Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](=O)[C:10]([OH:12])=[O:11].C1CCN2C(=NCCC2)CC1.[NH2:25][C:26]1[C:31]([CH:32]=O)=[CH:30][N:29]=[C:28]([S:34][CH3:35])[N:27]=1>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:10]([OH:12])=[O:11])=[N:25][C:26]2[N:27]=[C:28]([S:34][CH3:35])[N:29]=[CH:30][C:31]=2[CH:32]=1
Reactant: O=C(O)C(=O)Cc1ccccc1Br
Reactant: CSc1ncc(C=O)c(N)n1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CSc1ncc2cc(-c3ccccc3Br)c(C(=O)O)nc2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 53.4 %

Procedure:
3.372 g 3-(2-bromophenyl)2-oxopropionic acid in 20 ml DMF were treated with 4.434 g DBU under cooling and stirred for 10 min at RT. 2.728 g 4-amino-2-methylsulfanylpyrimidine-5-carbaldehyde were added and the mixture was stirred at 85° C. for 4.5 hrs. Stirring was continued over night at RT, then the solvent was evaporated and the residue dispensed in aqueous sodium carbonate solution. The mixture is extracted with ethyl acetate, then acidified to pH 2 and again extracted with chloroform. The chloroform extracts were dried and evaporated and the residue triturated with hot ethyl acetate. 2.786 g of the title product were thus obtained after filtration.
Reaction SMILES: [CH:1]1([N:6]2[C@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:11]=[CH:10][CH2:9][C@@H:8]([N:19]3C(=O)C4C(=CC=CC=4)C3=O)[C:7]2=[O:30])[CH2:5][CH2:4][CH2:3][CH2:2]1.O.NN>CO>[NH2:19][C@@H:8]1[CH2:9][CH:10]=[CH:11][C@@H:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:7]1=[O:30]
Reactant: O=C1c2ccccc2C(=O)N1[C@@H]1CC=C[C@@H](c2ccccc2)N(C2CCCC2)C1=O
Agent: NN
Solvent: O
Solvent: CO
Product: N[C@@H]1CC=C[C@@H](c2ccccc2)N(C2CCCC2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.3 %

