Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[CH:24]=O>C(O)C.[OH-].[Na+]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=[CH:24][C:15]2[CH:16]=[CH:17][C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:14]=2)[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CC#N)cc1OC
Reactant: O=Cc1ccc2ccccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C(C#N)=Cc2ccc3ccccc3c2)cc1OC
Yield: 82.5 %

Procedure:
A mixture of 3,4-dimethyoxyphenylacetonitrile (1.77 g, 10.0 mmol, purchased from Tokyo Kasei,) and 2-naphthoaldehyde (1.56 g, 10.0 mmol, purchased from Tokyo Kasei) in 30 ml of ethanol was heated to dissolve. Two drops of 20% aqueous sodium hydroxide solution was then added and the reaction mixture was stirred over night. The precipitate was collected and washed with ethanol then with hexane, and dried to give 2.60 g (yield: 82.5%) of α-(3,4-dimethoxyphenyl-β-(naphthalen-2-yl)acrylonitrile as a yellow crystalline.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[CH:11][C:7]([CH2:8][C:9]#[N:10])=[CH:6][CH:5]=1.Cl[CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.[OH-].[Na+]>CN(C=O)C.C1(C)C=CC=CC=1>[Cl:3][C:4]1[CH:12]=[CH:11][C:7]([CH:8]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:9]#[N:10])=[CH:6][CH:5]=1
Reactant: N#CCc1ccc(Cl)cc1
Reactant: ClCCN1CCOCC1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: N#CC(CCN1CCOCC1)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
To a flask was added 1.4 g. (0.033 mole) of a 55% oil dispersion of sodium hydride. After washing the sodium hydride with hexane to remove the mineral oil, 20 ml. of a 2 to 1 mixture of toluene and DMF was added followed by the slow addition of 5.0 ml. (0.033 mole) of 4-chlorobenzyl cyanide. The resulting deep burgundy solution was stirred for one hour. The hydrochloride salt of 4-(2-chloroethyl)morpholine, 6.4 g. (0.033 mole), was neutralized with sodium hydroxide in a separate vessel and the resulting 4-(2-chloroethyl)morpholine free base was dissolved in 10 ml. of a 2 to 1 mixture of toluene and DMF. The free base solution was added slowly to the 4-chlorobenzyl cyanide solution at 0° C. and the reaction stirred at room temperature for two days. The reaction was poured into ice water and the organic layer extracted with ether. The ether extract was washed twice with 10% aqueous hydrochloric acid, the aqueous material made basic using concentrated ammonium hydroxide, and the desired free base material extracted into ethyl acetate. The ethyl acetate solution was dried, filtered, and concentrated. The crude product was purified by flash chromatography to give 3.7 g. (42% yield) of 2-(4-chlorophenyl)-4-(4-morpholinyl)butyronitrile as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[N:8]=[N:7][C:6]([C:9]2[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=2)=[CH:5][CH:4]=1.Br[C:19]1[CH:20]=[CH:21][C:22]2[C:23]3[CH2:32][N:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:30][CH2:29][C:24]=3[N:25]([CH3:28])[C:26]=2[CH:27]=1>>[CH3:28][N:25]1[C:26]2[CH:27]=[C:19]([N:12]3[CH:13]=[CH:14][C:9]([C:6]4[N:7]=[N:8][C:3]([C:2]([F:1])([F:16])[F:17])=[CH:4][CH:5]=4)=[CH:10][C:11]3=[O:15])[CH:20]=[CH:21][C:22]=2[C:23]2[CH2:32][N:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:30][CH2:29][C:24]1=2
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CC2
Reactant: O=c1cc(-c2ccc(C(F)(F)F)nn2)cc[nH]1
Product: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)nn5)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Yield: 45.7 %

