Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:10][CH2:9][C:8]([C:16]([O:18][CH3:19])=[O:17])=[CH:7][C:6]=2[CH:20]=1.B([O-])([O-])O[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][CH3:35])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.C(O)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>[CH2:12]([N:11]1[C:5]2[CH:4]=[CH:3][C:2]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][CH3:35])=[CH:25][CH:24]=3)=[CH:20][C:6]=2[CH:7]=[C:8]([C:16]([O:18][CH3:19])=[O:17])[CH2:9][CH2:10]1)[CH:13]([CH3:15])[CH3:14]
Reactant: COC(=O)C1=Cc2cc(Br)ccc2N(CC(C)C)CC1
Reactant: CCCOCCOc1ccc(OB([O-])[O-])cc1
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: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3CC(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.9 %

Procedure:
In toluene/ethanol/water (=10/1/1, 41 ml) was dissolved methyl 7-bromo-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxylate (0.90 g). To the solution were added 4-(2-propoxyethoxy)phenyl borate (0.72 g) and potassium carbonate (0.81 g) and the mixture was stirred for 30 minutes under argon atmosphere. To the mixture was added tetrakistriphenylphosphinepalladium (123 mg) and the mixture was heated to reflux for 14 hours. After cooling to room temperature, the solution was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified with silica gel column chromatography (hexane/ethyl acetate=8/1) to give methyl 1-isobutyl-7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1-benzazepine-4-carboxylate (0.79 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]([C:12]([OH:14])=[O:13])[NH2:11])[CH:6]=[CH:7][C:8]=1[OH:9].Cl.[CH3:16]O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]([C:12]([O:14][CH3:16])=[O:13])[NH2:11])[CH:6]=[CH:7][C:8]=1[OH:9]
Reactant: CO
Reactant: COc1cc(C(N)C(=O)O)ccc1O
Agent: Cl
Product: COC(=O)C(N)c1ccc(O)c(OC)c1

Procedure:
A cooled suspension of 94 g. (0.476 mole) of 2-(3'-methoxy-4'-hydroxyphenyl)glycine in 500 ml. of absolute methanol was gassed at a rapid rate with HCl for 20 minutes. At first a clear solution was obtained and then crystalline product separated in quantity. After 20 hours the methyl ester hydrochloride was filtered and washed sparingly with methanol; 99.6 g. after air drying. A cooled solution of the hydrochloride in 800 ml. of water was adjusted to pH 8 (NaOH) giving a crystalline precipitate of the ester free base; 81.3 g. The IR and NMR spectra were consistent.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:13][CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:21]1([S:27](Cl)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>C1COCC1.CCOCC>[C:21]1([S:27]([N:11]2[CH2:12][CH2:13][CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:10]2)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2ccccc2)C1
Reaction time: 2 h

Procedure:
To a solution of 3-(tert-butoxycarbonylamino)pyrrolidine (0.7 g) in THF (20 ml) cooled to 0° C. was added triethylamine (0.52 ml) followed by the addition of benzenesulfonyl chloride (0.48 ml) dropwise over 5 minutes. After stirring for 2 hours the mixture was poured into water and the organics extracted into ether. The ether extractions were combined, washed with brine, dried (MgSO4) and concentrated in vacuo to give crude material. Trituration with ether gave subtitle compound as a colourless solid (0.9 g).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([C@@H:13]2[CH2:17][C@H:16]([OH:18])[CH2:15][N:14]2[C:19]2[C:24]([Cl:25])=[CH:23][C:22]([C:26]([F:29])([F:28])[F:27])=[CH:21][N:20]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C>CS(C)=O>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([C@@H:13]2[CH2:17][C:16](=[O:18])[CH2:15][N:14]2[C:19]2[C:24]([Cl:25])=[CH:23][C:22]([C:26]([F:27])([F:28])[F:29])=[CH:21][N:20]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)[C@@H]2C[C@H](O)CN2c2ncc(C(F)(F)F)cc2Cl)no1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C)c1cc(NC(=O)[C@@H]2CC(=O)CN2c2ncc(C(F)(F)F)cc2Cl)no1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (2S,4S)-1-(3-chloro-5-trifluoromethyl-pyridin-2-yl)-4-hydroxy-pyrrolidine-2-carboxylic acid (5-tert-butyl-isoxazol-3-yl)-amide (183 mg, 0.423 mmol) in dimethyl sulfoxide (5 mL) is added triethylamine (0.118 mL, 0.846 mmol) and sulfur trioxide pyridine complex (115 mg, 0.72 mmol). The reaction is stirred at room temperature for 4 hours. More triethylamine (0.18 mL, 1.27 mmol) and sulfur trioxide pyridine complex (155 mg, 0.97 mmol) are added to the reaction mixture and the stirring is continued for another 2 hours. The reaction is quenched with 1N hydrochloric acid aqueous solution and the solid precipitated out of the solution is filtered and dissolved in dichloromethane and washed with saturated sodium bicarbonate aqueous solution and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by chromatography on silica eluting with ethyl acetate/hexanes and further purification using pre LC-MS provides the title compound, ESI m/z 431 [M+H+].
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:3]=1/[CH:4]=[C:5]1/[C:6](=[O:22])[C:7]2[C:12]([CH2:13]/1)=[CH:11][C:10]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[C:9]([O:20][CH3:21])[CH:8]=2>CO.[Pd]>[F:1][C:2]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:23][C:3]=1[CH2:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:20][CH3:21])=[C:10]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH:11]=2)[C:6]1=[O:22]
Reactant: COc1cc2c(cc1N1CCOCC1)C/C(=C\c1cc(C(F)(F)F)ccc1F)C2=O
Agent: [Pd]
Solvent: CO
Product: COc1cc2c(cc1N1CCOCC1)CC(Cc1cc(C(F)(F)F)ccc1F)C2=O
Reaction time: 6 h