Procedure:
To a solution of 2-[(3R,7S)-1-cyclopentyl-2-oxo-7-phenyl-2,3,4,7-tetrahydro-1H-azepin-3-yl]-1H-isoindole-1,3(2H)-dione (100 mg) in MeOH (4 ml), was added hydrazine hydrate (27 mg) at RT under N2. The mixture was allowed to stir overnight at RT. The reaction was evaporated and the residue was taken up in DCM and washed with water. The organics were dried (Na2SO4), filtered and evacuated to afford the title compound (65 mg, 96% crude yield) yellow oil. 1H NMR (300 MHz, CDCl3) δ 1.38-2.31 (m, 1H), 3.46-3.56 (m, 1H), 4.91 (d, 1H, J=8 Hz), 5.24-5.34 (m, 1H), 5.88-5.96 (m, 1H), 6.25-6.33 (m, 1H), 7.21-7.36 (m, 5H).
Reaction SMILES: C([O:5][C:6](=[O:39])[C@@H:7]([NH:29][S:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)(=[O:32])=[O:31])[CH2:8][NH:9][C:10](=[O:28])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][NH:20]C(OC(C)(C)C)=O)=[CH:13][CH:12]=1)(C)(C)C.O1CCOCC1.[ClH:46]>>[ClH:46].[NH2:20][CH2:19][CH2:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]([NH:9][CH2:8][C@H:7]([NH:29][S:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)(=[O:32])=[O:31])[C:6]([OH:39])=[O:5])=[O:28])=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)NCCOc1ccc(C(=O)NC[C@H](NS(=O)(=O)c2ccccc2)C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Product: NCCOc1ccc(C(=O)NC[C@H](NS(=O)(=O)c2ccccc2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A suspension of 2-3 (105 mg, 0.19 mmol) in 6N HCl (5 mL) was treated with dioxane (5 mL) to effect a homogeneous solution. After stirring for 20 h at ambient temperature, the solvents were evaporated and the resulting residue azeotroped with toluene to afford 12-1 as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:49]=[CH:50][CH:51]=1)[CH2:6][N:7]([CH2:15][C@@H:16]([OH:48])[C@@H:17]([NH:27][C:28](=[O:47])[C:29]1[CH:34]=[C:33]([NH:35][C:36](=[O:43])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:32]=[C:31]([C:44](=[O:46])[CH3:45])[CH:30]=1)[CH2:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=1)[C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:49]=[CH:50][CH:51]=1)[CH2:6][N:7]([CH2:15][C@@H:16]([OH:48])[C@@H:17]([NH:27][C:28](=[O:47])[C:29]1[CH:30]=[C:31]([CH:44]([OH:46])[CH3:45])[CH:32]=[C:33]([NH:35][C:36](=[O:43])[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:34]=1)[CH2:18][C:19]1[CH:20]=[C:21]([F:26])[CH:22]=[C:23]([F:25])[CH:24]=1)[C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:12])[CH3:13]
Reactant: COc1cccc(CN(C[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(NC(=O)c3ccccc3)cc(C(C)=O)c2)C(=O)OC(C)(C)C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cccc(CN(C[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(NC(=O)c3ccccc3)cc(C(C)O)c2)C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
tert-Butyl 3-methoxybenzyl((2R,3S)-3-(3-acetyl-5-(benzamido)-benzamido)-4-(3,5-difluorophenyl)-2-hydroxybutyl)carbamate (15 mg, 0.021 mmol) was dissolved in MeOH (0.1 mL) and sodium borohydride (1.0 mg, 0.028 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated and partitioned between ethyl acetate and H2O. The organic layer was separated and concentrated under vacuum to give the title compound (14 mg): HPLC retention time: 2.267 min (method A). MS (ESI) (M+H)+ 732.39.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[N:8]([CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[C:6]=2[N:7]=1.[CH3:19][Si](C=[N+]=[N-])(C)C>CO>[CH3:19][O:12][C:11]([C:9]1[N:8]([CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[C:6]2[N:7]=[C:2]([Cl:1])[N:3]=[CH:4][C:5]=2[CH:10]=1)=[O:13]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CCC(CC)n1c(C(=O)O)cc2cnc(Cl)nc21
Solvent: CO
Product: CCC(CC)n1c(C(=O)OC)cc2cnc(Cl)nc21
Reaction time: 2 h

Procedure:
To a solution of 2-chloro-7-(1-ethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (13 mg, 0.049 mmol) in MeOH (0.5 mL) is added (trimethylsilyl)diazomethane (0.07 mL of a 2.0 M in hexanes). The reaction mixture is stirred for 2 h and concentrated in vacuo to give 13 mg of 2-chloro-7-(1-ethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid methyl ester. The crude product is used as it is.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:5]=1[C:6](=[O:19])[CH:7]1[CH:12]([C:13]2=[O:18])[CH2:11][CH:10]=[CH:9][CH2:8]1)([O-])=O.O>COCCO>[NH2:1][C:4]1[C:5]2[C:6](=[O:19])[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13](=[O:18])[C:14]=2[CH:15]=[CH:16][CH:17]=1
Reactant: O=C1c2cccc([N+](=O)[O-])c2C(=O)C2CC=CCC12
Solvent: COCCO
Solvent: O
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O
Temperature: 40 °C

