Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:4][CH:5]([CH3:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+].C([O:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1)(=O)C1C=CC=CC=1>CC(C)=O>[CH2:1]([N:4]([CH:5]([CH3:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[S:34]([C:31]1[CH:32]=[CH:33][C:28]([OH:27])=[CH:29][CH:30]=1)(=[O:36])=[O:35])[CH:2]=[CH2:3]
Reactant: O=C(Oc1ccc(S(=O)(=O)Cl)cc1)c1ccccc1
Reactant: C=CCNC(C)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCN(C(C)c1ccccc1)S(=O)(=O)c1ccc(O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
To a solution of 1.61 g (0.01 mol) of N-allyl-N-α-methylbenzylamine and 1.38 g of potassium carbonate in 15 ml of acetone was dropped a solution of 2.62 g (0.084 mol) of 4-benzoyloxybenzenesulfonyl chloride in 5 ml of acetone under ice-cooling conditions. The mixture was subjected to the reaction at room temperature for 30 minutes and then at 50° C. for 1 hour. After completion of the reaction, the inorganic salt was removed by filtration and the acetone was distilled off, then, the contents were admixed with 150 ml of a 20% potassium hydroxide solution in ethanol, followed by refluxing for 30 minutes. After completion of the reaction, the reaction mixture was poured into ice-water to permit crystals to precipitate. The crystals were washed with a dilute acidic solution and a dilute alkaline solution, followed by sufficiently washing with water, drying in vacuum and recrystallizing from a mixed solvent of benzene and n-hexane to obtain 2.00 g of N-allyl-N-α-methylbenzyl-4-hydroxybenzenesulfonamide (melting point 128° to 129° C.).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])[CH:5]=[CH:6][C:7]=1[CH3:8].[CH:15]1[CH:20]=[C:19]2[C:21]([C:23](O)([OH:26])[C:24](=[O:25])[C:18]2=[CH:17][CH:16]=1)=[O:22]>S(=O)(=O)(O)O>[OH:26][C:23]1([C:5]2[CH:6]=[C:7]([CH3:8])[C:2]([CH3:1])=[CH:3][C:4]=2[NH:9][C:10](=[O:14])[CH:11]([CH3:12])[CH3:13])[C:24](=[O:25])[C:18]2[C:19](=[CH:20][CH:15]=[CH:16][CH:17]=2)[C:21]1=[O:22]
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C
Agent: O=S(=O)(O)O
Product: Cc1cc(NC(=O)C(C)C)c(C2(O)C(=O)c3ccccc3C2=O)cc1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 93.8 %

Procedure:
N-(3,4-dimethylphenyl)isobutyramide (1.00 mg, 5.61 mmol) and ninhydrin (1.07 mg, 5.61 mmol) were dissolved in conc. sulfuric acid (15 mL) and stirred at room temperature for 5 hrs. The reaction was stopped by slowing pouring the solution to 200 g of ice and stirring. The reaction mixture was extracted with ethylacetate and water, washed with brine. The washed organic layer was dried over sodium sulfate, concentrated in a vacuum, and purified through silica gel column chromatography (30% ethylacetate in hexane) to afford the title compound (yellow solid, 1.85 g, 94%).
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12])(=O)C.O=S(Cl)Cl.[CH3:22][N:23]1[C:27]([CH2:28][N:29]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][C:36]=3[NH2:38])[CH:31]=[CH:30]2)=[CH:26][N:25]=[CH:24]1>C1COCC1>[OH:4][C:5]1[CH:6]=[C:7](/[CH:13]=[CH:14]/[C:15]([NH:38][C:36]2[CH:35]=[CH:34][CH:33]=[C:32]3[C:37]=2[N:29]([CH2:28][C:27]2[N:23]([CH3:22])[CH:24]=[N:25][CH:26]=2)[CH:30]=[CH:31]3)=[O:17])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: COc1ccc(/C=C/C(=O)O)cc1OC(C)=O
Reactant: Cn1cncc1Cn1ccc2cccc(N)c21
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: COc1ccc(/C=C/C(=O)Nc2cccc3ccn(Cc4cncn4C)c23)cc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.1 %

