Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[C:18]([N+:20]([O-])=O)[CH:17]=[CH:16][C:4]=1[O:5][CH2:6][CH2:7][N:8]1[CH:13]([CH3:14])[CH2:12][CH2:11][CH2:10][CH:9]1[CH3:15]>ClCCl.CO>[CH3:15][CH:9]1[CH2:10][CH2:11][CH2:12][CH:13]([CH3:14])[N:8]1[CH2:7][CH2:6][O:5][C:4]1[CH:16]=[CH:17][C:18]([NH2:20])=[CH:19][C:3]=1[O:2][CH3:1]
Reactant: COc1cc([N+](=O)[O-])ccc1OCCN1C(C)CCCC1C
Solvent: ClCCl
Solvent: CO
Product: COc1cc(N)ccc1OCCN1C(C)CCCC1C

Procedure:
Prepared analogously to Example 3.1.b. from 0.84 g (2.72 mmol) of 1-[2-(2-methoxy-4-nitrophenoxy)ethyl]-2,6-dimethylpiperidine. Yield: 0.65 g (86% of theory); C16H26N2O2 (M=278.39); calc.: molecular ion peak (M+H)+: 279; found: molecular ion peak (M+H)+: 279; Rf value: 0.1 (silica gel, dichloromethane/methanol (9:1)).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]2([CH2:17][CH2:16][CH2:15][NH:14][CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:18](OC(=O)C)(=[O:20])[CH3:19].C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]2([CH2:17][CH2:16][CH2:15][N:14]([C:18](=[O:20])[CH3:19])[CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC2(CCCNC2)C1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCCC2(CCN(C(=O)OC(C)(C)C)C2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.1 %

Procedure:
To a solution of 2,7-diaza-spiro[4.5]decane-2-carboxylic acid tert-butyl ester (140 mg, 0.58 mmol) in DCM (5.8 mL) was added acetic anhydride (82 μL, 0.87 mmol) and triethylamine (244 μL, 1.75 mmol) and the reaction mixture was stirred (rt, 16 h). The reaction mixture was diluted with DCM (6 mL), washed with water (3×4 mL) and brine (1×4 mL). The organic layer was dried, filtered and concentrated in vacuo to provide 7-acetyl-2,7-diaza-spiro[4.5]decane-2-carboxylic acid tert-butyl ester as a brown oil (164 mg, 100%). This intermediate was dissolved in DCM (0.75 mL), treated with HCl (4M in dioxane, 0.75 mL) and stirred (rt, 16 h). The dispersion was concentrated in vacuo to yield then desired product (128 mg, 100%). MS (ESI): mass calcd. for C10H18N2O, 182.14; m/z found, 183.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:20])[CH:5]=[C:6]([Cl:19])[C:7]=1[O:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:12]=2[N:13]=1.[N+:21]([C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[S:34](Cl)(=[O:36])=[O:35])([O-:23])=[O:22]>>[Cl:19][C:6]1[CH:5]=[C:4]([NH:20][S:34]([C:25]2[CH:26]=[CH:27][C:28]([C:30]([F:32])([F:33])[F:31])=[CH:29][C:24]=2[N+:21]([O-:23])=[O:22])(=[O:35])=[O:36])[CH:3]=[C:2]([Cl:1])[C:7]=1[O:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: Nc1cc(Cl)c(Oc2nc3ccc(Cl)cc3s2)c(Cl)c1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1S(=O)(=O)Cl
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1S(=O)(=O)Nc1cc(Cl)c(Oc2nc3ccc(Cl)cc3s2)c(Cl)c1