Procedure:
Compound 76 (50 mg, 0.118 mmol) was dissolved in methanol 20 mL, Pd/C 30.6 mg added, and the reaction stirred under hydrogen balloon for 6 h. The result was filtered through celite bed and washed with excess methanol. The organic layer was concentrated to get the crude which was purified by flash chromatography using 100-200 mesh silica gel. The compound was eluted at 26% ethyl acetate in hexane as half white coloured solid compound 2-(2-fluoro-5-(trifluoromethyl)benzyl)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one 77. 1HNMR (400 MHz, CDCl3) δ ppm 7.51 (dd, 1H), 7.48 (m, 1H), 7.15 (m, 2H), 6.82 (s, 1H), 3.89 (m, 3H), 3.87 (m, 4H), 3.40 (m, 1H), 3.17 (m, 4H), 3.11 (m, 1H), 3.02 (m, 1H), 2.70 (m, 2H); MS (ESI) m/z 424.0 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][C:15]3[N:19]4[N:20]=[C:21]([C:24]5[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=5)[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[CH3:32][NH:33][CH3:34].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][C:15]3[N:19]4[N:20]=[C:21]([C:24]5[CH:31]=[CH:30][C:27]([CH2:28][N:33]([CH3:34])[CH3:32])=[CH:26][CH:25]=5)[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(OCc3nnc4ccc(-c5ccc(C=O)cc5)nn34)ccnc2c1
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc2c(OCc3nnc4ccc(-c5ccc(CN(C)C)cc5)nn34)ccnc2c1
Reaction time: 0.33 h

Procedure:
A mixture of 4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)benzaldehyde (prepared according to General Method A) (0.150 g, 0.36 mmol) and dimethylamine, 2.0 m solution in thf (0.36 ml, 0.73 mmol) in THF (5 mL) was allowed to stir for 20 min. Added sodium triacetoxyborohydride (0.15 g, 0.73 mmol) and stirred for 4 h. Concentrated. Suspended in DMSO, filtered through a 0.45 uM acrodisc. Purified on RPHPLC. Took fractions that contained product and made basic with 9% sodium carbonate. Removed volatiles in vacuo. Product crashed out and was isolated by filtration. MS m/z=441.2 [M+1]+. Calc'd for C2H24N6O2: 440.2.
Reaction SMILES: [C:1]([C:3]([O:5][CH2:6][CH3:7])=[O:4])#[N:2].[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2OC(=O)[S:18][N:17]=2)=[CH:12][CH:11]=1.C(=O)=O>CC1C=CC(C)=CC=1>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:2]=[C:1]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[S:18][N:17]=2)=[CH:12][CH:11]=1
Reactant: CCOC(=O)C#N
Reactant: COc1ccc(-c2nsc(=O)o2)cc1
Agent: O=C=O
Solvent: Cc1ccc(C)cc1
Product: CCOC(=O)c1nc(-c2ccc(OC)cc2)ns1
Yield: 77 %

