Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[CH3:27][C:28]1[CH:33]=[C:32]([CH2:34][OH:35])[CH:31]=[CH:30][N:29]=1>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=3)[N:10]=2)=[C:2]([O:35][CH2:34][C:32]2[CH:31]=[CH:30][N:29]=[C:28]([CH3:27])[CH:33]=2)[CH:7]=1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Reactant: Cc1cc(CO)ccn1
Product: Cc1cc(COc2cc(F)ccc2-c2ncnc(Nc3cccc(CS(C)(=O)=O)c3)n2)ccn1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (70 mg; 0.184 mmol), intermediate 42.1, and (2-methyl-pyridin-4-yl)-methanol (91 mg; 0.736 mmol), example 87 was prepared analogously to the procedure for the preparation of example 42.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]2[O:10][CH:11]=[C:12]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24]O)=[CH:18][CH:17]=3)[N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(P(CCCC)CCCC)CCC.[NH:39]1[CH:43]=[N:42][CH:41]=[N:40]1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.O>[C:1]1(/[CH:7]=[CH:8]/[C:9]2[O:10][CH:11]=[C:12]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][N:39]4[CH:43]=[N:42][CH:41]=[N:40]4)=[CH:18][CH:17]=3)[N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1nc[nH]n1
Reactant: OCCCc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Agent: CCCCP(CCCC)CCCC
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Solvent: O
Product: C(=C/c1nc(COc2ccc(CCCn3cncn3)cc2)co1)\c1ccccc1
Yield: 61.7 %

Procedure:
To a solution of 3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propanol (760 mg), tributyl phosphine (1.01 g) and 1,2,4-triazole (280 mg) in tetrahydrofuran (15 ml) was added dropwise, at 0° C., diethyl azodicarboxylate (700 mg). The mixture was heated for one hour under reflux, poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and concentrated. The residue was subjected to a silica gel column chromatography. The crystals obtained from the fraction eluted with ethyl acetate-hexane (2:1, v/v) were recrystallized from ethyl acetate-hexane to give 1-[3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl]-1,2,4-triazole (540 mg, 70%) as colorless prisms, mp 108-109° C.
Reaction SMILES: [N:1]1([CH2:8][CH2:9][OH:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][N:15]=1.O>CN(C)C=O>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([O:10][CH2:9][CH2:8][N:1]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:15][CH:16]=1
Reactant: Brc1ccc(Br)nc1
Reactant: OCCN1CCCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc(OCCN2CCCCCC2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.1 %

Procedure:
To a solution of 2-azepan-1-ylethanol (5.0 g) in N,N-dimethylformamide (100 ml) was added 60% sodium hydride (1.5 g) under a nitrogen atmosphere, the solution was stirred for 1 hour at room temperature, 2,5-dibromopyridine (7.5 g) was then added thereto followed by stirring for 4.5 hours at room temperature. Water was added thereto followed by stirring, the solution was extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by NH silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (9.1 g).
Reaction SMILES: [Na].[C:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[OH:14])[N:10]=[CH:9][CH:8]=[C:7]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[O:24])=[C:18]([F:33])[CH:17]=1)#[N:3].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:41][CH2:42][CH2:43][N:44]([CH2:47][CH3:48])[CH2:45][CH3:46].O>CN(C)C=O>[C:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH2:41][CH2:42][CH2:43][N:44]([CH2:47][CH3:48])[CH2:45][CH3:46])[N:10]=[CH:9][CH:8]=[C:7]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[O:24])=[C:18]([F:33])[CH:17]=1)#[N:3]
Reactant: CCN(CC)CCCCl
Reactant: N#Cc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4)c(F)c3)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)CCCOc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(F)cc4)c(F)c3)c2cc1C#N
Temperature: 65 °C
Reaction time: 7 h
Yield: 23.5 %

