Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]([N:11]1[C:19]2[C:14](=[N:15][C:16]([NH:20][CH2:21][C:22]([NH2:24])=O)=[CH:17][N:18]=2)[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].O=P(Cl)(Cl)Cl>C(Cl)Cl.CO>[S:1]([N:11]1[C:19]2[N:18]=[CH:17][C:16]3[N:15]([C:22]([NH2:24])=[CH:21][N:20]=3)[C:14]=2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(NCC(N)=O)cnc32)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2ncc(N)n23)cc1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 42.8 %

Procedure:
To 2-(5-tosyl-5H-pyrrolo[3,2-b]pyrazin-2-ylamino)acetamide (0.845 g, 2.45 mmol, prepared using E from Preparation #S.1.1 and HCl) under nitrogen was added POCl3 (5.0 mL, 54 mmol). After about 15 min, a reflux condenser was attached and the mixture was warmed to about 100° C. After about 2 h, the solution was allowed to cool to ambient temperature. The mixture was concd under reduced pressure. The residue was slurried in DCM (10 mL) and slowly treated with MeOH (10 mL). The reaction mixture was stirred for about 5 min then concd under reduced pressure. The residue was dissolved in MeOH (20 mL) and then concentrated under reduced pressure. The residue was dissolved in 1,4-dioxane (5 mL) and 2N aqueous HCl (5 mL). The solution was warmed to about 100° C. for about 3 h. The solution was allowed to cool to ambient temperature and the volatiles were removed under reduced pressure. The aqueous mixture was slurried in saturated aqueous NaHCO3/water (1:1, 100 mL) and DCM (50 mL). The solid was collected by filtration, rinsed with water and DCM, and dried to afford 3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-amine (0.343 g, 43%): LC/MS (Table 1, Method n) Rt=0.56 min; MS m/z: 328 (M+H)+.
Reaction SMILES: ClN1C(=O)CCC1=O.[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[N:16][OH:17])[CH:10]=1.[CH2:18]([C:23]1[N:24]([CH2:51][CH2:52][CH3:53])[N:25]=[C:26]2[C:35]=1[C:34]1[CH2:33][CH2:32][CH2:31][CH2:30][C:29]=1[N:28]=[C:27]2[N:36]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:19][CH2:20][C:21]#[CH:22].C(N(CC)CC)C>C1COCC1.ClCCl>[CH2:51]([N:24]1[C:23]([CH2:18][CH2:19][CH2:20][C:21]2[O:17][N:16]=[C:15]([C:11]3[CH:10]=[N:9][CH:14]=[CH:13][CH:12]=3)[CH:22]=2)=[C:35]2[C:26]([C:27]([N:36]([C:44]([O:46][C:47]([CH3:48])([CH3:50])[CH3:49])=[O:45])[C:37]([O:39][C:40]([CH3:41])([CH3:42])[CH3:43])=[O:38])=[N:28][C:29]3[CH2:30][CH2:31][CH2:32][CH2:33][C:34]=32)=[N:25]1)[CH2:52][CH3:53]
Reactant: C#CCCCc1c2c3c(nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c2nn1CCC)CCCC3
Reactant: ON=Cc1cccnc1
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCn1nc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc3c(c2c1CCCc1cc(-c2cccnc2)no1)CCCC3
Temperature: 25 °C
Reaction time: 4 h
Yield: 21.9 %