Procedure:
(E)-3-(3-Acetoxy-4-methoxyphenyl)acrylic acid (0.099 g, 0.420 mmol) was suspended in dry THF (8 ml). SOCl2 (0.037 ml, 0.504 mmol) was added and the mixture was stirred at RT for 1 h. The solvent was evaporated to dryness and the residue was dissolved in dry THF (8.00 ml). TEA (0.059 ml, 0.420 mmol) and 1-(3-methyl-3H-imidazol-4-ylmethyl)-1H-indol-7-ylamine (0.095 g, 0.420 mmol) were added. The mixture was stirred at RT for 18 hrs, heated at reflux for 5 hrs and then at RT for 48 hrs. The solvent was removed in vacuo and the residue was partitioned between EtOAc (10 ml) and H2O (2×10 ml). Organic phase was dried over sodium sulphate and concentrated to dryness. The crude was charged onto a SCX cartridge and eluted firstly with MeOH and then with NH3/MeOH. The title (E)-3-(3-hydroxy-4-methoxy-phenyl)-N-[1-(3-methyl-3H-imidazol-4-ylmethyl)-1H-indol-7-yl]-acrylamide (56 mg) was obtained after column chromatography (eluent: DCM 100% to DCM/MeOH 98:2).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].Cl.[NH2:6][CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8]1.Cl.[C:17]1(=[O:23])[O:22][CH2:21][CH2:20][CH2:19][CH2:18]1>ClCCCl.ClC(Cl)C.CCN(CC)CC>[CH2:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:15][CH:7]1[NH:6][C:21](=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17][OH:23]
Reactant: O=C1CCCCO1
Reactant: NC1Cc2ccccc2C1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Solvent: ClCCCl
Product: O=C(CCCCO)NC1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2.7 mL (18.75 mmol) of Et3N in 5 mL of 1,2-dichloroethane was added drop by drop under ice cooling to a suspension of 1.85 g (13.75 mmol) AlCl3 in 10 mL of dichloroethane. At room temperature a solution of 2.33 g (13.75 mmol) 2-aminoindane HCl (and Et3N for the solvation of the hydrochloride) and 1.16 mL (12.5 mmol) delta-valerolactone in 7.5 mL 1,2-dichloroethane was added to the mixture. After one hour of stirring at room temperature the mixture was quenched with ice water and stirred for another 30 minutes. The suspension was filtered by Celite. After adding of dichloromethane, separating of the organic layer, washing it with water, drying it with Na2SO4 and evaporating of the solvent, followed.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:14]=[CH:15][C:16]=1[N+:17]([O-])=O)[O:8][CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[CH3:12][N:11]([CH3:13])[CH2:10][CH2:9][O:8][C:7]1[CH:14]=[CH:15][C:16]([NH2:17])=[C:5]([O:4][CH:1]([CH3:2])[CH3:3])[CH:6]=1
Reactant: [H][H]
Reactant: CC(C)Oc1cc(OCCN(C)C)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)Oc1cc(OCCN(C)C)ccc1N
Yield: 95.1 %

Procedure:
A mixture of [2-(3-isopropoxy-4-nitrophenoxy)ethyl]dimethylamine (2.0 g, 7.5 mmol) and 5% Pd—C (0.3 g) in ethyl acetate (70 mL) was shaken under 50 psi of hydrogen for 24 hours. The mixture was filtered through Celite and evaporated, providing 1.7 g of the product as a light gold oil, in 98% yield; 1H NMR (CDCl3) δ 1.34 (d, J=6.0 Hz, 6H), 2.32 (s, 6H), 2.68 (t, J=5.8 Hz, 2H), 3.48 (br, 2H), 3.98 (t, J=5.8 Hz, 2H), 4.48 (septet, J=6.0 Hz, 1H), 6.35 (dd, J=8.4 Hz, J=2.5 Hz, 1H), 6.50 (d, J=2.5 Hz, 1H), 6.63 (d, J=8.4 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C([BH3-])#N.[Na+]>C(O)(=O)C.O.[OH-].[Na+]>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2
Reactant: Fc1ccc2[nH]ccc2c1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Fc1ccc2c(c1)CCN2
Reaction time: 1 h

