Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:6]([NH:7][CH3:8])=[CH:5][N:4]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[N:3]=1.[C:15]([O:19][C:20]([NH:22][C@@H:23]1[CH2:27][CH2:26][C@H:25]([C:28]([OH:30])=O)[CH2:24]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].CN1CCOCC1>CN(C=O)C.CCOC(C)=O.O>[C:15]([O:19][C:20](=[O:21])[NH:22][C@@H:23]1[CH2:24][C@H:25]([C:28](=[O:30])[N:7]([C:6]2[C:2]([Cl:1])=[N:3][N:4]([C:9]3[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=3)[CH:5]=2)[CH3:8])[CH2:26][CH2:27]1)([CH3:16])([CH3:17])[CH3:18]
Reactant: CNc1cn(-c2cccnc2)nc1Cl
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](C(=O)O)C1
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: O
Product: CN(C(=O)[C@@H]1CC[C@H](NC(=O)OC(C)(C)C)C1)c1cn(-c2cccnc2)nc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-chloro-N-methyl-1-(pyridin-3-yl)-1H-pyrazol-4-amine (0.109 g, 0.523 mmol) and (1S,3R)-3-((tert-butoxycarbonyl)amino)cyclopentanecarboxylic acid (0.120 g, 0.523 mmol) in DMF (2.09 mL) was added 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyl uronium hexafluorophosphate (HATU, 0.219 g, 0.576 mmol) to give a brown solution. To this solution was added 4-methylmorpholine (0.115 mL, 1.05 mmol). The reaction was stirred at room temperature overnight. The material was diluted with EtOAc and water. The organic layer was dried with MgSO4, filtered and concentrated to give orange oil, which was purified by silica gel chromatography eluting with EtOAc/hexanes provided the title compound F45 as an orange oil (0.100 g, 39%).
Reaction SMILES: Br[C:2]1[C:3]([CH3:9])=[C:4]([C:7]#[N:8])[S:5][CH:6]=1.[CH:10]([B-](F)(F)F)=[CH2:11].[K+]>CCO>[CH:10]([C:2]1[C:3]([CH3:9])=[C:4]([C:7]#[N:8])[S:5][CH:6]=1)=[CH2:11]
Reactant: Cc1c(Br)csc1C#N
Reactant: C=C[B-](F)(F)F
Agent: [K+]
Solvent: CCO
Product: C=Cc1csc(C#N)c1C

Procedure:
A mixture of 4-bromo-3-methylthiophene-2-carbonitrile (3.00 g, 14.8 mmol), potassium vinyltrifluoroborate (2.40 g, 17.8 mmol) and Pd (dppf)2Cl2 (0.5 g) in 30 mL of EtOH and 30 mL of TEA was refluxed under Ar for 4 hours. The reaction mixture was concentrated, and the residue was purified by column chromatography (petrol ether:EtOAc=50:1) to afford 4-ethenyl-3-methylthiophene-2-carbonitrile.
Reaction SMILES: C[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=2)[N:3]=1.[NH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:16]1([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:12]([F:13])([F:14])[F:15])[CH:8]=3)[N:3]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1
Reactant: C1CNCCN1
Reactant: Cc1ccc2cc(C(F)(F)F)ccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc2nc(N3CCNCC3)ccc2c1
Temperature: 140 °C
Reaction time: 3 h
Yield: 65.1 %

