Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:34])=[C:5]([C:25]([O:32][CH3:33])=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[C:11]([CH:16]=1)[C:12]([O:14]C)=[O:13]>[OH-].[Na+].O1CCOCC1.O>[CH3:1][O:2][C:3]1[C:4]([CH3:34])=[C:5]([C:25]([O:32][CH3:33])=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)=[C:11]([CH:16]=1)[C:12]([OH:14])=[O:13]
Reactant: COC(=O)c1cc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)ccc1-c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(-c2ccc(Cc3c(C)c(OC)c(OC)c(OC)c3OC)cc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.1 %

Procedure:
Methyl 5-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-(4-methoxyphenyl)benzoate (472 mg, 1.0128 mmol) was dissolved in a mixed solution of a 1N aqueous solution of sodium hydroxide (10 ml) and 1,4-dioxane (20 ml) followed by stirring at room temperature for 16 hours. The reaction solution was diluted with water (100 ml), washed with ether, acidified with concentrated hydrochloric acid and extracted with ether. The extract was washed with water and dried and the solvent was evaporated therefrom to give the title compound (440 mg, 0.9734 mmol, 96%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][CH:3]=1.Br[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=1>>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=2)=[CH:3][CH:4]=1
Reactant: Cc1cccc(Br)c1
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Product: Cc1cccc(-c2ccc(N)cc2)c1

Procedure:
The title compound was prepared by Suzuki coupling of 1-bromo-4-nitrobenzene and 1-bromo-3-methylbenzene.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([C:23]([CH3:25])=[CH2:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([CH2:37][N:38]3[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]3)[CH:34]=2)[CH2:29]1)=[O:27])C1C=CC=CC=1.N#N.C([O-])([O-])=O.[K+].[K+]>C(O)(C)C.O>[OH:8][C:9]1[CH:14]=[C:13]([OH:15])[C:12]([CH:23]([CH3:24])[CH3:25])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([CH2:37][N:38]3[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]3)[CH:34]=2)[CH2:29]1)=[O:27]
Reactant: C=C(C)c1cc(C(=O)N2Cc3ccc(CN4CCN(C)CC4)cc3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Product: CC(C)c1cc(C(=O)N2Cc3ccc(CN4CCN(C)CC4)cc3C2)c(O)cc1O
Reaction time: 1.08 h
Yield: 93.8 %

Procedure:
The product from Step 11 (0.9 Kg, 1.53 mol) was dissolved in isopropanol (6.8 L) and water (1.04 L) and after purging with N2 10% Pd/C (90 g) and K2CO3 (0.212 Kg, 1.53 mol) were added and the suspension was hydrogenated for 60 to 70 mins under an 3 Barr pressure of H2. The solution was diluted with water (0.5 L) and filtered. To the filtrate was added aqueous HCl (30% hydrochloric acid, 0.85 Kg diluted with water 5.42 Kg) and the solution was concentrated at 60° C. under vacuum (removing 10 L isopropanol). Water (0.45 L) was added to the solution and concentration continued (until a further 10 L isopropanol had been removed). The aqueous phase was washed with EtOAc (4.61 L), diluted with acetonitrile (4.06 L) and neutralised to pH 7.5-8.5 by addition of conc ammonia solution (0.35 Kg). The suspension was stirred for 2.5 h and then the solid was removed by filtration. The residue was washed with acetonitrile (2×0.8 L) and dried at 40° C. to constant weight to give the title compound 588 g (94% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[O:7])=[CH:4][C:3]=1[C:19]1[C:24]([Cl:25])=[CH:23][C:22]([Cl:26])=[CH:21][N:20]=1.[H-].[Na+].Br[CH2:30][O:31][C:32](=[O:34])[CH3:33].CO>CN(C=O)C>[CH3:30][O:31][C:32](=[O:34])[CH2:33][N:8]([C:6](=[O:7])[C:5]1[CH:17]=[CH:18][C:2]([Cl:1])=[C:3]([C:19]2[C:24]([Cl:25])=[CH:23][C:22]([Cl:26])=[CH:21][N:20]=2)[CH:4]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16]
Reactant: CC(=O)OCBr
Reactant: COc1ccccc1NC(=O)c1ccc(Cl)c(-c2ncc(Cl)cc2Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)CN(C(=O)c1ccc(Cl)c(-c2ncc(Cl)cc2Cl)c1)c1ccccc1OC
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To 4-chloro-3-(3,5-dichloro-pyridin-2-yl)-N-(2-methoxy-phenyl)-benzamide (40 mg, 0.1 mmol) in DMF (0.6 mL) at 0-5° C., NaH (8 mg, 0.2 mmol, 60% in mineral oil) was added and the mixture was stirred for 25 min at rt. Upon addition of bromomethylacetate (21 μL, 0.2 mmol), the mixture was stirred at room temperature for 12 hrs. Addition of MeOH (0.3 mL) was followed by filtration and purification on preparative HPLC to afford [[4-chloro-3-(3,5-dichloro-pyridin-2-yl)-benzoyl]-(2-methoxy-phenyl)-amino]-acetic acid methyl ester 17-1.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:27]2[S:31][C:30]([N:32]([CH:40]([CH3:42])[CH3:41])C(=O)OC(C)(C)C)=[N:29][CH:28]=2)=[C:8]2[C:16]=1[NH:15][C:14]1[CH2:13][CH:12]([C:17](=[O:26])[NH:18][CH:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)[CH2:11][CH2:10][C:9]2=1)(=[O:3])[NH2:2]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH:40]([NH:32][C:30]1[S:31][C:27]([C:7]2[CH:6]=[CH:5][C:4]([C:1]([NH2:2])=[O:3])=[C:16]3[C:8]=2[C:9]2[CH2:10][CH2:11][CH:12]([C:17]([NH:18][CH:19]4[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]4)=[O:26])[CH2:13][C:14]=2[NH:15]3)=[CH:28][N:29]=1)([CH3:42])[CH3:41]
Reactant: CC(C)N(C(=O)OC(C)(C)C)c1ncc(-c2ccc(C(N)=O)c3[nH]c4c(c23)CCC(C(=O)NC2CCN(C)CC2)C4)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Nc1ncc(-c2ccc(C(N)=O)c3[nH]c4c(c23)CCC(C(=O)NC2CCN(C)CC2)C4)s1
Yield: 61.7 %

