Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=O.Cl.[CH3:13][N:14]1[C:18]([CH2:19][C:20]([NH2:22])=[S:21])=[CH:17][N:16]=[CH:15]1>>[CH3:13][N:14]1[C:18]([CH2:19][C:20]2[S:21][C:2]3[CH2:10][C:9]4[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=4[C:3]=3[N:22]=2)=[CH:17][N:16]=[CH:15]1
Reactant: O=C1c2ccccc2CC1Br
Reactant: Cn1cncc1CC(N)=S
Agent: Cl
Product: Cn1cncc1Cc1nc2c(s1)Cc1ccccc1-2

Procedure:
Starting compounds: 2-bromo-1-indanone, (1-methyl-5-imidazolyl)thioacetamide hydrochloride
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Br:22][C:23]1[C:27]([CH3:29])([CH3:28])[O:26][C:25](=O)[CH:24]=1.Cl>C1COCC1.O>[Br:22][C:23]1[C:27]([CH3:29])([CH3:28])[O:26]/[C:25](=[C:6]2/[C:7](=[O:11])[NH:8][C:9]3[C:5]/2=[CH:4][CH:3]=[C:2]([F:1])[CH:10]=3)/[CH:24]=1
Reactant: CC1(C)OC(=O)C=C1Br
Reactant: O=C1Cc2ccc(F)cc2N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1Br
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 6-fluorooxindole (3 g, 20 mmol) in THF (50 mL) at 0° C., was added 40 mL of 1M LHMDS in THF. The reaction mixture was stirred at 0° C. for 15 minutes. A solution of 4-bromo-5,5-dimethyl-5H-furan-2-one (5) (1.91 g, 10 mmol) in 5 mL of THF was added to the above reaction mixture. The reaction was stirred at 0° C. for further 30 minutes and then at room temperature for 2.5 hrs. To the reaction, 80 mL of 2M HCl was added. The resulting mixture was stirred at 50-55° C. for one hour, cooled down to room temperature, poured to 1000 mL of water and was stirred at room temperature for one hour. The precipitates formed were collected and washed with water, dried in vacuum to give the title compound as a yellow solid product (2.4 g, yield: 74%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[C:14]([NH:20][C:21](=[O:33])[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]4([C:31]#[N:32])[CH2:30][CH2:29]4)[CH:23]=3)[CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[N:5]=2.Cl.Cl.[CH3:36][N:37]1[CH2:42][CH2:41][N:40]([CH2:43][C:44](O)=[O:45])[CH2:39][CH2:38]1.Cl.C(N=C=NCCCN(C)C)C.CO>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:31]([C:28]1([C:24]2[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=2)[C:21]([NH:20][C:14]2[CH:15]=[CH:16][C:17]([O:18][CH3:19])=[C:12]([O:11][C:6]3[N:5]=[C:4]4[S:3][C:2]([NH:1][C:44](=[O:45])[CH2:43][N:40]5[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]5)=[N:10][C:9]4=[CH:8][CH:7]=3)[CH:13]=2)=[O:33])[CH2:30][CH2:29]1)#[N:32]
Reactant: COc1ccc(NC(=O)c2cccc(C3(C#N)CC3)c2)cc1Oc1ccc2nc(N)sc2n1
Reactant: CN1CCN(CC(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: COc1ccc(NC(=O)c2cccc(C3(C#N)CC3)c2)cc1Oc1ccc2nc(NC(=O)CN3CCN(C)CC3)sc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.2 %

