Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[N:2]1([CH:7]2[CH2:11][CH2:10][NH:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3]1.[O:12]([C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>C(Cl)Cl.C(N(CC)CC)C>[ClH:1].[O:12]([C:19]1[CH:20]=[CH:21][C:22]([C:23]([N:9]2[CH2:10][CH2:11][CH:7]([N:2]3[CH2:6][CH2:5][CH2:4][CH2:3]3)[CH2:8]2)=[O:24])=[CH:26][CH:27]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: C1CCN(C2CCNC2)C1
Reactant: O=C(O)c1ccc(Oc2ccccc2)cc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(Oc2ccccc2)cc1)N1CCC(N2CCCC2)C1
Reaction time: 8 h

Procedure:
A stirred mixture of the HCl salt of 3-(pyrrolidino)pyrrolidine (0.44 g, 2.1 mmol) and 4-phenoxy benzoic acid (0.34 g, 1.6 mmol) in CH2Cl2 is treated with 0.85 mL of triethylamine at room temperature. The reaction mixture is treated with solid benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (1.2 g, 2.4 mmol), stirred overnight under nitrogen, diluted with CH2Cl2, washed sequentially with water and brine, dried over MgSO4 and concentrated in vacuo. The resultant residue is chromatographed and treated with HCl in ether to afford the title compound as a white solid, identified by NMR and MS analyses.
Reaction SMILES: [CH3:1][N:2]1[C@@:6]2([CH2:20][C:9]3[CH:10]=[C:11]4[C:16](=[CH:17][C:8]=3[CH2:7]2)[N:15]=[C:14]([CH:18]=[O:19])[CH:13]=[CH:12]4)[C:5](=[O:21])[NH:4][C:3]1=[O:22].[CH3:23]/C=C(/C=O)\C>O>[CH3:23][C:13]1[C:14]([CH:18]=[O:19])=[N:15][C:16]2[C:11]([CH:12]=1)=[CH:10][C:9]1[CH2:20][C@@:6]3([CH2:7][C:8]=1[CH:17]=2)[C:5](=[O:21])[NH:4][C:3](=[O:22])[N:2]3[CH3:1]
Reactant: CN1C(=O)NC(=O)[C@]12Cc1cc3ccc(C=O)nc3cc1C2
Reactant: C/C=C(\C)C=O
Solvent: O
Product: Cc1cc2cc3c(cc2nc1C=O)C[C@]1(C3)C(=O)NC(=O)N1C

Procedure:
Essentially following the procedures described for Intermediate 13, but using trans-2-methyl-2-butenal in place of crotonaldehyde, the title compound was prepared. MS: m/z=327 (M+1+H2O).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]([OH:9])=O)=[CH:3]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:21]([O:28][C:29](=[O:33])[CH2:30][CH2:31][NH2:32])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.P(C#N)(=O)(OCC)OCC.C(N(CC)CC)C>CN(C)C=O>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]([NH:32][CH2:31][CH2:30][C:29]([O:28][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:33])=[O:9])=[CH:3]1
Reactant: NCCC(=O)OCc1ccccc1
Reactant: Cn1ccc(C(=O)O)c1
Agent: CCOP(=O)(C#N)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1ccc(C(=O)NCCC(=O)OCc2ccccc2)c1

Procedure:
Into a solution of 5.01 g (40 mmol) of 1-methyl-3-pyrrolecarboxylic acid and 16.87 g (48 mmol) of β-alanine benzyl ester p-toluenesulfonate in 200 ml of dimethylformamide (hereinafter called “DMF”), a solution of 7.83 g (48 mmol) of diethyl phosphorocyanidate in 50 ml of DMF was added dropwise under ice cooling and stirring. A solution of 9.71 g (96 mmol) of triethylamine in 50 ml of DMF was then added dropwise, and the reaction mixture was stirred at room temperature for 67 hours.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([CH3:13])[CH:7]2[CH3:12].[BH4-].[Na+]>CO>[NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:13])[CH:7]2[CH3:12]
Reactant: CC1c2cccc(N)c2C=CN1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC1c2cccc(N)c2CCN1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.4 %