Procedure:
4-(6-(Trifluoromethyl)pyridazin-3-yl)pyridin-2(1H)-one (60 mg, 0.25 mmol) and tert-butyl 7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (90 mg, 0.25 mmol) were reacted following the procedure of Example 30 (step g) to provide the title compound (60 mg, 46%) as a yellow solid: 1H NMR (500 MHz, CDCl3) δ 8.10 (d, J=8.8 Hz, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.66 (d, J=7.0 Hz, 1H), 7.56 (d, J=8.2 Hz, 1H), 7.38 (d, J=1.3 Hz, 1H), 7.26-7.24 (m, 2H), 7.10 (d, J=7.8 Hz, 1H), 4.66 (s, 2H), 3.66 (t, J=3.3 Hz, 2H), 3.86 (s, 3H), 2.84 (t, J=3.3 Hz, 2H), 1.51 (s, 9H).
Reaction SMILES: Br[C:2]1[C:7]2=[CH:8][N:9]([C:11]3[C:18]([Cl:19])=[CH:17][C:16]([CH:20]=[CH2:21])=[CH:15][C:12]=3[C:13]#[N:14])[N:10]=[C:6]2[C:5]([F:22])=[CH:4][N:3]=1.[CH3:23][C:24]1[N:29]=[CH:28][N:27]=[C:26]([NH2:30])[CH:25]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:19][C:18]1[C:11]([N:9]2[CH:8]=[C:7]3[C:2]([NH:30][C:26]4[CH:25]=[C:24]([CH3:23])[N:29]=[CH:28][N:27]=4)=[N:3][CH:4]=[C:5]([F:22])[C:6]3=[N:10]2)=[C:12]([CH:15]=[C:16]([CH:20]=[CH2:21])[CH:17]=1)[C:13]#[N:14]
Reactant: C=Cc1cc(Cl)c(-n2cc3c(Br)ncc(F)c3n2)c(C#N)c1
Reactant: Cc1cc(N)ncn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: C=Cc1cc(Cl)c(-n2cc3c(Nc4cc(C)ncn4)ncc(F)c3n2)c(C#N)c1
Temperature: 80 °C
Yield: 57.5 %

Procedure:
A mixture of 2-(4-bromo-7-fluoropyrazolo[4,3-c]pyridin-2-yl)-3-chloro-5-vinylbenzonitrile (67 mg, 0.18 mmol), 6-methylpyrimidin-4-ylamine (24 mg, 0.22 mmol), Pd2(dba)3 (4 mg, 0.005 mmol), Xantphos (10 mg, 0.018 mmol) and cesium carbonate (117 mg, 0.36 mmol) in dioxane (2.0 mL) was de-gassed and purged with nitrogen and the reaction mixture was heated at 80° C. in a sealed vial overnight. The resultant mixture was allowed to cool to room temperature, before being partitioned between ethyl acetate and water. The layers were separated and the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (70% ethyl acetate in cyclohexane) to afford the title compound as a brown glass (42 mg, 58% yield). 1H NMR (400 MHz, CDCl3): δ 8.72 (s, 1H), 8.55 (br s, 1H), 8.26 (br s, 1H), 7.98-7.75 (m, 3H), 6.80-6.68 (dd, J=17.6, 6.7 1H), 5.99 (d, J=17.5 Hz, 1H), 5.64 (d, J=10.9 Hz, 1H), 2.55 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:9]=[CH:10][C:11]2[CH:15]=[C:14]([C:16]3[C:21]([CH3:22])=[CH:20][N:19]=[C:18](Cl)[N:17]=3)[S:13][C:12]=2[CH:24]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:26][CH2:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]1>O1CCOCC1>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:9]=[CH:10][C:11]2[CH:15]=[C:14]([C:16]3[C:21]([CH3:22])=[CH:20][N:19]=[C:18]([NH:26][CH2:27][CH2:28][CH2:29][N:30]4[CH2:31][CH2:32][N:33]([CH3:36])[CH2:34][CH2:35]4)[N:17]=3)[S:13][C:12]=2[CH:24]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCN(CCCN)CC1
Reactant: Cc1cnc(Cl)nc1-c1cc2ccc(NC(=O)OC(C)(C)C)cc2s1
Solvent: C1COCCO1
Product: Cc1cnc(NCCCN2CCN(C)CC2)nc1-c1cc2ccc(NC(=O)OC(C)(C)C)cc2s1
Yield: 78.2 %