Procedure:
Ethyl cyanoformate (16.9 g, 0.171 mol) is added to a stirred solution of 5-(4-methoxyphenyl)-[1,3,4]oxathiazolin-2-one (11.9 g, 0.057 mol) in p-xylene (100 ml). The mixture is heated to 115°-132° C. for 10 hours, during which time carbon dioxide is liberated. The solvent is evaporated in vacuo and the residue is triturated with di-isopropyl ether. The crystalline solid is filtered off, washed with a small amount of diisopropyl ether and dried, to give ethyl 3-(4-methoxyphenyl)-[1,2,4]thiadiazole-5-carboxylate (11.6 g, 77%) as beige crystals, m.p. 61°-63° C.
Reaction SMILES: C([O:8][C:9]1[C:14]([C:15]2[CH:32]=[C:31]([C:33]([CH3:36])([CH3:35])[CH3:34])[C:30]([O:37][CH3:38])=[CH:29][C:16]=2[CH2:17][N:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]([CH3:27])[C:19]2=[O:28])=[CH:13][CH:12]=[CH:11][N:10]=1)C1C=CC=CC=1>CO.[Pd]>[C:33]([C:31]1[C:30]([O:37][CH3:38])=[CH:29][C:16]([CH2:17][N:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]([CH3:27])[C:19]2=[O:28])=[C:15]([C:14]2[C:9](=[O:8])[NH:10][CH:11]=[CH:12][CH:13]=2)[CH:32]=1)([CH3:36])([CH3:34])[CH3:35]
Reactant: COc1cc(Cn2c(=O)n(C)c3ccccc32)c(-c2cccnc2OCc2ccccc2)cc1C(C)(C)C
Agent: [Pd]
Solvent: CO
Product: COc1cc(Cn2c(=O)n(C)c3ccccc32)c(-c2ccc[nH]c2=O)cc1C(C)(C)C
Reaction time: 2 h

Procedure:
step 3—A mixture of 98 (99 mg) and 10% Pd/C (15 mg) in MeOH (20 mL) under 1 atmosphere of H2 at RT was stirred for 2 h. The catalyst was filtered and the filtrate was concentrated. The crude residue was purified on a preparative SiO2 TLC plate developed with 5% MeOH/DCM to afford 63.7 mg (78%) of I-69.
Reaction SMILES: [CH3:1][C:2]1[CH:21]=[CH:20][C:5]2[NH:6][C:7]([CH:9]3[CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]3)=[N:8][C:4]=2[CH:3]=1.[ClH:22]>O1CCOCC1>[ClH:22].[ClH:22].[NH:11]1[CH2:12][CH:9]([C:7]2[NH:6][C:5]3[CH:20]=[CH:21][C:2]([CH3:1])=[CH:3][C:4]=3[N:8]=2)[CH2:10]1
Reactant: Cc1ccc2[nH]c(C3CN(C(=O)OC(C)(C)C)C3)nc2c1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc2[nH]c(C3CNC3)nc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
To tert-butyl 3-(5-methyl-1H-benzo[d]imidazol-2-yl)azetidine-1-carboxylate (prepared in the previous step) was added 4 M HCl in dioxane (30 mL). The reaction mixture was stirred at RT. After 30 min, a solid coated the inside of the flask. The liquid was removed from the flask and the remaining solid was dried under high vacuum. The solid was dissolved in MeOH (20 mL) and diluted with ether (50 mL). The precipitate was collected by filtration and dried under high vacuum to give 2-(azetidin-3-yl)-5-methyl-1H-benzo[d]imidazole dihydrochloride (2.99 g, 11.5 mmol 84% yield over three steps) as a dark red solid.
Reaction SMILES: [C:1]([C:3]1[CH:28]=[CH:27][C:6]([CH2:7][NH:8][C:9](=[O:26])[CH:10]([O:23][CH2:24][CH3:25])[N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[F:21])[C:12]2=[O:22])=[C:5]([N+:29]([O-])=O)[CH:4]=1)#[N:2]>C(OCC)(=O)C.[Pd]>[NH2:29][C:5]1[CH:4]=[C:3]([C:1]#[N:2])[CH:28]=[CH:27][C:6]=1[CH2:7][NH:8][C:9](=[O:26])[CH:10]([O:23][CH2:24][CH3:25])[N:11]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[F:21])[C:12]1=[O:22]
Reactant: CCOC(C(=O)NCc1ccc(C#N)cc1[N+](=O)[O-])N1C(=O)c2cccc(F)c2C1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(C(=O)NCc1ccc(C#N)cc1N)N1C(=O)c2cccc(F)c2C1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 101.7 %

