyl ether. The ether phase was discarded. The residue was treated with sodium bicarbonate aqueous solution and ethyl ether. The ether phase was washed successively with sodium bicarbonate aqueous solution, water, and dried over magnesium sulfate. Evaporation to dryness under vacuum gave 209 mg (72% of yield) of the expected product, 2-oxo-3-(5-phenyl-[1,3,4]oxadiazol-2-ylsulfanyl)-propionic acid ethyl ester. Proton NMR showed the product was sufficiently pure to be used without further purification. 1H-NMR (CDCl3, 300 MHz) δ (ppm): 7.90-7.80 (m, 2H), 7.60-7.35 (m, 3H), 4.41 (q, J=7.1 Hz, 2H), 3.44 (br. s, 2H), 1.26 (t, J=7.1 Hz, 3H).