Procedure:
To a solution of N-{3-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-4-methoxyphenyl}-3-(1-cyanocyclopropyl)benzamide (457 mg, 998 μmol) produced in Example C1(vii) in pyridine (10 mL) were added (4-methylpiperazin-1-yl)acetic acid dihydrochloride (474 mg, 2.05 mmol), N,N-dimethylpyridine-4-amine (51.3 mg, 420 μmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (403 mg, 2.10 mmol), and the mixture was stirred at room temperature for 2 hr. Methanol (10 mL) was added to the reaction solution, and the mixture was stirred for 30 min. The solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL) and tetrahydrofuran (10 mL), and the solution was washed with 0.1N hydrochloric acid (50 mL), saturated aqueous sodium hydrogen carbonate solution (50 mL) and saturated brine (50 mL). The earlier 0.1N hydrochloric acid washing solution was neutralized (pH 7.0) with 1N aqueous sodium hydroxide solution, and extracted with ethyl acetate (50 mL×2). The combined organic layer was dried over anhydrous magnesium sulfate, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate/methanol=100/0→80/20), and recrystallized from a mixture of ethyl acetate and diisopropyl ether to give the title compound (419 mg, 70%) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10]>>[Br:1][C:2]1[C:3]([NH:8][C:9](=[O:11])[CH3:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ncccc1Br
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ncccc1Br
Temperature: 100 °C

Procedure:
3-Bromo-pyridin-2-ylamine (1.00 g, 5.78 mmol) was dissolved in acetic anhydride (12.4 mL). This solution was heated at 100° C. for 16 h and cooled to room temperature. The mixture was concentrated in vacuo, diluted with EtOAc (100 mL) and poured into a mixture of ice and saturated NaHCO3 solution (150 mL). This mixture was then saturated with solid NaHCO3 and extracted with EtOAc (3×150 mL). The combined EtOAc extracts were dried (MgSO4), filtered and concentrated in vacuo to give 1.49 g of N-(3-Bromo-pyridin-2-yl)-acetamide in a quantitative yield. HPLC Rt=1.79 min (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm) LC/MS: M+H+=215.
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([N:10]2[CH2:14][CH2:13][C@@H:12]([N:15]([CH3:24])[C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][N:17]=3)[CH2:11]2)=[N:3][CH:2]=1.[Cl-].N.[N-:27]=[N+:28]=[N-:29].[Na+]>CN(C)C=O>[N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([N:10]2[CH2:14][CH2:13][C@@H:12]([N:15]([CH3:24])[C:16]3[CH:23]=[CH:22][C:19]([C:20]4[N:27]=[N:28][NH:29][N:21]=4)=[CH:18][N:17]=3)[CH2:11]2)=[N:3][CH:2]=1
Reactant: CN(c1ccc(C#N)cn1)[C@@H]1CCN(c2ncnc3[nH]ccc23)C1
Reactant: [N-]=[N+]=[N-]
Agent: N
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(c1ccc(-c2nn[nH]n2)cn1)[C@@H]1CCN(c2ncnc3[nH]ccc23)C1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
A mixture of (R)-6-((1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)(methyl)amino)nicotinonitrile (100 mg, 0.3 mmol), ammonia chloride (84 mg, 1.57 mmol) and sodium azide (108 mg, 1.66 mmol) in N,N-dimethylformamide (5.0 mL) was stirred at 120° C. for 16 h. The volatile was removed under vacuum and the residue was purified by chromatography on silica gel to give the title compound. MS (m/z): 363.0 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH3:18])[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][N:12]=[CH:11][C:10]=3[N:9]=[C:8]([NH2:17])[C:7]=2[N:6]=[CH:5]1.[H][H]>FC(F)(F)C(O)=O.[Pt]=O>[CH3:1][CH:2]([CH3:18])[CH2:3][N:4]1[C:16]2[C:15]3[CH2:14][CH2:13][NH:12][CH2:11][C:10]=3[N:9]=[C:8]([NH2:17])[C:7]=2[N:6]=[CH:5]1
Reactant: [H][H]
Reactant: CC(C)Cn1cnc2c(N)nc3cnccc3c21
Agent: O=[Pt]
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Cn1cnc2c(N)nc3c(c21)CCNC3
Yield: 0.1 %