Procedure:
To a solution of (RS)-N-(4-cyano-2-nitro-benzyl)-2-ethoxy-2-(4-fluoro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-acetamide (0.310 g) in ethyl acetate (7.3 ml) was added 10% Pd/C (60 mg) and the mixture vigorously stirred at r.t. under a hydrogen atmosphere for 24 h. The catalyst was filtered off over a celite pad and the cake was carefully washed with ethyl acetate. The filtrate was evaporated to yield (RS)-N-(2-amino-4-cyano-benzyl)-2-ethoxy-2-(4-fluoro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-acetamide (0.293 g) as yellow viscous oil, MS 397.2 ([M+H]+).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=O.Cl.[C:16]1([C:22]2([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:30]3[CH:26]([CH2:27][NH:28][CH2:29]3)[C:25](=[O:31])[CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>ClCCl>[C:32]1([C:22]2([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:30]3[CH:26]([CH2:27][N:28]([C:10](=[O:12])[CH2:9][C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[C:2]([F:1])([F:14])[F:13])[CH2:29]3)[C:25](=[O:31])[CH2:24][CH2:23]2)[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Reactant: O=C(O)Cc1ccccc1C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCC(c2ccccc2)(c2ccccc2)C2CN(C(=O)Cc3ccccc3C(F)(F)F)CC12
Reaction time: 0.75 h
Yield: 50.6 %

Procedure:
N,N'-Carbonyldiimidazole (1.13 g) is added to a solution of 2-(2-(trifluoromethyl)phenyl)acetic acid (1.42 g) in dry dichloromethane (30 cc), cooled to +5° C. The mixture is stirred for 1 hour 45 minutes at +5° C. and a solution of (3aRS,7aRS)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (2.3 g) and triethylamine (0.98 cc) in dichloromethane (40 cc) is then added. The reaction mixture is stirred at 20° C. for 18 hours, then washed with distilled water (3×50 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from acetonitrile (10 cc). The crystals obtained are drained, washed with isopropyl ether (10 cc) and dried. (3aRS,7aRS)-7,7-diphenyl-2-[(2-(trifluoromethyl)phenyl)acetyl]-4-perhydroisoindolone (1.68 g) melting at 207° C. is obtained.
Reaction SMILES: [CH:1]([C@:4]1([C:16]([O:18][CH3:19])=[O:17])[CH2:8][CH2:7][C@@H:6]([NH:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH2:5]1)([CH3:3])[CH3:2].C=O.[C:22](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH:1]([C@:4]1([C:16]([O:18][CH3:19])=[O:17])[CH2:8][CH2:7][C@@H:6]([N:9]([CH3:22])[CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COC(=O)[C@@]1(C(C)C)CC[C@@H](NC2CCOCC2)C1
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)[C@@]1(C(C)C)CC[C@@H](N(C)C2CCOCC2)C1
Reaction time: 0.58 h
Yield: 95.4 %

Procedure:
Methyl (1S,3R)-1-isopropyl-3-(tetrahydro-2H-pyran-4-ylamino)cyclopentanecarboxylate (1.0 g, 3.7 mmol) was combined with 37% aqueous formaldehyde solution (3.0 mL, 37 mmol) in 50 mL of DCM. After stirring for 35 min, 4 Å powdered molecular sieves, and sodium triacetoxyborohydride (3.9 g, 19 mmol) were added and the reaction mixture was stirred overnight under a nitrogen atmosphere. The reaction mixture was diluted with DCM, filtered through celite, and the filtrate was washed with saturated NaHCO3 solution, and brine. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated to afford 1.0 g of methyl (1S,3R)-1-isopropyl-3-[methyl(tetrahydro-2H-pyran-4-yl)amino]cyclopentanecarboxylate.
Reaction SMILES: [CH2:1]([N:5]1[C:10]([CH3:11])=[CH:9][C:8]([CH3:13])([CH3:12])[N:7]([CH3:14])[CH2:6]1)[CH2:2][CH2:3][CH3:4]>C(O)C>[CH2:1]([N:5]1[CH:10]([CH3:11])[CH2:9][C:8]([CH3:12])([CH3:13])[N:7]([CH3:14])[CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1CN(C)C(C)(C)C=C1C
Solvent: CCO
Product: CCCCN1CN(C)C(C)(C)CC1C
Reaction time: 18 h
Yield: 95.3 %