Procedure:
After dissolving 480 mg of 6-cyano-4-{4-[4-fluoroanilinocarbonyl]amino-3-fluorophenoxy}quinolin-7-ol sodium salt in 5 ml of dimethylformamide, 350 mg of potassium carbonate and 204 mg of 3-chloropropyldiethylamine were added and the mixture was heated and stirred at 65° C. for 7 hours. After standing to cool, water was added and extraction was performed with ethyl acetate and tetrahydrofuran, after which the solvent was distilled off under reduced pressure and the residue was purified by NH silica gel column chromatography (ethyl acetate-methanol system) to obtain 135 mg of the title compound.
Reaction SMILES: [CH2:1]([O:3][CH2:4]Cl)[CH3:2].[NH:6]1[CH:10]=[N:9][CH:8]=[N:7]1>C1(C)C=CC=CC=1>[CH2:1]([O:3][CH2:4][N:6]1[CH:10]=[N:9][CH:8]=[N:7]1)[CH3:2]
Reactant: CCOCCl
Reactant: c1nc[nH]n1
Solvent: Cc1ccccc1
Product: CCOCn1cncn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of chloromethyl ethyl ether (23.5 g) in toluene (300 ml ), was added dropwise, over an hour, to a solution of 1,2,4-triazole (50 g) in toluene (50 ml), and the reaction stirred at room temperature for 18 hours. On cooling, the reaction mixture was evaporated to dryness in vacuo, the residue triturated with dichloromethane, and the resulting suspension filtered. The filtrate was evaporated in vacuo and purified by column chromatography over silica gel (5/95 methanol/dichloromethane) to afford the title compound as a colorless oil, 23.9 g.
Reaction SMILES: Cl.C(N[CH2:7][C:8]1[C:9]([OH:30])=[C:10]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)[CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[CH:13]=1)(C)(C)C.BrC1C=C(Br)C=C(C=[O:36])C=1O>>[Cl:21][C:16]1[CH:15]=[C:14]([C:12]2[CH:13]=[C:8]([CH:7]=[O:36])[C:9]([OH:30])=[C:10]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)[CH:11]=2)[CH:19]=[CH:18][C:17]=1[Cl:20]
Reactant: CC(C)(C)NCc1cc(-c2ccc(Cl)c(Cl)c2)cc(-c2ccc(Cl)c(Cl)c2)c1O
Reactant: O=Cc1cc(Br)cc(Br)c1O
Agent: Cl
Product: O=Cc1cc(-c2ccc(Cl)c(Cl)c2)cc(-c2ccc(Cl)c(Cl)c2)c1O

Procedure:
3,3″,4,4″-Tetrachloro-4′-hydroxy-[1,1′:3′,1″-terphenyl]-5′-carbaldehyde was prepared using the procedure described in Intermediate 5 from 3,5-dibromosalicylaldehyde and 3,4-chlorophenylboronic acid.
Reaction SMILES: [C:1]1([CH2:7][S:8][C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[CH:11]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24](=[O:29])[CH2:25]S(C)=O.N1CCCCC1>C1(C)C=CC=CC=1>[C:1]1([CH2:7][S:8][C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]2[NH:17][C:18]3[C:19]([C:24](=[O:29])[CH:25]=2)=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccccc1SCc1ccccc1
Reactant: CS(=O)CC(=O)c1ccccc1N
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: O=c1cc(-c2ccccc2SCc2ccccc2)[nH]c2ccccc12
Reaction time: 3 h
Yield: 55.3 %