Procedure:
A solution of tert-butyl 5-(8-carbamoyl-2-(1-methylpiperidin-4-ylcarbamoyl)-2,3,4,9-tetrahydro-1H-carbazol-5-yl)thiazol-2-yl(isopropyl)carbamate (Example 3-111, 35 mg, 0.059 mmol) in DCM (1 mL) and TFA (1 mL) was stirred at rt for 2 h. The solution was concentrated and the residue was partitioned between DCM and 1 M aqueous sodium bicarbonate. The organic phase was concentrated and the residue was purified by preparative HPLC. The appropriate effluent fractions were made basic with 1 M aqueous sodium hydroxide, extracted twice with DCM, and the combined organic phases were washed with water, dried and concentrated to provide 5-(2-(isopropylamino)thiazol-5-yl)-N2-(1-methylpiperidin-4-yl)-2,3,4,9-tetrahydro-1H-carbazole-2,8-dicarboxamide (Example 4-1, 18 mg, 61%) as a white solid. 1H NMR (400 MHz, methanol-d4) δ 7.51 (1H, d, J=7.91 Hz), 6.95 (1H, d, J=7.91 Hz), 6.89 (1H, s), 3.81-3.89 (1H, m), 3.64-3.73 (1H, m), 2.79-3.07 (4H, m), 2.59-2.75 (3H, m), 2.27 (3H, s), 2.09-2.18 (2H, m), 1.97-2.06 (1H, m), 1.84-1.92 (2H, m), 1.70-1.83 (1H, m), 1.48-1.61 (2H, m), 1.27 (6H, d, J=6.15 Hz). Mass spectrum m/z 495.2 (M+H)+. Also obtained was 4-(2-(isopropylamino)thiazol-5-yl)-N7-(1-methylpiperidin-4-yl)-9H-carbazole-1,7-dicarboxamide as a white solid (Example 4-2, 5.2 mg, 18%). 1H NMR (400 MHz, methanol-d4) δ 8.04-8.10 (2H, m), 7.88-7.93 (1H, m), 7.52-7.58 (1H, m), 7.25 (1H, s), 7.14-7.20 (1H, m), 3.87-3.98 (2H, m), 2.88-2.97 (2H, m), 2.31 (3H, s), 2.15-2.24 (2H, m), 1.95-2.03 (2H, m), 1.64-1.79 (2H, m), 1.32 (6H, d, J=6.59 Hz). Mass spectrum m/z 491.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][O:16][CH3:17])[N:9]=[CH:8][N:7]=[C:6]2[O:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22].[C:26]([C:30]1[CH:34]=[C:33]([NH:35][C:36](=O)[O:37]C2C=CC=CC=2)[O:32][N:31]=1)([CH3:29])([CH3:28])[CH3:27]>>[C:26]([C:30]1[CH:34]=[C:33]([NH:35][C:36]([NH:22][C:21]2[CH:23]=[CH:24][CH:25]=[C:19]([O:18][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH:20]=2)=[O:37])[O:32][N:31]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: COCCOc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)on1
Product: COCCOc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)no4)c3)c2cc1OC
Yield: 68 %