Procedure:
To an ice cold solution of 5-amino-1,2-dihydro-1,2-dimethyl isoquinoline (4 g, 23.2 mmol) in methanol (80 ml) was added sodium borohydride (3.51 g, 92.8 mmol) portionwise. The mixture was allowed to stir at room temperature overnight before concentration in vacuo; the residue was then partitioned between water and dichloromethane. The organic layer was dried over sodium sulfate and concentrated in vacuo to afford a light brown oil (4.023 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][C:9]([NH:11][CH3:12])=S.O1CCCC1>[Hg]=O.C(#N)C>[CH3:12][NH:11][C:9]1[NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[N:8]=1
Reactant: CNC(=S)Nc1ccncc1N
Agent: O=[Hg]
Solvent: C1CCOC1
Solvent: CC#N
Product: CNc1nc2ccncc2[nH]1

Procedure:
A mixture of 7.3 parts of N-(3-amino-4-pyridinyl)-N'-methylthiourea, 15 parts of mercury (II)oxide, 90 parts of tetrahydrofuran and 80 parts of acetonitrile was stirred and refluxed for 20 hours. The reaction mixture was filtered hot over Hyflo and the filter-cake was washed with 240 parts of boiling ethanol. The filtrate was evaporated in vacuo and the residue was boiled in acetonitrile. The product was filtered off and dried, yielding 5 parts of N-methyl-3H-imidazo[4,5-c]pyridin-2-amine; mp. 255.7° C. (intermediate 96).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7](=[O:12])[C:8]([F:11])([F:10])[F:9])[O:5][CH:6]=1.[C:13]([C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1)([OH:15])=[O:14]>>[F:9][C:8]([F:11])([F:10])[C:7]([C:4]1[O:5][CH:6]=[C:2]([C:20]2[CH:21]=[C:16]([CH:17]=[CH:18][CH:19]=2)[C:13]([OH:15])=[O:14])[CH:3]=1)=[O:12]
Reactant: O=C(c1cc(Br)co1)C(F)(F)F
Reactant: O=C(O)c1cccc(B(O)O)c1
Product: O=C(O)c1cccc(-c2coc(C(=O)C(F)(F)F)c2)c1
Yield: 26 %

Procedure:
This compound was synthesized from 1-(4-bromofuran-2-yl)-2,2,2-trifluoroethanone and 3-carboxyphenylboronic acid as described in example 88 step 3 (150 mg, yield 26%) as a pale yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 13.14 (br s, 1H), 8.99 (s, 1H), 8.44 (s, 1H), 8.31 (m, 1H), 8.07-8.04 (m, 1H), 7.93-7.90 (m, 1H), 7.60-7.55 (t, J=7.7 Hz, 1H). MS (ESI) m/z: Calculated for C13H7F3O4: 284.03. found: 282.9 (M−H)−.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.CC([Si](C)(C)[O:24][C@H:25]1[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C@@H:26]1[CH3:37])(C)C>C1COCC1>[OH:24][C@H:25]1[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C@@H:26]1[CH3:37]
Reactant: C[C@@H]1[C@@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@@H]1[C@@H](O)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Tetrabutyl ammonium fluoride (16.7 mL, 1N in THF, 16.73 mmol) was added to a solution of 1,1-dimethylethyl(2R,3S)-3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-2-methyl-1-pyrrolidinecarboxylate in THF and stirred for 16 hours at room temperature. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography to yield the title compound (1.55 g, 7.8 mmol). 1H NMR (400 MHz, DMSO-D6) δ ppm 1.0 (m, 3 H) 1.4 (s, 9 H) 1.6 (m, 1 H) 1.9 (m, 1 H) 3.3 (m, 2 H) 3.5 (m, 1 H) 3.8 (m, 1 H) 4.9 (s, 1 H). ES+=202.15.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[C:8]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[C:12]([O:19][CH2:20][CH3:21])[CH:11]=1)#[N:9]>C1C=CC=CC=1.CO>[C:8]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([O:16][CH3:1])=[O:15])=[C:12]([O:19][CH2:20][CH3:21])[CH:11]=1)#[N:9]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CCOc1cc(C#N)ccc1C(=O)O
Solvent: c1ccccc1
Solvent: CO
Product: CCOc1cc(C#N)ccc1C(=O)OC
Reaction time: 1 h
Yield: 72.3 %