Procedure:
To a mixture of 40 grams of 1-butyl 3,4,4,6-tetramethyl 1,2,3,4-tetrahydropyrimidine prepared as described in example 7, and 177 grams of absolute ethanol was added over a 1/2 hour period 4.7 grams of sodium hydridoborate. The reaction mixture was stirred for 18 hours and the ethanol evaporated under diminished pressure. To the resulting product was added water and stirring was continued for 24 hours. The organic layer was separated, dissolved in ether, and the ethereal solution washed with diminished pressure to yield 38.5 grams of 1-butyl 3,4,4,6-tetramethyl hexahydropyrimidine. C13 n.m.r., solvent CDCl3 ; ref. T.M.S.; ##STR13## 71.2(2); 52.4(4); 46.4(5); 52.1(6); 29.7(7); 20.4(8); 15.3(9); 34.7(10); 49.6(11); 29.5(12); 20.9(13); 14.0(14).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([N:12]([CH3:31])[C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:21]=1[NH:20][C:19]([C:22]1[S:23][CH:24]([CH2:27][C:28]([OH:30])=O)[CH2:25][N:26]=1)=[CH:18]2)(=[O:11])=[O:10].[OH:32][CH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(OCC)(=O)C.CN(C)C=O>[OH:32][CH:33]1[CH2:38][CH2:37][N:36]([C:28](=[O:30])[CH2:27][CH:24]2[S:23][C:22]([C:19]3[NH:20][C:21]4[C:17]([CH:18]=3)=[CH:16][CH:15]=[CH:14][C:13]=4[N:12]([CH3:31])[S:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])(=[O:11])=[O:10])=[N:26][CH2:25]2)[CH2:35][CH2:34]1
Reactant: COc1ccccc1S(=O)(=O)N(C)c1cccc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Reactant: OC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccccc1S(=O)(=O)N(C)c1cccc2cc(C3=NCC(CC(=O)N4CCC(O)CC4)S3)[nH]c12
Temperature: 25 °C
Yield: 74 %

Procedure:
To a mixture of (2-{7-[[(2-methoxyphenyl)sulfonyl](methyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetic acid (150 mg), 4-hydroxypiperidine (43 mg), 1H-1,2,3-benzotriazol-1-ol (67 mg) and N,N-dimethylformamide (8 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (94 mg) under ice-cooling, and the mixture was stirred from under ice-cooling to room temperature for 15 hr. The reaction solution was diluted with ethyl acetate, washed with water, aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:methanol=100:0-90:10), and the obtained colorless oil was crystallized from ethyl acetate-hexane to give the title compound (131 mg, yield 74%) as colorless prism crystals. MS:543(MH+). melting point 166-167° C.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9](OS(C(F)(F)F)(=O)=O)=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1)=[CH:15][C:14]([Cl:25])=[CH:13][CH:12]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>>[C:1]([O:5][C:6]([C:8]1[C:9]([N:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1)=[CH:15][C:14]([Cl:25])=[CH:13][CH:12]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)c1c(OS(=O)(=O)C(F)(F)F)nc2ccc(Cl)cc2c1-c1cccc(Cl)c1
Reactant: C1CCNCC1
Product: CC(C)(C)OC(=O)c1c(N2CCCCC2)nc2ccc(Cl)cc2c1-c1cccc(Cl)c1