Procedure:
Mixtures of each 5.0 parts of 5-nitro-1,4,4a,9a-tetrahydroanthraquinone with 30 parts of water, 70 parts of methylcellosolve and reducing agents and basic compounds, of kinds and in amounts as indicated in the following Table 4, were stirred at 90°-100°C for times, as indicated in the Table 4, then cooled to 40°C and filtered to recover crystals. The crystals were washed with water and dried under reduced pressure. In all of these Examples, the products were confirmed by infrared absorption spectrum to be 1-aminoanthraquinone. The yields of 1-aminoanthraquinone obtained in the form of crystals were as shown in the Table 4.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Li]CCCC.[Cl:13][C:14]1[CH:15]=[CH:16][C:17](/[C:20](/[C:28]2[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([F:38])[CH:29]=2)=[N:21]\[S@@:22]([C:24]([CH3:27])([CH3:26])[CH3:25])=[O:23])=[N:18][CH:19]=1>C1COCC1>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C@@:20]([NH:21][S@:22]([C:24]([CH3:27])([CH3:26])[CH3:25])=[O:23])([C:28]2[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([F:38])[CH:29]=2)[CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[N:18][CH:19]=1
Reactant: Cc1ccccn1
Reactant: CC(C)(C)[S@@](=O)/N=C(/c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[S@](=O)N[C@@](Cc1ccccn1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
2-Methyl pyridine (48 μL, 0.49 mmol) in THF (90 μL) was cooled at −78° C. for 10 min, followed by the addition of n-BuLi (246 μL, 0.49 mmol, 2M solution in cyclohexane). The reaction turned into maroon and was stirred at −78° C. for 40 min. (R,Z)-N-((5-chloropyridin-2-yl)(3-fluoro-5-(trifluoromethyl)phenyl)methylene)-2-methylpropane-2-sulfinamide (100 mg, 0.25 mmol) in THF (1 mL) was added and the dark green colored reaction mixture was stirred at −78° C. for another 2 h. Quenched with H2O (10 mL), the reaction mixture was extracted by EtOAc (2×15 mL). The combined organic layers were dried over MgSO4, filtered and concentrated. The residue was purified by preparative HPLC YMC ODS S5 28×100 mm Ballistic column 40-100% MeOH (90% in water, 0.1% TFA) gradient over 12 min with flow rate 40 mL/min and UV detection at 220 nm. (S)-N-((S)-1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-(pyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide at a retention time of 9.66 min and was isolated as a clear oil (48 mg, yield 38%) LCMS: 1.76 min [M+1] 500.2 (2 min gradient, MeOH/H2O 0.1% TFA); HPLC: 3.72 min (4 min gradient, MeOH/H2O 0.2% PPA); Purity 100%; NMR: 400 MHz 1H (CDCl3) 8.45 ppm, 1 H, d, J=2.64 Hz; 8.28 ppm, 1 H, d, J=4.39 Hz; 7.93 ppm, 1 H, s; 7.68 ppm, 1 H, d, J=8.79 Hz; 7.48 ppm, 1 H, dd, J=8.57, 2.42 Hz; 7.35 ppm, 1 H, t, J=6.81 Hz; 7.31 ppm, 1 H, s; 7.10 ppm, 1 H, d, J=7.91 Hz; 6.97 ppm, 2 H, m; 6.79 ppm, 1 H, d, J=7.47 Hz; 4.10 ppm, 1 H, d, J=14.06 Hz; 3.86 ppm, 1 H, d, J=14.50 Hz; 1.25 ppm, 9 H, s.
Reaction SMILES: [C:1]1([C:7](=O)[C:8](=[N:12][OH:13])[C:9](=O)[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl.[CH2:17]([NH:24][NH2:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCO>[CH2:17]([N:24]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:8]([N:12]=[O:13])[C:9]([CH3:10])=[N:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NNCc1ccccc1
Reactant: CC(=O)C(=NO)C(=O)c1ccccc1
Agent: Cl
Solvent: CCO
Product: Cc1nn(Cc2ccccc2)c(-c2ccccc2)c1N=O
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a 0° C. solution of 2.32 g of 1-phenyl-butane-1,2,3-trione 2-oxime in 31 mL of EtOH was added a suspension of 2.43 g benzyl hydrazine dihydrochloride in 9 mL EtOH. The reaction mixture was warmed to rt and stirred for 96 h. The reaction mixture was concentrated under reduced pressure and purified by means of MPLC (120 g SiO2, 45% EtOAc:Heptane) to obtain 1-benzyl-3-methyl-4-nitroso-5-phenyl-1H-pyrazole. A suspension of 2.55 g 1-benzyl-3-methyl-4-nitroso-5-phenyl-1H-pyrazole, 34 mL EtOAc and 500 mg 10% Pd/C was reacted under 40 psi H2 atmosphere using a Parr apparatus. After 4 h, the suspension was filtered through Celite (EtOH eluting) and the filtrate was concentrated under reduced pressure and purified by means of MPLC (120 g SiO2, 60% EtOAc:Heptane) to give the title compound as an orange oil.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3]([O-:6])(=[O:5])=[O:4].[F:9][C:10]1[CH:15]=[C:14]([C:16]([O:18]C)=[O:17])[CH:13]=[CH:12][C:11]=1[N+:20]([CH3:23])([CH3:22])[CH3:21].FC(F)(F)C(O)=O>O>[F:1][C:2]([F:8])([F:7])[S:3]([O-:6])(=[O:5])=[O:4].[C:16]([C:14]1[CH:13]=[CH:12][C:11]([N+:20]([CH3:22])([CH3:21])[CH3:23])=[C:10]([F:9])[CH:15]=1)([OH:18])=[O:17]
Reactant: COC(=O)c1ccc([N+](C)(C)C)c(F)c1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: C[N+](C)(C)c1ccc(C(=O)O)cc1F