Procedure:
A catalytic amount of platinum oxide was added to a solution of 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,7]naphthyridin-4-amine (0.4 g, 1.66 mol)) in trifluoroacetic acid. The reaction mixture was reduced on a Parr apparatus at 50 psi (3.5 Kg/cm2) hydrogen pressure overnight. The reaction mixture was filtered and washed with methanol to remove the catalyst. The filtrate was concentrated under vacuum. The residue was combined with dichloromethane and aqueous sodium bicarbonate was added until the mixture was basic. The dichloromethane layer was separated. The aqueous layer was extracted five times with dichloromethane (100 mL). The dichloromethane extracts were combined, dried over magnesium sulfate and concentrated under vacuum. The resulting residue was recrystallized from toluene to provide 0.34 g of 6,7,8,9-tetrahydro-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,7]naphthyridin-4-amine as a solid, m.p. 220-223° C. Analysis: Calculated for C13H19N5+¼H2O: % C, 62.50% H, 7.87; % N, 28.03; Found: % C, 62.50; % H, 7.72; % N, 27.46.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]([CH2:8][CH:9]1[CH2:14][N:13]([C:15]2[C:25]([F:26])=[CH:24][C:18]([C:19]([O:21]CC)=[O:20])=[C:17]([F:27])[C:16]=2[F:28])[CH2:12][CH2:11][O:10]1)[CH3:7])=[O:5])[CH3:2].[OH-].[Na+]>CO.O>[CH2:1]([O:3][C:4]([N:6]([CH2:8][CH:9]1[CH2:14][N:13]([C:15]2[C:25]([F:26])=[CH:24][C:18]([C:19]([OH:21])=[O:20])=[C:17]([F:27])[C:16]=2[F:28])[CH2:12][CH2:11][O:10]1)[CH3:7])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(F)c(N2CCOC(CN(C)C(=O)OCC)C2)c(F)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCOC(=O)N(C)CC1CN(c2c(F)cc(C(=O)O)c(F)c2F)CCO1
Yield: 68.6 %

Procedure:
To a solution of 19.1 g of ethyl 4-[2-(N-ethoxycarbonyl-N-methylaminomethyl)morpholino]-2,3,5-trifluorobenzoate in 100 ml of methanol is added dropwise a solution of 7.56 g of sodium hydroxide in 100 ml of water under ice-cooling. After stirring under ice-cooling for 20 minutes, the methanol is distilled off under reduced pressure. The solution is washed with ethyl acetate, made acid with 6 N hydrochloric acid and then extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, the ethyl acetate is distilled off under reduced pressure. To the residue is added isopropyl ether. The obtained crystals are filtered with suction and dried to give 12.2 g of 4-[2-(N-ethoxycarbonyl-N-methylaminomethyl)-morpholino]-2,3,5-trifluorobenzoic acid in 68% yield, melting at 170°-172° C.
Reaction SMILES: N1C=CC=C1.COC(O)[C:9]([F:12])([F:11])[F:10].Cl.[CH:15]1[CH:19]=[C:18]([CH2:20][C:21]2[NH:25][CH:24]=[CH:23][CH:22]=2)[NH:17][CH:16]=1>O1CCCC1>[NH:25]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH:20]([C:18]1[NH:17][CH:16]=[CH:15][CH:19]=1)[C:9]([F:12])([F:11])[F:10]
Reactant: COC(O)C(F)(F)F
Reactant: c1c[nH]c(Cc2ccc[nH]2)c1
Agent: Cl
Solvent: c1cc[nH]c1
Solvent: C1CCOC1
Product: FC(F)(F)C(c1ccc[nH]1)c1ccc[nH]1
Yield: 80 %

