Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([C:25]#[C:26][CH3:27])[CH2:20][C:21]([O:23]C)=[O:22])=[CH:15][CH:14]=1)[C:6](=[O:28])[C:5]2([CH3:30])[CH3:29].Cl.O>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([C:25]#[C:26][CH3:27])[CH2:20][C:21]([OH:23])=[O:22])=[CH:15][CH:14]=1)[C:6](=[O:28])[C:5]2([CH3:30])[CH3:29]
Reactant: CC#CC(CC(=O)OC)c1ccc(OCN2C(=O)C(C)(C)c3cc(Br)ccc32)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC#CC(CC(=O)O)c1ccc(OCN2C(=O)C(C)(C)c3cc(Br)ccc32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
730 mg of methyl 3-[4-(5-bromo-3,3-dimethyl-2-oxo-2,3-dihydroindol-1-ylmethoxy)phenyl]-hex-4-ynoate were dissolved in a mixture of THF/MeOH/2N NaOH=1:1:1 (5 ml of each) and stirred at room temperature. After 1 hour, the mixture was acidified to pH 1 by addition of 2N HCl. 50 ml of water were added, the mixture was extracted three times with 50 ml each time of ethyl acetate. The combined organic phases were dried over MgSO4, then concentrated under reduced pressure and purified on silica gel with the n-heptane/ethyl acetate solvent mixture as a linear gradient of 100% n-heptane=>100% ethyl acetate. This gave 620 mg of 3-[4-(5-bromo-3,3-dimethyl-2-oxo-2,3-dihydroindol-1-ylmethoxy)phenyl]-hex-4-ynoic acid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].CS(O[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=O)=O>>[CH2:21]([O:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=Cc1cccc(O)c1
Reactant: CS(=O)(=O)OCCCCCOCc1ccccc1
Product: O=Cc1cccc(OCCCCCOCc2ccccc2)c1

Procedure:
Alkylation reaction of 3-hydroxybenzaldehyde with 5-(benzyloxy)pentyl methanesulfonate gave 3-(5-(benzyloxy)pentyloxy)benzaldehyde as a clear oil. Yield (1.3 g, 66%): 1H NMR (400 MHz, CDCl3) δ 9.97 (s, 1H), 7.42-7.46 (m, 2H), 7.25-7.39 (m, 6H), 7.15-7.18 (m, 1H), 4.51 (s, 2H), 4.02 (t, J=6.4 Hz, 2H), 3.51 (t, J=6.4 Hz, 2H), 1.82-1.89 (m, 2H), 1.68-1.76 (m, 2H), 1.54-1.62 (m, 2H).
Reaction SMILES: C([O:3][C:4](=[O:41])[CH2:5][NH:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([N:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C@H:22]([N:29]([C:37](=[O:39])[CH3:38])[C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)[CH2:21][C@@H:20]2[CH3:40])=[O:18])=[CH:13][CH:12]=1)C.C(O)C.[OH-].[Na+]>O1CCCC1>[C:37]([N:29]([C:30]1[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=1)[C@H:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:19]([C:17]([C:14]2[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][CH2:7][NH:6][CH2:5][C:4]([OH:41])=[O:3])=[CH:12][CH:13]=2)=[O:18])[C@@H:20]([CH3:40])[CH2:21]1)(=[O:39])[CH3:38]
Reactant: CCOC(=O)CNCCCOc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCCCNCC(=O)O)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
{[3-(4-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}phenoxy)propyl]amino}acetic ethyl ester was hydrolyzed to the acid by dissolving in tetrahydrofuran and ethanol and sodium hydroxide (1N) was added. The mixture was stirred at room temperature overnight. The mixture was cooled to rt, acidified to form a white precipitate. The solid was filtered to give {[3-(4-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}phenoxy)propyl]amino}acetic acid 0.005 g, 75% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][C:13]([CH2:17][OH:18])=[CH:14][CH:15]=3)[CH2:10][O:9]2)=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+].Cl[O-].[Na+].O>C(OCC)(=O)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]=[O:18])=[CH:14][CH:15]=3)[CH2:10][O:9]2)=[CH:4][CH:3]=1
Reactant: OCc1ccc2c(c1)COC2c1ccc(F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [Br-]
Solvent: O
Solvent: CCOC(C)=O
Product: O=Cc1ccc2c(c1)COC2c1ccc(F)cc1
Temperature: 5 °C
Reaction time: 1 h
Yield: 84.2 %