Procedure:
5-Fluoroindole (3 g, 22.2 mmol) in glacial acetic acid (35 mL) was treated with sodium cyanoborohydride (2.79 mg, 44.4 mmol) portionwise at room temperature with stirring. After one hour, the reaction was diluted with water and basified with 40% sodium hydroxide with cooling. The mixture was extracted 3 times with dichloromethane, dried and concentrated to give 5-fluoroindoline. It was used in the next step without further purification. 1H-NMR (300 MHz, dimethylsulfoxide-d6) δ 6.86 (m, 1H), 6.68 (dt, 1H), 6.42 (dd, 1H), 5.32 (br s, 1H, NH), 3.38 (m, 2H, CH2), 2.87 (t, 2H, CH2).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][C:6]1[CH:7]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:10][CH:11]=1>>[N+:1]([C:7]1[C:6]([CH3:5])=[CH:11][CH:10]=[CH:9][C:8]=1[C:12]([F:13])([F:15])[F:14])([O-:4])=[O:2]
Reactant: Cc1cccc(C(F)(F)F)c1
Reactant: O=[N+]([O-])O
Product: Cc1cccc(C(F)(F)F)c1[N+](=O)[O-]
Temperature: 10 °C

Procedure:
6 gms of 90% nitric acid is cooled to -5° C. and 2 gms of 3-methyl benzotrifluoride was added dropwise with stirring. The two phase system was allowed to warm to 10° C. during addition. After stirring 2 hours, the reaction mixture was poured onto ice, extracted with methylene chloride and washed with dilute aqueous sodium bicarbonate. After vacuum removal of solvent on a rotary evaporator, near quantitative oil was obtained which had isomer distribution:
Reaction SMILES: N[C@@H:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[BrH:13].N([O-])=O.[Na+]>O>[Br:13][C@H:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4]
Reactant: Br
Reactant: COC(=O)[C@@H](N)c1ccccc1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)[C@H](Br)c1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 40.5 %