Procedure:
Under a nitrogen atmosphere, N-chlorosuccinimide (2.1 g, 16 mmol) was added to a solution of 3-pyridine aldoxime (2.0 g, 16 mmol) in THF (10 mL). The solution was stirred at ambient temperature for 4 hours. A solution of di(tert-butyl) 1-pent-4-ynyl-2-propyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonate (4.00 g, 8.05 mmol), prepared as described in Example 615, and anhydrous triethylamine (2.5 mL, 18 mmol) in THF (10 mL) was added and the reaction solution was heated at 60° C. for 18 hours. The reaction solution was concentrated under reduced pressure to provide a black oil. The oil was dissolved in dichloromethane, washed sequentially with potassium carbonate, water, and brine, dried over sodium sulfate, and filtered. The filtrate was purified by column chromatography (silica gel, elution with a gradient of 20-80% ethyl acetate in hexanes) to provide 1.0877 g of di(tert-butyl) 2-propyl-1-[3-(3-pyridin-3-ylisoxazol-5-yl)propyl]-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonate.
Reaction SMILES: [CH3:1]/[C:2](/[CH2:7][CH2:8]/[CH:9]=[C:10](\[CH3:17])/[CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])=[CH:3]/[C:4]([OH:6])=O.C(#N)C.C(OP(Cl)(=O)OCC)C.[NH2:30][C:31]1[CH:36]=[C:35]([CH3:37])[C:34]([OH:38])=[C:33]([CH3:39])[CH:32]=1>C(N(CC)CC)C>[CH3:1]/[C:2](/[CH2:7][CH2:8]/[CH:9]=[C:10](\[CH3:17])/[CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])=[CH:3]/[C:4]([NH:30][C:31]1[CH:36]=[C:35]([CH3:37])[C:34]([OH:38])=[C:33]([CH3:39])[CH:32]=1)=[O:6]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C\C(=O)O
Reactant: Cc1cc(N)cc(C)c1O
Agent: CCOP(=O)(Cl)OCC
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C\C(=O)Nc1cc(C)c(O)c(C)c1
Reaction time: 0.5 h
Yield: 42.9 %

Procedure:
Under ice-cooling, to a solution of 0.9 g of 3,7,11-trimethyl-(2Z,6E)-2,6,10-dodecatrienoic acid in 10 m of acetonitrile are added 578 mg of triethylamine, then 854 mg of diethylphosphorochloridate. After the mixture is stirred for 30 minutes, 522 mg of 4-amino-2,6-dimethylphenol is added and the reaction mixture is stirred at room temperature. Ice chips are added into the reaction mixture, the mixture is extracted with isopropyl ether and the extracted with 10% hydrochloric acid, water, 5% aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride, followed by drying and then evaporation of the solvent. The residue is purified by silica gel column chromatography [solvent: ethyl acetate-hexane (1:3)] to give 580 mg of 4-[3,7,11-trimethyl-(2Z,6E)-2,6,10-dodecatrienoylamino]-2,6-dimethylphenol
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH3:5].II.[O:8]=[CH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>C1COCC1>[OH:8][CH:9]([CH2:2][CH2:3][CH2:4][CH3:5])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CCOC(=O)C(CCCCCCCCCCCC=O)C(=O)OCC
Reactant: CCCCBr
Agent: II
Solvent: C1CCOC1
Product: CCCCC(O)CCCCCCCCCCCC(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.6 %

Procedure:
1-Bromobutane (0.92 ml, 8.512 mmol) in dry THF (5 ml) was slowly added to a stirred suspension of Mg metal (0.25 g, 10.059 mmol) and a catalytic amount of Iodine in dry THF (10 ml) at reflux temperature, and the reaction mixture stirred for 30 min after the completion of the addition. The prepared Grignard reagent was cooled to room temperature, then added dropwise over 15 min to a stirred solution of diethyl 2-(12-oxododecyl)malonate (2.65 g, 7.738 mmol) in THF (30 ml) at −10 to −15° C. and stirred at this temperature for 30 min. The reaction mixture was slowly warmed to room temperature and stirring continued for another one hour. The reaction was quenched with saturated ammonium chloride solution (10 ml), diluted with water (20 ml), extracted with diethyl ether (3×50 ml), dried on anhydrous MgSO4 and concentrated. The crude product was purified by silica gel column (4-6% EtOAc in hexane) and provided diethyl 2-(12-hydroxyhexadecyl)malonate (1.94 g, 62.5%) as a colorless liquid.
Reaction SMILES: CC(OC([N:8](C(OC(C)(C)C)=O)[N:9]([C:17]1[C:22]([F:23])=[C:21]([N:24]([N:31]2[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]2)[CH2:25][C:26]2[S:27][CH:28]=[CH:29][N:30]=2)[N:20]=[C:19]([Cl:38])[N:18]=1)C(OC(C)(C)C)=O)=O)(C)C.Cl>C(Cl)Cl>[Cl:38][C:19]1[N:20]=[C:21]([N:24]([N:31]2[CH2:32][CH2:33][N:34]([CH3:37])[CH2:35][CH2:36]2)[CH2:25][C:26]2[S:27][CH:28]=[CH:29][N:30]=2)[C:22]([F:23])=[C:17]([NH:9][NH2:8])[N:18]=1
Reactant: CN1CCN(N(Cc2nccs2)c2nc(Cl)nc(N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c2F)CC1
Agent: Cl
Solvent: ClCCl
Product: CN1CCN(N(Cc2nccs2)c2nc(Cl)nc(NN)c2F)CC1
Reaction time: 8 h
Yield: 151 %