Procedure:
1-(4′-Fluorophenyl)-1,3-dihydroisobenzofuran-5-ylmethanol (20.6 g) was dissolved in ethyl acetate (160 ml) and to the obtained solution were added sodium hydrogencarbonate (2.9 g), tetrabutylammonium bromide (1.6 g) and 4-hydroxy-2,2,6,6-tetramethyl-1-piperidinoxy (0.13 g). The mixture was cooled to 5° C. Thereto was added dropwise 12.9% aqueous sodium hypochlorite solution (52.7 g) at 5-1° C. and the mixture was stirred for 1 hr. Water (100 ml) was added to the reaction mixture and the mixture was extracted twice with ethyl acetate (100 ml). The extract was washed with 5% aqueous sodium hydrogencarbonate solution and saturated brine, and silica gel (3 g) was added. The mixture was filtered and the solvent was evaporated to give 1-(4′-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbaldehyde (17.2 g, 84.2%).
Reaction SMILES: [NH2:1][C:2]1[CH:38]=[CH:37][C:5]([CH:6]=[CH:7][C:8]([NH:10][CH2:11][C:12]([N:14]([C:16]2[C:17]([Cl:36])=[C:18]([C:32]([Cl:35])=[CH:33][CH:34]=2)[CH2:19][O:20][C:21]2[CH:22]=[CH:23][CH:24]=[C:25]3[C:30]=2[N:29]=[C:28]([CH3:31])[CH:27]=[CH:26]3)[CH3:15])=[O:13])=[O:9])=[CH:4][C:3]=1[CH3:39].C(N(CC)CC)C.[C:47](Cl)(=[O:51])[CH:48]([CH3:50])[CH3:49]>ClCCl>[Cl:36][C:17]1[C:16]([N:14]([CH3:15])[C:12](=[O:13])[CH2:11][NH:10][C:8](=[O:9])[CH:7]=[CH:6][C:5]2[CH:37]=[CH:38][C:2]([NH:1][C:47](=[O:51])[CH:48]([CH3:50])[CH3:49])=[C:3]([CH3:39])[CH:4]=2)=[CH:34][CH:33]=[C:32]([Cl:35])[C:18]=1[CH2:19][O:20][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:30]=1[N:29]=[C:28]([CH3:31])[CH:27]=[CH:26]2
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)C=Cc4ccc(N)c(C)c4)c3Cl)c2n1
Reactant: CC(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)C=Cc4ccc(NC(=O)C(C)C)c(C)c4)c3Cl)c2n1
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
To a solution of 8-[3-[N-(4-amino-3-methylcinnamoylglycyl)-N-methylamino]-2,6-dichlorobenzyloxy]-2-methylquinoline (200 mg) and triethylamine (35.9 mg) in dichloromethane was dropwise added isobutyryl chloride (41.6 mg) at 0° C. under nitrogen atmosphere, and the mixture was stirred for 30 minutes at the same temperature. The mixture was concentrated, and the residue was dissolved in methanol (3 ml). To the solution was added saturated sodium bicarbonate solution (1 ml), and the mixture was stirred for 2 hours at ambient temperature and concentrated. To the residue were added ethyl acetate and water, and the organic layer was washed with water, saturated sodium bicarbonate solution and brine, dried and concentrated. The residue was purified by preparative thin-layer chromatography (dichloromethane:methanol=15:1, V/V) to give 8-[2,6-dichloro-3-[N-methyl-N-(4-isobutyramido-3-methylcinnamoylglycyl)amino]benzyloxy]-2-methylquinoline (195 mg) as an amorphous powder.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:15][O:16][CH2:17]Cl.O>CC(C)=O>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:15][O:16][CH3:17])[CH:3]=1
Reactant: Oc1cccc(I)c1
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COCOc1cccc(I)c1
Temperature: 25 °C
Reaction time: 65 h
Yield: 102.5 %

