Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C@H:2]1[CH2:10][OH:11].C(N(CC)CC)C.[CH3:19][O:20][C:21]1[CH:26]=[C:25]([CH3:27])[C:24]([S:28](Cl)(=[O:30])=[O:29])=[C:23]([CH3:32])[CH:22]=1>ClCCl>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH3:32])[C:24]([S:28]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:3][C@H:2]2[CH2:10][OH:11])(=[O:29])=[O:30])=[C:25]([CH3:27])[CH:26]=1
Reactant: OC[C@@H]1Cc2ccccc2N1
Reactant: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C)c(S(=O)(=O)N2c3ccccc3C[C@H]2CO)c(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
To a cold (0° C.) solution of (S)-indolin-2-ylmethanol (4.60 mmol, 1.2 equiv.) and triethylamine (2.5 equiv.) in dichloromethane (20 ml) was added dropwise 4-methoxy-2,6-dimethylbenzenesulfonyl chloride (3.83 mmol, 1.0 equiv.) in dichloromethane (5 ml) and the reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with dichloromethane, washed successively with water and brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the crude product was purified by silica gel column chromatography. Yield: 72%.
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH:4]=[C:5]([C:10]([CH3:12])=O)[C:6]([O:8][CH3:9])=[O:7].[NH2:17][C:18]([CH3:31])=[CH:19][C:20]([NH:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:21]>>[CH3:31][C:18]1[NH:17][C:10]([CH3:12])=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:4]([C:3]2[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=2[CH3:1])[C:19]=1[C:20]([NH:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:21]
Reactant: CC(N)=CC(=O)NCC(=O)OC(C)(C)C
Reactant: COC(=O)C(=Cc1ccccc1C)C(C)=O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)NCC(=O)OC(C)(C)C)C1c1ccccc1C
Temperature: 120 °C
Reaction time: 0.17 h
Yield: 49.5 %

Procedure:
A mixture of 327 mg (1.5 mmol) of methyl 2-(2-methylbenzylidene)acetoacetate and 318 g (1.5 mmol) of t-butyl 2-[N-(3-amino-2-butenoyl)amino]acetate was stirred in a light-shielding condition at 120° C. for 10 minutes. After cooling to room temperature, the reaction mixture was chromatographed on a silica gel column for purification, whereby 308 mg (49.5%) of the captioned compound was obtained as an oily material.
Reaction SMILES: [CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[C:7]([OH:10])(=[O:9])[CH3:8]>>[C:7]([O:10][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)(=[O:9])[CH3:8]
Reactant: C1=CCCCC1
Reactant: CC(=O)O
Product: CC(=O)OC1CCCCC1
Temperature: 100 °C

Procedure:
In a 200 ml autoclave were placed the above-mentioned commercially available dodecatungstosilicic acid 5.0 g, the above-mentioned commercially available acetic acid 61.5 g and the above-mentioned commercially available cyclohexene 13.5 g and nitrogen gas was fed thereinto until the pressure reached 5 kg/cm2 (gauge), and then a reaction was carried out with stirring by heating at 100° C. for 1 hour. The result is shown in Table 1, that is, cyclohexyl acetate was produced in high yield.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH:9]=[O:10])[CH:6]=[C:5]([CH3:11])[C:4]=1[CH:12]=[CH:13][C:14]([OH:16])=[O:15])[CH3:2].CCN(C(C)C)C(C)C>C(O)C.[Pd]>[CH2:1]([C:3]1[CH:8]=[C:7]([CH2:9][OH:10])[CH:6]=[C:5]([CH3:11])[C:4]=1[CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH3:2]
Reactant: CCc1cc(C=O)cc(C)c1C=CC(=O)O
Agent: [Pd]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCc1cc(CO)cc(C)c1CCC(=O)O
Reaction time: 16 h
Yield: 100 %