Procedure:
A mixture of [2-(2-chloro-5-methylpyrimidin-4-yl)-benzo[b]thiophen-6-yl]-carbamic acid tert-butyl ester (0.32 g, 0.85 mmol) and 1-(3-aminopropyl)-4-methylpiperazine (0.41 g, 2.6 mmol) in 1,4-dioxane (15 mL) is refluxed for 48 hours. Solvent is removed and the residue is chromatographed on silica gel, eluting with 2.0 M NH3/MeOH in dichloromethane 0-10%, to obtain the title compound as a yellow solid (0.33 g, 78% yield). ES+(m/z) 497 [M+H].
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[S:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[CH:11]([NH2:19])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.Cl>C(Cl)(Cl)Cl>[S:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[CH:11]([NH:19][C:3](=[O:4])[CH2:2][Cl:1])[CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: NC(Cc1ccccc1)c1cccs1
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(CCl)NC(Cc1ccccc1)c1cccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.2 %

Procedure:
A solution of chloroacetyl chloride (4 mL, 0.05 mol) in chloroform (40 mL) was added dropwise to a solution of α-(2-thienyl)benzeneethanamine (10 g, 0.049 mol) and triethylamine (14 mL, 0.098 mol) in chloroform (180 mL) at 0° C. The mixture was stirred to room temperature for 1 hour. Dilute HCl (300 mL of 0.75N) was added and the reaction mixture was partitioned. The chloroform layer was separated, dried (MgSO4) and concentrated to give the amide as a light brown solid (11 g).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][O:10][CH2:9][C@H:8]1[C:13]([CH:15]1C(=O)OC(C)(C)OC1=O)=[O:14])=[O:6])[CH:2]=[CH2:3].C(O)(=O)C>O>[C:13]([C@@H:8]1[CH2:9][O:10][CH2:11][CH2:12][N:7]1[C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])(=[O:14])[CH3:15]
Reactant: C=CCOC(=O)N1CCOC[C@H]1C(=O)C1C(=O)OC(C)(C)OC1=O
Solvent: O
Solvent: CC(=O)O
Product: C=CCOC(=O)N1CCOC[C@H]1C(C)=O
Yield: 71.4 %

Procedure:
A solution of 5-[(3S)-4-allyloxycarbonylmorpholin-3-yl]carbonyl-2,2-dimethyl-1,3-dioxane-4,6-dione (8.30 g) in a mixture of glacial acetic acid (17 ml) and water (25 ml) was refluxed for 2 hours. After cooling, the mixture was concentrated under reduced pressure to give a syrup. A solution of the syrup in ethyl acetate (100 ml) was washed in turn with water (100 ml), saturated sodium hydrogen carbonate (100 ml), and brine (100 ml). The solution was dried over magnesium sulfate and evaporated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (40 g) and eluted with a mixture of hexane and ethyl acetate (8:2, V/V) to give (3S)-3-acetyl-4-allyloxycarbonylmorpholine (3.7 g) as a syrup.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]([C:10]1[S:11][C:12]([S:32][CH3:33])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:24]3[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=3[NH2:31])[CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2].[S:35]([CH2:39][CH2:40][CH2:41][C:42](O)=[O:43])(=[O:38])(=[O:37])[NH2:36].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[C:1]([O:5][C:6](=[O:34])[NH:7][C:8](=[NH:9])[C:10]1[S:11][C:12]([S:32][CH3:33])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:24]3[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=3[NH:31][C:42](=[O:43])[CH2:41][CH2:40][CH2:39][S:35](=[O:38])(=[O:37])[NH2:36])[CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NS(=O)(=O)CCCC(=O)O
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2N)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2NC(=O)CCCS(N)(=O)=O)c1
Reaction time: 24 h
Yield: 60 %