Procedure:
N-[3,5-Dichloro-4-(6-chloro-benzothiazol-2-yloxy)-phenyl]-2-nitro-4-trifluoromethyl-benzenesulfonamide was synthesized (48%) from 3,5-dichloro-4-(6-chloro-benzothiazol-2-yloxy)-phenylamine (420) and 2-nitro-4-trifluoromethylbenzenesulfonyl chloride (Aldrich) in a similar manner as described in Examples 70-91. 1H NMR (400 MHz, DMSO-d6) δ 11.65 (br s, 1H), 8.61 (s, 1H), 8.32-8.28 (m, 2H), 8.15 (d, J=2.2 Hz, 1H), 7.68 (d, J=8.7 Hz, 1H), 7.46 (dd, J=8.7, 2.2 Hz, 1H), 7.34 (s, 2H). MS (EI): m/z 596 (M−H).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH2:24].[OH-].[Na+].OO>C1COCC1.C(Cl)(Cl)Cl>[NH:19]1[C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[N:16]=[C:15]1[CH:14]([CH:11]1[CH2:10][CH2:9][CH:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:13][CH2:12]1)[OH:24]
Reactant: C(=C1CCC(Cc2ccccc2)CC1)c1nc2ccccc2[nH]1
Reactant: O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: OC(c1nc2ccccc2[nH]1)C1CCC(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Example 3 was prepared by the following procedure. To a stirred solution of 20 mg of 2-(4-benzyl-cyclohexylidenemethyl)-1H-benzimidazole in 10 mL of THF cooled in an ice bath was added 1 mL of 1M borane·TBF. After stirring for 24 h warming to room temperature, 0.5 mL of water was added followed by 0.5 mL of 6N sodium hydroxide and 0.5 mL of 30% hydrogen peroxide. After 30 min, the solution was diluted with 100 mL of chloroform, washed 2×10 mL of water, dried over magnesium sulfate and concentrated to dryness.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[C:5]([CH2:7][C:8](OCC)=[O:9])#[N:6]>>[C:5]([CH2:7][C:8]([NH:4][CH:1]1[CH2:3][CH2:2]1)=[O:9])#[N:6]
Reactant: NC1CC1
Reactant: CCOC(=O)CC#N
Product: N#CCC(=O)NC1CC1
Temperature: 45 °C
Reaction time: 1.5 h
Yield: 100.1 %

Procedure:
To a flask charged with cyclopropylamine (12.3 g, 215.3 mmol) was added ethyl cyanoacetate (9.8 g, 86.1 mmol). The reaction was stirred at 45° C. for 1.5 hour, cooled and concentrated under reduced pressure to give 10.7 g title compound (˜100%) as a light yellow solid. 1H NMR (300.132 MHz, CDCl3) δ 6.20 (bs, 1H), 3.34 (s, 2H), 2.75 (m, 2H), 0.83 (m, 2H), 0.59 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:18])[C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17])[NH2:5].[Cl:19]N1C(=O)CCC1=O.C1C=CC=CC=1>C(OCC)(=O)C.ClN1C(=O)CCC1=O>[F:17][C:11]1[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]=1[O:9][C:8]1[C:2]([Cl:1])=[CH:3][C:4]([NH2:5])=[C:6]([Cl:19])[C:7]=1[Cl:18]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1cc(Cl)c(Oc2ccc(F)cc2F)c(Cl)c1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: Nc1cc(Cl)c(Oc2ccc(F)cc2F)c(Cl)c1Cl
Reaction time: 1 h
Yield: 58.8 %

Procedure:
Into a 300 milliliter round bottom reaction flask was charged 14.9 grams (51.4 mmol) of 3,5-dichloro-4-(2,4-difluorophenoxy) aniline, 7.2 grams (53.9 mmol) of N-chlorosuccinimide (NCS), and 100 milliliters of benzene. The reaction mixture was refluxed for 2 hours after which time additional NCS (350 milligrams, 2.6 mmol) was added. Reflux was then continued for an additional 1 hour. The mixture was allowed to cool, diluted with ethyl acetate (200 milliliters), washed with H2O, saturated NaHCO3 and brine; dried over Na2SO4 and concentrated under reduced pressure. The oily product obtained was purified by flash column chromatography (1:1 hexane toluene) to afford 4-(2,4-difluorophenoxy)-2,3,5-trichloroaniline (9.8 grams, 30.2 mmol, 59%) as a dark brown oil. The structure of this material was verified by its H'-NMR spectrum (CDCl3) 7.30-6.10 (m, 3H), 6.75 (s, 1H), 4.18 (br s, 2H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH3:4].[C:5]1([CH:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]([OH:15])[CH2:13]Br)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(O)C>[CH3:1][N:2]([CH2:13][CH:12]([OH:15])[CH:11]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:3][CH3:4]
Reactant: OC(CBr)C(c1ccccc1)c1ccccc1
Reactant: CCNC
Solvent: CCO
Product: CCN(C)CC(O)C(c1ccccc1)c1ccccc1