Procedure:
Pyrrole (150 mmol) and trifluoroacetaldehyde methyl hemiacetal (75 mmol) in tetrahydrofuran are heated at reflux with catalytic amounts of hydrochloric acid for 2 hours under an inert atmosphere. GC analysis of the reaction mixture indicated the presence of the desired dipyrromethane in greater than 80% yield. Neutralization of the acid followed by work up and chromatography gave the pure bis(pyrrol-2-yl)-trifluoromethylmethane 3 (R3 =CF3)). MS:m/z=214. This preparation has been disclosed in Wijesekera U.S. patent application Ser. No. 08/143,261 filed on Oct. 26, 1993.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](=[O:14])[C:11](Cl)=[O:12])=[CH:2]1.[CH2:15]([NH:22][CH3:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC#N>[CH2:15]([N:22]([CH3:23])[C:11](=[O:12])[C:10]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)=[O:14])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)C(=O)c1c[nH]c2ccccc12
Reactant: CNCc1ccccc1
Solvent: CC#N
Product: CN(Cc1ccccc1)C(=O)C(=O)c1c[nH]c2ccccc12

Procedure:
N-Benzyl-2-(1H-indol-3-yl)-N-methyl-2-oxo-acetamide was synthesized following scheme I above starting from (1H-indol-3-yl)-oxo-acetyl chloride and benzyl-methyl-amine. Yield (54%). HPLC ret. time 2.96 min, 10-99% CH3CN, 5 min run; 1H NMR (400 MHz, DMSO-d6) δ 12.35 (s, 1H), 8.25 (s, 0.5H), 8.13-8.11 (m, 1.5H), 7.54 (m, 1H), 7.44-7.23 (m, 7H), 4.68 (s, 1H), 4.47 (s, 1H), 2.88 (s, 1.5H), 2.85 (s, 1.5H); ESI-MS 293.3 m/z (MH+).
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C:8]([O:12][CH3:13])(=[O:11])[CH:9]=[O:10]>C(=O)([O-])O.[Na+]>[OH:10][C@@H:9]([CH2:1][C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=1)[C:8]([O:12][CH3:13])=[O:11]
Reactant: C=C1CCCCC1
Reactant: COC(=O)C=O
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)[C@@H](O)CC1=CCCCC1
Temperature: -10 °C
Yield: 70.6 %

Procedure:
A solution of an (S)-binaphthol-dichlorotitanium complex (0.1 mmole) which had been prepared in the same manner as in Example 1 was cooled to -10° C. and there was added thereto 96 mg (1 mmole) of methylenecyclohexane and 88 mg (1 mmole) of methyl glyoxylate, followed by reaction for 8 hours. Then, 10 ml of an aqueous sodium hydrogen carbonate solution was added to terminate the reaction. The reaction mixture was filtered through Celite and extracted with two 20 ml portions of diethyl ether and two 20 ml portions of ethyl acetate, and the extract was dried over anhydrous magnesium sulfate. Thereafter, the solvents were distilled off, and hexane was added to the residue to crystallize binaphthol. The remaining solution was purified by mean of silica gel column chromatography to obtain 0.13 g of methyl (S)-2-hydroxy-3-(1-cyclohexenyl)propanoate. The yield was 73%.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]([CH3:21])[C:11]3[C:16]([C:17]=2[C:18]#[N:19])=[CH:15][CH:14]=[C:13]([Cl:20])[CH:12]=3)[CH:6]=[N:7][CH:8]=1.[CH:22]1([N:27]=[C:28]=[O:29])[CH2:26][CH2:25][CH2:24][CH2:23]1>>[Cl:20][C:13]1[CH:12]=[C:11]2[C:16]([C:17]([C:18]#[N:19])=[C:9]([C:5]3[CH:4]=[C:3]([CH2:2][NH:1][C:28]([NH:27][CH:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)=[O:29])[CH:8]=[N:7][CH:6]=3)[N:10]2[CH3:21])=[CH:15][CH:14]=1
Reactant: Cn1c(-c2cncc(CN)c2)c(C#N)c2ccc(Cl)cc21
Reactant: O=C=NC1CCCC1
Product: Cn1c(-c2cncc(CNC(=O)NC3CCCC3)c2)c(C#N)c2ccc(Cl)cc21

