Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[C:19]([F:21])[CH:20]=3)[C:15]([OH:17])=O)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:22][CH:23]([CH3:26])[CH2:24][OH:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[C:19]([F:21])[CH:20]=3)[C:15]([NH:22][CH:23]([CH3:26])[CH2:24][OH:25])=[O:17])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC(N)CO
Reactant: Nc1ncnc2ccc(-c3cc(F)cc(C(=O)O)c3)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(CO)NC(=O)c1cc(F)cc(-c2ccc3ncnc(N)c3n2)c1

Procedure:
Following the same reaction and purification procedure as above, the acid 3 (60 mg, 0.21 mmol) was reacted with 2-aminopropan-1-ol (CAS 78-91-1) (0.03 mL, 0.42 mmol), HATU (166 mg, 0.42 mmol) and DIPEA (0.18 mL, 1.1 mmol) in DMF (1 mL) at room temperature to provide 3-(4-aminopyrido[3,2-d]pyrimidin-6-yl)-5-fluoro-N-(1-hydroxypropan-2-yl)benzamide 9. LC/MS (ESI+): m/z 342 (M+H). 1H NMR (400 MHz, DMSO) δ 8.64 (d, J=10.3 Hz, 1H), 8.56 (d, J=8.7 Hz, 2H), 8.43 (d, J=5.5 Hz, 1H), 8.38 (d, J=7.9 Hz, 1H), 8.30 (s, 1H), 8.21 (d, J=8.8 Hz, 1H), 8.03 (s, 1H), 7.75 (d, J=9.4 Hz, 1H), 4.77 (t, J=5.8 Hz, 1H), 4.17-3.99 (m, 1H), 3.52 (dt, J=11.2, 5.7 Hz, 1H), 3.46-3.36 (m, 1H), 1.19 (d, J=6.7 Hz, 3H).
Reaction SMILES: [H-].[Na+].[CH3:3]O.[Br:5][C:6]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][N:7]=1.CI>CN(C)C=O>[Br:5][C:6]1[C:11]([O:12][CH3:3])=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: Oc1cccnc1Br
Reactant: CO
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cccnc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 56 %

Procedure:
Under a nitrogen atmosphere, sodium hydride 60% in oil (605 mg, 15.1 mmol) was added in portions to methanol (10 ml) under ice cooling. Twenty minutes later, a dimethylformamide (20 ml) solution of 2-bromo-3-hydroxypyridine (2.5 g, 14.4 mmol) was added. From the resulting mixture, methanol was distilled off under reduced pressure. To the residue was added methyl iodide (0.94 ml, 15.1 mmol), followed by stirring at room temperature for 3 hours. After the reaction mixture was concentrated to dryness, water (50 ml) and ether (50 ml) were added to the concentrate. The organic layer was separated and washed with a saturated aqueous solution of sodium bicarbonate and brine. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel chromatography (hexane:ethyl acetate=8:1) to give the title compound (1.51 g, 56%) as colorless needle crystals.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]([CH3:21])[CH3:20])[C:14]=1[NH:22][C:23](=[O:38])[CH2:24][NH:25][CH2:26][C:27]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1)[CH3:12]>C(OCC)(=O)C>[CH3:12][CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]([CH3:20])[CH3:21])[C:14]=1[NH:22][C:23](=[O:38])[CH2:24][N:25]([C:8]([NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:9])[CH2:26][C:27]1([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1)[CH3:10]
Reactant: O=C=Nc1ccccc1
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CNCC1(c2ccccc2)CCCC1
Solvent: CCOC(C)=O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CN(CC1(c2ccccc2)CCCC1)C(=O)Nc1ccccc1
Reaction time: 96 h