Procedure:
(Trimethylsilyl)diazomethane (2 M in hexanes, 1.47 mL, 2.93 mmol) was added to a solution of 4-cyano-2-ethoxybenzoic acid (280 mg, 1.47 mmol) in benzene (8.0 mL) and methanol (1.6 mL). The reaction was stirred for 1 h and then degassed with air for 30 min. Evaporation of the solvent and purification of the crude residue by flash column chromatography (silica gel, eluting with 0-20% ethyl acetate in hexanes) gave methyl 4-cyano-2-ethoxybenzoate as a yellow solid (218 mg, 71%).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][NH:4]1.S(O[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1)(=O)(=O)C.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(#N)C>[OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]1[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1
Reactant: COc1cccc(CCOS(C)(=O)=O)c1
Reactant: OC[C@H]1CCCCN1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: COc1cccc(CCN2CCCC[C@@H]2CO)c1
Temperature: 90 °C

Procedure:
(R)-2-hydroxymethylpiperidine (288 mg, 2.50 mmol), 3-methoxyphenethyl mesylate (863 mg, 3.75 mmol), sodium carbonate (398 mg, 3.75 mmol) and sodium iodide (30 mg, 0.20 mmol) were added to acetonitrile (25 ml), and they were heated under reflux at 90° C. for 6 hours. The solvent was evaporated under reduced pressure. The residue was distributed in ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with water and dried over magnesium sulfate. Then the solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography. The product was eluted with dichloromethane and then with dichloromethane and methanol (20:1). The appropriate fractions were combined, and the solvent was evaporated under reduced pressure to obtain (R)-2-hydroxymethyl-1-(3-methoxyphenethyl) piperidine in the form of a light yellow oil (322 mg, 52%).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18](=O)[CH2:19][O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:13](=[O:28])[CH2:12]1)=[O:10])[CH3:7].O>O1CCOCC1>[CH2:6]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]2[N:17]=[C:18]([CH2:19][O:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[O:28][C:13]=2[CH2:12]1)=[O:10])[CH3:7]
Reactant: CCOC(=O)N1CCC(NC(=O)COc2ccccc2)C(=O)C1
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: CCOC(=O)N1CCc2nc(COc3ccccc3)oc2C1
Temperature: 100 °C
Reaction time: 2 h
Yield: 84.5 %

Procedure:
Phosphorus oxychloride (9.3 mL, 99.9 mmol) was added to a stirred solution of 3-oxo-4-(2-phenoxy-acetylamino)-piperidine-1-carboxylic acid ethyl ester (30.3 g, 90.8 mmol) in 1,4-dioxane (454 mL). The mixture was stirred at 100° C. for 2 hours. The mixture was cooled at 0° C., treated with water and extracted with AcOEt. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The product was purified by flash column chromatography (AcOEt in DCM 0/100 to 30/70). The desired fractions were collected and evaporated in vacuo to yield 2-phenoxymethyl-6,7-dihydro-4H-oxazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester (23.2 g, 84% yield) as a colourless oil.
Reaction SMILES: [F:1][C:2]1([F:23])[C:6](=[CH2:7])[CH2:5][N:4](C(OC(C)(C)C)=O)[C:3]1([C:16]1[C:17]([F:22])=[N:18][CH:19]=[CH:20][CH:21]=1)O.Cl>C(O)(=O)C>[F:23][C:2]1([F:1])[C:3]([C:16]2[C:17]([F:22])=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:4][CH2:5][C:6]1=[CH2:7]
Reactant: C=C1CN(C(=O)OC(C)(C)C)C(O)(c2cccnc2F)C1(F)F
Agent: Cl
Solvent: CC(=O)O
Product: C=C1CN=C(c2cccnc2F)C1(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
To a solution of tert-butyl 3,3-difluoro-2-(2-fluoropyridin-3-yl)-2-hydroxy-4-methylenepyrrolidine-1-carboxylate (20.0 g) in acetic acid (70 mL) was added dropwise concentrated hydrochloric acid (20 mL). The obtained mixture was stirred at room temperature for 1 hr, and concentrated under reduced pressure. Saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane:ethyl acetate=2:1) to give the title compound as a yellow oil (yield 11.6 g, 90%).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:12]=[CH:11][C:4]=2[N:5]([CH3:10])[C:6](=[O:9])[CH2:7][N:8]=1.C1(B(O)O)C=CC=CC=1.[Cl:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1B(O)O>>[Cl:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:2]1[C:3]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:12]=[CH:11][C:4]=2[N:5]([CH3:10])[C:6](=[O:9])[CH2:7][N:8]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: CN1C(=O)CN=C(Cl)c2cc(-c3ccccc3)ccc21
Agent: OB(O)c1ccccc1
Product: CN1C(=O)CN=C(c2ccccc2Cl)c2cc(-c3ccccc3)ccc21
Yield: 61 %