Procedure:
2-(5-Aminomethyl-pyridin-3-yl)-6-chloro-1-methyl-1H-indole-3-carbonitrile (Example 186e) and cyclopentyl isocyanate are processed according to the method described in Example 196 to give 1-[5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-3-cyclopentyl-urea as a solid. 1H NMR (400 MHz, MeOD) δ ppm 1.31-1.54 (m, 2H), 1.56-1.68 (m, 2H), 1.68-1.78 (m, 2H), 1.86-2.13 (m, 2H), 3.83 (s, 3H), 3.94-4.09 (m, 1H), 4.52 (s, 2H), 7.38 (dd, J=8.3, 1.8 Hz, 1H), 7.72 (d, J=8.6 Hz, 1H), 7.77 (d, J=1.5 Hz, 1H), 8.08 (t, J=2.0 Hz, 1H), 8.72 (d, J=2.0 Hz, 1H), 8.76 (d, J=2.0 Hz, 1H). HRMS (ESI) m/z 408.1591 [(M+H)+ Calcd for C22H23N5OCl: 408.1591].
Reaction SMILES: [CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.OO.[C:9]([OH:12])(=[O:11])[CH3:10]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:9]([O:12][CH:1]1[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1)(=[O:11])[CH3:10]
Reactant: CC(=O)O
Reactant: C1=CCCCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: OO
Product: CC(=O)OC1C=CCCC1
Yield: 50 %

Procedure:
A 500 ml three-neck flask was charged with 15 g of cyclohexene (0.18 moles), 150 g of acetic acid and 80 mg of palladium acetate (0.36 mmoles). The temperature was taken to 50°, and then 10.6 g (0.22 moles) of 70% by weight hydrogen peroxide were introduced in 8 h. The reaction was continued for 2 more hours, while keeping the temperature at 50°. The acetic acid was then distilled (35°, 20×102Pa). The residue was distilled under vacuum (64°-68°, 15×102Pa) to provide cyclohex-2-en-1-yl acetate, 90% pure (13 g, yield 50%). cyclohex-2-en-1-yl-acetate
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].C(N(CC)CC)C.[CH3:19][O:20][CH2:21][C:22](Cl)=[O:23].[OH-].[Na+]>C(Cl)Cl>[CH3:19][O:20][CH2:21][C:22]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH3:11])=[O:9])=[O:23]
Reactant: COCC(=O)Cl
Reactant: COC(=O)c1ccccc1N
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC(=O)Nc1ccccc1C(=O)OC
Reaction time: 1 h
Yield: 80.6 %

Procedure:
To a solution of 3.02 g (20 mmol) of methyl anthranilate in 30 ml of methylene chloride was added 2.22 g (22 mmol) of triethylamine. Into the mixture, a solution of 2.39 g (22 mmol) of methoxyacetyl chloride in 15 ml of methylene chloride was dropwise added under chilling with ice. The resulting mixture was then stirred for 1 hour. After adding ice, the stirred mixture was made alkaline by addition of 1 N aqueous sodium hydroxide and then extracted with chloroform. The organic portion was collected and washed sequentially with 3 N HCl, 6 N HCl, water and saturated aqueous sodium chloride. The washed chloroform portion was dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure to obtain 3.6 g of the desired compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+]([O-])=O)=[CH:4][C:3]=1[CH2:11][C:12]([NH:14][C:15]1[CH:33]=[CH:32][CH:31]=[CH:30][C:16]=1[O:17][C:18]1[CH:19]=[C:20]([C:27]([OH:29])=[O:28])[C:21](=[CH:25][CH:26]=1)[C:22]([OH:24])=[O:23])=[O:13].COC(=O)C1C(=CC(OC2C=CC=CC=2NC(=O)CC2C=C([N+:63]([O-:65])=[O:64])C=CC=2Cl)=CC=1)C(OC)=O>O>[N+:63]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:11][C:12]([NH:14][C:15]1[CH:33]=[CH:32][CH:31]=[CH:30][C:16]=1[O:17][C:18]1[CH:19]=[C:20]([C:27]([OH:29])=[O:28])[C:21](=[CH:25][CH:26]=1)[C:22]([OH:24])=[O:23])=[O:13])([O-:65])=[O:64]
Reactant: COC(=O)c1ccc(Oc2ccccc2NC(=O)Cc2cc([N+](=O)[O-])ccc2Cl)cc1C(=O)OC
Reactant: O=C(Cc1cc([N+](=O)[O-])ccc1Cl)Nc1ccccc1Oc1ccc(C(=O)O)c(C(=O)O)c1
Solvent: O
Product: O=C(Cc1ccccc1[N+](=O)[O-])Nc1ccccc1Oc1ccc(C(=O)O)c(C(=O)O)c1