Procedure:
A solution of 4.00 g (11.1 mmol) 3b, 96 ml dest. water and 96 ml trifluoroacetic acid was refluxed for 2 days. The reaction mixture was evaporated, dried by use of oil pump vacuum over night and treated with diethyl ether. The resulting solid was filtered, washed extensively with diethyl ether and dried by oil pump vacuum. The solid crude product 3c was obtained in 92% yield (3.54 g, 10.2 mmol) and crude compound 3c was used for the next step without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[CH2:5][N:6]1[CH2:11][C:10](=[O:12])[N:9]([CH2:13][CH2:14][CH2:15]Cl)[C:8](=[O:17])[CH2:7]1.[CH2:22]([O:29][C:30]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([O:29][C:30]([N:32]1[CH2:37][CH2:36][N:35]([CH2:15][CH2:14][CH2:13][N:9]2[C:10](=[O:12])[CH2:11][N:6]([CH2:5][C:4]3[CH:18]=[CH:19][CH:20]=[CH:21][C:3]=3[O:2][CH3:1])[CH2:7][C:8]2=[O:17])[CH2:34][CH2:33]1)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: COc1ccccc1CN1CC(=O)N(CCCCl)C(=O)C1
Product: COc1ccccc1CN1CC(=O)N(CCCN2CCN(C(=O)OCc3ccccc3)CC2)C(=O)C1

Procedure:
This compound was prepared according to the process described in Example 5 by condensing 4-(2-methoxybenzyl)-1-(3-chloropropyl)piperazine-2,6-dione with 4benzyloxycarbonylpiperazine.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11].[CH2:12](O)[CH3:13]>S(=O)(=O)(O)O>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:12][CH3:13])=[O:7])=[CH:4][C:3]=1[CH3:11]
Reactant: Cc1cc(C(=O)O)ccc1N
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(N)c(C)c1
Yield: 99 %