Procedure:
To a solution of 3-(2-ethyl-4-formyl-6-methyl-phenyl)-acrylic acid (2.75 g, 12.6 mmol) and DIPEA (1.8 g, 13.8 mmol) in ethanol (80 mL), Pd/C (275 mg, 10% Pd, moistened with 50% water) is added. The mixture is stirred for 16 h at it under 1 atm of H2. The catalyst is filtered off and the filtrate is concentrated. The residue is dissolved in EA, washed with 2 N aq. HCl, followed by 1 N aq. HCl and brine. The organic extract is dried over Na2SO4, filtered and evaporated to give 3-(2-ethyl-4-hydroxymethyl-6-methyl-phenyl)-propionic acid (2.8 g) as a white solid; LC-MS: tR=0.76 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[CH:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:6]=2[CH:22]=1.ClC1C=CC=C(C(OO)=[O:31])C=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[CH:13][N:14]=[C:10]3[CH2:9][N+:8]([O-:31])=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:6]=2[CH:22]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1cnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=[N+]([O-])C2
Temperature: 0 °C

Procedure:
A stirred solution of 1.0 g. of 8-chloro-1-methyl-6-phenyl-4H-imidazo[1,2-a][1,4]benzodiazepine (Ia) in absolute ethanol in an ice bath is treated with 1.0 g. of m-chloroperbenzoic acid. The mixture is allowed to stand in the ice bath for about 8 hous and at room temperature at about 24° C. for approximately 18 hours. It is then concentrated in vacuo, the residue thus obtained is suspended in aqueous, cold, dilute potassium carbonate solution and extracted with methylene chloride. The extract is washed with water, dried and concentrated in vacuo. The residue thus obtained is chromatographed on 100 g. of silica gel to give 8-chloro-1-methyl-6-phenyl-4H-imidazo[1,2-a][1,4]benzodiazepine-5-oxide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]1[CH:13]=[C:14]([C:16]([O:18]CC)=[O:17])[N:15]=[C:8]1[CH:7]=[CH:6]2.[OH-].[Na+].C>O.C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]1[CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=[C:8]1[CH:7]=[CH:6]2
Reactant: CCOC(=O)c1cn2c(ccc3cc(OC)ccc32)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc2c(ccc3nc(C(=O)O)cn32)c1

Procedure:
840 mg of ethyl 7-methoxyimidazo-[1,2-a]-quinoline-2-carboxylate were suspended in a mixture of 100 ml of water and 150 ml of ethanol and 3.5 ml of N sodium hydroxide solution were added. The mixture was heated on a steam bath for 30 minutes and the resulting solution was decolorized with charcoal, filtered and acidified with 3.7 ml of N hydrochloric acid. The mixture was cooled in ice to obtain colorless crystals of 7-methoxyimidazo-[1,2-a]-quinoline-2-carboxylic acid melting at 265°-266° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[F:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[F:18])[NH2:14]>>[NH2:14][C:13]1[CH:12]=[C:11]([F:10])[C:17]([F:18])=[CH:16][C:15]=1[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[Cl:1])=[O:5]
Reactant: O=Cc1ccccc1Cl
Reactant: Nc1ccc(F)c(F)c1
Product: Nc1cc(F)c(F)cc1C(=O)c1ccccc1Cl

Procedure:
(2-amino-4,5-difluorophenyl)-(2-chlorophenyl)-methanone (Xmm) was prepared by reacting 2-chlorobenzaldehyde with 0.30 moles of 3,4-difluoro aniline in a manner analogous to Example 1. MH+/Z=268.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:3][CH2:2]1.[C:34](Cl)(=[O:36])[CH3:35]>>[C:34]([N:1]1[CH2:2][CH2:3][CH:4]([CH2:7][NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:5][CH2:6]1)(=[O:36])[CH3:35]
Reactant: O=C(NCC1CCNCC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Reactant: CC(=O)Cl
Product: CC(=O)N1CCC(CNC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting from 4-(5-Cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (piperidin-4-ylmethyl)-amide (example A144) and acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14]OC.[NH2:17][CH2:18][C:19]1[CH:20]=[C:21]([OH:32])[C:22]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[CH:23][CH:24]=1>>[F:31][C:28]1[CH:27]=[CH:26][C:25]([C:22]2[CH:23]=[CH:24][C:19]([CH2:18][NH:17][CH:14]=[C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([I:1])[CH:3]=4)[C:8](=[O:12])[NH:7][C:6]3=[O:13])=[CH:20][C:21]=2[OH:32])=[CH:30][CH:29]=1
Reactant: COC=C1C(=O)NC(=O)c2ccc(I)cc21
Reactant: NCc1ccc(-c2ccc(F)cc2)c(O)c1
Product: O=C1NC(=O)c2ccc(I)cc2C1=CNCc1ccc(-c2ccc(F)cc2)c(O)c1
Yield: 60 %