Procedure:
{[4-(2′-Amino-6′-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (0.013 g, 0.025 mmol) [example 25, step c] was added to a solution of 4-sulfamoyl-butyric acid (0.011 g, 0.068 mmol), EDCI (0.013 g, 0.068 mmol) and HOBt (0.009 g, 0.068 mmol) in DMF [0.5 mL] at room temperature. The reaction was stirred for 24 hours and then evaporated. Column chromatography (25% EtOAc in hexanes) of the residue yielded the title compound (0.010 g, 60%) as a solid. ESI-MS (m/z): Calcd. for C28H34N4O7S4: 666.13; found: 666.8.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:14][NH2:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:28](Cl)(=[O:37])[C:29]1[C:30]([O:35][CH3:36])=[CH:31][CH:32]=[CH:33][CH:34]=1.CCOCC>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:14][NH:15][C:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[O:35][CH3:36])=[O:37])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCC1(c2ccccc2)CCN(Cc2ccccc2)CC1
Reactant: COc1ccccc1C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccccc1C(=O)NCC1(c2ccccc2)CCN(Cc2ccccc2)CC1
Reaction time: 12 h

Procedure:
To a solution of 2.1 g (7.6 mmol) of 1-N-Benzyl-4-phenyl-4-aminomethylpiperidine and 1.2 mL of pyridine (15.2 mmol) and 20 mg of 4-dimethylaminopyridine (DMAP) in 20 mL of methylene chloride was added 2.6 g (15.2 mmol) of o-anisoyl chloride at 0° C. The reaction mixture was stirred for 12 hr and was poured into 200 ml of ether. It was washed with saturated NaHCO3 solution, dried over MgSO4 and concentrated. The residue was purified by chromatography (silica, hexanes: ethyl acetate, 1:4) to afford the title compound.
Reaction SMILES: [C:1](N1C=CN=C1)([N:3]1C=CN=[CH:4]1)=O.[F:13][C:14]1[CH:22]=[CH:21][C:20]2[NH:19][C:18]3[C:23](=[O:37])[N:24]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:25]=[C:26]([CH2:27][C:28]([OH:30])=O)[C:17]=3[C:16]=2[CH:15]=1.CNC.O>O1CCCC1>[F:13][C:14]1[CH:22]=[CH:21][C:20]2[NH:19][C:18]3[C:23](=[O:37])[N:24]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:25]=[C:26]([CH2:27][C:28]([N:3]([CH3:4])[CH3:1])=[O:30])[C:17]=3[C:16]=2[CH:15]=1
Reactant: O=C(O)Cc1nn(-c2ccccc2)c(=O)c2[nH]c3ccc(F)cc3c12
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(=O)Cc1nn(-c2ccccc2)c(=O)c2[nH]c3ccc(F)cc3c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.7 %

Procedure:
A suspension of 1.7 g (10.5 mmol) of 1,1′-carbonylbis-1H-imidazole and of 3 g (8.9 mmol) of 8-fluoro-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetic acid in 300 ml of tetrahydrofuran is stirred at 40° C. for 3 h. The mixture is cooled to room temperature, 10 ml of liquefied dimethylamine are added and the mixture is stirred for 2 h. After standing overnight, 300 ml of water are added and the precipitate is collected by filtration and recrystallized from dimethylformamide. 0.8 g (2.2 mmol) of solid is obtained.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[C:7]([CH3:20])=[CH:8][C:9](B3OC(C)(C)C(C)(C)O3)=[CH:10][C:5]=2[O:4][C:3]1=[O:21].[OH:22]O>C(O)(=O)C>[OH:22][C:9]1[CH:8]=[C:7]([CH3:20])[C:6]2[N:2]([CH3:1])[C:3](=[O:21])[O:4][C:5]=2[CH:10]=1
Reactant: OO
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc2oc(=O)n(C)c12
Solvent: CC(=O)O
Product: Cc1cc(O)cc2oc(=O)n(C)c12