Procedure:
Excess N methyl-N-ethylamine was added to a solution of 1,1 -diphenyl-3-bromo-propan-2-ol (2 g.) in ethanol. After 60 hours the solution was evaporated and the residue was evaporated and the residue dissolved in dilute hydrochloric acid and ether. Basification of the acid extract and subsequent isolation through ether in the usual manner gave 3-(N-methyl-N-ethylamino)-1,1 -diphenyl-propan-2-ol isolated as the hydrochloride (1 25 g., 60%), m.p. 159° - 161°.
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9]2[C:14]([CH2:15][C:16]([OH:18])=[O:17])=[CH:13][C:12]([NH:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:11][N:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:27]O>CCOC(C)=O>[CH3:27][O:17][C:16](=[O:18])[CH2:15][C:14]1[C:9]([NH:8][CH2:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[N:10][CH:11]=[C:12]([NH:19][C:20](=[O:25])[C:21]([CH3:22])([CH3:24])[CH3:23])[CH:13]=1
Reactant: CO
Reactant: CC(C)(C)C(=O)Nc1cnc(NCC2CCCCC2)c(CC(=O)O)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)Cc1cc(NC(=O)C(C)(C)C)cnc1NCC1CCCCC1
Reaction time: 8 h
Yield: 90 %

Procedure:
To a solution of the product 2-[(cyclohexylmethyl)amino]-5-[(2,2-dimethyl-1-oxopropyl)amino]-3-pyridineacetic acid in dry MeOH (7.5 mL) was added 4N HCl solution (in dioxane, 2.5 mL) at 0° C. The reaction mixture was stirred overnight at r.t, and then condensed under vacuum, diluted with AcOEt (50 mL), washed with 1N NH4OH (100 mL), brine (50 mL), and dried over MgSO4. Removal of solvent afforded desired title product (325 mg, 90%). 1H-NMR (CDCl3): δ 0.98 (m, 2H), 1.19 (m, 3H), 1.24 (s, 9H), 1.58 (m, 1H), 1.67 (m, 3H), 1.76 (m, 2H), 3.20 (d, J=6.8 Hz, 2H), 3.39 (s, 2H), 3.63 (s, 3H), 4.98 (brs, 1H), 7.24 (brs, 1H), 7.680 (s, 1H), 7.92 (s, 1H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[C:6]([N+:26]([O-:28])=[O:27])=[C:7]([CH2:12][S:13]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH:8]=[C:9](F)[CH:10]=1.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>CN(C=O)C.O>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([N:33]2[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]2)[CH:8]=[C:7]([CH2:12][S:13]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])[C:6]=1[N+:26]([O-:28])=[O:27]
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1c(CS(=O)(=O)c2cccc3ccccc23)cc(F)cc1OCCCl
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCN(c2cc(CS(=O)(=O)c3cccc4ccccc34)c([N+](=O)[O-])c(OCCCl)c2)CC1
Temperature: 40 °C
Reaction time: 10 h
Yield: 850 %