Procedure:
Following the same procedure for the preparation of 4-{[(2-Hydroxy-biphenyl-4-ylmethyl)-amino]-methylene}-6-iodo-4H-isoquinoline-1,3-dione-2, the title compound is prepared from 6-iodo-4-methoxymethylene-4H-isoquinoline-1,3-dione (90 mg, 0.27 mmol) and 4-Aminomethyl-4′-fluoro-biphenyl-2-ol (66 mg, 0.3 mmol) in 60% yield: MS (ESI): 513.1 (M−1)−1.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([CH2:14][CH:15]2[CH2:19][CH2:18][N:17]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:16]2=[O:26])=[C:9]([Cl:27])[CH:8]=1)(=O)=O.[C:30]([C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][C:37]=1[F:38])#[N:31].C(=O)([O-])[O-].[Na+].[Na+].O>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:13][C:11]1[CH:12]=[C:7]([C:34]2[CH:35]=[CH:36][C:37]([F:38])=[C:32]([C:30]#[N:31])[CH:33]=2)[CH:8]=[C:9]([Cl:27])[C:10]=1[CH2:14][CH:15]1[CH2:19][CH2:18][N:17]([CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[C:16]1=[O:26]
Reactant: O=C1C(Cc2c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc2Cl)CCN1C1CCCCC1
Reactant: N#Cc1cc(B(O)O)ccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cc(-c2cc(Cl)c(CC3CCN(C4CCCCC4)C3=O)c(Cl)c2)ccc1F
Temperature: 60 °C
Reaction time: 0.08 h
Yield: 87.3 %

Procedure:
To a solution of 3,5-dichloro-4-((1-cyclohexyl-2-oxopyrrolidin-3-yl)methyl)phenyl trifluoromethanesulfonate (Example 240) (1.34 g, 2.83 mmol) in THF (30 mL) in a round bottom flask was added 3-cyano-4-fluorophenylboronic acid (560 mg, 3.39 mmol), sodium carbonate (900 mg, 8.48 mmol) and water (10 mL). The mixture was stirred at 60° C. for 5 minutes, palladium tetrakis (163 mg, 0.14 mmol) was added. Reaction mixture was brought to 80° C. and stirred for 3 hours. Cooled and partitioned between ethyl acetate and HCL(1 N). Organic was separated, wash with water, brine; dry over sodium sulfate, filter, and concentrate. Purify by silica gel (25-50% ethyl acetate in hexane) to afford 1.10 g (88%) of the title compound: Mass spectrum (LCMS) m/z=445.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([OH:15])[CH:9]=1)=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][C:28]1[C:36]2[C:31](=[N:32][CH:33]=[N:34][C:35]=2[Cl:37])[N:30]([CH3:38])[N:29]=1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([O:15][CH2:27][C:28]2[C:36]3[C:31](=[N:32][CH:33]=[N:34][C:35]=3[Cl:37])[N:30]([CH3:38])[N:29]=2)[CH:9]=1)=[O:6]
Reactant: Cn1nc(CBr)c2c(Cl)ncnc21
Reactant: Cc1ccc(NC(=O)c2ccc(F)c(Cl)c2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2ccc(F)c(Cl)c2)cc1OCc1nn(C)c2ncnc(Cl)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-chloro-4-fluoro-N-(3-hydroxy-4-methyl-phenyl)-benzamide (105.9 mg, 0.379 mmol) and potassium carbonate (59.6 mg, 0.431 mmol) in dimethylformamide was stirred at room temperature for 30 minutes before 3-bromomethyl-4-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (90.7 mg, 0.347 mmol, Example 5) was added. The reaction was stirred at room temperature overnight and then concentrated under reduced pressure to remove dimethylformamide. The residue was dissolved in ethyl acetate, washed with water, dried and concentrated. The crude product was either used directly for the next step or purified by flash chromatography (silica gel, hexanes-ethyl acetate, 90/10 to 50/50) to give pure 3-chloro-N-[3-(4-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-ylmethoxy)-4-methyl-phenyl]-4-fluoro-benzamide as a white solid. (Yield 35.5 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[CH:9]=1)=[O:4].[C:14](Cl)(=[O:16])[CH3:15].[Cl-].[Cl-].[Cl-].[Al+3]>C(=S)=S>[C:14]([C:11]1[CH:12]=[CH:13][C:7]2[O:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:9][C:8]=2[CH:10]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)Cl
Reactant: COC(=O)c1cc2ccccc2o1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: COC(=O)c1cc2cc(C(C)=O)ccc2o1