Procedure:
(S)-methyl 2-amino-2-phenylacetate (5 g, 24.8 mmol, 1 equiv) was dwassolved in a mixture of 48% hydrogen bromide (13 ml, 198 mmol, 8 equiv) and water (19 ml). An aqueous solution of sodium nitrite (5.48 g, 79.36 mmol, 3.2 equiv) was added slowly and the mixture stirred at 0° C. for 1.5 h. The reaction was degassed in vacuo and extracted with ether. The organic layer was further washed with water and brine, dried over MgSO4, and concentrated in vacuo. The resulting residue was purified using the Biotage flash chromatography system (SNAP 100 g cartridge, Rf=0.5, gradient—1%-10% ethyl acetate in hexanes) to afford the (R)-methyl 2-bromo-2-phenylacetate as a light yellow oil (2.3 g, 40% yield); 1H NMR (400 MHz, DMSO-d6): δ 3.72 (s, 3H); 5.95 (s, 1H); 7.36-7.42 (m, 3H); 7.54 (d, 2H, J=1.6 Hz); 7.56 (d, 1H, J=2 Hz); MS for C9H9BrO2 m/z 229.98 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][NH:9][CH2:10][CH:11]1[C:16](=[O:17])[NH:15][C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[S:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22](OC(=O)C)(=[O:24])C>C(O)=O.CCOC(C)=O>[CH2:1]([O:8][N:9]([CH2:10][CH:11]1[C:16](=[O:17])[NH:15][C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[S:12]1)[CH:22]=[O:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=C1Nc2ccccc2SC1CNOCc1ccccc1
Solvent: O=CO
Solvent: CCOC(C)=O
Product: O=CN(CC1Sc2ccccc2NC1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a solution of 2-(benzyloxyamino-methyl)-4H-benzo[1,4]thiazin-3-one (2.96 mmol) in 15 mL of formic acid at 0° C., acetic anhydride is added (15.1 mmol) and the reaction is stirred at room temperature overnight. The mixture is diluted with EtOAc and washed with water followed by brine and NaHCO3. Purification by column chromatography (hexane/EtOAc) gives N-benzyloxy-N-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-2-ylmethyl)-formamide. Yield: 81%. MS: (ES+): 329.2 [M+1].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH3:28])[C:15](=[O:27])[C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([SH:26])[CH:17]=2)=[C:4]([O:29][CH3:30])[CH:3]=1.I[CH:32]1[CH2:35][O:34][CH2:33]1.CCN(C(C)C)C(C)C.[NH4+].[Cl-]>C(#N)C.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH3:28])[C:15](=[O:27])[C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([S:26][CH:32]3[CH2:35][O:34][CH2:33]3)[CH:17]=2)=[C:4]([O:29][CH3:30])[CH:3]=1
Reactant: IC1COC1
Reactant: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(S)cc(C(F)(F)F)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(SC2COC2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of N-(4-(4-fluoro-2-methoxyphenyl)pyridin-3-yl)-3-mercapto-N-methyl-5-(trifluoromethyl)benzamide (0.1 g, 229 μmol, example 129, intermediate) in acetonitrile (2 mL) were added 3-iodooxetane (52.7 mg, 286 μmol, CAS RN 26272-85-5) and DIPEA (74.0 mg, 100 μL, 573 μmol) and the yellow solution was stirred at room temperature for 1.5 hours. Then heating was installed and the yellow solution was stirred at reflux for 2.5 hours. The colorless solution was poured on saturated aqueous NH4Cl solution and EtOAc and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were dried over MgSO4, filtered, and evaporated. The compound was purified by silica gel chromatography on a 10 g column using an MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Light brown foam (0.052 g; 46%). MS (ESI): m/z=493.12 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2([C:22]([NH2:24])=[O:23])[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11][CH2:10]2)[CH:5]=[CH:6][CH:7]=1.[CH:25](OCC)(OCC)OCC>>[CH2:15]([N:12]1[CH2:11][CH2:10][C:9]2([N:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=3)[CH:25]=[N:24][C:22]2=[O:23])[CH2:14][CH2:13]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(OCC)OCC
Reactant: Cc1cccc(NC2(C(N)=O)CCN(Cc3ccccc3)CC2)c1
Product: Cc1cccc(N2C=NC(=O)C23CCN(Cc2ccccc2)CC3)c1
Temperature: 150 °C
Reaction time: 66 h

Procedure:
4-(3-methyl-phenyl-amino)-1-(phenylmethyl)-4-piperidine-carboxamide (12.94 g) was dissolved in 80 ml triethyl orthoformate and stirred at 150° C. for 66 hours. After cooling to 0° C., the reaction mixture was filtered and the light brown powder washed with ether to yield 8-benzyl-1-(3-methyl-phenyl)-1,3,8-triazaspiro[4,5]dec-2-en-4-one (2.1g). M.p. 301.5-302.6° C.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].Br[CH2:11][C:12]1[N:16]([CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[N:15]=[C:14]([CH2:27][CH3:28])[C:13]=1[O:29][C:30]1[CH:35]=[C:34]([Cl:36])[CH:33]=[C:32]([Cl:37])[CH:31]=1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:11][C:12]2[N:16]([CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:24])[CH3:25])[N:15]=[C:14]([CH2:27][CH3:28])[C:13]=2[O:29][C:30]2[CH:31]=[C:32]([Cl:37])[CH:33]=[C:34]([Cl:36])[CH:35]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCNCC1
Reactant: CCc1nn(CCNC(=O)OC(C)(C)C)c(CBr)c1Oc1cc(Cl)cc(Cl)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nn(CCNC(=O)OC(C)(C)C)c(CN2CCN(C(C)=O)CC2)c1Oc1cc(Cl)cc(Cl)c1
Reaction time: 5 h
Yield: 92.5 %