Procedure:
A mixture of 1-[3-(2-chloroethoxy)-5-fluoro-2-nitrophenylmethanesulfonyl]-naphthalene (0.42 g, 0.1 mmoles) and N-methylpiperazine (0.168 g, 1.1 mmoles) in DMF was stirred under nitrogen at 40° C. for 10 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc. The extracts were combined, washed sequentially with water and brine, dried over Na2SO4, and concentrated under vacuum to afford the title compound (0.45 g, 0.85 mmoles), identified by HNMR and mass spectral analysis.
Reaction SMILES: [Cl:1][C:2]1[C:3]([I:15])=[CH:4][C:5]2[N:9]=[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])[NH:7][C:6]=2[CH:14]=1.[H-].[Na+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C>[CH2:18]([N:7]1[C:6]2[CH:14]=[C:2]([Cl:1])[C:3]([I:15])=[CH:4][C:5]=2[N:9]=[C:8]1[S:10]([CH3:13])(=[O:12])=[O:11])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: CS(=O)(=O)c1nc2cc(I)c(Cl)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1nc2cc(I)c(Cl)cc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 6-chloro-5-iodo-2-methanesulfonyl-1H-benzoimidazole (12.1 g, 34 mmol) in DMF (100 ml) at 0° C. was added NaH (60% dispersion in mineral oil, 1.5 g, 38 mmol). After 10 minutes, the mixture was warmed to rt and stirred for 45 minutes. Benzyl bromide (6.4 g, 38 mmol) was then slowly added and the reaction was stirred overnight at rt. The volatiles were then removed by rotary evaporation and the residue was partitioned between EtOAc and half-saturated ammonium chloride solution. The resulting emulsion was filtered through celite to obtain a cleaner partition. The EtOAc layer was washed with H2O, brine, and dried with MgSO4. After rotary evaporation, the oily residue was stirred in diethyl ether overnight. The mixture was filtered and the beige solid thus obtained was dried under vacuum at rt for 24 hours to yield the title compound. The filtrate was evaporated to an oil and purified by flash chromatography (SiO2, 220 g). A second crop of the title compound was eluted from the column with 40% EtOAc in hexane.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[C@@H:9]([CH2:10][N:11]=[N+]=[N-])[O:8][CH2:7][O:6]1)=[N+]=[N-]>C(O)C.[Pd]>[NH2:1][CH2:4][C@@H:5]1[C@@H:9]([CH2:10][NH2:11])[O:8][CH2:7][O:6]1
Reactant: [N-]=[N+]=NC[C@H]1OCO[C@@H]1CN=[N+]=[N-]
Agent: [Pd]
Solvent: CCO
Product: NC[C@H]1OCO[C@@H]1CN
Yield: 97.3 %

Procedure:
A solution of (4R,5R)-4,5-bis(azidomethyl)-1,3-dioxolane (1.93 g, 10.5 mmol) in ethanol (20 ml) was hydrogenated in the presence of 10% palladium on activated carbon (0.2 g) at 50 psi at 40° C. for 2 hours. The reaction mixture was filtered through a pad of celite and evaporated to dryness under a reduced pressure to give 1.35 g of (4R,5R)-4,5-bis(aminomethyl)-1,3-dioxolane as a colorless oil.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]3[N:15]([S:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)(=[O:28])=[O:27])[C:16]([C:18]4[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=4)=[CH:17][C:10]=23)[C:6]([C:35]2[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=2)=[N:5]1)[CH3:3].[NH:44]1[CH2:48][CH2:47][CH2:46][CH2:45]1>>[CH3:3][CH:2]([N:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]3[N:15]([S:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)(=[O:28])=[O:27])[C:16]([C:18]4[CH:25]=[CH:24][C:21]([CH2:22][N:44]5[CH2:48][CH2:47][CH2:46][CH2:45]5)=[CH:20][CH:19]=4)=[CH:17][C:10]=23)[C:6]([C:35]2[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=2)=[N:5]1)[CH3:1]
Reactant: C1CCNC1
Reactant: CC(C)n1cc(-c2ccnc3c2cc(-c2ccc(C=O)cc2)n3S(=O)(=O)c2ccccc2)c(-c2ccc([N+](=O)[O-])cc2)n1
Product: CC(C)n1cc(-c2ccnc3c2cc(-c2ccc(CN4CCCC4)cc2)n3S(=O)(=O)c2ccccc2)c(-c2ccc([N+](=O)[O-])cc2)n1