Procedure:
2-[(Phenylmethyl)thio]benzaldehyde (2.28 g, 10 mmole, 1 equiv.), 1-(2-aminophenyl)-2-(methylsulfinyl)ethanone (1.97 g, 10 mmole, 1 equiv.), and piperidine (0.5 ml, 5 mmole, 0.5 equiv.) were combined in toluene (50 ml), and the mixture was heated to reflux under a Dean-Stark trap. After 3 hr, the reaction was concentrated and the residue was chromatographed on silica gel (50% EtOAc/CHCl3) to afford 2-[2-[(phenylmethyl)thio]phenyl]-4(1H)-quinolinone (1.90 g, 55%) as a brownish-yellow foam. Recrystallization from CHCl3 /EtOAc gave light yellow crystals (1.39 g): mp 196-197° C.; TLC (50% EtOAc/CHCl3) Rf 0.31; 1H NMR (CDCl3) δ8.63 (br s, 1 H), 8.36 (dd, J=8.1, 0.8 Hz, 1 H), 7.50-7.62 (m, 2 H), 7.28-7.45 (m, 4 H), 7.16-7.26 (m, 4 H), 7.00-7.08 (m, 2 H), 6.24 (d, J=1.8 Hz, 1 H), 3.97 (s, 2 H); IR (KBr) 2100-3200 (br), 1632, 1594, 1530, 1497, 1439 cm-1 ; MS (NH3), m/e (%) 344.1 (100, (M+H)+), 254.2 (26.9). Anal. Calcd for C22H17NOS: C, 76.54; H, 4.87; N, 3.91; S, 9.12. Found: C, 76.94; H, 4.99; N, 4.08; S, 9.34.
Reaction SMILES: Br[CH:2]([C:4]1[O:5][C:6](=[O:19])[C:7]2[C:12]([C:13]=1[C:14]1[S:18][CH:17]=[N:16][CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:3].[NH:20]1[C:24]2=[N:25][CH:26]=[N:27][C:28]([NH2:29])=[C:23]2[CH:22]=[N:21]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:29][C:28]1[N:27]=[CH:26][N:25]=[C:24]2[N:20]([CH:2]([C:4]3[O:5][C:6](=[O:19])[C:7]4[C:12]([C:13]=3[C:14]3[S:18][CH:17]=[N:16][CH:15]=3)=[CH:11][CH:10]=[CH:9][CH:8]=4)[CH3:3])[N:21]=[CH:22][C:23]=12
Reactant: Nc1ncnc2[nH]ncc12
Reactant: CC(Br)c1oc(=O)c2ccccc2c1-c1cncs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(c1oc(=O)c2ccccc2c1-c1cncs1)n1ncc2c(N)ncnc21
Yield: 52.7 %

Procedure:
The title compound was made in a similar way as that of the compound of example 15, 3-(1-bromoethyl)-4-(thiazol-5-yl)-1H-isochromen-1-one (intermediate C12, 56 mg, 0.17 mmol), 1H-pyrazolo[3,4-d]pyrimidin-4-amine (45 mg, 0.33 mmol) and K2CO3 (46 mg, 0.33 mmol) in DMF (1 ml) at 80° C. for 3 hrs to give the title compound (35 mg, 54%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:21]=[CH:20][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][C:12](=[O:15])[CH:11]([C:16]([O:18][CH3:19])=[O:17])[CH2:10]2)=[CH:6][CH:5]=1.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:22]([C:11]1([C:16]([O:18][CH3:19])=[O:17])[C:12](=[O:15])[CH2:13][CH2:14][N:9]([CH2:8][C:7]2[CH:6]=[CH:5][C:4]([Cl:3])=[CH:21][CH:20]=2)[CH2:10]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)C1CN(Cc2ccc(Cl)cc2)CCC1=O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C1(Cc2ccccc2)CN(Cc2ccc(Cl)cc2)CCC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58 %