Procedure:
To a solution of 2-benzofuranoic acid methyl ester in carbon disulphide (240 ml) cooled to 5° C. was added acetyl chloride (70 ml) followed portionwise over 1 hour by aluminium trichloride (40 g). The mixture was heated under reflux for 42 hours before cooling and decanting the carbon disulphide. The residual complex was destroyed by the addition of iced water (50 ml) and 2N HCl (50 ml). The resulting mixture was extracted with ethyl acetate (3×200 ml). The organic layers were combined, washed with water (100 ml), dried (MgSO4) and concentrated. The residue was purified by flash column chromatography, eluting with ethyl acetate/hexane (10:90 to 40:60, v/v), to give methyl 5-acetylbenzofuran-2-carboxylate as a solid (3.099 g); NMR 2.68 (3H,s), 4.00(3H,s), 7.6-8.35(4H,m).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][C:11]([NH:14]C(OC(C)(C)C)=O)([CH3:13])[CH3:12])[CH:5]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][C:11]([NH2:14])([CH3:12])[CH3:13])[CH:5]=1
Reactant: COC(=O)c1cccc(CC(C)(C)NC(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cccc(CC(C)(C)N)c1
Temperature: 25 °C
Yield: 98.3 %

Procedure:
A solution of 3-(2-tert-butoxycarbonylamino-2-methylpropyl)benzoic acid methyl ester (Preparation 33) (1.6 g, 5.2 mmol) in dichloromethane (160 ml) at 0° C. was treated with trifluoroacetic acid (13.6 ml) and left to warm to room temperature over 2 hours. The solvent was removed in vacuo and the product purified by cation exchange chromatography (methanol followed by 2M ammonia in methanol) to yield the title compound as an amber oil (1.06 g).
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:18]2[C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:20])[C:9]=2[C:8](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[CH2:32]([NH2:35])[CH2:33][CH3:34]>>[CH:1]([NH:4][C:5]1[C:18]2[C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:20])[C:9]=2[C:8]([NH:35][CH2:32][CH2:33][CH3:34])=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc(NC(C)C)c3c2C(=O)c2ccccc2C3=O)cc1
Reactant: CCCN
Product: CCCNc1ccc(NC(C)C)c2c1C(=O)c1ccccc1C2=O
Yield: 67 %

Procedure:
1-(isopropylamino)-4-(n-propylamino)anthraquinone was prepared by reaction of 1-(isopropylamino)-4-tosyloxyanthraquinone with n-propyl amine. The isolated and purified reaction product has the structure illustrated below. ##STR13## The yield was 67% and the m.p. 120°-121° C. Mass spec m/e 322 (M+), 307 (M-CH3), 293 (M-C2H5), 279 (307-CO), 251 (M-2CO); 1H-NMR (CD2Cl2)ε10.99 br s, 1H), 10.88 (br s, 1H), 8.39-8.22 (m, 2H); 7.77-7.59 (m, 2H), 7.27 (s, 2H), 3.90 (m, 1H), 3.46-3.28 (m, 2H), 1.81-1.58 (m, 2H), 1.39, 1.32 (d, 6H), 1.26-1.07 (t, 3H); VIS max (Xylenes) 598 nm (ε14 100), 646 (16 200).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]2[C:11](=O)[O:12][C:13](=[O:25])[C:14]=2[C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH3:24])[CH:16]=2)=[CH:2]1.[NH3:27]>CN(C=O)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]2[C:11](=[O:12])[NH:27][C:13](=[O:25])[C:14]=2[C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH3:24])[CH:16]=2)=[CH:2]1
Reactant: N
Reactant: Cn1cc(C2=C(c3csc4ccccc34)C(=O)OC2=O)c2ccccc21
Solvent: CN(C)C=O
Product: Cn1cc(C2=C(c3csc4ccccc34)C(=O)NC2=O)c2ccccc21
Temperature: 140 °C