Procedure:
Phenylisocyanate (0.092 g) was added to a solution of the product of Example 6 (0.250 g) in a few mL ethyl acetate at room temperature. The reaction mixture was allowed to sit 4 days at room temperature, concentrated, and the resulting white solid collected by filtration from a slurry in hexane. 0.30 g (94%). NMR (CDCl3) δ 1.14 (12H, d), δ 1.59-2.10 (8H, m), δ 3.04 (2H, m), δ 3.61 (2H, s), δ 4.12 (2H, bs), δ 5.55 (1H, s), δ 6.77-7.51 (13H, m), δ 8.26 (1H, bs). IR (KBr) 2963, 2871, 1668, 1599, 1534, 1501, 1446, 1312, 1240, 703 cm-1.
Reaction SMILES: [CH3:1][C@:2]1([CH2:17][OH:18])[O:6][C@@H:5]([N:7]2[CH:14]=[CH:13][C:11](=S)[NH:10][C:8]2=[O:9])[C@H:4]([OH:15])[C@@H:3]1[OH:16].[NH3:19]>>[CH3:1][C@:2]1([CH2:17][OH:18])[O:6][C@@H:5]([N:7]2[CH:14]=[CH:13][C:11]([NH2:19])=[N:10][C:8]2=[O:9])[C@H:4]([OH:15])[C@@H:3]1[OH:16]
Reactant: C[C@]1(CO)O[C@@H](n2ccc(=S)[nH]c2=O)[C@H](O)[C@@H]1O
Reactant: N
Product: C[C@]1(CO)O[C@@H](n2ccc(N)nc2=O)[C@H](O)[C@@H]1O
Temperature: 25 °C

Procedure:
Compound 11 (890 mg, 1.93 mmol) was treated with methanolic ammonia (previously saturated at −10° C.), (12 mL) at 100° C. in a stainless-steel bomb for 3 hours, then cooled to room temperature. The solvent was evaporated under reduced pressure and the residue was partitioned between methylene chloride (40 mL) and water (40 mL). The aqueous layer was washed with methylene chloride (2×40 mL), concentrated under reduced pressure. The crude material was purified by silica gel column chromatography [eluent: methylene chloride/methanol/ammonium hydroxide 65:30:5]. The collected fractions were evaporated under reduced pressure and in absolute ethanol (6.3 mL). To the solution was added a 2N hydrochloric acid solution (1.5 mL) and the mixture was stirred before being concentrated under reduced pressure. The procedure was repeated twice and 12 was precipitated from absolute ethanol. Mp: 213–214 (dec.); UV (methanol): λmax=280 nm (ε=9800), λmin=245 nm (ε=3600); 1H-NMR (DMSO-d6): δ 9.82 (s, 1H, NH2), 8.72 (s, 1H, NH2), 8.34 (d, 1H, H-6, J6-5=7.8 Hz), 6.21 (d, 1H, H-5, J5-6=7.8 Hz), 5.83 (d, 1H, H-1′, J1′-2′=5.8 Hz), 4.22 (d, 1H, OH-2′, JOH-2′=6.5 Hz), 5.6–4.7 (m, 3H, OH-2′, OH-3′ and OH-5′), 4.28 (t, 1H, H-2′, J=5.6 Hz), 3.99 (d, 1H, H-3′, J=5.3 Hz), 3.43 (m, 2H, H-5′ and H-5″), 1.14 (s, 3H, CH3); MS (matrix GT): FAB>0 m/z 515 (2M+H)+, 258 (M+H)+, 147 (S)+, 112 (BH2)+ FAB<0 m/z 256 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:27][OH:28])[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[S:29](Cl)([CH3:32])(=[O:31])=[O:30]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:27][O:28][S:29]([CH3:32])(=[O:31])=[O:30])[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)CCCCCCCNC(=O)C(CO)NS(=O)(=O)c1ccc(Cl)cc1
Product: COC(=O)CCCCCCCNC(=O)C(COS(C)(=O)=O)NS(=O)(=O)c1ccc(Cl)cc1