Procedure:
To a suspension of 4-amino-3-methylbenzoic acid (5.00 g, 33.1 mmol) in ethanol (50 ml), concentrated sulfuric acid (5.00 ml) was slowly added. The mixture was heated under reflux for 3 hours. The solvent was distilled off under a reduced pressure. After the volume of the mixture was approximately halved, the mixture was neutralized with a saturated sodium bicarbonate solution. The mixture was subjected to extraction with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate and then concentrated to give the title compound (5.87 g, 99%) as a light-brown solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:24]4[O:23][CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][C:18]=4[C:17]([CH3:32])=[C:16]([Cl:33])[CH:15]=3)[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12.Cl.O=[C:36]1[CH2:39][N:38]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:37]1.C([BH3-])#N.[Na+]>O1CCOCC1>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:24]4[O:23][CH2:22][CH2:21][N:20]([CH:36]5[CH2:37][N:38]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:39]5)[CH2:19][C:18]=4[C:17]([CH3:32])=[C:16]([Cl:33])[CH:15]=3)[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: Cc1c(Cl)cc(C(C)n2nc(C)c3c(N)ncnc32)c2c1CN(C(=O)OC(C)(C)C)CCO2
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1c(Cl)cc(C(C)n2nc(C)c3c(N)ncnc32)c2c1CN(C1CN(C(=O)OC(C)(C)C)C1)CCO2
Temperature: 60 °C
Yield: 3.1 %

Procedure:
tert-Butyl 9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-methyl-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (100 mg, 0.2 mmol) was treated with 4 N HCl in dioxane (1 mL), and then the solvent was evaporated. The residue was stirred in methanol (5 mL) and tert-butyl 3-oxoazetidine-1-carboxylate (140 mg, 0.84 mmol) was added. Sodium cyanoborohydride (120 mg, 1.9 mmol) was added and the mixture was warmed to 60° C. for 1.5 hours. Purification by preparative LCMS (pH 10) gave the desired compound (3.3 mg, 10%). LCMS calculated for C26H35ClN7O3 (M+H)+: m/z=528.2; found: 528.3. 1H NMR (300 MHz, CD3OD): δ 8.14 (s, 1 H), 7.33 (s, 1 H), 6.33 (m, 1 H), 4.00 (m, 2 H), 3.82 (m, 1 H), 3.74 (m, 2 H), 3.63 (m, 3 H), 3.41 (m, 1 H), 2.76 (m, 2 H), 2.58 (s, 3 H), 2.37 (s, 3 H), 1.79 (m, 3 H), 1.42 (s, 9H).
Reaction SMILES: CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.[C:20]([O:24][C:25]([NH:27][CH2:28][C:29]([NH:31][C@H:32]1[CH2:36][N:35]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C@H:34]([C:44](O)=[O:45])[CH2:33]1)=[O:30])=[O:26])([CH3:23])([CH3:22])[CH3:21].[Cl:47][C:48]1[CH:49]=[C:50]([CH:58]=[C:59]([Cl:61])[CH:60]=1)[O:51][CH:52]1[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1.ON1C2C=CC=CC=2N=N1>O1CCCC1.CN(C)C=O>[C:20]([O:24][C:25]([NH:27][CH2:28][C:29]([NH:31][C@H:32]1[CH2:36][N:35]([C:37]([O:39][C:40]([CH3:42])([CH3:41])[CH3:43])=[O:38])[C@H:34]([C:44]([N:55]2[CH2:56][CH2:57][CH:52]([O:51][C:50]3[CH:58]=[C:59]([Cl:61])[CH:60]=[C:48]([Cl:47])[CH:49]=3)[CH2:53][CH2:54]2)=[O:45])[CH2:33]1)=[O:30])=[O:26])([CH3:21])([CH3:22])[CH3:23]
Reactant: Clc1cc(Cl)cc(OC2CCNCC2)c1
Reactant: CC(C)(C)OC(=O)NCC(=O)N[C@@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(=O)N[C@@H]1C[C@@H](C(=O)N2CCC(Oc3cc(Cl)cc(Cl)c3)CC2)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 105.6 %