Procedure:
Following the procedure described for Intermediate 101 using 4-[4-[1-(1-methylethyl)-3-(4-nitrophenyl)-1H-pyrazol-4-yl]-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]benzaldehyde and pyrrolidine provided the title compound. ESMS [M+H]+=647.6.
Reaction SMILES: [C:1]([NH:4][CH:5]([CH3:10])[CH:6]=[C:7](Cl)Cl)(=[O:3])[CH3:2].[CH3:11][O-:12].[Na+]>CO>[CH3:2][C:1]1[O:3][C:6]([CH2:7][O:12][CH3:11])=[C:5]([CH3:10])[N:4]=1
Reactant: CC(=O)NC(C)C=C(Cl)Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCc1oc(C)nc1C
Yield: 64.5 %

Procedure:
A solution of 1.8 g of 3-acetamido-1,1-dichlorobut-1-ene and 1,0 g of sodium methylate in 20 ml of methanol is heated at the boiling point under reflux for 24 hours. Thereafter, the methanol is distilled off, the residue is taken up in 5 ml of water and 30 ml of methylene chloride and the organic phase is separated off and distilled in vacuo. 0.9 g of 2,4-dimethyl-5-methoxymethyl-oxazole is obtained, boiling point 54° C./20 mbar.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]([C:15]2[S:16][CH:17]=[N:18][N:19]=2)[C:10]=1[S:11]([NH2:14])(=[O:13])=[O:12])=[O:5])[CH3:2].[CH3:20][O:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[N:25]=[C:24]([N:30](C2C=CC=CC=2)[C:31](=O)[O-:32])[N:23]=1>C(#N)C>[CH3:29][O:28][C:26]1[CH:27]=[C:22]([O:21][CH3:20])[N:23]=[C:24]([NH:30][C:31]([NH:14][S:11]([C:10]2[N:9]([C:15]3[S:16][CH:17]=[N:18][N:19]=3)[CH:8]=[N:7][C:6]=2[C:4]([O:3][CH2:1][CH3:2])=[O:5])(=[O:13])=[O:12])=[O:32])[N:25]=1
Reactant: CCOC(=O)c1ncn(-c2nncs2)c1S(N)(=O)=O
Reactant: COc1cc(OC)nc(N(C(=O)[O-])c2ccccc2)n1
Solvent: CC#N
Product: CCOC(=O)c1ncn(-c2nncs2)c1S(=O)(=O)NC(=O)Nc1nc(OC)cc(OC)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 62.6 %

Procedure:
0.23 g of 1,8-diazobicyclo(5,4,0)-7-undecene was added dropwise to a mixture of 0.45 g of 4-ethoxycarbonyl-1-(1,3,4-thiadiazol-2-yl)imidazole-5-sulfonamide, 0.41 g of N-(4,6-dimethoxypyrimidine-2-yl)phenylcarbamate and 5 ml of acetonitrile. After stirring the reaction mixture at room temperature for 20 minutes, 20 ml of ice water was added thereto and the mixture was filtered. The filtrate was made acidic with use of conc. hydrochloric acid, and resulting precipitated crystals were collected by filtration, washed with water and ethyl ether, and dried to obtain 0.45 g of the title compound. m.p.: 169° to 171° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:5])[CH2:3][OH:4].C(N(CC)CC)C.[P:13](Cl)([Cl:16])([Cl:15])=[O:14]>C(OCC)C>[P:13]([Cl:16])([Cl:15])([O:4][CH2:3][CH:2]([CH3:5])[CH3:1])=[O:14]
Reactant: CC(C)CO
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)COP(=O)(Cl)Cl
Temperature: 0 °C
Yield: 101.1 %