Procedure:
The procedure described in Example 65 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-3-hydroxy-N-(7-methoxycarbonylheptyl)propanamide (504 mg) was reacted with mesyl chloride to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-3-methanesulfonyloxy-N-(7-methoxycarbonylheptyl)propanamide (503.2 mg).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:19]2[CH:41]=[CH:40][C:22]([C:23]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[NH:32]C(=O)OC(C)(C)C)=[O:24])=[CH:21][CH:20]=2)=[N:5][CH:6]=[C:7]([CH2:9][N:10]2[CH2:15][CH2:14][N:13]([CH:16]([CH3:18])[CH3:17])[CH2:12][CH2:11]2)[CH:8]=1)#[N:2].Cl.O>C(OCC)(=O)C>[NH2:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[NH:25][C:23](=[O:24])[C:22]1[CH:21]=[CH:20][C:19]([C:4]2[C:3]([C:1]#[N:2])=[CH:8][C:7]([CH2:9][N:10]3[CH2:15][CH2:14][N:13]([CH:16]([CH3:17])[CH3:18])[CH2:12][CH2:11]3)=[CH:6][N:5]=2)=[CH:41][CH:40]=1
Reactant: CC(C)N1CCN(Cc2cnc(-c3ccc(C(=O)Nc4ccccc4NC(=O)OC(C)(C)C)cc3)c(C#N)c2)CC1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)N1CCN(Cc2cnc(-c3ccc(C(=O)Nc4ccccc4N)cc3)c(C#N)c2)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
t-Butyl {2-[(4-{3-cyano-5-[(4-isopropylpiperazin-1-yl)methyl]pyridin-2-yl}benzoyl)amino]phenyl}carbamate (586 mg, 1.06 mmol; prepared as described in Method 19) was dissolved in ethyl acetate (7 ml) and 3M aqueous hydrochloric acid (7 ml) was added. The resulting suspension was stirred for 6 hours at ambient temperature then 3M aqueous hydrochloric acid (1.75 ml) added. The suspension was stirred for a further 2 hours then 3M aqueous hydrochloric acid (3.5 ml) was added and stirred for 30 minutes. The suspension was poured into water (50 ml) and washed with ethyl acetate (3×15 ml). The resulting aqueous solution was basified using a 2M aqueous solution of sodium hydroxide. A pale yellow precipitate crashed out which was filtered and washed with water. The pale yellow solid was dried in a vacuum oven at 50° C. ovenight (294 mg, 62%); NMR Spectrum: (CDCl3) 0.99 (d, 6H), 2.48 (m, 8H), 2.60 (m, 1H) 3.56 (s, 2H), 3.79 (br s, 2H), 6.80 (m, 2H), 7.03 (m, 1H), 7.32 (d, 1H), 7.81 (br s, 1H), 7.99 (s, 4H), 8.04 (s, 1H), 8.74 (s, 1H); Mass Spectrum: M+H+ 455.
Reaction SMILES: [CH3:1][C:2]1([C:11]([O:13]C)=[O:12])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[O:3]1.[OH-].[K+]>CS(C)=O.O>[CH3:1][C:2]1([C:11]([OH:13])=[O:12])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[O:3]1
Reactant: COC(=O)C1(C)Cc2ccccc2O1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC1(C(=O)O)Cc2ccccc2O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 2-methyl-2,3-dihydrobenzofuran-2-carboxylate (Step B, 0.22 g, 1.1 mmol) in 5 mL of dimethylsulfoxide was added potassium hydroxide (0.64 g, 11 mmol) in 0.5 mL of water. After stirring at room temperature for 1 h, the reaction mixture was partitioned between ether (50 mL) and 1 M hydrochloric acid (50 mL). The organic layer was separated and the aqueous layer extracted with ether (3×50 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give the title compound. 1H NMR (500 MHz, CD3OD): δ 7.17 (d, 1H), 7.12 (t, 1H), 6.86 (t, 1H), 6.79 (d, 1H), 3.60 (d, 1H), 3.18 (d, 1H), 1.67 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH:11]1([C:14]2[CH:19]=[C:18]([CH:20]3[CH2:22][CH2:21]3)[CH:17]=[CH:16][C:15]=2[N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH2:13][CH2:12]1>>[Br:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([N:26]2[CH2:27][CH2:28][N:23]([C:15]3[CH:16]=[CH:17][C:18]([CH:20]4[CH2:21][CH2:22]4)=[CH:19][C:14]=3[CH:11]3[CH2:13][CH2:12]3)[CH2:24][CH2:25]2)=[O:8])=[CH:9][CH:10]=1
Reactant: c1cc(N2CCNCC2)c(C2CC2)cc1C1CC1
Reactant: O=C(O)c1ccc(Br)nc1
Product: O=C(c1ccc(Br)nc1)N1CCN(c2ccc(C3CC3)cc2C2CC2)CC1
Yield: 100 %