Procedure:
N-Methylmorpholine (120 μL) and ]-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (188 mg) were added to a solution of trans-4-(N-tert-butoxycarbonylglycylamino)-N-tert-butoxycarbonyl-L-proline (Compound D103 (B), 400 mg), 4-(3,5-dichlorophenoxy)piperidine (518 mg), and 1-hydroxybenzotriazole (140 mg) in tetrahydrofuran (12 mL) and N,N-dimethylformamide (4 mL) at room temperature. After stirring at room temperature for 12 hr, the reaction mixture was partitioned between ethyl acetate and 1 N hydrochloric acid. The organic layer was washed with saturated sodium hydrogen carbonate and brine. After drying over anhydrous sodium sulfate, the organic layer was evaporated in vacuo. The residue was washed with hexane to give the titled compound (671 mg) as a white solid: 1H NMR (400 MHz, CDCl3) δ 1.43 (s, 9H), 1.46 (s, 9H), 1.70-2.00 (m, 4H), 2.14-2.29 (m, 2H), 3.35-3.82 (m, 8H), 4.51-4.60 (m, 2H), 4.64 (br t, 0.5H), 4.78 (m, 0.5H), 5.11 (br s, 1H), 6.40 (m, 1H), 6.77-6.80 (m, 2H), and 6.96-6.98 (m, 1H); IR (KBr) 3311, 2978, 1701, 1655, 1570, 1441, 1255, 1163, 1049 cm−1; mass spectrum (FAB+) m/e 615 (M).
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]([Br:23])=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])(=[O:16])=[O:15])[CH2:11][C@H:10]2[CH2:28][O:29][C:30](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[O:8])[CH2:5][CH2:4]1)#[N:2].C(O)=[O:50]>>[Br:23][C:20]1[CH:21]=[CH:22][C:17]([S:14]([C@H:12]2[CH2:11][C@@H:10]([CH2:28][O:29][CH:30]=[O:50])[C@H:9]([C:7](=[O:8])[NH:6][C:3]3([C:1]#[N:2])[CH2:4][CH2:5]3)[CH2:13]2)(=[O:16])=[O:15])=[C:18]([C:24]([F:26])([F:27])[F:25])[CH:19]=1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(Br)cc3C(F)(F)F)C[C@H]2COC(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Reactant: O=CO
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(Br)cc3C(F)(F)F)C[C@H]2COC=O)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 25 %

Procedure:
A mixture of (1R,2R,4S)-4-(4-bromo-2-trifluoromethyl-benzenesulfonyl)-2-trityloxymethyl-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (example 152 step 7, 10 mg) in concentrated formic acid (0.2 mL) was stirred at room temperature during 1.5 h. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogenocarbonate. The organic layer was washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel with a gradient of cyclohexane:ethyl acetate (3:1 to 1:1 v/v) as eluant to afford the title compound (2 mg, 25%) as a colorless oil. MS (EI): 524 (M)+.
Reaction SMILES: [Li][CH2:2]CCC.CCCCCC.[CH:12]([C:14]1[S:15][CH:16]=[C:17]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[C:18]=1[CH3:19])=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOCC>[CH:12]([C:14]1[S:15][CH:16]=[C:17]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[C:18]=1[CH3:19])=[CH2:2]
Reactant: Cc1c(C2CCCCC2)csc1C=O
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCCCCC
Solvent: CCOCC
Product: C=Cc1scc(C2CCCCC2)c1C
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 50 %