Procedure:
To a solution of 2-methyl-6-(trifluoromethyl)quinoline (1.5 g, 7.10 mmol) in N,N-dimethylformamide (50 ml) was added piperazine (2.8 g, 32.51 mmol) and potassium carbonate (1.8 g, 12.93 mmol). The resulting solution was stirred for 3 hours at 140° C. and then quenched by the addition of water (200 ml). The crude product was extracted with ethyl acetate (3×100 ml) and the organic layers were combined. The resulting mixture was washed with saturated aqueous sodium chloride (3×100 ml), dried over anhydrous sodium sulfate, filtered, and then concentrated under vacuum. The crude residue was purified by silica gel chromatography using 1-5% methanol in dichloromethane to elute. The product-containing fractions were combined and concentrated to afford 2-(piperazin-1-yl)-6-(trifluoromethyl)quinoline as a brown solid (1.3 g, 65%). (ES, m/z): [M+H]+ 282; 1H NMR (300 MHz, DMSO): δ 8.17-8.23 (t, J=9.3, 2H), 7.66-7.77 (m, 2H), 7.63 (d, J=9.3 Hz, 1H), 3.78-3.81 (t, J=4.5 Hz, 4H), 2.92-2.96 (t, J=4.5 Hz, 4H).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)([C:20]#[N:21])[CH:18]([CH2:29][CH:30]([CH3:32])[CH3:31])[NH:17][CH:16]2[C:33]([OH:35])=O)[CH:12]=[CH:13][CH:14]=1.[NH2:36][CH2:37][CH2:38][CH2:39][OH:40].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>C(Cl)Cl>[OH:40][CH2:39][CH2:38][CH2:37][NH:36][C:33]([CH:16]1[CH:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[CH:10]=2)[C:19]([C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)([C:20]#[N:21])[CH:18]([CH2:29][CH:30]([CH3:31])[CH3:32])[NH:17]1)=[O:35]
Reactant: NCCCO
Reactant: CC(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CC1NC(C(=O)NCCCO)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Yield: 40.2 %

Procedure:
In a manner similar to the method described in Example 1e, rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-isobutyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 31c (0.6 g, 1.1 mmol) was reacted with 3-amino-1-propanol (Aldrich) (0.4 g, 5.3 mmol), HATU and iPr2NEt in CH2Cl2 at room temperature to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-isobutyl-pyrrolidine-2-carboxylic acid (3-hydroxy-propyl)-amide as a white solid (0.21 g, 40%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][C:11]2=[O:16])=[CH:6][C:3]=1[C:4]#[N:5].C(N(CC)CC)C.[Cl:24][C:25]1[S:29][C:28]([C:30]([NH:32][C@@H:33]2[C@@H:37]([OH:38])[CH2:36][C@H:35]([C:39](O)=[O:40])[CH2:34]2)=[O:31])=[CH:27][CH:26]=1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>C(#N)C.CN(C=O)C>[C:4]([C:3]1[CH:6]=[C:7]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][C:11]2=[O:16])[CH:8]=[CH:9][C:2]=1[NH:1][C:39]([C@@H:35]1[CH2:34][C@H:33]([NH:32][C:30]([C:28]2[S:29][C:25]([Cl:24])=[CH:26][CH:27]=2)=[O:31])[C@@H:37]([OH:38])[CH2:36]1)=[O:40])#[N:5]
Reactant: O=C(N[C@H]1C[C@@H](C(=O)O)C[C@@H]1O)c1ccc(Cl)s1
Reactant: N#Cc1cc(N2CCOCC2=O)ccc1N
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#Cc1cc(N2CCOCC2=O)ccc1NC(=O)[C@@H]1C[C@H](NC(=O)c2ccc(Cl)s2)[C@@H](O)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 2.3 %

Procedure:
To a stirred suspension of 2-amino-5-(3-oxo-morpholin-4-yl)-benzonitrile (114 mg; example 21B) in acetonitrile/DMF 9:1 (5 ml) were added triethylamine (0.22 ml), (1R,3S,4S)-3-[(5-chloro-thiophene-2-carbonyl)-amino]-4-hydroxy-cyclopentanecarboxylic acid (198 mg) and BOP-Cl (174 mg). The reaction mixture was stirred at 80° C. overnight, then cooled to r.t. and concentrated. The crude product was purified by column chromatography (silica gel; gradient: CH2Cl2→CH2Cl2/MeOH 9:1) to give 5-chloro-thiophene-2-carboxylic acid {(1S,2S,4R)-4-[2-cyano-4-(3-oxo-morpholin-4-yl)-phenylcarbamoyl]-2-hydroxy-cyclopentyl}-amide (6 mg). Off-white solid. MS: 489.0 ([M+H]+).
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[CH2:9](NC(=O)[C@H]([C@H](CC)C)N)C1C=CC=CC=1.C(N(CC)CC)C.C1C2C(=CC=CC=2)C(C(O)=O)C(C(O)=O)C1C(O)=O>C1COCC1>[NH2:1][C@H:2]([C:3]([OH:5])=[O:4])[C@H:6]([CH2:7][CH3:8])[CH3:9]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: CC[C@H](C)[C@H](N)C(=O)NCc1ccccc1
Agent: O=C(O)C1Cc2ccccc2C(C(=O)O)C1C(=O)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@H](N)C(=O)O
Yield: 285.5 %