Procedure:
A mixture of 1-(2,4-dichlorophenyl)piperazine (3 g), di-tert-butyl dicarbonate (3.23 g), triethylamine (5.5 mL) and methanol (30 mL) was stirred at room temperature for 5 hr. Water and ethyl acetate were added for partitioning, the organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give 4-(2,4-dichlorophenyl)piperazine-1-carboxylic acid tert-butyl ester (3.3 g). To a solution of 4-(2,4-dichlorophenyl)piperazine-1-carboxylic acid tert-butyl ester (3.3 g) in tetrahydrofuran (15 mL) were added 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (809 mg), palladium acetate (442 mg), tripotassium phosphate (11 g) and cyclopropylboronic acid (2.54 g), and the mixture was refluxed for 7 hr. After cooling, the mixture was extracted with ethyl acetate, washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give 4-(2,4-dicyclopropylphenyl)piperazine-1-carboxylic acid tert-butyl ester (3.3 g). 4-(2,4-Dicyclopropylphenyl)piperazine-1-carboxylic acid tert-butyl ester (3.3 g) was dissolved in dichloromethane (20 mL), 4N hydrogen chloride/dioxane (10 mL) was added, and the mixture was stirred at room temperature for 3.5 hr. Diethyl ether (100 mL) was added, and the precipitate was collected by filtration. To the obtained precipitate were added ethyl acetate and 1N aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate and washed with saturated brine. The solvent was evaporated to give 1-(2,4-dicyclopropylphenyl)piperazine (1.6 g). By reaction and treatment in the same manner as in Preparation Example 27 and using 6-bromonicotinic acid (237 mg) and 1-(2,4-dicyclopropylphenyl)piperazine (300 mg), the title compound (500 mg) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1>>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(Br)cc2C1
Product: CC(C)(C)OC(=O)N1Cc2ccc(N3CCCC3)cc2C1

Procedure:
Prepared in analogy to Example A3 (d) from 5-Bromo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (CAS: 201940-08-1) and pyrrolidine. Orange solid. MS (m/e): 289.2 (M+H+, 100%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[N:15]([CH3:20])[S:16]([CH3:19])(=[O:18])=[O:17])[C:5]([Cl:21])=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:36]=[CH:35][C:26]2[N:27]([CH2:33][CH3:34])[C:28](=[O:32])[CH2:29][CH2:30][CH2:31][C:25]=2[C:24]=1[O:37][CH3:38].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(=O)([O-])[O-]>C(O)(C)C>[Cl:21][C:5]1[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[N:15]([CH3:20])[S:16]([CH3:19])(=[O:18])=[O:17])=[N:7][C:2]([NH:22][C:23]2[CH:36]=[CH:35][C:26]3[N:27]([CH2:33][CH3:34])[C:28](=[O:32])[CH2:29][CH2:30][CH2:31][C:25]=3[C:24]=2[O:37][CH3:38])=[N:3][CH:4]=1
Reactant: CN([C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl)S(C)(=O)=O
Reactant: CCN1C(=O)CCCc2c1ccc(N)c2OC
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])[O-]
Solvent: CC(C)O
Product: CCN1C(=O)CCCc2c1ccc(Nc1ncc(Cl)c(N[C@@H]3CCCC[C@H]3N(C)S(C)(=O)=O)n1)c2OC
Yield: 27.2 %

Procedure:
N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-N-methyl-methanesulfonamide (79 mg, 0.22 mmol), 7-Amino-1-ethyl-6-methoxy-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (52 mg, 0.22 mmol), and 10-Camphorsulfonic acid (80 mg, 0.34 mmol) in Isopropyl alcohol (3 mL) and was heated in a microwave vial for 2 h at 120° C. Upon cooling, the mixture was treated with MP-Carbonate (2.69 mmol/g loading; 0.29 g, 0.78 mmol) for 1 h, was filtered and was concentrated in vacuo. Chromatography (ISCO, 2×12 g silica gel, 0-80% EtOAc:Hex) afforded N-{(1R,2R)-2-[5-Chloro-2-(1-ethyl-6-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-N-methyl-methanesulfonamide as a white foam (33 mg, 27%). LCMS: 551 (M+H), 1H-NMR (CDCl3): 8.35 (d, 1H, J=8.9 Hz), 7.94 (s, 1H), 7.35 (s, 1H), 6.96 (d, 1H, J=8.9 Hz), 5.72 (d, 1H, J=7.4 Hz), 4.06 (m, 1H), 3.82 (m, 4H), 3.5 (br s, 1H), 3.0 (br s, 1H), 2.85 (s, 3H), 2.78 (s, 3H), 2.47 (m, 1H), 2.29 (m, 2H), 1.84 (m, 3H), 1.71 (m, 1H), 1.25-1.5 (m, 6H), 1.13 (t, 3H, J=7.1 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH:13]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH2:29]>ClCCCl>[C:20]1([NH:11][C:12](=[O:29])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([S:8]([N:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH2:14][CH:13]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:27])[CH3:26])[CH2:12]3)(=[O:10])=[O:9])=[CH:6][CH:7]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)NC1Cc2ccccc2N(S(=O)(=O)c2ccc(N)cc2)C1
Reactant: O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NC1Cc2ccccc2N(S(=O)(=O)c2ccc(NC(=O)Nc3ccccc3)cc2)C1