Procedure:
To a solution of m-iodophenol (3.00 g, 13.6 mmol) in acetone (30 ml) were added potassium carbonate (2.30 g, 16.6 mmol) and chloromethyl methyl ether (1.20 g, 14.9 mmol) under ice cooling and the mixture was stirred for 65 hours at room temperature. To the reaction mixture were further added potassium carbonate (0.600 g, 4.30 mmol) and chloromethyl methyl ether (0.300 g, 3.70 mmol), and the mixture was stirred for 2 hours at room temperature. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated sodium chloride solution, and dried over magnesium sulfate. The solvent was removed under reduced pressure to give the subject compound (3.68 g, 102%).
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:12][CH3:13])[CH:3]=1.[N:14]12[CH2:21][C:18]([CH2:22][NH2:23])([CH2:19][CH2:20]1)[CH2:17][CH2:16][CH2:15]2>O1CCCC1>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([NH:23][CH2:22][C:18]23[CH2:21][N:14]([CH2:20][CH2:19]2)[CH2:15][CH2:16][CH2:17]3)=[O:8])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: NCC12CCCN(CC1)C2
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Solvent: C1CCOC1
Product: COc1cc(N)c(Cl)cc1C(=O)NCC12CCCN(CC1)C2
Reaction time: 1 h
Yield: 69.8 %

Procedure:
A suspension of 4-amino-5-chloro-2-methoxybenzoic acid (1.72 g, 8.5 mmol) in anhydrous tetrahydrofuran (10 mL) under nitrogen was treated with 1,1-carbonyldiimidazole (1.46 g, 9.0 mmol), stirred for one hour, then degassed under a stream of nitrogen for 10 minutes. A solution of 1-azabicyclo[3.2.1]octane-5-methanamine (1.27 g, 9.0 mmol) in anhydrous tetrahydrofuran (8 mL) was added, and stirring was continued at room temperature for 18 hours and at 50° C. for one hour. The mixture was concentrated in vacuo and partitioned between toluene (100 mL) containing a little 2-propanol and saturated sodium carbonate (50 mL). The organic layer was separated and the organic solution was dried (Na2SO4). concentrated in vacuo, and triturated from cold ether. Recrystallization from acetonitrile (2 crops) afforded 1.92 g (70%) of colorless crystals; mp 185°-187° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14]([OH:16])=O)[CH2:12][C@@:11]2([CH2:17][OH:18])[C@@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:19][C:20]1[C:21]([F:28])=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][NH2:24].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14](=[O:16])[NH:24][CH2:23][C:22]2[CH:25]=[CH:26][CH:27]=[C:20]([Cl:19])[C:21]=2[F:28])[CH2:12][C@@:11]2([CH2:17][OH:18])[C@@H:9]1[CH2:10]2)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NCc1cccc(Cl)c1F
Reactant: CC(C)(C)OC(=O)N1[C@H]2C[C@@]2(CO)C[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1[C@H]2C[C@@]2(CO)C[C@H]1C(=O)NCc1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a diastreoisomeric mixture of (1R,3S,5S) and (1S,3S,5R)-5-hydroxymethyl-2-aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-tert-butyl ester (312 mg, 1.21 mmol), 3-chloro-2-fluorobenzylamine (232 mg, 1.46 mmol), HBTU (690 mg, 1.82 mmol) in CH2Cl2 (6 mL) was added DIPEA (0.623 mL, 3.64 mmol). The resulting solution was stirred at RT under nitrogen overnight. DIPEA (0.21 mL, 1.21 mmol), HBTU (230 mg, 0.6 mmol) and 3-chloro-2-fluorobenzylamine (97 mg, 0.606 mmol) were added and the mixture was further stirred overnight at RT under N2. The mixture was poured into an aqueous solution of HCl 1N (pH-1) and extracted with CH2Cl2 (2×). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 40:60) to give (1S,3S,5R)-3-(3-chloro-2-fluoro-benzylcarbamoyl)-5-hydroxymethyl-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester: TLC, Rf (EtOAc)=0.55 (stained with ninhydrine); MS (UPLC-MS): 399.2/401.2 [M+H]+, 299.2/301.2 [MH−Boc]+, 343.2/345.2 [MH−tBu]+, 443.2/445.3 [M+HCOO]−; tR (HPLC conditions f): 1.95 min, and (1R,3S,5S)-3-(3-chloro-2-fluoro-benzylcarbamoyl)-5-hydroxymethyl-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester: TLC, Rf (EtOAc)=0.45 (stained with ninhydrine); MS (UPLC-MS): 399.2/401.2 [M+H]+, 299.2/301.2 [MH−Boc]+, 343.2/345.2 [MH−tBu]+, 443.2/445.3 [M+HCOO]−; tR (HPLC conditions f): 1.89 min.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:28][C:29]1[CH:30]=[C:31]([C:35]2[O:39][N:38]=[C:37]([CH:40](O)[CH3:41])[N:36]=2)[CH:32]=[CH:33][CH:34]=1>C1COCC1>[Br:1][CH:40]([C:37]1[N:36]=[C:35]([C:31]2[CH:32]=[CH:33][CH:34]=[C:29]([Cl:28])[CH:30]=2)[O:39][N:38]=1)[CH3:41]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(O)c1noc(-c2cccc(Cl)c2)n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(Br)c1noc(-c2cccc(Cl)c2)n1
Reaction time: 8 h