Procedure:
The title compound was prepared in analogy to example 92 step A from 6-chloro-4-(3-chloro-phenyl)-2-trifluoromethanesulfonyloxy-quinoline-3-carboxylic acid tert-butyl ester (prepared as described in example 91 step C, 150 mg, 0.29 mmol) and piperidine (0.057 ml, 0.58 mmol). Pale yellow solid (95 mg, 72%). LC-MS (ESI): 457 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH:10]([NH:21][CH3:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[C:32]([F:35])([F:34])[F:33])[CH:27]=O.[BH3-]C#N.[Na+]>CO.CC(O)=O>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH:10]([N:21]([CH2:27][C:26]2[CH:29]=[CH:30][C:31]([C:32]([F:33])([F:34])[F:35])=[C:24]([F:23])[CH:25]=2)[CH3:22])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(C(F)(F)F)c(F)c1
Reactant: CNC1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CN(Cc1ccc(C(F)(F)F)c(F)c1)C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of [(3RS,4SR)-1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-amine (3.5 g, 0.010 mol) in MeOH (60 ml) was added 3-fluoro-4-trifluoromethyl-benzaldehyde (2.10 g, 0.0109 mol). Then a solution of NaBH3CN (0.79 g, 0.012 mol) in MeOH (15 ml) and AcOH (0.1 ml) were added. The reaction mixture was stirred overnight at RT, concentrated under vacuo, diluted with EtOAc, washed with H2O. The organic phases were dried over Na2SO4 and the product purified by flash chromatography (SiO2, EtOAc/Heptane 1:4) to afford 3.31 g (6 2%) of the title compound as a colorless oil.
Reaction SMILES: [C:1](=[O:23])([O:20][CH2:21][CH3:22])[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[CH:10]1[CH:17]2[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:19][CH:11]1[CH2:12]3)[CH2:16]2.[N+:24]([O-])([O-:26])=[O:25].[K+]>OS(O)(=O)=O>[C:1](=[O:23])([O:20][CH2:21][CH3:22])[O:2][C:3]1[CH:8]=[C:7]([N+:24]([O-:26])=[O:25])[C:6]([CH3:9])=[CH:5][C:4]=1[CH:10]1[CH:11]2[CH2:19][CH:15]3[CH2:14][CH:13]([CH2:18][CH:17]1[CH2:16]3)[CH2:12]2
Reactant: O=[N+]([O-])[O-]
Reactant: CCOC(=O)Oc1ccc(C)cc1C1C2CC3CC(C2)CC1C3
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCOC(=O)Oc1cc([N+](=O)[O-])c(C)cc1C1C2CC3CC(C2)CC1C3
Temperature: 25 °C
Reaction time: 3 h
Yield: 25 %

Procedure:
To a cooled solution of 2-admantyl-4-methyl-phenyl ethyl carbonate (1.32 g, 4.2 mmol) in H2SO4 (98%, 10 mL) was added KNO3 (510 mg, 5.0 mmol) in small portions at 0° C. The mixture was stirred for 3 h while warming to room temperature, poured into ice and then extracted with dichloromethane. The combined organic layers were washed with NaHCO3 and brine, dried over MgSO4 and concentrated to dryness. The residue was purified by column chromatography (0-10% EtOAc—Hexane) to yield 2-admantyl-4-methyl-5-nitrophenyl ethyl carbonate (378 mg, 25%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:26])[CH:12]([C:19]2[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=2)[CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[N:6][CH:5]=1.C(N(CC)C(C)C)(C)C.Cl.[C:38](Cl)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[N:41][CH:40]=1>O1CCCC1>[CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:26])[CH:12]([C:19]2[CH:20]=[CH:21][C:22]([NH:25][C:38]([C:39]3[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=3)=[O:45])=[CH:23][CH:24]=2)[CH2:13][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18]2)=[N:6][CH:5]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: COC(=O)c1ccc(NC(=O)C(CC2CCCC2)c2ccc(N)cc2)nc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(NC(=O)C(CC2CCCC2)c2ccc(NC(=O)c3cccnc3)cc2)nc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 72.6 %

Procedure:
A solution of 6-[2-(4-amino-phenyl)-3-cyclopentyl-propionylamino]-nicotinic acid methyl ester (236.1 mg, 0.65 mmol) in tetrahydrofuran (15 mL) at 25° C. was treated with N,N-diisopropylethylamine (0.27 mL, 1.54 mmol) and nicotinoyl chloride hydrochloride (115 mg, 0.64 mmol). The reaction mixture was stirred at 25° C. for 48 h. At this time, the reaction was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 90/10 ethyl acetate/hexanes) afforded 6-(3-cyclopentyl-2-{4-[(pyridine-3-carbonyl)-amino]phenyl}-propionylamino)-nicotinic acid methyl ester (219.6 mg, 72.3%) as a white solid: mp 110-1 15° C.; EI-HRMS m/e calcd for C27H28N4O4 (M+) 472.2110, found 472.2109.