Procedure:
4-{2-[2-(2-Chloro-5-nitrophenyl)acetylamino]phenoxy}phthalic acid (Compound 175) from 4-{2-[2-(2-chloro-5-nitrophenyl)acetylamino]phenoxy}phthalic acid dimethyl ester as white crystals (yield: 26 mg (74%)). Mp: 176-178.2° C. LC/MS: m/e 470 (MH+), 453 (MH+-H2O).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]2[N:9]=[CH:10][C:11]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=3[Cl:20])=[C:4]2[N:3]=1.[OH-].[NH4+:22]>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([NH2:22])[N:5]2[N:9]=[CH:10][C:11]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=3[Cl:20])=[C:4]2[N:3]=1
Reactant: Clc1cc(Cl)n2ncc(Cc3cccc(Cl)c3Cl)c2n1
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Nc1cc(Cl)nc2c(Cc3cccc(Cl)c3Cl)cnn12
Temperature: 40 °C
Reaction time: 30 h

Procedure:
To a suspension of 5,7-dichloro-3-[(2,3-dichlorophenyl)methyl]pyrazolo[1,5-a]pyrimidine (2 g, 5.8 mmol), and 30% ammonium hydroxide solution (3.32 g, 28.8 mmol) in 1,4-dioxane (25 mL) stirred at 40° C. for 30 hours. Reaction mixture was concentrated in vacuo. The residue was dissolved with ethyl acetate (250 mL) and 5% NaHCO3 solution (35 mL). Organic layer was separated, washed with brine (35 mL) and dried. The titled product was obtained and used for next step. (1.7 g, 90%); LC/MS: MS (ES+) m/e 327 (MH+).
Reaction SMILES: O=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[N:5]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:4][CH2:3]1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:29].[Na+]>C(O)C>[NH2:29][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[N:5]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:4][CH2:3]1
Reactant: [BH3-]C#N
Reactant: CC(C)(C)OC(=O)N1CCC(=O)c2cc(C(F)(F)F)ccc21
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(N)c2cc(C(F)(F)F)ccc21

Procedure:
1.3 g of tert-butyl 4-oxo-6-(trifluoromethyl)-3,4-dihydroquinoline-1(2H)-carboxylate (Example 159A, 4 mmol, 1 equivalent) were initially charged in 12.6 ml of ethanol, and 4.6 g of ammonium acetate (59.5 mmol, 15 equivalents) and 0.3 g of sodium cyanoborohydride (4.8 mmol, 1.2 equivalents) were added. The reaction mixture was divided and each portion was irradiated in a microwave oven at 130° C. for 1 min. The mixture was then concentrated and the residue was taken up in ethyl acetate and washed with water. The organic phase was dried over sodium sulphate, filtered and concentrated. The crude product obtained was purified on silica gel (mobile phase: dichloromethane/ethyl acetate: 5/1, then dichloromethane/methanol:10/1). This gave 0.84 g (78% of theory) of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[NH:9]1[CH:13]=[N:12][N:11]=[N:10]1.C(=O)([O-])[O-].[K+].[K+].O>CN1CCCC1=O>[N:9]1([C:2]2[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=2)[CH:13]=[N:12][N:11]=[N:10]1
Reactant: c1nnn[nH]1
Reactant: Brc1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Brc1ccc(-n2cnnn2)nc1