Procedure:
A solution of 396 mg (2.22 mmol) N-bromosuccinimid in 2 ml THF was added dropwise to a solution of 583 mg (2.22 mmol) triphenylphosphine in 2 ml THF at 0° C. After stirring for 20 min 416 mg (1.85 mmol) 1-[5-(3-chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-ethanol in 2 ml THF was added. Stirring was continued overnight at room temperature before the solvent was removed under reduced pressure. Flash chromatography (heptane/EtOAc 6:1) afforded 168 mg (32%). 1H NMR (CDCl3), d (ppm): 2.12 (d, 3 H) 5.21 (q, 1 H) 7.47 (t, 1 H) 7.57 (m, 1 H) 8.03 (d, 1 H) 8.15 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]([CH2:13][C:14]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]2[C:15]=1[CH:16]=[CH:17][C:18](=[O:27])[N:19]2[CH3:26])(C(OCC)=O)[C:3]([O:5]CC)=[O:4].C(O)(=O)C.Cl>O>[Cl:1][CH:2]([CH2:13][C:14]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]2[C:15]=1[CH:16]=[CH:17][C:18](=[O:27])[N:19]2[CH3:26])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(Cl)(Cc1ccc(OC)c2c1ccc(=O)n2C)C(=O)OCC
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(CC(Cl)C(=O)O)c2ccc(=O)n(C)c12
Temperature: 25 °C
Yield: 81.4 %

Procedure:
Diethyl 2-chloro-2-(8-methoxy-1-methyl-2-oxo-1,2-dihydroquinolin-5-ylmethyl)malonate (5.1 g) was added to a mixture of 20 ml of acetic acid and 15 ml of 6N hydrochloric acid, followed by heating under reflux for 9 hours. After cooling to room temperature, water was added to the reaction mixture, followed by cooling with ice. The precipitated solid was collected by filtration, washed with water and dried to thereby obtain 3.1 g of 2-chloro-3-(8-methoxy-1-methyl-2-oxo-1,2-dihydroquinolin-5-yl)propionic acid as a light yellow powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:7][CH:8]=2)[NH:3]1>CO.[Pd]>[CH3:1][C:2]1([CH3:16])[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:7][CH:8]=2)[NH:3]1
Reactant: COC(=O)c1cccc2c1NC(C)(C)C=C2
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cccc2c1NC(C)(C)CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of methyl 2,2-dimethyl-1,2-dihydroquinoline-8-carboxylate (Example 47, step 3) (1.00 g, 4.63 mmol) in methanol (20 mL) containing a catalytic amount of 10% palladium on carbon was placed under an atmosphere of hydrogen at ambient pressure and temperature. After stirring at room temperature for 2 h the reaction mixture was filtered through a pad of celite and concentrated under vacuum. Purification by silica gel chromatography (2.5% EtOAc/hexanes) afforded the desired compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:36]=[CH:35][CH:34]=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:32]=[CH:31][C:17]([C:18]([N:20]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[CH:16][CH:15]=1)=[O:12].[C:37](Cl)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(N(CC)CC)C>ClCCl>[C:37]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:36]=[CH:35][CH:34]=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:32]=[CH:31][C:17]([C:18]([N:20]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[CH:16][CH:15]=1)=[O:12])(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NCCCCCCOc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCCc3ccccc32)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCCCCCOc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCCc3ccccc32)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1-{4-[2-(6-aminohexyloxy)benzoylamino]benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine (0.70 g), benzoyl chloride (0.20 ml), triethylamine and dichloromethane (20 ml) is stirred at room temperature for 1 hour. The reaction mixture is washed successively with water and saturated saline solution, and dried over magnesium sulfate. The solvent is concentrated and the resulting residue is recrystallized from ethanol to give 1-{4-[2-(6-benzoylaminohexyloxy)benzoylamino]benzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (0.71 g) as white powder, m.p. 178°-178.5° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-])=O)[CH:16]=3)[CH2:13][CH3:14])[C:10]3[CH:24]=[CH:25][CH:26]=[N:27][C:9]=3[CH2:8][O:7][C:6]=2[CH:28]=1>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[C:12]([C:15]3[CH:16]=[C:17]([NH2:21])[CH:18]=[CH:19][CH:20]=3)[CH2:13][CH3:14])[C:10]3=[CH:24][CH:25]=[CH:26][NH:27][C:9]3=[CH:8][O:7][C:6]=2[CH:28]=1
Reactant: CCC(=C1c2ccc(F)cc2OCc2ncccc21)c1cccc([N+](=O)[O-])c1
Solvent: CCO
Product: CCC(=C1C2=CC=CNC2=COc2cc(F)ccc21)c1cccc(N)c1
Reaction time: 2 h
Yield: 99.9 %