Procedure:
Tris(1,1-dimethylethyl)2-{2-chloro-5-fluoro-6-[(4-methyl-1-piperazinyl)(1,3-thiazol-2-ylmethyl)amino]-4-pyrimidinyl}-1,1,2-hydrazinetricarboxylate (0.2014 g, 0.299 mmol) was dissolved in DCM (20 mL) under a nitrogen atmosphere. Then 2M HCl (2.99 mL, 5.98 mmol) was added, and the reaction was stirred overnight. The reaction mixture was evaporated to provide crude 2-chloro-5-fluoro-6-hydrazino-N-(4-methyl-1-piperazinyl)-N-(1,3-thiazol-2-ylmethyl)-4-pyrimidinamine as a yellow solid (0.1683 g). LCMS: (M+H)+=373.0.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2].[CH:28]([O:31][C:32]1[N:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)([CH3:30])[CH3:29].C(N(CC)CC)C.N1C=CC=CC=1>ClCCl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:1]([C:3]1[N:4]([C:35]2[CH:36]=[N:37][C:32]([O:31][CH:28]([CH3:30])[CH3:29])=[CH:33][CH:34]=2)[C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2]
Reactant: CCCc1nc(CC)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CC(C)Oc1ccc(B(O)O)cn1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCc1nc(CC)n(-c2ccc(OC(C)C)nc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 48 h
Yield: 56.6 %

Procedure:
To a suspension of 4′-[(2-ethyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (0.5 g), 6-isopropoxy-3-pyridylboronic acid (0.51 g), triethylamine (0.97 mL), pyridine (0.57 mL) and molecular sieves 4 A (1 g) in dichloromethane (10 mL) was added copper(II) acetate (0.51 g), and the mixture was stirred for 2 days. The reaction mixture was diluted with ethyl acetate, the insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.39 g, 56%).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][N:3]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:1][CH:2]1[C:11]2[C:6](=[C:7]([C:12]([F:14])([F:13])[F:15])[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][NH:3]1
Reactant: CC1=NCCc2c1cccc2C(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CC1NCCc2c1cccc2C(F)(F)F

Procedure:
In close analogy to the procedure described above, 1-Methyl-5-trifluoromethyl-3,4-dihydro-isoquinoline is reacted with sodium triacetoxyborohydride to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])/[CH:4]=[C:5](\[NH2:7])/[CH3:6].N1C=CC=CC=1.[F:15][C:16]1[CH:17]=[C:18]([CH:26]=[CH:27][CH:28]=1)[O:19][CH2:20][CH2:21][CH2:22][C:23](Cl)=[O:24]>C(Cl)Cl>[F:15][C:16]1[CH:17]=[C:18]([CH:26]=[CH:27][CH:28]=1)[O:19][CH2:20][CH2:21][CH2:22][C:23]([NH:7]/[C:5](/[CH3:6])=[CH:4]\[C:3]([O:2][CH3:1])=[O:8])=[O:24]
Reactant: COC(=O)/C=C(/C)N
Reactant: O=C(Cl)CCCOc1cccc(F)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)/C=C(/C)NC(=O)CCCOc1cccc(F)c1
Yield: 27.5 %

Procedure:
To a solution of (Z)-methyl-3-aminobut-2-enoate (1.70 g, 14.8 mmol) and pyridine (1.20 g, 15.2 mmol) in DCM (25 mL) was added a solution of 4-(3-fluorophenoxy)butanoyl chloride (3.28 g, 15.1 mmol) in DCM (5 mL) with stirring and the mixture was stirred for 1 h. It was then washed with brine (50 mL×3), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=3:1) to give the title compound as a white solid (1.20 g, 28%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]4[O:22][CH2:21][O:20][C:17]=4[CH:18]=3)[CH2:13][CH2:12][N:11]=2)=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]2[C:19]3[C:14](=[CH:15][C:16]4[O:22][CH2:21][O:20][C:17]=4[CH:18]=3)[CH2:13][CH2:12][NH:11]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(CCC2=NCCc3cc4c(cc32)OCO4)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Fc1ccc(CCC2NCCc3cc4c(cc32)OCO4)cc1