Procedure:
The title compound was prepared as described in Example 113C by using 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline described in Example 117B (102 mg, 0.3 mmol) and phenyl 3-tert-butylisoxazol-5-ylcarbamate described in Example 132A (101 mg, 0.39 mmol) to give 1-(3-tert-butylisoxazol-5-yl)-3-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)urea (103 mg, 68%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 10.19 (s, 1H), 9.03 (s, 1H), 8.56 (s, 1H), 7.58 (s, 2H), 7.42 (t, 2H), 7.30 (d, 1H), 6.99 (d, 1H), 6.04 (s, 1H), 4.34 (bs, 2H), 3.99 (s, 3H), 3.77 (bs, 2H), 3.36 (s, 3H), 1.25 (s, 9H); LC-MS (ESI) m/z 508 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([CH:10]2[CH2:14][CH2:13][CH2:12][O:11]2)[C:7]([C:15]([F:18])([F:17])[F:16])=[CH:6][C:5]=1[NH:19]C(=O)C.OS(O)(=O)=O>CO.O>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([CH:10]2[CH2:14][CH2:13][CH2:12][O:11]2)[C:7]([C:15]([F:17])([F:18])[F:16])=[CH:6][C:5]=1[NH2:19]
Reactant: COC(=O)c1cc(C2CCCO2)c(C(F)(F)F)cc1NC(C)=O
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: COC(=O)c1cc(C2CCCO2)c(C(F)(F)F)cc1N
Temperature: 25 °C
Yield: 70.3 %

Procedure:
A solution of 2-acetylamino-5-(tetrahydro-furan-2-yl)-4-trifluoromethyl-benzoic acid methyl ester (8.25 g, 24.9 mmol) in MeOH (100 mL) and water (10 mL) was cooled to 0° C. Concd H2SO4 (6.88 mL, 125 mmol) was added dropwise. The solution was refluxed for 45 min, cooled to r.t., diluted with ice/water and extracted with EtOAc. The organic phase was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 1:4 EtOAc/hexanes) to give the title product (5.06 g, 68%) as colorless crystals. m.p.: 131-136° C., API-ES: m/z 290 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](Cl)=[N:7]2.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][NH2:18]>>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([NH:18][CH2:17][C:16]1[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=1[O:14][CH3:13])=[N:7]2
Reactant: COc1ccccc1CN
Reactant: Clc1ccc2c(Br)cccc2n1
Product: COc1ccccc1CNc1ccc2c(Br)cccc2n1