Procedure:
To a solution of 1.8 ml (20 mmol) of 2-methyl-1-propanol in diethyl ether (40 ml) is added 2.02 g (20 mmol) of triethylamine, followed by 1.9 ml (20 mmol) of phosphorus oxychloride with stirring and cooling at 0° C. The mixture is stirred at 0° C. for 1 hr. It is then filtered and evaporated under reduced pressure to give 3.86 g of a colorless oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[C:11](O[C:14](=[O:25])[C:15]=2[C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)=[O:12])=[CH:2]1.O>CN(C=O)C>[NH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]([C:15]2[C:14]([N:1]([C:9]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:11](=[O:12])[C:10]=2[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)=[O:25])=[CH:17]1
Reactant: O=C1OC(=O)C(c2c[nH]c3ccccc23)=C1c1c[nH]c2ccccc12
Solvent: CN(C)C=O
Solvent: O
Product: O=C1C(c2c[nH]c3ccccc23)=C(c2c[nH]c3ccccc23)C(=O)N1c1ccccc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 191.7 %

Procedure:
To a solution of 2,3-bis(1H-indol-3-yl)maleic anhydride (100 mg, 0.3 mmol) synthesized according to a known method (Tetrahedron, Vol. 44, p. 2887, 1988) and dissolved in DMF (10 mL) and water (10 mL) was added anilne (0.12 mL, 1.2 mmol), and the whole was stirred at 100 ° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to remove DMF, and the concentrate was extracted with ethyl acetate. The extract was washed with water, dried over sodium sulfate, and then concentrated under reduced pressure. The residue was purified by column chromatography over silica gel (ethyl acetate:n-hexane=2:1) to obtain 2,3-bis(1H-indol-3-yl)N-phenylmaleimide (116 mg, 94.4%) as red solids.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11]([OH:13])=O)=[CH:4][C:3]=1[C:17](=[O:25])[NH:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1.[NH3:26]>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:10]([C:11](=[O:13])[NH2:26])[CH:9]=2)=[CH:4][C:3]=1[C:17]([NH:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)=[O:25]
Reactant: Nc1ncc(-c2cccc(C(=O)O)c2)cc1C(=O)Nc1ccncc1
Reactant: N
Product: NC(=O)c1cccc(-c2cnc(N)c(C(=O)Nc3ccncc3)c2)c1

Procedure:
Reaction of 3-[6-amino-5-(pyridin-4-ylcarbamoyl)-pyridin-3-yl]-benzoic acid with ammonia gives “A99”; method 2: HPLC/MS: 1.64 min, [M+H]=334.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.F[C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][CH:19]([CH3:21])[CH3:20])[C:12]#[N:13].O>CS(C)=O>[N:3]1([C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=2[O:17][CH2:18][CH:19]([CH3:21])[CH3:20])[C:12]#[N:13])[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: CC(C)COc1ccc(C#N)cc1F
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)COc1ccc(C#N)cc1-n1ccnc1
Temperature: 110 °C

Procedure:
A reaction mixture solution prepared by suspending 41.1 mg of 3-fluoro-4-hydroxybenzonitrile, 33.4 mg of isobutyl bromide and 62.2 mg of potassium carbonate in 1 mL of dimethylformamide was heated at 110° C. for 5 hours under a nitrogen atmosphere. After the addition of water to the reaction mixture solution, extraction was performed using ethyl acetate. The organic layer was washed with saline, followed by drying and concentrating under reduced pressure to obtain a crude product of 3-fluoro-4-(2-methylpropoxy)benzonitrile. (2) A reaction mixture prepared by adding 15.7 mg of sodium hydride and 24.5 mg of imidazole to the crude product of 3-fluoro-4-(2-methylpropoxy)benzonitrile obtained above and suspending the above in 1 mL of dimethylsulfoxide was heated at 110° C. for 5 hours under a nitrogen atmosphere. After the addition of water to the reaction mixture solution, extraction was performed using ethyl acetate. The organic layer was washed with saline, followed by drying and concentrating under reduced pressure to obtain a crude product of 3-(1H-imidazol-1-yl)-4-(2-methylpropoxy)benzonitrile.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[F:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][NH2:40])=[CH:37][CH:36]=1>C1COCC1.CCOC(C)=O>[F:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][NH:40][S:20]([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([C:10]3[N:9]=[C:8]([C:6]4[CH:5]=[C:4]([C:24]5[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:26][CH:25]=5)[CH:3]=[C:2]([CH3:1])[N:7]=4)[CH:13]=[CH:12][CH:11]=3)[CH:15]=2)(=[O:22])=[O:21])=[CH:37][CH:36]=1
Reactant: NCc1ccc(F)cc1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)Cl)c3)n2)n1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)NCc4ccc(F)cc4)c3)n2)n1
Yield: 46.6 %