Procedure:
A solution of 1-(2-p-fluorophenylethyl)-6,7-methylenedioxy-3,4-dihydroisoquinoline (0.78 g, 2.67 mmol) in methanol (7 ml) was treated with sodium borohydride (0.30 g, 8.01 mmol) and heated at reflux for two hours. The mixture was cooled and evaporated. The residue was mixed with 1N sodium hydroxide and ethyl acetate and extracted into ethyl acetate. The pooled extracts were washed with saturated sodium chloride, dried, and evaporated to a pale yellow oil (0.56 g, 70%). 1H NMR (CDCl3) δ 7.18 (m, 2 H); 6.97 (m, 2 H); 6.58 (m, 2 H), 5.88 (s, 2 H); 3.90 (m, 1 H); 3.21 (m, 1 H); 2.99 (m, 1 H); 2.81-2.62 (m, 4 H); 2.06 (m, 2 H). HPLC-MS (C-18, methanol/water/TFA linear gradient elution, 5 ml/min, 220 nm) single peak at 1.13 min; MS (ES+) obsd m/z=299.87.
Reaction SMILES: CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[CH:41]=[C:40]([C:42]([NH:44][CH2:45][C:46]([OH:48])=O)=[O:43])[N:39]=[N:38]2)[CH:32]=1.NC1C=NC=CC=1.Cl.[F:57][C:58]1[CH:59]=[C:60]([CH:68]=[C:69]([C:71]([F:74])([F:73])[F:72])[CH:70]=1)[O:61][CH:62]1[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]1>CN(C=O)C>[F:57][C:58]1[CH:59]=[C:60]([CH:68]=[C:69]([C:71]([F:73])([F:72])[F:74])[CH:70]=1)[O:61][CH:62]1[CH2:63][CH2:64][N:65]([C:46](=[O:48])[CH2:45][NH:44][C:42]([C:40]2[N:39]=[N:38][N:37]([C:33]3[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=3)[CH:41]=2)=[O:43])[CH2:66][CH2:67]1
Reactant: Fc1cc(OC2CCNCC2)cc(C(F)(F)F)c1
Reactant: O=C(O)CNC(=O)c1cn(-c2cccnc2)nn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Nc1cccnc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCC(Oc2cc(F)cc(C(F)(F)F)c2)CC1)c1cn(-c2cccnc2)nn1
Reaction time: 0.03 h
Yield: 32 %

Procedure:
DIPEA (97 mg, 0.75 mmol) followed by HOBt (35 mg, 0.26 mmol) and EDCI (50 mg, 0.26 mmol) were added to a stirred solution of [(1-pyridin-3-yl-1H-[1,2,3]triazole-4-carbonyl)-amino]-acetic acid (prepared by the method used for the synthesis of Intermediate 64, starting from 3-aminopyridine, and subsequently, application of Step 3 of the General Scheme) (62 mg, 0.25 mmol) in DMF (3 mL). After 2 minutes of stirring, 4-(3-fluoro-5-trifluoromethyl-phenoxy)-piperidine hydrochloride (prepared by the method used for the synthesis of Intermediate 15) (75 mg, 0.25 mmol) was added and the resulting mixture was stirred at room temperature overnight. The reaction mixture was partitioned between cold water and ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. Purification by column chromatography (using silica gel 60-120 and 40% EtOAc in hexane as eluent) afforded 38.5 mg (32% Yield) of 1-pyridin-3-yl-1H-[1,2,3]triazole-4-carboxylic acid {2-[4-(3-fluoro-5-trifluoromethyl-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 493, 98%. 1H NMR (300 MHz, DMSO-d6): δ 9.43 (s, 1H), 9.2 (d, 1H), 8.75 (d, 1H), 8.5 (t, 1H), 7.7 (m, 1H), 7.26 (m, 3H), 4.85 (m, 1H), 4.3 (m, 2H), 3.9 (m, 1H), 3.7 (m, 1H), 3.4 (m, 1H), 3.3 (m, 1H), 2.0 (m, 2H), 1.6 (m, 2H).
Reaction SMILES: OC1C=CC(C=O)=CC=1.BrCC1CCC1.[OH:16][C:17]1[CH:18]=[CH:19][C:20]([CH3:23])=[N:21][CH:22]=1.Cl[CH2:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][OH:31])=[CH:28][CH:27]=1>>[CH3:23][C:20]1[N:21]=[CH:22][C:17]([O:16][CH2:25][C:26]2[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[CH:28][CH:27]=2)=[CH:18][CH:19]=1
Reactant: OCc1ccc(CCl)cc1
Reactant: Cc1ccc(O)cn1
Agent: BrCC1CCC1
Agent: O=Cc1ccc(O)cc1
Product: Cc1ccc(OCc2ccc(C=O)cc2)cn1
Yield: 113.7 %