Procedure:
N-Acetylpiperazine (42 mg, 0.330 mmol) in N,N-dimethylformamide (1 ml) was added to a stirred solution of the bromide of Example 137 (148 mg, 0.300 mmol) and diisopropylethylamine (57 μL, 0.330 mmol) in N,N-dimethylformamide (2 ml) at room temperature. The reaction was stirred for 5 hours and the mixture was concentrated under reduced pressure. A solution of the residue in dichloromethane (30 ml) was washed with 1M aqueous potassium carbonate solution (10 ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol (98:2, by volume) to provide the title compound (150 mg) as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]1[CH:24]=[C:23]2[C:18]([CH2:19][CH2:20][NH:21][CH:22]2[C:25]([F:28])([F:27])[F:26])=[CH:17][CH:16]=1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:21]3[CH2:20][CH2:19][C:18]4[C:23](=[CH:24][C:15]([F:14])=[CH:16][CH:17]=4)[CH:22]3[C:25]([F:26])([F:27])[F:28])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: Fc1ccc2c(c1)C(C(F)(F)F)NCC2
Product: O=C(c1cc2ncc(Cl)cn2n1)N1CCc2ccc(F)cc2C1C(F)(F)F

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 7-fluoro-1-trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].Cl[C:26](Cl)([O:28][C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[C:37]([C:41]1C=[CH:45][CH:44]=[CH:43][C:42]=1O)([CH3:40])([CH3:39])[CH3:38].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:28][C:26]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[C:37]([CH3:40])([CH3:39])[CH3:38])=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)c1ccccc1O
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)Oc4ccccc4C(C)(C)C)c(C)c3C)c2cc1OC
Yield: 62.2 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 2-(tert-butyl)phenol (35 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (48 mg, yield 60%).
Reaction SMILES: [CH:1]1([CH2:6][N:7]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([O:20][CH2:21][C:22]([O:24]C)=[O:23])[C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][C:12]=3[C:26](=[O:28])[NH2:27])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].[OH-].Cl>C1COCC1.CO>[CH:1]1([CH2:6][N:7]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([O:20][CH2:21][C:22]([OH:24])=[O:23])[C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][C:12]=3[C:26](=[O:28])[NH2:27])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2CC1CCCC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: NC(=O)c1cccc2c1c1c(OCC(=O)O)cccc1n2CC1CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A slurry of [9-[(cyclopentyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester (20 mg, 0.065 mmol) in 0.3 mL of THF and 0.1 mL of MeOH was treated with 0.1 mL of 1 N aq LiOH (0.1 mmol), and the mixture stirred at room temperature for 2 hours. The reaction was acidified with 0.2 N HCl, and the organics were removed in vacuo. The white precipitate was filtered away from the aqueous layer and rinsed with Et2O to afford 15 mg (0.0409 mmol; 63%) the title acid as a white powder. MS (ES) m/e 367 (M+1), 350 (M+H—NH3), 365 (M−1).
Reaction SMILES: [OH-:1].[K+].[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]#[CH:11].[C:12](Cl)(=[O:19])[CH2:13][CH2:14][CH2:15][C:16](Cl)=[O:17]>O>[C:12]([O:19][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]#[CH:11])(=[O:1])[CH2:13][CH2:14][CH2:15][C:16]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]#[CH:11])=[O:17]
Reactant: O=C(Cl)CCCC(=O)Cl
Reactant: C#Cc1ccccc1O
Reactant: [OH-]
Agent: [K+]
Solvent: O
Product: C#Cc1ccccc1OC(=O)CCCC(=O)Oc1ccccc1C#C
Yield: 78 %