Procedure:
Using the procedure described in Example 5, a solution of L-proline-L-isoleucine benzylamide (162 mg, 0.51 mmol), and triethylamine (355 uL, 5.0 eq), THF (2 mL), was treated with 212 mg (2.0 eq) of 1-chloro-2-(1,2,3,4-tetrahydro-napththalen-2-yl)-2-oxoethane (prepared from 1,2,3,4-tetrahydro-2-napththoic acid using the procedure described in Example 1) to provide 191 mg (77%) of L-isoleucine, N-[1-(2-(1,2,3,4-tetrahydro-napththalen-2-yl)-2-oxoethyl)-L-prolyl] benzylamide.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:49][O:50][C:51]1[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][C:52]=1[C:59]1[CH:64]=[CH:63][CH:62]=[C:61]([NH2:65])[CH:60]=1>CN(C=O)C>[CH3:49][O:50][C:51]1[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][C:52]=1[C:59]1[CH:64]=[CH:63][CH:62]=[C:61]([NH:65][C:22]([C:17]2[C:18](=[O:21])[O:19][C:20]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[OH:10])=[O:24])[CH:60]=1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Reactant: COc1ccc(OC)c(-c2cccc(N)c2)c1
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: COc1ccc(OC)c(-c2cccc(NC(=O)c3cc4cccc(O)c4oc3=O)c2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 25.8 %

Procedure:
DIEA (0.013 mL, 0.072 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.013 g, 0.065 mmol) and HATU (0.027 g, 0.072 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 2′,5′-dimethoxy-biphenyl-3-ylamine (0.015 g, 0.065 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and lyophilized for 48 hours to give 0.007 g of product in 27% yield: LCMS (ESI) m/z 418 (MH+).
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].[CH2:5]([NH:12][C:13]1[C:14]2[S:22][CH:21]=[C:20]([CH3:23])[C:15]=2[N:16]=[C:17](Cl)[N:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>O>[CH2:1]([NH:4][C:17]1[N:18]=[C:13]([NH:12][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:14]2[S:22][CH:21]=[C:20]([CH3:23])[C:15]=2[N:16]=1)[CH:2]=[CH2:3]
Reactant: Cc1csc2c(NCc3ccccc3)nc(Cl)nc12
Reactant: C=CCN
Solvent: O
Product: C=CCNc1nc(NCc2ccccc2)c2scc(C)c2n1
Temperature: 140 °C
Yield: 77.7 %

Procedure:
In 2.28 g (40.0 mmol) of allylamine was dissolved 250 mg (0.9 mmol) of 4-benzylamino-2-chloro-7-methylthieno[3,2-d]pyrimidine, and the resulting solution was heated in a sealed tube at 140° C. for 24 hours. After the reaction mixture was cooled, 100 ml of water was added thereto, followed by extraction with ethyl acetate (20 ml×3). The organic layer was washed with 20 ml of water and dried over anhydrous sodium sulfate, and then the solvent was distilled off. The residue was purified by silica gel column chromatography (eluent: ethyl acetate-hexane=1/4) to give 217 mg (yield: 81.3%) of the title compound.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:38])[C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)[C:20]([O:33][CH2:34][CH2:35]O)=[C:19]([Br:37])[CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)[C:20]([O:33][CH2:34][CH2:35][N:39]3[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]3)=[C:19]([Br:37])[CH:18]=2)=[O:38])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(NCCCCCCCCc1ccccc1)c1cc(Br)c(OCCO)c(-c2cccc(C(F)(F)F)c2)c1
Reactant: C1CNCCN1
Product: O=C(NCCCCCCCCc1ccccc1)c1cc(Br)c(OCCN2CCNCC2)c(-c2cccc(C(F)(F)F)c2)c1