Procedure:
In a three-necked flask, under a azote atmosphere, sodium hydride (0.115 g, 60% in mineral oil, 2.871 mmol) was added at 0° C. by small portions to a solution of methyl 1-(4-chlorobenzyl)-4-oxopiperidine-3-carboxylate obtained above (0.809 g, 2.871 mmol) in 1.80 mL of anhydrous DMF. The resulting mixture was stirred 30 min at room temperature and then a solution of benzyl bromide (0.341 mL, 2.871 mmol) in 2.20 mL of anhydrous DMF was added. The reaction was followed by HPLC and UPLC-MS. After 24 h at room temperature, it was diluted with ethyl acetate. The organic phase was washed with H2O, brine, dried over Na2SO4 and concentrated in vacuo to give a yellow oil that was purified by flash chromatography (SiO2, petroleum ether:ethyl acetate 95:5 as eluent). Evaporation and drying in vacuo of the pure fractions gave pure methyl 3-benzyl-1-(4-chlorobenzyl)-4-oxopiperidine-3-carboxylate as a colorless oil. (0.623 g, 1.675 mmol, 58% yield). 372.2.
Reaction SMILES: [CH2:1]1[C:3]2([CH2:7][CH:6]([N:8]([CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:29]=[C:28]4[C:23]([C:24]([O:30][C:31]5[CH:32]=[CH:33][C:34]([NH:37][C:38]([C:40]6[C:41](=[O:53])[N:42]([C:47]7[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=7)[N:43]([CH3:46])[C:44]=6[CH3:45])=[O:39])=[N:35][CH:36]=5)=[CH:25][CH:26]=[N:27]4)=[CH:22][CH:21]=3)C(OC(C)(C)C)=O)[CH2:5][O:4]2)[CH2:2]1.Cl.C1COCC1.C([O-])(O)=O.[Na+]>C1COCC1>[CH2:2]1[C:3]2([CH2:7][CH:6]([NH:8][CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:29]=[C:28]4[C:23]([C:24]([O:30][C:31]5[CH:32]=[CH:33][C:34]([NH:37][C:38]([C:40]6[C:41](=[O:53])[N:42]([C:47]7[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=7)[N:43]([CH3:46])[C:44]=6[CH3:45])=[O:39])=[N:35][CH:36]=5)=[CH:25][CH:26]=[N:27]4)=[CH:22][CH:21]=3)[CH2:5][O:4]2)[CH2:1]1
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(OCCCN(C(=O)OC(C)(C)C)C5COC6(CC6)C5)ccc34)cn2)c(=O)n(-c2ccccc2)n1C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(OCCCNC5COC6(CC6)C5)ccc34)cn2)c(=O)n(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
To a solution of N-(5-(7-((N-(4-oxaspiro[2.4]heptane-6-yl)-tert butoxycarbonylamino)propoxy)quinolin-4-yloxy)pyridin-2-yl)-2,3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazole-4-carboxamide (50 mg, 0.069 mmol) in dry THF (2 mL) was added 2 M HCl/THF (8 mmol). After stirring at room temperature for 4 hrs, 10 mL of saturated NaHCO3 aqueous solution was added to quench the reaction. The mixture was extracted with EtOAc (15 mL×2). The combined organic phases were dried over Na2SO4, concentrated in vacuo. The crude product was chromatographed with a silica gel column (5:1 (v/v) EtOAc/MeOH) to give the title compound as a white solid (30 mg, 69%).
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH:4]([OH:6])[CH3:5].[C:8](OC=C)(=[O:11])[CH2:9][CH3:10].[O-][Mn](=O)(=O)=O.[K+]>CO.ClCCl>[C:8]([O:6][CH:4]([CH3:5])[CH2:3][N:2]([CH3:7])[CH3:1])(=[O:11])[CH2:9][CH3:10]
Reactant: C=COC(=O)CC
Reactant: CC(O)CN(C)C
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: CCC(=O)OC(C)CN(C)C
Reaction time: 70 h
Yield: 38.1 %

Procedure:
Racemic 1-dimethylamino-2-propanol (100 g, 0.97 mol) was stirred with vinyl propionate (106 ml, 0.97 mol) at ambient temperature and Novozym 435 (6 g) was added. The reaction mixture was stirred slowly for 70 hours and after this time tlc (10% methanol/dichloromethane--visualise KMnO4 solution) indicated that the reaction had gone to 50% conversion. The enzyme was removed by filtration and the filter bed was washed with ethyl acetate (2×100 ml). The organic layer was then washed with water (4×100 ml) and the combined washes were back extracted with ethyl acetate (400 ml). The organic layer was then washed with brine (200 ml) and dried (MgSO4). The ethyl acetate was removed in vacuo to leave 58.7 g (0.37 mol, 70% based on maximum yield of 84.5 g) of (-)-1-dimethylamino-2-propyl propanoate as a yellow oil. δH (220 MHz; CDCl3) 1.13 (3H, t, 7 Hz, CH3CH2CO), 1.21 (3H, d, 6 Hz, H-3), 2.25 (6H, s, N(CH3)2),2.10-2.60 (4H, m, H-1 & CH3CH2CO), 5.09 (1H, m, H-2). The optical purity was not measured at this stage.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([N:22]=C(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([NH2:22])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(N=C(c4ccccc4)c4ccccc4)nc3N21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(N)nc3N21
Reaction time: 1 h
Yield: 58.9 %