Procedure:
0.20 g (0.70 mmol) 3,4-dimethyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3H-benzoxazol-2-one were dissolved in 2.0 mL glacial acetic acid and combined with 0.40 mL (4.6 mmol) hydrogen peroxide solution (35% in water) and stirred. The precipitate formed was suction filtered, washed with water and dried i. vac.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13]([O:15]CC)=[O:14])[C:7](=[O:18])[N:6]2[CH3:19].[OH-].[Na+].Cl>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13]([OH:15])=[O:14])[C:7](=[O:18])[N:6]2[CH3:19]
Reactant: CCOC(=O)c1nc2ccc(OC)cc2n(C)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc2nc(C(=O)O)c(=O)n(C)c2c1

Procedure:
3,4-Dihydro-6-methoxy-4-methyl-3-oxo-2-quinoxalinecarboxylic acid, ethyl ester (1.5 g) and aqueous sodium hydroxide (25 ml., 2N) were heated on a steam bath for 5 minutes. The solution was acidified with dilute hydrochloric acid to pH1 and the solid was collected and dried, m.p. 223° (d) (100%).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:10]=[N:11][C:12]([C:15]2[N:16]([CH:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[C:17]3[C:22]([C:23]=2[C:24]#[N:25])=[CH:21][C:20]([F:26])=[C:19]([CH3:27])[CH:18]=3)=[CH:13][CH:14]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=[O:34]>O>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([CH:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[C:17]3[C:22]([C:23]=2[C:24]([NH2:25])=[O:34])=[CH:21][C:20]([F:26])=[C:19]([CH3:27])[CH:18]=3)=[N:11][CH:10]=1)(=[O:7])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc2c(cc1F)c(C#N)c(-c1ccc(S(=O)(=O)NC(C)(C)C)cn1)n2C1CCCC1
Reactant: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1cc2c(cc1F)c(C(N)=O)c(-c1ccc(S(=O)(=O)NC(C)(C)C)cn1)n2C1CCCC1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 20 %

Procedure:
Into a solution of N-tert-butyl-6-(3-cyano-1-cyclopentyl-5-fluoro-6-methyl-1H-indol-2-yl)pyridine-3-sulfonamide (90 mg, 0.2 mmol) in TFA (2.0 mL) was added 2 drops of water. The mixture was stirred at 40° C. for 30 min and then evaporated. The residue was purified on silica gel eluting with 5 to 30% ethyl acetate in CH2Cl2 to provide the title compound (19 mg, 20%). MS m/z 473.3 M+H+; 1H NMR (500 MHz, DMSO-d6): δ 9.10 (1H, dd, J=2.0, 1.0 Hz), 8.29 (1H, dd, J=10.5, 2.5 Hz), 7.89 (1H, s), 7.81 (1H, dd, J=8.5, 1.0 Hz), 7.59 (1H, d, J=10.5 Hz), 7.49 (1H, d, J=6.5 Hz), 7.02 (2H, br s), 4.63-4.56 (1H, m), 2.46 (3H, s), 2.16-2.08 (2H, m), 1.96-1.85 (4H, m), 1.60-1.56 (2H, m), 1.17 (9H, s).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8](O)=O)[CH:5]=[CH:4][CH:3]=1.NC1C=C(C(O)=O)C=CN=1.NC1C=C(C(O)=O)C=NC=1.[NH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[NH2:38].[OH-].[Na+]>>[NH:31]1[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[N:38]=[C:8]1[C:6]1[N:7]=[C:2]([NH2:1])[CH:3]=[CH:4][CH:5]=1
Reactant: Nc1cccc(C(=O)O)n1
Reactant: Nc1ccccc1N
Agent: Nc1cc(C(=O)O)ccn1
Agent: Nc1cncc(C(=O)O)c1
Agent: [Na+]
Product: Nc1cccc(-c2nc3ccccc3[nH]2)n1
Temperature: 0 °C
Yield: 61.6 %