Procedure:
The title compound was prepared as a yellow oil (0.302 g, 45%) from N-(8-phenyl-octyl)-3-bromo-5-(m-trifluoromethylphenyl)-4-(2-hydroxyethoxy)-benzamide and piperazine using a procedure similar to Example 185. 1H NMR (DMSO-d6) 8.58 (t, 1H); 8.12 (d, 1H); 7.90-7.84 (m, 3H); 7.69 (d, 1H); 7.52 (dd, 1H); 7.26-7.10 (m, 5H); 3.61 (t, 2H); 3.23 (dd, 2H); 2.62 (t, 4H); 2.52 (t, 2H); 2.36 (t, 2H); 2.18 (m, 5H); 1.50 (m, 4H); 1.24 (m, 8H); IR (film) 3290, 2920, 2850, 1720, 1630, 1600, 1545, 1460, 1330, 1170, 1120, 1080 cm−1; mass spectrum [(+)ESI], mnz 660/662 (M+H)+; Anal. Calcd. for C34H41Br F3N3O2: C, 61.82; H, 6.26; N, 6.36, Found: C, 58.20; H, 6.00; N, 5.47.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([CH:10]([C:16](OCC)=[O:17])[C:11](OCC)=[O:12])[CH2:6][CH2:5]1)[CH2:2][CH3:3].O.Cl>C1(C)C=CC=CC=1>[CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([CH:10]([CH2:11][OH:12])[CH2:16][OH:17])[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCCC1CCC(C(C(=O)OCC)C(=O)OCC)CC1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: CCCC1CCC(C(CO)CO)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 45 %

Procedure:
340 cm] (1.3 mol) of a 70% NaAlH2 (OC2H4OCH3)2 in toluene with 340 cm3 of anhydrous toluene was stirred at room temperature while adding 57 g (0.2 mol) of diethyl 4-propylcyclohexylmalonate dropwise for 30 minutes, after which it was stirred for 5 hours on a hot water bath at 80°-90° C. The reactant was cooled to room temperature, and 50 cm3 of water and 1,000 cm3 of 15% HCl were dropped while stirring. The oily layer was removed, and the water layer was extracted with toluene and combined with the oily layer and washed with 10% HC1 and water. The toluene was removed, and the residue was recrystallized from hexane to obtain 18 g (0.09 mol) of 2-(4'-propylcyclohexyl)propane-1,3-diol (trans-cis form mixture).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[C-:20]#[N:21].[Na+]>O.C(O)C>[C:20]([CH2:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)#[N:21]
Reactant: [C-]#N
Reactant: FC(F)(F)c1ccc(Cc2ccc(CCl)cc2)cc1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#CCc1ccc(Cc2ccc(C(F)(F)F)cc2)cc1
Temperature: 80 °C

Procedure:
In a 50 ml round-bottom two-necked flask, 2.0 g were suspended in 2.0 ml of water and heated to 80° C. A 9.2 g amount of 4-(4'-chloromethylbenzyl)benzotrifluoride was dissolved in 7.1 ml of ethanol. This solution was added dropwise into the NaCN suspension. The proportion of undissolved substances increased. The reaction mixture turned brown. The feedstock was boiled under reflux for 5 hours. After the reaction mixture had cooled down to room temperature, the solid substance was removed by filtration and washed with 30 ml ethanol. The filtration was concentrated in a rotary evaporator (bath temp. 30° C., water-jet vacuum). The oily residue was dissolved in 50 ml of diethyl ether and washed to neutrality four times with 30 ml of water each time. The organic phase was dried over sodium sulfate. The drying agent was removed by filtration and the ether was removed by distillation in a rotary evaporator (bath temp. 30° C., water-jet vacuum). The raw product (8.0 g) was chromatographed on silica gel 60 (0.63-0.200) with ether/pentane (1/4) and the 4-(4'-cyanomethylbenzyl)benzotrifluoride (5.8 g) thus obtained was recrystallized from 44 ml of solvent blend (petroleum benzin 60°-80°C0-diethyl ether 5:1 v/v). The precipitated crystallizate was removed by filtration via a D-4 glass suction funnel and washed with 25 ml of ice-cold petroleum benzin. The product was dried in a vacuum drying oven (oil pump) at room temperature for 5 hours.
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH3:26])[C:3]([O:5][CH2:6][N:7]1[C:15]2[N:14]=[CH:13][N:12](CC3C=CC=CC=3)[C:11]=2[C:10](=[O:23])[N:9]([CH3:24])[C:8]1=[O:25])=[O:4]>C(O)(=O)C.[C].[Pd]>[CH3:1][C:2]([CH3:27])([CH3:26])[C:3]([O:5][CH2:6][N:7]1[C:15]2[N:14]=[CH:13][NH:12][C:11]=2[C:10](=[O:23])[N:9]([CH3:24])[C:8]1=[O:25])=[O:4]
Reactant: Cn1c(=O)c2c(ncn2Cc2ccccc2)n(COC(=O)C(C)(C)C)c1=O
Agent: [Pd]
Solvent: CC(=O)O
Product: Cn1c(=O)c2[nH]cnc2n(COC(=O)C(C)(C)C)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.3 %