Procedure:
Prepared from 5-chloro-1-methyl-7-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one using the same method described for Example 9 and instead of using benzene boronic acid, we used 2-chlorophenyl boronic acid. The title compound (115 mg) was obtained as a beige solid, (yield=61%).
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([CH2:9][CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[S:8][C:4]=2[CH:3]=1.Cl[C:19]1[N:24]=[CH:23][C:22]([CH2:25][CH2:26][CH3:27])=[CH:21][N:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([CH2:9][CH:10]3[CH2:11][CH2:12][N:13]([C:19]4[N:24]=[CH:23][C:22]([CH2:25][CH2:26][CH3:27])=[CH:21][N:20]=4)[CH2:14][CH2:15]3)[S:8][C:4]=2[CH:3]=1
Reactant: CCCc1cnc(Cl)nc1
Reactant: Brc1ccc2nc(CC3CCNCC3)sc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1cnc(N2CCC(Cc3nc4ccc(Br)cc4s3)CC2)nc1
Temperature: 110 °C
Reaction time: 3 h
Yield: 47.8 %

Procedure:
To a solution of 6-bromo-2-(piperidin-4-ylmethyl)benzo[d]thiazole (380 mg, 1.221 mmol) and 2-chloro-5-propylpyrimidine (249 mg, 1.587 mmol) in DMF (8 mL) was added potassium carbonate (675 mg, 4.88 mmol). The reaction mixture was stirred at 110° C. for 3 h. The reaction mixture was cooled to rt, diluted with water (15 mL), and extracted with EtOAc (3×10 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated. The crude product was purified by column chromatography (silica gel, hexanes-EtOAc gradient 0 to 50% EtOAc) to afford 6-bromo-2-((1-(5-propylpyrimidin-2-yl)piperidin-4-yl)methyl)benzo[d]thiazole (252 mg, 0.584 mmol, 48% yield) as a light brown solid. LCMS (m/z)=432 (M+H)+.
Reaction SMILES: Cl.Cl.COC1C=CC(N2CCNCC2)=CC=1.C(Cl)(=O)CC(C)C.[F:24][C:25]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([F:33])=[CH:27][C:26]=1[N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.[CH2:40]([S:48](Cl)(=[O:50])=[O:49])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]>>[F:24][C:25]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([F:33])=[CH:27][C:26]=1[N:34]1[CH2:39][CH2:38][N:37]([S:48]([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])(=[O:50])=[O:49])[CH2:36][CH2:35]1
Reactant: COc1cc(F)c(N2CCNCC2)cc1F
Reactant: CCCCCCCCS(=O)(=O)Cl
Agent: CC(C)CC(=O)Cl
Agent: COc1ccc(N2CCNCC2)cc1
Agent: Cl
Product: CCCCCCCCS(=O)(=O)N1CCN(c2cc(F)c(OC)cc2F)CC1

Procedure:
Production Example 3 was repeated except that 1-(4-methoxyphenyl)piperazine dihydrochloride and isovaleryl chloride were replaced with 1-(2,5-difluoro-4-methoxyphenyl)-piperazine (456 mg) and 1-octanesulfonyl chloride (470 μL), respectively, to provide crude 4-(2,5-difluoro-4-methoxyphenyl)-1-(octylsulfonyl)piperazine (681 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+].Cl>CO>[Cl:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=2)[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(-c2cnn(C)c2)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1cc(-c2ccc(C(=O)O)c(Cl)c2)cn1

Procedure:
To a solution of 2-chloro-4-(1-methyl-1H-pyrazol4-yl)-benzoic acid, methyl ester (6.25 ) from Example 113 in methanol (80 ml) was added 1N sodium hydroxide (30 ml). The reaction was heated under reflux for one hour. The volume of solvent was reduced in vacuo by three quarters and the residue treated with 2N hydrochloric acid at 0° C. A precipitate was filtered and dried in vacuo to yield 5.84 g the title compound, MS m/z: 237 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:4]=1[NH2:5].[N+:12]([C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([N+:24]([O-:26])=[O:25])[CH:23]=1)[C:18](Cl)=[O:19])([O-:14])=[O:13].O>C(#N)C.CC(N(C)C)=O.N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:4]=1[NH:5][C:18](=[O:19])[C:17]1[CH:16]=[C:15]([N+:12]([O-:14])=[O:13])[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=1
Reactant: COc1ccc(OC)c(N)c1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Solvent: CC#N
Solvent: CC(=O)N(C)C
Solvent: c1ccncc1
Product: COc1ccc(OC)c(NC(=O)c2cc([N+](=O)[O-])cc([N+](=O)[O-])c2)c1
Reaction time: 3 h
Yield: 106.2 %