Procedure:
5-Bromo-2-chloroquinoline (CAS 99455-13-7, 2.4 g, 10 mmol) and 2-methoxybenzylamine (2.7 g, 20 mmol) were stirred in a sealed tube at 120° C. for 3 days. The reaction mixture was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 100:0->80:20 gradient). (5-Bromo-quinolin-2-yl)-(2-methoxy-benzyl)-amine was obtained as a light yellow solid (2.3 g, 67%), MS: m/e=343.1, 345.0 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][C:7](=[O:13])[NH:8]2)([O-:3])=[O:2].[H-].[Na+].Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>CN(C=O)C>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:7](=[O:13])[NH:8]2)([O-:3])=[O:2]
Reactant: O=C1Cc2c(cccc2[N+](=O)[O-])N1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1C(=O)Nc2cccc([N+](=O)[O-])c21
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-nitro-1,3-dihydro-2H-indol-2-one (3.00 g, 16.8 mmol, described in Intermediate 17) in DMF (100 mL) at 0° C. was added sodium hydride (60% dispersion in mineral oil; 740 mg, 18.5 mmol) and the resulting mixture was stirred for 30 min. Ethyl bromoacetate (1.87 mL, 16.8 mmol) in DMF (10 mL) was added dropwise over 10 min. The reaction mixture was stirred at 0° C. for 2 h, then quenched with H2O (200 mL). The mixture was extracted with EtOAc (5×200 mL) and the combined organic extracts were washed with brine (100 mL), then dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 0:100, followed by crystallization from hexane:EtOAc to give the title compound. MS: m/z=265 (M+1).
Reaction SMILES: [CH2:1]([O:3][CH2:4][N:5]1[C:13]2[C:12](=[O:14])[NH:11][C:10](=[O:15])[N:9]([CH3:16])[C:8]=2[N:7]=[CH:6]1)[CH3:2].[CH2:17](I)[CH3:18].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:3][CH2:4][N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH2:17][CH3:18])[C:10](=[O:15])[N:9]([CH3:16])[C:8]=2[N:7]=[CH:6]1)[CH3:2]
Reactant: CCI
Reactant: CCOCn1cnc2c1c(=O)[nH]c(=O)n2C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOCn1cnc2c1c(=O)n(CC)c(=O)n2C
Temperature: 70 °C
Reaction time: 5 h

Procedure:
30 g (0.134 mol) of 7-ethoxymethyl-3-methylxanthine were suspended in 500 ml of absolute DMF with 25 g (0.161 mol) of ethyl iodide and 22.2 g (0.161 mol) of potassium carbonate and the mixture was stirred at 70° C. for 5 hours. The solution was filtered and the residue which remained was crystallized in diisopropyl ether. 28.7 g (85% of theory) of the title substance were obtained and employed without purification in Example 4b).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:25]2[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=2)=[CH:9]/[CH2:10][O:11][C:12]2[CH:23]=[CH:22][C:15]([O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:14]([CH3:24])[CH:13]=2)=[CH:4][CH:3]=1.[CH3:32][N:33]([CH2:35][C:36]#[CH:37])[CH3:34]>O1CCCC1.C(N(CC)CC)C.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:32][N:33]([CH3:34])[CH2:35][C:36]#[C:37][C:28]1[CH:29]=[CH:30][C:25](/[C:8](/[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:9]\[CH2:10][O:11][C:12]2[CH:23]=[CH:22][C:15]([O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:14]([CH3:24])[CH:13]=2)=[CH:26][CH:27]=1
Reactant: C#CCN(C)C
Reactant: COC(=O)COc1ccc(OC/C=C(/c2ccc(F)cc2)c2ccc(I)cc2)cc1C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(/c2ccc(F)cc2)c2ccc(C#CCN(C)C)cc2)cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl (Z)-[4-[3-(4-Fluorophenyl)-3-(4-iodophenyl)allyloxy]-2-methylphenoxy]acetate (400 mg, 0.75 mmol; example 10 was dissolved in a mixture of anhydrous tetrahydrofuran (10 mL) and anhydrous triethylamine (20 mL). The solution was degassed and a solution of N,N-dimethylpropargylamine (125 mg, 1.50 mmol) in anhydrous tetrahydrofuran (2 mL) was added under inert atmosphere. The resulting solution was degassed once more, copper(I) iodide (23 mg, 0.12 mmol) and tetrakis(triphenylphosphine)palladium (70 mg, 0.06 mmol) were added and the mixture was degassed again. The reaction mixture was stirred at ambient temperature overnight and the resulting suspension was filtered through a paddle of silica gel. Silica gel was washed thoroughly with ethyl acetate; the filtrate was evaporated in vacuo and the residue was dissolved in dichloromethane (50 mL). The solution was washed with water (2×30 mL) and brine (2×30 mL), dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography (silica gel Fluka 60, dichloromethane/methanol 99:1) yielding methyl (E)-[4-[3-[4-[3-(dimethylamino)propynyl)phenyl]-3-(4-fluorophenyl)allyloxy]-2-methylphenoxy]acetate as yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[NH2:20])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(N(CC)CC)C.[O:28]=[C:29](Cl)OC(Cl)(Cl)Cl>C(Cl)Cl>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][CH:9]([N:12]2[C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[NH:20][C:29]2=[O:28])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CCOC(=O)N1CCC(Nc2ccc(F)cc2N)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N1CCC(n2c(=O)[nH]c3cc(F)ccc32)CC1
Reaction time: 18 h
Yield: 70.3 %