Procedure:
Instead of 4-hydroxybenzaldehyde and (bromomethyl)cyclobutane, 5-hydroxy-2-methylpyridine (767 mg) and 4-(chloromethyl)benzyl alcohol (1.00 g) were respectively used and treated by the same techniques as in Reference Examples 9-1 and 19-1 to give the titled compound as a pale yellow solid (1.65 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:19]([OH:21])=O)[CH:13]([C:15]([F:18])([F:17])[F:16])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:22][C:23]1[CH:24]=[C:25]([CH:37]=[CH:38][C:39]=1[F:40])[CH2:26][C:27]1([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:29][CH2:28]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>CN(C=O)C.N1C=CC=CC=1>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:19]([NH:22][C:23]1[CH:24]=[C:25]([CH:37]=[CH:38][C:39]=1[F:40])[CH2:26][C:27]1([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:28][CH2:29]1)=[O:21])[CH:13]([C:15]([F:16])([F:17])[F:18])[CH3:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC([C@H](NC(=O)OCc1ccccc1)C(=O)O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)C1(Cc2ccc(F)c(N)c2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC([C@H](NC(=O)OCc1ccccc1)C(=O)Nc1cc(CC2(C(=O)OC(C)(C)C)CC2)ccc1F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4.80 g (15.7 mmol) of N-[(benzyloxy)carbonyl]-4,4,4-trifluorovaline (racemic diastereomer mixture) and 5.01 g (18.9 mmol) of tert-butyl 1-(3-amino-4-fluorobenzyl)cyclopropanecarboxylate were dissolved in a mixture of 40 ml of DMF and 10 ml of pyridine, and 6.58 g (17.3 mmol) of HATU were added at RT. The reaction mixture was stirred at RT overnight and then added to water. The mixture was extracted three times with ethyl acetate, and the combined organic phases were then washed successively with sat. sodium bicarbonate solution, 1 N hydrochloric acid and sat. sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 20:1→10:1). This gave 5.34 g of the target product (61.5% of theory, diastereomer ratio about 2.5:1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:19][CH2:20][CH:21]=O)[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:23][C:24]1[C:29]([NH2:30])=[CH:28][CH:27]=[C:26]([N:31]2[CH2:35][CH2:34][C@@H:33]([N:36]3[CH2:40][CH2:39][CH2:38][C@@H:37]3[CH3:41])[CH2:32]2)[N:25]=1>>[CH2:1]([O:3][C:4]([C:6]1([CH2:19][CH2:20][CH2:21][NH:30][C:29]2[C:24]([CH3:23])=[N:25][C:26]([N:31]3[CH2:35][CH2:34][C@@H:33]([N:36]4[CH2:40][CH2:39][CH2:38][C@@H:37]4[CH3:41])[CH2:32]3)=[CH:27][CH:28]=2)[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(CCC=O)CCN(C(=O)OC(C)(C)C)CC1
Reactant: Cc1nc(N2CC[C@@H](N3CCC[C@@H]3C)C2)ccc1N
Product: CCOC(=O)C1(CCCNc2ccc(N3CC[C@@H](N4CCC[C@@H]4C)C3)nc2C)CCN(C(=O)OC(C)(C)C)CC1