Procedure:
In 2 l of acetonitrile, 1.2 l of dimethylacetamide and 0.186 l of pyridine was dissolved 306.4 g of 2,5-dimethoxyaniline. While cooling the resulting solution with ice, 507.8 g of 3,5-dinitrobenzoyl chloride was slowly added thereto. While keeping the temperature of the reaction mixture at 15° C., the mixture was stirred for 3 hours and poured into 600 ml of water. The precipitated crystal was recovered by filtration, washed with acetonitrile and dried to obtain 737.5 g of the compound (7-A). Yield: 99%.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:27](OC)=[O:28])=[C:7]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[N:8]2[C:16]3[CH:15]=[CH:14][C:13]([O:17][CH3:18])=[CH:12][C:11]=3[CH2:10][C:9]=12)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].[H-].[OH-].[Na+]>ClCCl.CCOCC.O>[OH:28][CH2:27][C:6]1[C:5]([CH2:3][OH:2])=[C:9]2[CH2:10][C:11]3[CH:12]=[C:13]([O:17][CH3:18])[CH:14]=[CH:15][C:16]=3[N:8]2[C:7]=1[C:19]1[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=1
Reactant: COC(=O)c1c(C(=O)OC)c(-c2ccc(OC)cc2)n2c1Cc1cc(OC)ccc1-2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: ClCCl
Solvent: CCOCC
Product: COc1ccc(-c2c(CO)c(CO)c3n2-c2ccc(OC)cc2C3)cc1
Reaction time: 0.25 h

Procedure:
A solution of 6-methoxy-3-(4-methoxyphenyl)-8H-3a-aza-cyclopenta[a]indene-1,2-dicarboxylic acid dimethyl ester (1.73 g, 3.56 mmol) in anhydrous dichloromethane (20 mL) was added dropwise to a stirred suspension of LiAlH4 (0.45 g, 11.85 mmol) in anhydrous ether (40 mL) at 0° C. The mixture was stirred for 15 min after the addition was completed. The excess hydride was carefully decomposed by the slow, sequential addition of water (1 mL), 15% NaOH aqueous solution (1 mL), and water (3 mL). The solid inorganic salt was removed by filtration and washed with dichloromethane. The combined filtrate and washings was concentrated in vacuo to dryness. The solid product was suspended in ether, collected by filtration, and dried to yield (2-hydroxymethyl-6-methoxy-3-(4-methoxyphenyl)-8H-3a-azacyclopenta[a]inden-1-yl)methanol (DA-1130), 1.35 g (91%): mp 186-187° C.; 1H NMR (DMSO-d6) δ 3.71 and 3.84 (each 3H, s, 2×OMe), 3.87 (2H, s, CH2), 4.24 and 4.53 (each 2H, d, J=4.4 Hz, 2×CH2O), 4.56 and 4.71 (each 1H, t, J=4.4 Hz, exchangeable, 2×OH), 6.64 (1H, d, J=8.7 Hz, ArH), 6.69 (1H, dd, J=2.5 Hz and J=8.7 Hz, ArH), 7.07 (2H, d, J=8.7 Hz, 2×ArH), 7.10 (1H, d, J=2.3 Hz, ArH), 7.40 (2H, d, J=8.7 Hz, 2×ArH). Anal. Calcd. for C21H21NO4.1.3H2O: C, 67.29; H, 6.29; N, 3.74. Found: C, 67.19; H, 5.90; N, 3.58.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:11][O:12][CH2:13][CH2:14][OH:15].[NH2:16][C:17]1[CH:24]=[C:23](F)[C:20]([C:21]#[N:22])=[CH:19][N:18]=1>C1COCC1>[NH2:16][C:17]1[CH:24]=[C:23]([O:15][CH2:14][CH2:13][O:12][CH3:11])[C:20]([C:21]#[N:22])=[CH:19][N:18]=1
Reactant: COCCO
Reactant: N#Cc1cnc(N)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: COCCOc1cc(N)ncc1C#N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of KHMDS in THF (1 M, 48.1 ml, 48.1 mmol) was added to a solution of 2-methoxy ethanol (1.68 g, 21.88 mmol) in THF (90 ml) at room temperature. After 2 minutes 6-amino-4-fluoronicotinonitrile (intermediate 21, 3.00 g, 21.9 mmol) was added and the reaction mixture stirred for 16 h at room temperature. The reaction mixture was partitioned between saturated aqueous NH4Cl and EtOAc, extracted with EtOAc (2×), the combined EtOAc layers were washed with brine, dried over MgSO4 and evaporated. The residue was triturated with EtOAc and the title compound obtained by filtration as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ 8.14 (s, 1H), 6.91 (s, br, 2H), 6.03 (s, 1H), 4.19-4.13 (m, 2H), 3.34-3.28 (m, 2H), 2.51 (s, 3H).
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:24])[NH:9][C:10]2[S:11][CH:12]=[C:13]([C:15](=O)[C:16]([O:18][CH2:19][CH:20]([CH3:22])[CH3:21])=[O:17])[N:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:25]1[CH2:31][C:29](=[O:30])[N:28]([CH2:32][C:33]([OH:35])=[O:34])[C:26]1=[S:27].[Cl-].[NH4+].N>C(O)C>[CH2:19]([O:18][C:16]([C:15](=[C:31]1[S:25][C:26](=[S:27])[N:28]([CH2:32][C:33]([OH:35])=[O:34])[C:29]1=[O:30])[C:13]1[N:14]=[C:10]([NH:9][C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:24])[S:11][CH:12]=1)=[O:17])[CH:20]([CH3:22])[CH3:21]
Reactant: O=C(O)CN1C(=O)CSC1=S
Reactant: CC(C)COC(=O)C(=O)c1csc(NC(=O)Nc2ccccc2)n1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)COC(=O)C(=C1SC(=S)N(CC(=O)O)C1=O)c1csc(NC(=O)Nc2ccccc2)n1