Procedure:
A suspension of 6-aminopyridine-2-carboxylic acid (112 mg), or 2-aminopyridine-4-carboxylic acid (112 mg, 0.82 mmol), or 5-aminopyridine-3-carboxylic acid (112 mg, 0.82 mmol) with 1,2-diaminobenzene (177 mg, 1.64 mmol) was heated in 4 mL of PPA (180 degree) for 2 h. The reaction mixture was each poured into 50 mL ice-water and neutralized with 2 N NaOH (chilled) during vigorous stirring. The resulting precipitate was filtered and washed with 20 mL warm water to afford 105 mg of desired 6-(1H-benzo[d]imidazol-2-yl)pyridin-2-amine (MS, M++H=211.1).
Reaction SMILES: [OH-].[K+].C(OC([O:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[CH2:16])=[CH:13][CH:12]=1)=O)(C)(C)C>O.CO.[OH-].C[N+](C)(C)C>[CH:15]([C:14]1[CH:17]=[CH:18][C:11]([OH:10])=[CH:12][CH:13]=1)=[CH2:16]
Reactant: C=Cc1ccc(OC(=O)OC(C)(C)C)cc1
Agent: C[N+](C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C=Cc1ccc(O)cc1
Temperature: 0 °C
Reaction time: 0.11 h

Procedure:
In a 2 L Erlenmeyer flask, 140 g (2.5 mol) of KOH was dissolved in 250 mL of water, and the solution was diluted with 250 mL of methanol and 10 mL of tetramethylammoniumhydroxide. Then, 110 g (0.50 mol) of 4-(t-butyloxycarbonyloxy)styrene (tBOCstyrene) was added and the mixture heated to boiling. After 5-8 minutes, the mixture cleared to a yellow solution and was cooled by the addition of 500 mL of a 1/1 ice-water mixture. This mixture was washed with 250 mL of dichloromethane and 250 mL of ethyl ether. The pH of the aqueous solution was reduced to 11-12 by the addition of dry ice, resulting in the formation of a cream colored precipitate (4-vinylphenol) in a yellow solution.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][OH:7])([O-:3])=[O:2].[SH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](O)=[O:24].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[SH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:7][CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2])=[O:24]
Reactant: O=[N+]([O-])c1ccccc1CO
Reactant: O=C(O)CCCCCCCCCCS
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(CCCCCCCCCCS)OCc1ccccc1[N+](=O)[O-]

Procedure:
One equivalent of 2-nitrobenzyl alcohol (2.17 g, 14.15 mmol) was combined with one equivalent of 11-mercaptoundecanoic acid (3.09 g, 14.15 mmol), 0.1 equivalents DMAP (0.173 g, 1.42 mmol) and dissolved in 50 mL CH2Cl2. To this mixture a solution of DCC (2.92 g, 14.15 mmol) in 30 mL CH2Cl2 was slowly added while stirring. Upon addition a white precipitate formed after a few minutes. The mixture was stirred at room temperature overnight. Vacuum filtration removed the white precipitate and the filtrate was concentrated by rotovap. Silica gel column chromatography was employed for purification using C1H2Cl2/MeOH (v/v 50:1) as the eluent. The product was dried over Na2SO4, the solvent removed by rotovap, and dried under vacuum thus producing a yellow solid. Yield: 3.57 g (71.4%). 1H-NMR (CDCl3) δ (ppm): 8.1 (d, 1H, Ar), 7.6 (t, 1H, Ar), 7.5 (d, 1H, Ar), 7.4 (t, 1H, Ar), 5.5 (s, 2H, O—CH2), 2.6 (t, 1H, SH) 2.5 (q, 2H, CH2—SH), 2.4 (t, 2H, CH2—C═O), 1.6 (m, 4H, CH2), 1.2 (m, 12H, CH2). 13C-NMR (CDCl3) δ (ppm): 173.5, 147.0, 134.1, 132.7, 129.5, 129.2, 125.5, 63.2, 34.6, 34.4, 29.8, 29.7, 29.6, 29.5, 29.4, 28.8, 25.3, 25.1. MS (ESI): (M+Na)+=376.19 (calc. 376.47).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH2:6][CH2:5]2.F[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20].FC1C=CC2N3CCC4C3=C(C=CC=4)C(N3CCN(C)CC3)=NC=2C=1>>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])[CH2:7][CH2:6][CH2:5]2
Reactant: Cc1ccc2c(c1)CCCN2
Reactant: O=[N+]([O-])c1ccccc1F
Agent: CN1CCN(C2=Nc3cc(F)ccc3N3CCc4cccc2c43)CC1
Product: Cc1ccc2c(c1)CCCN2c1ccccc1[N+](=O)[O-]