Procedure:
To a solution of methyltriphenylphosphonium bromide (4.983 g, 13.96 mmol) in ether at 0° C. was added dropwise 1.6 M n-BuLi solution in hexane (8.7 ml, 13.96 mmol). The solution was stirred at 0° C. for 40 min and then was warmed to room temperature. A solution of 2-formyl-3-methyl-4-cyclohexylthiophene dimer (2.7 g, 6.98 mmol) in a minimum of ether was added. The solution was stirred overnight. The reaction mixture was then diluted with ether and washed with water and brine, and dried over MgSO4. The solvent was removed in vacuo and the crude product was purified by column chromatography using hexane as the eluant to afford 2-vinyl-3-methyl-4-cyclohexylthiophene dimer 1.32 g (50% yield) as a white solid. 1H NMR (CDCl3) δ 6.98 (s, 1H), 6.90 (dd, 1H), 5.52 (d, 1H), 1.15 (d, 1H), 2.22 (s, 1H), 2.19 (s, 1H), 2.11 (s, 1H), 2.10 (s, 1H), 2.09 (s, 1H), 2.08 (s, 1H). 13C NMR (CDCl3) δ 147.93, 146.37, 137.41, 136.09, 134.78, 129.97, 128.44, 127.57, 118.61, 112.7, 40.07, 38.86, 33.74, 31.37, 27.19, 26.91, 26.30, 26.12, 13.61, 13.33.
Reaction SMILES: CC1N=CC=CC=1C(N)=O.[C:11]([C:15]1[N:20]=[C:19]([O:21][CH3:22])[C:18]([CH:23]([NH2:25])[CH3:24])=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12].[C:26]([C:28]1[C:33]2[N:34]([CH2:37][C:38](O)=[O:39])[CH:35]=[N:36][C:32]=2[CH:31]=[CH:30][CH:29]=1)#[N:27].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:11]([C:15]1[N:20]=[C:19]([O:21][CH3:22])[C:18]([CH:23]([NH:25][C:38](=[O:39])[CH2:37][N:34]2[C:33]3[C:28]([C:26]#[N:27])=[CH:29][CH:30]=[CH:31][C:32]=3[N:36]=[CH:35]2)[CH3:24])=[CH:17][CH:16]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: N#Cc1cccc2ncn(CC(=O)O)c12
Reactant: COc1nc(C(C)(C)C)ccc1C(C)N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cc1ncccc1C(N)=O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COc1nc(C(C)(C)C)ccc1C(C)NC(=O)Cn1cnc2cccc(C#N)c21

Procedure:
The title compound was synthesized according to the procedure described for the synthesis of 2-methylnicotinamide, starting from [1-(6-tert-butyl-2-methoxypyridin-3-yl)ethyl]amine (intermediate 27) (85 mg, 0.48 mmol), 7-cyanobenzimidazole-1-acetic acid (96 mg 0.48 mmol) HATU (173 mg, 0.5 mmol) and DIPEA (209 μl, 1.20 mmol). The product was recovered by filtration following precipitation induced by the addition of water. (Yield 27 mg, 46%). 1H NMR (400 MHz, DMSO-D6) δ ppm 1.27 (s, 9 H), 1.32 (d, J=6.84 Hz, 3 H), 3.86 (s, 3 H), 5.02 (t, J=7.03 Hz, 1 H), 5.25 (d, J=4.69 Hz, 2 H), 6.91 (d, J=7.62 Hz, 1 H), 7.31-7.37 (m, 1 H), 7.62 (dd, J=7.62, 0.39 Hz, 1 H), 7.71 (dd, J=7.71, 1.07 Hz, 1 H), 8.01 (dd, J=8.20, 0.98 Hz, 1 H), 8.34 (s, 1 H), 8.78-8.83 (m, J=7.81 Hz, 1 H). MS [MH+] calc. 392.2086 found 392.3.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:10]=[N:11][CH:12]=[C:13]([NH:15][CH2:16][CH3:17])[CH:14]=1)OCCC)#[N:2].[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][CH2:26][NH2:27]>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[N:11][CH:12]=[C:13]([NH:15][CH2:16][CH3:17])[CH:14]=1)=[N:27][CH2:26][CH2:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[Cl:18])#[N:2]
Reactant: CCCOC(=NC#N)c1cncc(NCC)c1
Reactant: NCCc1ccccc1Cl
Solvent: CO
Product: CCNc1cncc(C(=NCCc2ccccc2Cl)NC#N)c1
Reaction time: 1.75 h
Yield: 81 %

Procedure:
To a solution of propyl N-cyano-5-ethylamino-3-pyridinecarboximidate (98 mg, 0.42 mmol) in methanol (3 ml) was added 2-(2-chlorophenyl)ethylamine(79 mg, 0.51 mmol), and the mixture was stirred for 105 minutes. The residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (Wako Gel C-200, 30 g; eluted with chloroform:methanol=100:1) and further crystallized from diethyl ether to give the title compound (110 mg, 0.34 mmol) as colorless crystals in the yield of 80%.