Procedure:
8-Fluoro-5-[1-(3-nitro-phenyl)-propylidene]-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cycloheptene (1.49 g, 3.96 mmol) is dissolved in ethanol (20 mL) and purged with nitrogen. Pd/C (0.15 g, 10%) is added and the mixture hydrogenated under 1 atm of hydrogen for 2 h. The mixture is purged with nitrogen, filtered though Celite®, and the solids are washed with ethanol. The filtrate is concentrated under reduced pressure to obtain 1.37 g (99%) of the title compound. LCMS m/e 347 [M+H]+.
Reaction SMILES: C([O-])(O)=O.[Na+].O.[CH:7]1([CH2:12][CH:13]([CH3:17])[CH2:14][CH2:15][OH:16])[CH2:11][CH2:10][CH2:9][CH2:8]1.[O-]Cl.[Na+]>[K+].[Br-].CC1(C)N([O])C(C)(C)CCC1.C1(C)C=CC=CC=1>[CH:7]1([CH2:12][CH:13]([CH3:17])[CH2:14][CH:15]=[O:16])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CC(CCO)CC1CCCC1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=C([O-])O
Agent: [Br-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(CC=O)CC1CCCC1
Temperature: 0 °C
Reaction time: 12 h
Yield: 59.9 %

Procedure:
KBr (0.6 g, 0.005 mol) and NaHCO3 (6.4 g, 0.076 mol) and 0.8 g (0.00566 mols) 2,2,6,6-Tetramethylpiperidine-1-oxyl (TEMPO) were mixed together with water (60 ml), toluene (250 g) and 4-cyclopentyl-3-methylbutan-1-ol (70.2 g 0.45 mol, purity:98%) the reaction temperature maintain 0° C. with continuous stirring. NaOCl (12% w/w aqueous 426.8 g, 0.745 mol) was added to the reaction mass over 2 h. Stirring was continued for another 12 h. The aqueous phase was removed, organic phase was washed with a solution of NaHCO3 and then with water. The organic phase thus obtained was concentrated and crude product purified by fractional distillation to provide 4-cyclopentyl-3-methylbutanal (41.58 g, yield: 60%, GC purity: 97%)
Reaction SMILES: N1C=CN=C1.[CH3:6][P:7](Cl)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].[C:16]([O:20][C:21]([N:23]1[C:31]2[C:26](=[CH:27][C:28]([OH:32])=[CH:29][CH:30]=2)[C:25]([C:33]2[N:34]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[C:35]3[C:40]([CH:41]=2)=[CH:39][C:38]([O:42][CH2:43][CH2:44][N:45]2[CH2:50][CH2:49][O:48][CH2:47][CH2:46]2)=[CH:37][CH:36]=3)=[N:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>ClCCl>[C:16]([O:20][C:21]([N:23]1[C:31]2[C:26](=[CH:27][C:28]([O:32][P:7]([CH3:6])([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[O:8])=[CH:29][CH:30]=2)[C:25]([C:33]2[N:34]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[C:35]3[C:40]([CH:41]=2)=[CH:39][C:38]([O:42][CH2:43][CH2:44][N:45]2[CH2:50][CH2:49][O:48][CH2:47][CH2:46]2)=[CH:37][CH:36]=3)=[N:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: CP(=O)(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)n1nc(-c2cc3cc(OCCN4CCOCC4)ccc3n2C(=O)OC(C)(C)C)c2cc(O)ccc21
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1nc(-c2cc3cc(OCCN4CCOCC4)ccc3n2C(=O)OC(C)(C)C)c2cc(OP(C)(=O)c3ccccc3)ccc21
Temperature: 25 °C
Yield: 31.4 %