Procedure:
160 mg of 3-(1-benzothiophen-3-yl)-4-(1-methyl-3-indolyl)furan-2,5-dione were treated with 2 ml of DMF and 20 ml of 33% aqueous ammonia and the mixture was heated at 140° C. for 5 hours. The cooled mixture was filtered and the residue was washed with water and dried. The solid was purified on silica gel with 50% ethyl acetate in petroleum ether to give 20 mg of 3-(1-benzothiophen-3-yl)-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione, m.p. 250°-255° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH3:14])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1)[CH3:2].[Li]CCCC.[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([S@@:27](/[N:29]=[CH:30]/[C:31]2[CH:32]=[CH:33][CH:34]=[C:35]3[C:40]=2[N:39]=[CH:38][CH:37]=[CH:36]3)=[O:28])=[CH:23][CH:22]=1.[NH4+].[Cl-]>C1(C)C=CC=CC=1.C1COCC1.C1(C)C=CC=CC=1>[CH2:1]([N:3]([CH2:13][CH3:14])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([CH:30]([NH:29][S@:27]([C:24]2[CH:23]=[CH:22][C:21]([CH3:20])=[CH:26][CH:25]=2)=[O:28])[C:31]2[CH:32]=[CH:33][CH:34]=[C:35]3[C:40]=2[N:39]=[CH:38][CH:37]=[CH:36]3)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCN(CC)C(=O)c1ccc(I)cc1
Reactant: Cc1ccc([S@](=O)/N=C/c2cccc3cccnc23)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCN(CC)C(=O)c1ccc(C(N[S@@](=O)c2ccc(C)cc2)c2cccc3cccnc23)cc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 23.1 %

Procedure:
N,N-diethyl 4-iodo-benzamide (3.1 g, 10 mmol) was dissolved in dry toluene/THF (9:1, 200 mL) and cooled to −78° C. under nitrogen. n-BuLi (7.8 mL, 1.3 M in hexane, 10 mmol) was added dropwise during 5 to 10 min. After further 5 min, 3 (1.0 g, 3.4 mmol) was added dissolved in toluene. (1 mL). The solution was stirred 10 min, then NH4Cl (aq.) was added. Concentration, aqueous workup and chromatography on silica gave a total of 0.70 g (44%) of a 70:30 mixture of diastereomers. The pure major isomer 5 (0.37 g) was obtained by one more chromatography. 1H NMR (CDCl3): δ 1.2 (m, 6H), 2.4 (s, 3H), 3.4 (m, 4H), 6.35 (d, J=7.5 Hz, 1H), 6.61 (d, J=7.5 Hz, 1H), 7.15–7.55 (m, 11H,) 7.75(m, 1H), 8.12 (m, 1H ), 8.75 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][C:13]2[C:21]3[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=3)[NH:15][C:14]=2[CH3:23])=[CH:8][CH:7]=1)[CH3:2].Br[C:26]1[CH:27]=[N:28][N:29]([CH2:31][CH3:32])[CH:30]=1>>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([S:12][C:13]2[C:21]3[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=3)[N:15]([C:26]3[CH:27]=[N:28][N:29]([CH2:31][CH3:32])[CH:30]=3)[C:14]=2[CH3:23])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCn1cc(Br)cn1
Reactant: CCOC(=O)Cc1ccc(Sc2c(C)[nH]c3cc(Cl)ccc23)cc1
Product: CCOC(=O)Cc1ccc(Sc2c(C)n(-c3cnn(CC)c3)c3cc(Cl)ccc23)cc1

Procedure:
Prepared according to the procedure described in Example 55, Step 2 using the following starting materials: [4-(6-Chloro-2-methyl-1H-indol-3-ylsulfanyl)-phenyl]-acetic acid ethyl ester and 4-bromo-1-ethyl-1H-pyrazole.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[O:11]1[CH2:16][CH2:15][CH:14]([CH2:17][OH:18])[CH2:13][CH2:12]1.[H-].[Na+]>CN(C=O)C>[CH3:7][N:6]1[C:2]([O:18][CH2:17][CH:14]2[CH2:15][CH2:16][O:11][CH2:12][CH2:13]2)=[C:3]([N+:8]([O-:10])=[O:9])[CH:4]=[N:5]1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Reactant: OCC1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ncc([N+](=O)[O-])c1OCC1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.8 %