Procedure:
To a solution of 0.23 g (0.49 mmol) (4R,9aR)-6-(benzhydrylidene-amino)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester in 2.5 ml methanol were added 0.46 g (7.4 mmol) ammonium formate and 104 mg (0.05 mmol) 5% palladium on charcoal and the suspension was stirred for 1 h at 60 deg C. The cooled reaction mixture was filtered through a short bed of dicalite speed plus, extracted with 10% aqueous sodium bicarbonate, brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by chromatography on silica gel (0.032–0.063 mm) to yield the product as a colorless oil (58.9%).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[NH:11][CH:12]=[CH:13][N:14]=2)[N:5]=1.[CH2:15]([N:18]1[C:22]2[CH:23]=[CH:24][C:25]([C:27]#[N:28])=[CH:26][C:21]=2[N:20]=[C:19]1[CH2:29]Cl)[CH2:16][CH3:17].[I-].[Na+]>CN(C=O)C.O>[CH2:15]([N:18]1[C:22]2[CH:23]=[CH:24][C:25]([C:27]#[N:28])=[CH:26][C:21]=2[N:20]=[C:19]1[CH2:29][N:11]1[CH:12]=[CH:13][N:14]=[C:10]1[C:6]1[N:5]=[C:4]([F:3])[CH:9]=[CH:8][CH:7]=1)[CH2:16][CH3:17]
Reactant: CCCn1c(CCl)nc2cc(C#N)ccc21
Reactant: Fc1cccc(-c2ncc[nH]2)n1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCn1c(Cn2ccnc2-c2cccc(F)n2)nc2cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a stirring suspension of sodium hydride (2.25 g of 60% in oil) in DMF (10 mL) at 0° a solution of 2-Fluoro-6-(1H-imidazol-2-yl)-pyridine (7.7 9, 47.2 mmol) in DMF (20 mL) is added. After stirring for 5 minutes, a solution of 1-n-Propyl-2-chloromethyl-5-cyanobenzimidazole (11 g, 47.2 mmol) and sodium iodide (20 mg) in DMF (80 mL) is added. The reaction mixture is stirred for 6 h, gradually warmed to room temperature. The reaction mixture is cooled, water added, the solid collected, rinsed with water and dried to afford the title compound, 1-Propyl-2-{[2-(2-fluoropyrid-6-yl)-1H-imidazol-1-yl]methyl}-5-cyano-1H-benzimidazole.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:22]([NH:24][NH:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10].C(N(CC)CC)C.[NH:41]1[CH:45]=[CH:44][CH:43]=[C:42]1[C:46](O)=[O:47].ClCCl.CO>ClCCl>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:22]([NH:24][N:25]([CH2:26][CH:27]([CH3:28])[CH3:29])[C:46]([C:42]1[NH:41][CH:45]=[CH:44][CH:43]=1)=[O:47])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10]
Reactant: CC(C)CNNC(=O)[C@H](CC(C)C)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Reactant: O=C(O)c1ccc[nH]1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)c1ccc[nH]1)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Temperature: 0 °C
Reaction time: 2 h
Yield: 40.8 %

Procedure:
A solution of 0.459 g of (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-4-methylvalerohydrazide in 5 ml of dichloromethane was treated under nitrogen at 0° C. with 0.28 ml of triethylamine and a solution of the acid chloride prepared from 0.166 g of 2-pyrrolecarboxylic acid in 3 ml of dichloromethane. The mixture was stirred at 0° C. for 2 hours and evaporated. The residue was dissolved in ethyl acetate. The solution was washed with 5% aqueous sodium hydrogen carbonate solution, water, 5% citric acid solution and saturated sodium chloride solution, dried over anhydrous magnesium sulphate and was evaporated to give a solid. Chromatography of this solid on silica gel using dichloromethane/methanol (50:1) for the elution followed by evaporation and trituration with diethyl ether gave 0.225 g of (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-4-methyl-2′-[(2-pyrrolyl)carbonyl]valerohydrazide in the form of a white solid.
Reaction SMILES: C[O:2]C([C@@]1(N)CC[C@H](C2C=CC(Br)=CC=2)C1)=O.[ClH:18].[CH3:19][O:20][C:21]([C@:23]1([NH2:35])[CH2:27][CH2:26][C@H:25]([C:28]2[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][CH:29]=2)[CH2:24]1)=[O:22]>>[OH2:2].[ClH:18].[NH2:35][C@:23]1([C:21]([O:20][CH3:19])=[O:22])[CH2:27][CH2:26][C@H:25]([C:28]2[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][CH:29]=2)[CH2:24]1
Reactant: COC(=O)[C@]1(N)CC[C@H](c2ccc(Br)cc2)C1
Agent: COC(=O)[C@@]1(N)CC[C@H](c2ccc(Br)cc2)C1
Agent: Cl
Product: O
Temperature: 25 °C