Procedure:
tert-butyl 1-(4-aminophenylsulfonyl)-1,2,3,4-tetrahydroquinolin-3-ylcarbamate (60.5 mg, 0.15 mmol) and isocyantobenzene (17.8 mg, 0.15 mmol) in 1,2-dichloroethane (3 mL) were stirred at room temperature for 20 hours. Water (1.5 mL) was added and the mixture extracted with ethyl acetate (3×1.5 mL). The combined organics were dried over sodium sulfate and concentrated to give tert-butyl 1-(4-(3-phenylureido)phenylsulfonyl)-1,2,3,4-tetrahydroquinolin-3-ylcarbamate.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:6][C:5]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:4][C:3]=1[N:16]1[N+:20]([O-])=[C:19]2[CH:22]=[CH:23][CH:24]=[CH:25][C:18]2=[N:17]1.C1(C)C=CC=CC=1.CNC.[H][H]>[C].[Pd].O>[OH:1][C:2]1[C:7]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:6][C:5]([C:12]([CH3:13])([CH3:14])[CH3:15])=[CH:4][C:3]=1[N:16]1[N:20]=[C:19]2[CH:22]=[CH:23][CH:24]=[CH:25][C:18]2=[N:17]1
Reactant: [H][H]
Reactant: CC(C)(C)c1cc(-n2nc3ccccc3[n+]2[O-])c(O)c(C(C)(C)C)c1
Agent: [Pd]
Agent: CNC
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(-n2nc3ccccc3n2)c(O)c(C(C)(C)C)c1
Temperature: 50 °C
Yield: 73.2 %

Procedure:
10 g (0.03 mol) of 2-(2'-hydroxy-3',5'-di-t-butylphenyl)benzotriazole-N-oxide, 100 mg of palladium carbon, 100 ml of a solvent mixture comprising toluene and water (ratio by volume, 4:1) and 3 g of 50% dimethylamine were charged into a 500-ml autoclave equipped with an agitator. After the air in the autoclave had been replaced by hydrogen, the pressure of hydrogen was set to 10 kg/cm2. The temperature was increased to 50° C. under agitation, and reaction was effected at the same temperature while agitation being continued until no more hydrogen was absorbed by the mixture. After the reaction had been completed, the autoclave was cooled, and the catalyst was filtered off. When part of the filtrate was subjected to quantitative analysis using GC, it was found that the yield of 2-(2'-hydroxy-3',5'-di-t-butylphenyl)benzotriazole is 85.6%. After the solvent had been distilled off from the filtrate, the residual solid was crystallized by ethanol and then washed with ethanol to obtain 7.1 g of 2-(2'-hydroxy-3',5'-di-t-butylphenyl)benzotriazole (yield, 71%; melting point, 152° to 155° C.).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C@@H:9]2[CH2:13][N:12]([C@H](C3C=CC=CC=3)C)[CH2:11][C@H:10]2[F:22])[CH2:8][CH2:7]1)=[O:5])[CH3:2].Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>ClCCl>[CH2:27]([O:26][C:24]([N:12]1[CH2:13][C@@H:9]([C:6]2([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:8][CH2:7]2)[C@H:10]([F:22])[CH2:11]1)=[O:25])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)C1([C@@H]2CN([C@@H](C)c3ccccc3)C[C@H]2F)CC1
Solvent: ClCCl
Product: CCOC(=O)C1([C@@H]2CN(C(=O)OCc3ccccc3)C[C@H]2F)CC1
Temperature: 25 °C
Reaction time: 25 h
Yield: 89.4 %

Procedure:
4-(R)-(1-Ethoxycarbonylcyclopropyl)-3-(S)-fluoro-1-[1-(S)-phenylethyl]pyrrolidine (3.786 g, 12.40 mmol) was dissolved in dry dichloromethane (120 ml), and benzyl chloroformate (3.37 ml, 25.0 mmol) was added dropwise to the thus prepared solution which was cooled in an ice bath. After stirring the reaction solution for 25 hours at room temperature, dichloromethane was evaporated under reduced pressure. Thereafter, the resulting residue was subjected to flash silica gel chromatography and eluted with an eluant of n-hexane:ethyl acetate=4:1, to thereby obtain 3.718 g (89.4%) of the title compound as a colorless oil.
Reaction SMILES: [C:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][C:28]([NH2:30])=[O:29].C(=O)([O-])[O-].[Na+].[Na+].C1C=CC=CC=1>C1(C)C(C)=CC=CC=1>[C:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:8]2[CH2:9][CH2:10][N:11]([CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][C:28]([NH2:30])=[O:29])[CH2:12][CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC(=O)COCCOCCCl
Reactant: c1ccc(C(=C2CCNCC2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: Cc1ccccc1C
Product: NC(=O)COCCOCCN1CCC(=C(c2ccccc2)c2ccccc2)CC1
Temperature: 110 °C
Yield: 77 %