Procedure:
In 10 ml of 1-methyl-2-pyrrolidone was dissolved 1.0 g of 2,5-dibromopyridine and the solution was added with 0.5 g of 1,2,3,4-tetrazole, along with 1.75 g of potassium carbonate. The reaction mixture was reacted at 100° C. for 3 hours with stirring. After completion of the reaction, the reaction mixture was added with water and extracted with ethyl acetate. The organic layer thus obtained was dehydrated, filtered and concentrated and the concentrate was subjected to column chromatography to give the title compound. 0.8 g.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=O)=[CH:4][CH:3]=1.Cl.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)[CH:24]([NH2:26])[CH3:25])=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([CH2:27][C:28]2[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=2)[CH:24]([NH:26][C:10](=[O:12])[C:9]([O:8][C:5]2[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=2)([CH3:14])[CH3:13])[CH3:25])=[CH:19][CH:18]=1
Reactant: Cc1ccc(OC(C)(C)C(=O)O)cn1
Reactant: CC(N)C(Cc1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: Cl
Product: Cc1ccc(OC(C)(C)C(=O)NC(C)C(Cc2ccc(Cl)cc2)c2ccc(Cl)cc2)cn1

Procedure:
The title compound was prepared by reacting 2-(6-methyl-3-pyridyloxy)-2-methylpropionic acid (Step B, 75 mg, 0.63 mmol) with 2-amino-3,4-bis(4-chlorophenyl)butane hydrochloride salt (Diastereomer α, Reference Example 1) (0.23 g, 0.63 mmol) following the procedure described in Example 62-63. LC-MS: m/e 471 (M+H)+ (3.1 min).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]([NH2:17])=[O:16])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[N:14]=1.[OH-].[K+].Cl[CH2:21][C:22]1[NH:23][CH2:24][CH2:25][CH2:26][N:27]=1.Cl>CS(C)=O>[NH2:1][C:2]1[C:3]([C:15]([NH2:17])=[O:16])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:21][C:22]3[NH:27][CH2:26][CH2:25][CH2:24][N:23]=3)[C:6]=2[N:14]=1
Reactant: NC(=O)c1cc2c(nc1N)[nH]c1ccccc12
Reactant: ClCC1=NCCCN1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: NC(=O)c1cc2c3ccccc3n(CC3=NCCCN3)c2nc1N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 10 %

Procedure:
To a stirred solution of 2-amino-9H-pyrido[2,3-b]indole-3-carboxamide (5, 100 mg, 0.44 mmol) in dimethyl sulfoxide (1 mL) was added powdered potassium hydroxide (370 mg, 6.6 mmol), and the resulting mixture stirred at room temperature for 10 min. 2-(Chloromethyl)-1,4,5,6-tetrahydropyrimidine.HCl (Stillings, M. R., J. Med. Chem. 1986, 29, 2280-2284; 220 mg, 1.3 mmol) in dimethyl sulfoxide (1 mL) was added dropwise to the mixture over 0.5 h at 5-10° C. Upon completion of addition, the reaction was allowed to stir overnight at room temperature. The crude reaction mixture was concentrated under reduced pressure and purified by HPLC (Phenomenex Luna 15 μm C18, aqueous HCOOH/CH3CN) to yield 2-amino-9-(1,4,5,6-tetrahydropyrimidin-2-ylmethyl)-9H-pyrido[2,3-b]indole-3-carboxamide (32, 14 mg, 10%). NH4OAc standard conditions. DAD Retention time =4.42 min. M+H=323. 1H NMR (300 MHz, MeOD): δ 8.73 (s, 1H), 8.49 (s, 1H), 7.94 (d, J=6.9 Hz, 1H), 7.42-7.40 (m, 2H), 7.33-7.27 (m, 1H), 5.29 (s, 2H), 3.45 (t, J=5.7 Hz, 4H), 2.04 (t, J=5.7 Hz, 2H).