Procedure:
A 500-ml., three-necked, round-bottomed flask equipped with a thermometer and mechanical stirrer was charged with a solution of potassium hydroxide, 39 g. (0.700 mole) in 360 ml. of water and then 11.7 g. (0.100 mole) of o-hydroxyphenyl acetylene (I) was added. The resulting mixture was stirred vigorously and cooled with an ice-water bath to a temperature of 10°, and then 34 g. (0.200 mole) of glutaryl chloride was added over a period of about 5 minutes. The temperature of the reaction mixture rose to 34° and subsided. After stirring at 10° C. for an additional 1.5 hours, the reaction mixture was extracted with four 200 ml-portions of ether. The combined ethereal extracts were washed with 200 ml. of 10% potassium hydroxide solution and two 200 ml-portions of water, dried, and concentrated in vacuo to give 13.0 g. (78% yield) of the desired product.
Reaction SMILES: [CH2:1]1[O:10][C:9]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=2[O:2]1.Cl[CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH2:1]1[O:10][C:9]2[CH:8]=[CH:7][C:5]([NH:6][CH2:12][CH2:13][CH2:14][O:15][C:16]3[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=3)=[CH:4][C:3]=2[O:2]1
Reactant: COC(=O)c1ccc(OCCCCl)cc1
Reactant: Nc1ccc2c(c1)OCO2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(OCCCNc2ccc3c(c2)OCO3)cc1
Yield: 75.3 %

Procedure:
3,4-Methylenedioxyaniline (1.80 g), methyl 4-(3chloropropoxy)benzoate (2.0 g) and sodium bicarbonate (1.47 g) in toluene (20 ml) were heated with stirring under refluxing for 29 hours. The reaction solution was concentrated under reduced pressure, and thereto were added water and an equivalent amount of conc. hydrochloric acid, then, the resulting precipitate was collected by filtration. After washed with water, the precipitate was recrystallized from aqueous methanol to give the desired product (2.17 g). mp. 124°-127° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]([CH2:7][CH:8]([C:11]#[N:12])[C:9]#[N:10])=[CH:5][CH:4]=1.[H-].[Na+].Br[CH2:18][CH2:19][F:20]>CN(C)C=O>[F:20][CH2:19][CH2:18][C:8]([CH2:7][C:6]1[CH:13]=[CH:14][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)([C:11]#[N:12])[C:9]#[N:10]
Reactant: COc1ccc(CC(C#N)C#N)cc1
Reactant: FCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CC(C#N)(C#N)CCF)cc1
Yield: 50.3 %

Procedure:
Using 0.37 g of (4-methoxybenzyl)malononitrile, 5 ml of N,N-dimethylformamide, 0.12 g of sodium hydride (60% in oil), and 0.25 g of 1-bromo-2-fluoroethane, and according to the process described in the Production Example 1, there was obtained 0.23 g of 2-(2-fluoroethyl)-2-(4-methoxybenzyl)malononitrile (the present compound (52)).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][N:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[CH2:11]=O.Cl.[CH3:14][NH:15][CH3:16]>C(O)CCC.C(OCC)C>[Cl:1][C:2]1[CH:10]=[CH:9][N:8]=[C:7]2[NH:6][CH:5]=[C:4]([CH2:14][N:15]([CH3:11])[CH3:16])[C:3]=12
Reactant: C=O
Reactant: CNC
Reactant: Clc1ccnc2[nH]ccc12
Agent: Cl
Solvent: CCCCO
Solvent: CCOCC
Product: CN(C)Cc1c[nH]c2nccc(Cl)c12
Temperature: 25 °C
Yield: 70.7 %

Procedure:
4-Chloro-7-azaindole (7.32 g, 48 mmol), paraformaldehyde (1.59 g, 52.8 mmol) and dimethylamine hydrochloride (4.32 g, 52.8 mmol) were suspended in 1-butanol (30 mL) and the mixture heated under reflux for 2 hours. The mixture was cooled to ambient temperature and diluted with diethyl ether (50 mL). The resultant solid was collected by filtration and washed with diethyl ether and left to air-dry. The solid was dissolved in water (100 mL) and the pH of the solution adjusted to 11 by the portion-wise addition of solid potassium carbonate. The aqueous phase was extracted with dichloromethane (3×40 mL). The combined organic phase was dried (MgSO4), filtered and evaporated to afford the title compound as a pale yellow solid (7.12 g, 70%). 1H NMR (300 MHz, CDCl3): 11.19 (s, 1H), 8.15 (d, J=5.2 Hz, 1H), 7.32 (s, 1H), 7.08 (d, J=5.2 Hz, 1H), 3.79 (s, 2H), 2.34 (s, 6H).