Procedure:
Starting with 6-methyl-1,2,3,4-tetrahydroquinoline and 2-fluoronitrobenzene and following steps 1a to 1f of Example 2, one may obtain, in sequence, 6-methyl-1-(2-nitrophenyl)-1,2,3,4 -tetrahydroquinoline, 1-(2-aminophenyl)-6-methyl-1,2,3,4-tetratetrahydroquinol. 1-(2-aminophenyl)-6-methyl-1,2,3,4-tetrahydroquinoline N-[2-(6-methyl-1-phenyl)-1,2,3,4-tetrahydrohydroquinoline, -1-yl]-4-methyl-1-piperazine carboxamide, and 5-methyl-7-(4-methyl-1-piperazinyl)-2,3-dihydro-1H-quino[18-ab][1,5]-benzodiazepine.
Reaction SMILES: [CH:1]([C:3]1[CH:21]=[CH:20][C:6]([CH2:7][CH2:8][NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[CH:5][CH:4]=1)=O.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:29][C:30](=[O:32])[CH3:31])C=CC=CC=1>C1(C)C=CC=CC=1>[O:32]=[C:30]([CH3:31])[CH:29]=[CH:1][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][CH2:8][NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[CH:5][CH:4]=1
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(CCNS(=O)(=O)c2ccc(Cl)cc2)cc1
Solvent: Cc1ccccc1
Product: CC(=O)C=Cc1ccc(CCNS(=O)(=O)c2ccc(Cl)cc2)cc1

Procedure:
A mixture of 3.2 g. (10 mnole) 4-chlorobenzenesulphonic acid-(4-formylphenethylamide), 50 ml. anhydrous toluene and 3.2 g. (10 mmole) 1-triphenylphosphoranylidene-2-propanone is refluxed for 5 hours, then cooled, stirred with silica gel and filtered off with suction. The filtrate is evaporated and purified by column chromatography (silica gel/methylene chloride). Yield 1.3 g. (36% of theory); m.p. 111°-113° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[C:22](Cl)(=[O:30])[O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.N1C=CC=CC=1.O(C(C)C)C(C)C>O.ClCCl>[C:24]1([O:23][C:22](=[O:30])[NH:21][C:18]2[CH:19]=[CH:20][C:15]([N:12]3[CH2:13][CH2:14][N:9]([C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)[CH2:10][CH2:11]3)=[CH:16][CH:17]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COc1ccc(N2CCN(c3ccc(N)cc3)CC2)cc1
Solvent: O
Solvent: c1ccncc1
Solvent: CC(C)OC(C)C
Product: COc1ccc(N2CCN(c3ccc(NC(=O)Oc4ccccc4)cc3)CC2)cc1
Reaction time: 0.5 h
Yield: 61 %

Procedure:
A mixture of 6 parts of 4-[4-(4-methoxyphenyl)-1-piperazinyl]benzenamine, 3.6 parts of phenyl carbonochloridate, 75 parts of pyridine and 98 parts of dichloromethane is stirred and warmed till all solid enters solution. Stirring is continued for 30 minutes at room temperature. The reaction mixture is poured onto 500 parts of water and 210 parts of 2,2'-oxybispropane are added. The whole is stirred for a while. The precipitated product is filtered off and crystallized from 1-butanol, yielding 5.2 parts (61%) of phenyl{4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl}carbamate; mp. 204.5° C.