Procedure:
To a solution of 4-(2-amino-4-fluoro-phenylamino)-piperidine-1-carboxylic acid ethyl ester (0.100 g, 0.36 mmol) and triethylamine (0.110 mg, 1.08 mmol) in methylene chloride (2 mL) at 0° C. was added a solution of diphosgene (0.71 mg, 0.36 mmol) in methylene chloride (4 mL) at room temperature. The reaction mixture was stirred for 18 h then quenched with a saturated aqueous solution of sodium bicarbonate. The organic phase was separated and washed with brine. The organic phase was purified by passing it through a plug of silica gel, using ethyl acetate as the eluent. The filtrate was evaporated, in vacuo, to a residue. The residue was triturated with hexanes/dichlormethane (95:5) and the solid collected by filtration. Vaccum drying yielded 4-(5-fluoro-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carboxylic acid ethyl ester (77.8 mg, 71%) as a light tan solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:8]=[C:7]([OH:9])[C:6]([O:10][CH2:11][CH2:12][CH3:13])=[CH:5][CH:4]=1.CO[CH:16]=[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([I:27])[CH:25]=2)[C:20](=[O:28])[NH:19][C:18]1=[O:29]>CN(C)C=O>[OH:9][C:7]1[N:8]=[C:3]([CH2:2][NH:1][CH:16]=[C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([I:27])[CH:25]=3)[C:20](=[O:28])[NH:19][C:18]2=[O:29])[CH:4]=[CH:5][C:6]=1[O:10][CH2:11][CH2:12][CH3:13]
Reactant: COC=C1C(=O)NC(=O)c2ccc(I)cc21
Reactant: CCCOc1ccc(CN)nc1O
Solvent: CN(C)C=O
Product: CCCOc1ccc(CNC=C2C(=O)NC(=O)c3ccc(I)cc32)nc1O

Procedure:
A mixture of 6-aminomethyl-3-propoxy-pyridin-2-ol (91 mg, 0.50 mmole), 7 mL of N,N-dimethylformamide is stirred, then 4-methoxymethylene-6-iodo-4H-isoquinoline-1,3-dione (165 mg, 0.50 mmole) is added and the reaction mixture stirred for 4 hours. The reaction mixture is evaporated to dryness, triturated with 5% methanol in chlororform, filtered washed with fresh 5% methanol in chloroform, washed with acetonitrile and dried to give a beige solid, 152 mg, (63%);m.p. 275-81° C. dec; MS (ES +): m/z 478.1 (M+H).
Reaction SMILES: C(O[N:5]1[C:10]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[CH:17][CH2:16][CH2:15]3)=[CH:9][CH:8]=[C:7]([NH:22][C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)=[O:24])[CH2:6]1)(=O)C.C(=O)([O-])[O-:37].[K+].[K+]>C(O)C>[C:18]1(=[O:37])[C:19]2[C:14](=[CH:13][C:12]([O:11][C:10]3[N:5]=[CH:6][C:7]([NH:22][C:23]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=4)=[O:24])=[CH:8][CH:9]=3)=[CH:21][CH:20]=2)[CH2:15][CH2:16][CH2:17]1
Reactant: CC(=O)ON1CC(NC(=O)Nc2ccc(C(F)(F)F)cc2)=CC=C1Oc1ccc2c(c1)CCC=C2
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C(Nc1ccc(C(F)(F)F)cc1)Nc1ccc(Oc2ccc3c(c2)CCCC3=O)nc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 70.9 %

Procedure:
To a solution of N1-{1-acetoxy-6-[(3,4-dihydronaphthalene-6-yl)oxy]pyridine-3-yl}-N3-[4-(trifluoromethyl)phenyl]urea (450 mg) in ethanol (20 ml), 980 mg of potassium carbonate was added and the mixture was stirred at room temperature for 40 minutes. After the reaction mixture was filtered and concentrated, the residue was dissolved in ethyl acetate and the solution was washed with water. After drying over anhydrous magnesium sulfate, the solvent was distilled off. The residue was washed with ether to obtain 290 mg of the titled compound as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][C@H:10]([CH3:18])[NH:9]2)=[CH:4][CH:3]=1.[N:19]([C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1)=[C:20]=[O:21]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][C@H:10]([CH3:18])[N:9]2[C:20]([NH:19][C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)=[O:21])=[CH:4][CH:3]=1
Reactant: C[C@H]1Cc2ccccc2[C@@H](c2ccc(Br)cc2)N1
Reactant: N#Cc1ccc(N=C=O)cc1
Solvent: ClCCl
Product: C[C@H]1Cc2ccccc2[C@@H](c2ccc(Br)cc2)N1C(=O)Nc1ccc(C#N)cc1
Reaction time: 5 h