Procedure:
2.349 g of [7-benzyl-1-methyl-2,6-dioxo-1,2,6,7-tetrahydropurin-3-yl]methyl 2,2-dimethylpropionate was dissolved in 100 ml of acetic acid, and 1 g of 10% palladium carbon was added thereto. The mixture was stirred under a hydrogen atmosphere at room temperature overnight. The reaction mixture was filtered and concentrated to give 1.871 g of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23](Br)[CH:24]=2)[NH:19][CH:18]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:27]([C:29]1([OH:34])[CH2:33][CH2:32][CH2:31][CH2:30]1)=[CH2:28]>CO>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([CH:28]=[CH:27][C:29]3([OH:34])[CH2:33][CH2:32][CH2:31][CH2:30]3)[CH:24]=2)[NH:19][CH:18]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC1(O)CCCC1
Reactant: O=C(OCc1ccccc1)N1CCC[C@@H]1Cc1c[nH]c2ccc(Br)cc12
Solvent: CO
Product: O=C(OCc1ccccc1)N1CCC[C@@H]1Cc1c[nH]c2ccc(C=CC3(O)CCCC3)cc12

Procedure:
Obtained by a procedure similar to that described in Example 1, from 3-(N-benzyloxycarbonyl-2(R)-pyrrolidinylmethyl)-5-bromo-1H-indole (Preparation 1) and 1-vinylcyclopentanol (Example 5(a)), as a foam. Rf 0.40 (SS 10). [α]D25 -31° (c=0.1, CH3OH). Found: C,75.58; H,7.24; N,6.22. C28H32N2O3 requires C,75.64; H,7.26; N,6.30%.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:18]=[CH:17][CH:16]=[N:15][C:4]=2[N:5]([CH2:13][CH3:14])[C:6]2[N:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1.[CH2:19]([NH2:22])[CH2:20][CH3:21]>C1(C)C=CC=CC=1>[CH2:13]([N:5]1[C:4]2[N:15]=[CH:16][CH:17]=[CH:18][C:3]=2[C:2]([NH:22][CH2:19][CH2:20][CH3:21])=[N:8][C:7]2[CH:9]=[CH:10][CH:11]=[N:12][C:6]1=2)[CH3:14]
Reactant: CCCN
Reactant: CCN1c2ncccc2N=C(Cl)c2cccnc21
Solvent: Cc1ccccc1
Product: CCCNC1=Nc2cccnc2N(CC)c2ncccc21

Procedure:
A mixture of 6-chloro-11-ethyl-11H-dipyrido[3,2-b:2',3'-e][1,4]diazepine (0.7 g, n-propylamine (0.8 g), and toluene (25 mL) was heated at reflux for ten days. At two day intervals during the ten day period, additional 1.6 g portions of n-propylamine was added to the refluxing mixture. The mixture was then concentrated in vacuo and the residue chromatographed over silica gel (eluted with 20% ethyl acetate/hexane) to give 0.15 g of the title compound, m.p. 114°-116° C.
Reaction SMILES: [C:1]([C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].O[N:15]1[C:19](=[O:20])[CH2:18][CH2:17][C:16]1=[O:21].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:1]([C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([O:11][N:15]2[C:19](=[O:20])[CH2:18][CH2:17][C:16]2=[O:21])=[O:10])=[CH:5][CH:4]=1)#[N:2]
Reactant: O=C1CCC(=O)N1O
Reactant: N#Cc1ccc(C=CC(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: N#Cc1ccc(C=CC(=O)ON2C(=O)CCC2=O)cc1
Yield: 79.5 %