Procedure:
The title compound was prepared from 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonyl chloride (example I.2) (0.200 g, 0.409 mmol) by treatment with commercially available 4-fluorobenzylamine (0.23 ml, 2.05 mmol) in THF (5 mL) at 23° C. for 16 h. Diluted with EtOAc, washed with 5% citric acid, sat. NaHCO3-sol. and brine, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with EtOAc followed by trituration with diethyl ether/heptane to give the title compound (0.110 g, 46%) as a white solid. MS (ISP) 578.2 [(M+H)+]; mp 175° C.
Reaction SMILES: [OH:1][CH:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]=[O:12])[C:5]=2[C:4](=[O:13])[O:3]1.[C:14](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[CH:2]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]=[O:12])[C:5]=1[C:4]([O:3][CH3:14])=[O:13])=[O:1]
Reactant: O=Cc1cccc2c1C(=O)OC2O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1c(C=O)cccc1C=O
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To a solution of 1-hydroxy-3-oxo-1,3-dihydro-2-benzofuran-4-carbaldehyde (720 mg) in anhydrous dimethylformamide (4 ml) was added potassium carbonate (613 mg). It was stirred for 30 minutes to give a thick white suspension. Iodomethane (0.4 ml) was added and stirred for 3 days. More methyl iodide (0.4 ml) was added and stirring continued for 24 hours. Most of the dimethylformamide was evaporated in vacuo. The pale yellow residue was partitioned between ethyl acetate (25 ml) and water (25 ml) and the organic phase was washed with aqueous lithium chloride (50 ml) and saturated brine (25 ml), dried over sodium sulphate and evaporated to give a pale yellow solid (645 mg).
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][N:5]([CH2:15][CH:16]1[CH2:18][O:17]1)[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7].[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([N:26]1[CH2:3][CH:2]([OH:1])[CH2:4][N:5]([S:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)(=[O:8])=[O:7])[CH2:15][CH:16]([OH:17])[CH2:18]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=S(=O)(c1ccccc1)N(CC1CO1)CC1CO1
Reactant: NCc1ccccc1
Product: O=S(=O)(c1ccccc1)N1CC(O)CN(Cc2ccccc2)CC(O)C1

Procedure:
IMS (2.5 L, 10 vol) was added to the dichloromethane solution from step (i) above. The solution was distilled until the internal temperature reached 70° C. Approximately 1250 mL of solvent was collected. More IMS (2.5 L, 10 vol) was added followed by benzylamine (120 mL, 0.7 eq.) in one portion (no exotherm seen), and the reaction was heated at reflux for 6 hours (no change from 2 hour sampling point). More benzylamine was added (15 mL) and the solution was heated for a further 2 hours. The IMS was distilled off (ca. 3.25 L) and toluene was added (2.5 L). More solvent was distilled (ca. 2.4 L) and then further toluene added (1 L). The head temperature was now 110° C. A further 250 mL of solvent was collected at 110° C. Theoretically, this left the product in ca. 2.4 L of toluene at 110° C. This solution was used in the next step.