Procedure:
A mixture of 29.9 g of 4-(diphenylmethylene)-piperidine, 36.3 g of 2-[2-(2-chloroethoxy)ethoxy]-acetamide and 18 g of sodium carbonate in 80 ml of xylene is heated for 20 hours at a temperature of from 90°to 110° C. Thereafter, 80 ml of benzene are added thereto. The precipitate obtained is filtered off and the organic phase is extracted with a dilute solution of hydrochloric acid (20 ml of concentrated hydrochloride acid and 80 ml of water). After the addition of 30 ml of a concentrated solution of sodium hydroxide and extraction with benzene, the benzene solution obtained is washed, dried over anhydrous potassium carbonate and the benzene evaporated in vacuo. The 2-[2-[2-[4-(diphenylmethylene)-1-piperidinyl]ethoxy]ethoxy]-acetamide obtained is used as such for the preparation of the corresponding acid (see Example 3.4).
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][NH:6][C:5]1=[O:9])(=[O:3])[CH3:2].C(N(CC)CC)C.C[Si](C)(C)Cl.[C:22](Cl)([Cl:24])=[O:23]>C1C=CC=CC=1>[C:1]([N:4]1[CH2:8][CH2:7][N:6]([C:22]([Cl:24])=[O:23])[C:5]1=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCNC1=O
Reactant: O=C(Cl)Cl
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC(=O)N1CCN(C(=O)Cl)C1=O
Reaction time: 18 h

Procedure:
20 parts by weight of N-acetyl-imidazolid-2-one mixed with 25 parts by weight of triethylamine and 150 parts by volume of dry benzene were first taken and 27 parts by weight of trimethylchlorosilane in 40 parts by volume of benzzene were added dropwise at room temperature over the course of 30 minutes, with stirring. The mixture was subsequently boiled for 18 hours under reflux, moisture being excluded, and the triethylamine hydrochloride which precipitated (22 parts by weight = 100%) was filtered off after cooling and carefully rinsed with dry benzene. The benzene solution thus obtained was treated with a solution of 17 parts by weight of phosgene in 50 parts by volume of benzene at 5° C and left to stand overnight at 5° C. Thereafter the solvent was stripped off in vacuo and the residue was dried under an oil pump. It was recrystallized from acetone/pentane mixture.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH:26]([C:40]2[CH:45]=[C:44]([O:46][CH2:47][CH3:48])[CH:43]=[C:42]([O:49][CH:50]([CH3:52])[CH3:51])[C:41]=2[F:53])[NH:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[N:38]=[C:37]([CH3:39])[O:36][N:35]=3)=[CH:30][CH:29]=2)[N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1.[F:54][C:55]([F:66])([F:65])[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>CCOC(C)=O.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>[CH2:47]([O:46][C:44]1[CH:43]=[C:42]([O:49][CH:50]([CH3:52])[CH3:51])[C:41]([F:53])=[C:40]([CH:26]([C:4]2[N:5]([C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:6]=[C:2]([C:57]3[CH:58]=[CH:59][CH:60]=[CH:61][C:56]=3[C:55]([F:66])([F:65])[F:54])[N:3]=2)[NH:27][C:28]2[CH:29]=[CH:30][C:31]([C:34]3[N:38]=[C:37]([CH3:39])[O:36][N:35]=3)=[CH:32][CH:33]=2)[CH:45]=1)[CH3:48]
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: CCOc1cc(OC(C)C)c(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nc(Br)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOc1cc(OC(C)C)c(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nc(-c3ccccc3C(F)(F)F)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 150 °C
Reaction time: 0.08 h

Procedure:
To a degassed mixture of Intermediate 66.3 (48 mg, 0.062 mmol), 2-trifluoromethylphenylboronic acid (18 mg, 0.093 mmol) and Na2CO3 (28 mg, 0.24 mmol) was added Pd(PPh3)4 (36 mg, 0.031 mmol). The mixture was stirred at 150° C. for 5 min in a microwave oven, then was diluted with EtOAc, washed with water and brine, dried (Na2SO4) and concentrated to afford Intermediate 77.1.