Procedure:
To a solution of (1R,3S)-1-(4-bromophenyl)-3-methyl-1,2,3,4-tetrahydroisoquinoline (50 mg, 165 example 81, step 2) in CH2Cl2 (1.0 mL) at RT was added 4-isocyanatobenzonitrile (37 mg, 256 μmol). The reaction was stirred 5 h and directly purified by reverse phase HPLC to give (1R,3S)-1-(4-bromophenyl)-N-(4-cyanophenyl)-3-methyl-3,4-dihydroisoquinoline-2(1H)-carboxamide as a white solid. MS (ESI pos. ion) m/z: 446, 448 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH2:16])[N:11]=1.CN([CH:20]=[O:21])C>>[NH2:16][C:12]1[N:11]=[C:10]([N:9]2[C:3]3[CH:4]=[C:5]([Br:8])[CH:6]=[CH:7][C:2]=3[NH:1][C:20]2=[O:21])[CH:15]=[CH:14][N:13]=1
Reactant: CN(C)C=O
Reactant: Nc1nccc(Nc2cc(Br)ccc2N)n1
Product: Nc1nccc(-n2c(=O)[nH]c3ccc(Br)cc32)n1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of 4-N-(2-amino-5-bromophenyl)pyrimidine-2,4-diamine (400 mg, 1.43 mmol) in DMF (4 mL) was added N,N′-carbonyldiimidazole (255 mg, 1.57 mmol). The reaction was stirred at 80° C. overnight. Another portion of N,N′-carbonyldiimidazole (69 mg, 0.43 mmol) was added and heating was continued for another 2 hr at 80° C. The reaction mixture was concentrated in vacuo, diluted with water (10 mL) and extracted with ethyl acetate (2×20 mL). The organics were dried over Na2SO4, filtered and concentrated in vacuo. The resulting yellow solid was slurried in ethyl acetate and filtered off to give the title compound as a yellow solid: 1H (500 MHz, DMSO) δ 6.93 (2H, br. s.), 7.00 (1H, d, J=8.35 Hz), 7.31 (1H, d, J=10.25 Hz), 7.45 (1H, d, J=5.67 Hz), 8.25 (1H, d, J=5.52 Hz), 8.58 (1H, s); LC-MS: m/z=+306.0, 307.9 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Br:22][C:23]1[CH:24]=[CH:25][C:26]([CH:29](OS(C(F)(F)F)(=O)=O)[C:30]([F:33])([F:32])[F:31])=[N:27][CH:28]=1>C1COCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][CH:29]([C:26]3[CH:25]=[CH:24][C:23]([Br:22])=[CH:28][N:27]=3)[C:30]([F:33])([F:32])[F:31])=[CH:15][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(OC(c1ccc(Br)cn1)C(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(NC(c3ccc(Br)cn3)C(F)(F)F)cc2)C1
Reaction time: 0.25 h
Yield: 35.7 %

Procedure:
To a stirred solution of (RS)-3-(4-amino-phenyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (50 mg, CAS 908334-28-1) in dry THF (0.1 ml) under an argon atmosphere was added sodium hydride (14 mg, 60% dispersion in mineral oil) and stirring was continued for 15 minutes. Trifluoro-methanesulfonic acid 1-(5-bromo-pyridin-2-yl)-2,2,2-trifluoro-ethyl ester (74 mg) was then added and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate and washed sequentially with water and with saturared brine. The organic phase was separated, dried over sodium sulphate, and concentrated in vacuo. The reside was purified by flash column chromatography (silical gel; gradient: heptane/EtOAc) to give (RS)-3-{4-[(RS)-1-(5-bromo-pyridin-2-yl)-2,2,2-trifluoro-ethylamino]-phenyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (34 mg, 36%) as a yellow oil. MS (ISP): 501.9 ([{81Br}M+H]+), 500.2 ([{79Br}M+H]+), 446.2 ([{81Br}M+H—C4H8]+), 444.1 ([{79Br}M+H—C4H8]+).