Procedure:
The title compound was synthesized in essentially the same manner using the procedures as set forth in Step 1 of Example 1, by condensing 4-(3-oxo-propyl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (69 mg, 0.22 mmol) and 2-methyl-6-((2S,3′R)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-ylamine to obtain 113 mg of a crude solid, which was used without purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[C@H:4]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]2[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:34])=[O:26])=[CH:20][CH:19]=1)[NH:5][C:6]([C:8]1([CH2:13][CH2:14][CH:15]=[CH2:16])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7]>[Pd].CCO>[CH3:1][O:2][C:3](=[O:35])[C@H:4]([CH2:17][C:18]1[CH:19]=[CH:20][C:21]([NH:24][C:25]([C:27]2[C:28]([Cl:34])=[CH:29][CH:30]=[CH:31][C:32]=2[Cl:33])=[O:26])=[CH:22][CH:23]=1)[NH:5][C:6]([C:8]1([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7]
Reactant: C=CCCC1(C(=O)N[C@@H](Cc2ccc(NC(=O)c3c(Cl)cccc3Cl)cc2)C(=O)OC)CCCC1
Agent: [Pd]
Solvent: CCO
Product: CCCCC1(C(=O)N[C@@H](Cc2ccc(NC(=O)c3c(Cl)cccc3Cl)cc2)C(=O)OC)CCCC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of 4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[[1-(3-butenyl)cyclopentyl]carbonyl]-L-phenylalanine methyl ester (0.19 mmol, 100 mg) and 10% palladium on carbon (200 mg) in EtOH (2 mL) was stirred under a hydrogen atmosphere at room temperature for 15 h. Then, the charcoal was filtered and washed with EtOH (10 mL). The filtrate was removed under vacuum to obtain 37.5 mg (37%) of as a white solid: mp 193-196° C. HR MS: Obs. mass, 519.1818. Calcd. mass, 519.1817 (M+H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C[Al](C)C.[C:11]([C:13]1[C:18]2[N:19]=[C:20]([C:22](OCC)=[O:23])[O:21][C:17]=2[C:16]([F:27])=[C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:14]=1[CH3:34])#[N:12].Cl>ClCCl>[F:27][C:16]1[C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:14]([CH3:34])[C:13]([C:11]#[N:12])=[C:18]2[C:17]=1[O:21][C:20]([C:22]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:23])=[N:19]2
Reactant: C1COCCN1
Reactant: CCOC(=O)c1nc2c(C#N)c(C)c(-c3ccccc3)c(F)c2o1
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1c(-c2ccccc2)c(F)c2oc(C(=O)N3CCOCC3)nc2c1C#N
Reaction time: 0.25 h
Yield: 81.8 %

Procedure:
Morpholine (269 μl, 3.08 mmol) was dissolved in dichloromethane (3 ml), and under nitrogen atmosphere at room temperature, trimethylaluminium (1.03 M hexane solution, 2.99 ml, 3.08 mmol) was added. After stirring at the same temperature for 15 minutes, a solution of ethyl 4-cyano-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-2-carboxylate (I-111) (500 mg, 1.54 mmol) dissolved in dichloromethane (7 ml) was added at the same temperature. After stirring at the same temperature for 30 hours, an aqueous 1 M hydrochloric acid solution was gradually added at 0° C. The solution was extracted three times with dichloromethane. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, the solvent was evaporated away under reduced pressure, and the resulting residue was purified by middle-pressure liquid chromatography (eluent, hexane:ethyl acetate=3:2) to obtain the entitled compound (460 mg, 82%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]2[C:14](=O)[C:13](=[CH:16][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[CH2:12][S:11][CH2:10]2)=[CH:4][CH:3]=1.[CH2:24]([NH:27][NH2:28])[CH2:25][CH3:26]>CO>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[NH:28][N:27]([CH2:24][CH2:25][CH3:26])[C:14]3[C:13](=[CH:16][C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=4)[CH2:12][S:11][CH2:10][C:9]2=3)=[CH:4][CH:3]=1
Reactant: CCCNN
Reactant: Cc1ccc(C=C2CSCC(=Cc3ccc(C)cc3)C2=O)cc1
Solvent: CO
Product: CCCN1NC(c2ccc(C)cc2)C2=C1C(=Cc1ccc(C)cc1)CSC2
Yield: 73 %

Procedure:
A mixture of tetrahydro-3,5-bis-(4-methylphenylmethylene)-4H-thiopyran-4-one (6.7 g, 20 mmole) and n-propylhydrazine (1.6 g, 22 mmole) in methanol (250 ml) is heated at reflux temperature for 5 hours, then cooled overnight. The pale yellow precipitate is collected by filtration. The filtrate is concentrated to about 50 ml and additional precipitate is again collected by filtration and combined with the previous batch to give 5.5 g of a crude product mixture.