Procedure:
Following a procedure similar to that described in Example 1, the desired compound was prepared from 160 mg of isobutyl 2-(3-phenylureido)thiazol-4-ylglyoxylate, 90 mg of rhodanine-3-acetic acid, 50 mg of ammonium chloride, 0.05 ml of 28% v/v aqueous ammonia and 2 ml of ethanol. The resulting product was a yellow powder having the following physical properties.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][C:11]2[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[NH:13][C:12]=2[CH:20]=O)[CH2:4][CH2:3]1.[CH3:22][NH:23][S:24]([C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][C:31](=[O:36])[CH2:30]2)(=[O:26])=[O:25]>>[CH3:22][NH:23][S:24]([C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][C:31](=[O:36])/[C:30]/2=[CH:20]\[C:12]1[NH:13][C:14]2[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=2[C:11]=1[CH2:10][CH2:9][CH2:8][N:5]1[CH2:4][CH2:3][CH:2]([OH:1])[CH2:7][CH2:6]1)(=[O:26])=[O:25]
Reactant: CNS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: O=Cc1[nH]c2c(c1CCCN1CCC(O)CC1)CCCC2
Product: CNS(=O)(=O)c1ccc2c(c1)/C(=C/c1[nH]c3c(c1CCCN1CCC(O)CC1)CCCC3)C(=O)N2

Procedure:
3-[3-(4-Hydroxy-piperidin-1-yl)-propyl]-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde (58 mg, 0.2 mmol) was condensed with 5-methylaminosulfonyloxindole (45 mg, 0.2 mmol) following the procedure used in Example 1 to provide (66 mg, 67%yield) of the desired compound.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH3:21])[N:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:20]([C:16]1[N:15]=[C:14]([C:12]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:13]=2)[CH:19]=[CH:18][CH:17]=1)[CH3:21]
Reactant: CCc1cccc(C#N)n1
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 22.4 %

Procedure:
A mixture of methyl thiosalicylate (1.3 g, 7.5 mmol), 2-cyano-6-ethylpyridine (0.99 g, 7.5 mmol), triethylamine (1.60 ml, 11.5 mmol) and toluene (6.0 ml) was refluxed for 16 hrs. After cooling, the precipitated crystals were collected by filtration and recrystallized from ethanol to give the titled compound (0.45 g, 22%).