Procedure:
To a solution of 5-chloro-1-methyl-4-nitro-1H-pyrazole (0.2 g, 1.24 mmol) and tetrahydro-2H-pyran-4-yl-methanol (0.223 g, 1.92 mmol) in DMF (20 mL) cooled to 0° C. was added sodium hydride (60% dispersion in mineral oil, 0.128 g, 3.2 mmol) portionwise. The mixture was warmed to room temperature and stirred for 1 hr. The mixture was concentrated under reduced pressure and the residue dissolved in EtOAc. The organic layer was washed with water, separated and passed through a phase separator cartridge. The solvent was removed under reduced pressure and the crude product was purified via silica gel column chromatography (0-80% EtOAc/isohexane) to give 1-methyl-4-nitro-5-((tetrahydro-2H-pyran-4-yl)methoxy)-1H-pyrazole as a clear oil (143 mg, 48%). 1H NMR (400 MHz, CDCl3) δ 7.98 (s, 1H), 4.28 (d, J=6.3 Hz, 2H), 4.07-3.96 (m, 4H), 3.71 (s, 3H), 2.22-2.09 (m, 1H), 1.82-1.62 (m, 4H)
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:20]([CH2:23][C:24]1[N:31]2[C:27]([S:28][C:29]([CH2:32][O:33][CH3:34])=[N:30]2)=[N:26][C:25]=1[C:35]([F:38])([F:37])[F:36])=[N+]=[N-]>C1COCC1.O>[CH3:34][O:33][CH2:32][C:29]1[S:28][C:27]2=[N:26][C:25]([C:35]([F:38])([F:36])[F:37])=[C:24]([CH2:23][NH2:20])[N:31]2[N:30]=1
Reactant: COCc1nn2c(CN=[N+]=[N-])c(C(F)(F)F)nc2s1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COCc1nn2c(CN)c(C(F)(F)F)nc2s1
Temperature: 25 °C
Reaction time: 60 h
Yield: 88 %

Procedure:
Triphenylphosphine (1.31 g, 4.98 mmol, 1 eq) is added at room temperature to a suspension of 5-(azidomethyl)-2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazole a18 (1.45 g, 4.98 mmol, 1 eq) in THF/H2O (18 ml/2 ml). The reaction mixture is stirred at room temperature for 60 h. The solvent is evaporated under reduced pressure, water is added to the residue, the solution is acidified to pH 2 with aqueous 5N HCl, then extracted with Et2O (1×50 ml). The aqueous layer is basified (pH 8) by addition of a Na2CO3 aqueous solution, and extracted with dichloromethane (2×50 ml), the cumulated organics layers are dried over MgSO4, filtered and evaporated under reduced pressure to afford 1-[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methanamine a19.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][C:5]1([OH:22])[CH2:10][CH2:9][N:8]([C:11]2[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.[H-].[Na+].[CH3:29]I>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[F:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][C:5]1([O:22][CH3:29])[CH2:6][CH2:7][N:8]([C:11]2[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=2)[CH2:9][CH2:10]1
Reactant: CI
Reactant: CCOC(=O)c1ccc(N2CCC(O)(Cc3ccccc3F)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1ccc(N2CCC(Cc3ccccc3F)(OC)CC2)cc1
Reaction time: 0.5 h

Procedure:
A solution of EXAMPLE 1C (17.89 g, 50.1 mmol) in THF (150 mL) and HMPA (33 mL) was treated with NaH (4.0 g of a 60% dispersion, 100 mmol) at 0° C., stirred for 30 minutes, treated with CH3I (20 mL, 321 mmol), and stirred overnight. The reaction mixture was partitioned between ethyl acetate and saturated aqueous NH4Cl. The organic layer was washed with water (2×), dried (MgSO4), and filtered. Filtration of the concentrate provided the desired product which was used without further purification. MS (ESI) m/e 372 (M+H)+.