Procedure:
The same procedures as in Example 117 were carried out from 4-cyanocinnamic acid (5.0 g), N-hydroxysuccinic acid imide (5.0 g), WSC.HCl (8.3 g), and methylene chloride (150 mL), to give the captioned compound (6.2 g, 79%) as crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:12](=[O:15])[CH2:13]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]([NH:30][C:31]1[CH:47]=[CH:46][C:34]([O:35][CH2:36][CH2:37][NH:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[CH:33][CH:32]=1)(=[O:29])[CH3:28].C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C(O)(C)C>[CH2:39]([N:38]([CH2:37][CH2:36][O:35][C:34]1[CH:33]=[CH:32][C:31]([NH:30][C:27](=[O:29])[CH3:28])=[CH:47][CH:46]=1)[CH2:13][C:12](=[O:15])[C:11]1[CH:16]=[CH:17][C:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]=1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: O=C(CBr)c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Reactant: CC(=O)Nc1ccc(OCCNCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(C)O
Product: CC(=O)Nc1ccc(OCCN(CC(=O)c2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)Cc2ccccc2)cc1
Temperature: 25 °C
Yield: 66.9 %

Procedure:
A mixture of 3,4-dibenzyloxyphenacyl bromide (32.8 g.), N-[2-(4-acetamidophenoxy)ethyl]benzylamine (22.8 g.), anhydrous sodium carbonate (8.4 g.) and ethanol (1 liter) was boiled under reflux for 2 hours, then filtered hot to remove the inorganic sediment and evaporated in vacuo to afford a thick syrup. The latter was dissolved in hot isopropanol and the solution cooled, the precipitated solid then being collected by filtration. To a hot solution of the solid in fresh isopropanol were added a few milliliters of ethyl acetate, and the solution was then allowed to cool to room temperature. The crystallized solid was collected by filtration, washed in diethyl ether and dried. Recrystallization from an isopropanol/ethyl acetate mixture afforded N-benzyl-N-(3,4-dibenzyloxybenzoyl)methyl-2-(4-acetamidophenoxy)ethylamine (32.8 g.), m.p. 104°-6° C.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:44]([CH2:45][CH2:46][CH3:47])[CH:43]=[N:42][C:41]=5[CH3:48])=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:49]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:58])C=1.CSC.O>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:44]([CH2:45][CH2:46][CH3:47])[CH:43]=[N:42][C:41]=5[CH3:48])=[O:58])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:49]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4c(C)ncn4CCC)cc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CSC
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4c(C)ncn4CCC)cc2)CCN3CC(C)C)cc1
Reaction time: 0.5 h
Yield: 50.1 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[[4-methyl-1-propylimidazol-5-yl]methyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (460 mg) in dichloromethane (15 ml) was added dropwise 70% solution of 3-chloroperbenzoic acid (175 mg) in dichloromethane (15 ml) at −78° C. Dimethylsulfide (0.1 ml) was added to the mixture, and the mixture was allowed to be at room temperature and stirred for 30 minutes. To the mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous solution of saturated sodium bicarbonate, and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was separated and purified by basic silica gel column chromatography (ethyl acetate), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[[4-methyl-1-propylimidazol-5-yl]methyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (236 mg) (Compound 388) as yellow amorphous.
Reaction SMILES: Br(O)(=O)=O.[Br:5][C:6]1[S:10][C:9]([NH2:11])=[N:8][CH:7]=1.N1C=CC=CC=1.[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](Cl)=[O:24].CO>C(Cl)Cl>[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([NH:11][C:9]1[S:10][C:6]([Br:5])=[CH:7][N:8]=1)=[O:24]
Reactant: O=C(Cl)CCCCBr
Reactant: Nc1ncc(Br)s1
Agent: [O-][Br+2]([O-])O
Solvent: c1ccncc1
Solvent: CO
Solvent: ClCCl
Product: O=C(CCCCBr)Nc1ncc(Br)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-bromothiazol-2-amine bromate (1 g) in methylene chloride (12 mL) was added a solution of pyridine (0.68 mL) and 5-bromopentanoyl chloride (0.54 mL) in methylene chloride (0.7 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was added with methanol (0.7 mL) and concentrated under reduced pressure. The obtained residue was added with 1 N hydrochloric acid (13 mL). The obtained solid was washed with tert-butyl methyl ether and dried to give the titled compound (1.06 g) having the following physical data.