Procedure:
16 mg of imidazole and 40.5 mg of methylphenylphosphinic chloride are added to a solution of 27 mg of 3-[1-tert-butoxycarbonyl-5-(2-morpholin-4-yl-ethoxy)-1H-indol-2-yl]-5-hydroxyindazole-1-carboxylic acid tert-butyl ester in 2 ml of dichloromethane. The solution obtained is stirred at ambient temperature. After stirring for 15 hours, a further 16 mg of imidazole and 40.5 mg of methylphenylphosphinic chloride are added and the mixture is stirred at ambient temperature for another 3½ hours in order for the reaction to be complete. The reaction mixture is then filtered and evaporated under reduced pressure in a rotary evaporator. The residue obtained is purified by LC/MS to obtain 10.5 mg of 3-[1-tert-butoxycarbonyl-5-(2-morpholin-4-ylethoxy)-1H-indol-2-yl]-5-(methylphenylphosphinoyloxy)indazole-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]#[N:20])=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][CH2:6][C:7]([NH:10][C:11](=[O:15])[CH2:12][CH2:13][CH3:14])([CH3:9])[CH3:8].[S:21](Cl)(=[O:24])(=[O:23])[NH2:22]>>[S:21]([NH:1][C:2]1[C:3]([C:19]#[N:20])=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][CH2:6][C:7]([NH:10][C:11](=[O:15])[CH2:12][CH2:13][CH3:14])([CH3:9])[CH3:8])(=[O:24])(=[O:23])[NH2:22]
Reactant: CCCC(=O)NC(C)(C)COc1cccc(N)c1C#N
Reactant: NS(=O)(=O)Cl
Product: CCCC(=O)NC(C)(C)COc1cccc(NS(N)(=O)=O)c1C#N
Yield: 100 %

Procedure:
Prepared as in Example 215a from N-(1-(3-amino-2-cyanophenoxy)-2-methylpropan-2-yl)butyramide (Example 229b) and sulfamoyl chloride in 100% yield. MS 355 (MH+).
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@H:9]2[CH2:13][C@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](F)=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][C@@H:10]2[O:25][CH3:26])=[O:8])[CH2:5][CH2:4]1)#[N:2].[F:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[C:1]([C:3]1([NH:6][C:7]([C@H:9]2[CH2:13][C@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([O:34][C:31]4[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=4)=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][C@@H:10]2[O:25][CH3:26])=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: CO[C@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2Cl)C[C@@H]1C(=O)NC1(C#N)CC1
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CO[C@H]1C[C@@H](S(=O)(=O)c2ccc(Oc3ccc(F)cc3)cc2Cl)C[C@@H]1C(=O)NC1(C#N)CC1
Temperature: 50 °C
Reaction time: 4 h
Yield: 68.7 %

Procedure:
(1R,2R,4R) and (1S,2S,4S)-4-(2-Chloro-4-fluoro-benzenesulfonyl)-2-methoxy-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (25 mg, 0.062 mmol, example 56) was dissolved in DMF (1.5 ml) and 4-fluorophenol (14 mg, 0.125 mmol) and Cs2CO3 (61 mg, 0.187 mmol) were added. The reaction mixture was stirred for 4 h at 50° C. Then water was added and the mixture was extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and concentrated. The remaining residue was purified by silica gel chromatography (DCM/EtOAc 9:1) to obtain the title compound (21 mg, 63%) as white solid. MS (EI): 491.1 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].C(N(CC)CC)C.[C:20](Cl)(=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22]>C1COCC1>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:4][C:3]=1[C:9]([F:10])([F:11])[F:12]
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
To a solution of commercially available 4-chloro-3-(trifluoromethyl)aniline (15.0 g, 76.7 mmol) in anhydrous THF (200 mL) cooled to 0-5° C. was added triethylamine (11.7 mL, 84.4 mmol) followed by pivaloyl chloride (10.4 mL, 84.4 mmol) over 30 min. The ice bath was removed and the mixture stirred at rt for 1 h. The mixture was diluted with ether and filtered. The filtrate was washed with water (2×) and brine, dried over MgSO4, filtered and concentrated. The residue was triturated with hexanes and the solid was filtered and dried in vacuo to afford compound 760A (20.4 g, 95%); MS (ES): m/z=280 [M+1]+.