Procedure:
The crude mixture of (1R,3S)-1-amino-3-(4-bromo-phenyl)-cyclopentanecarboxylic acid methyl ester; hydrochloride and (1S,3S)-1-amino-3-(4-bromo-phenyl)-cyclopentanecarboxylic acid methyl ester; hydrochloride (from General Procedure F) (approx. 2.6 mol) was combined with 15 L of aqueous 1,2-DME solution (4.8% water content). The slurry was mixed for 3 h at 50° C., allowed to cool to room temperature and mixed at room temperature for 15 h. The resulting mixture is filtered and dried in vacuo at 60° C. to provide (1R,3S)-methyl 1-amino-3-(4-bromophenyl)cyclopentanecarboxylate hydrochloride hydrate as a white solid (332 g, 36% yield). Chiral HPLC (Table 1, Method b). Rt=19.9 min., LCMS (Table 1, Method a) Rt=1.80 min (ELSD); m/z: 198 (M+H)+.
Reaction SMILES: [CH2:1]([S:8][C:9]([CH:12]1[N:17]([CH2:18][C:19]([O:21]CC)=[O:20])[C:15](=[O:16])[CH:14]([CH2:24][S:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:13]1)([CH3:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Cl>CO>[CH2:1]([S:8][C:9]([C@H:12]1[N:17]([CH2:18][C:19]([OH:21])=[O:20])[C:15](=[O:16])[C@@H:14]([CH2:24][S:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:13]1)([CH3:10])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CN1C(=O)C(CSCc2ccccc2)CC1C(C)(C)SCc1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(SCc1ccccc1)[C@@H]1C[C@H](CSCc2ccccc2)C(=O)N1CC(=O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 66.6 %

Procedure:
To a solution of 4-(1-benzylthio-1-methylethyl)-2-benzylthiomethyl-N-ethoxycarbonylmethyl-4-butanelactam (compound No.14-3, 1.50 g) in methanol (20 ml), 2N--KOH (6.4 ml) was added and the mixture was stirred for 1.5 hours at room temperature. The mixture was acidified with dilute hydrochloric acid and concentrated in vacuo. A product was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo to give 0.94 g (67%) of the titled compound.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:14]=3[C:15]=2[C:16](=[O:25])[C:17]2[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[CH:18]=2)=[CH:7][CH:6]=1.[CH2:32]([NH:34][CH2:35][CH3:36])[CH3:33]>>[CH2:32]([N:34]([CH2:35][CH3:36])[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:14]=3[C:15]=2[C:16](=[O:25])[C:17]2[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[CH:18]=2)=[CH:7][CH:6]=1)[CH3:33]
Reactant: CCNCC
Reactant: COc1ccc2oc(-c3ccc(OCCCl)cc3)c(C(=O)c3cc(C)cc(C)c3)c2c1
Product: CCN(CC)CCOc1ccc(-c2oc3ccc(OC)cc3c2C(=O)c2cc(C)cc(C)c2)cc1

Procedure:
Reaction of 2-[4'-(2-chloroethoxy)phenyl]-5-methoxy-3-(3',5'-dimethylbenzoyl)benzofuran with diethylamine by the procedure of Example 25 gives the title compound.
Reaction SMILES: [C:1](O)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].S(Cl)(Cl)=O.[Cl-:15].[Al+3].[Cl-:17].[Cl-]>>[CH:1]([Cl:17])([Cl:15])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4]
Reactant: O=C(O)c1ccccc1O
Reactant: [Cl-]
Agent: [Al+3]
Solvent: O=S(Cl)Cl
Product: Oc1ccccc1C(Cl)Cl
Temperature: 42.5 °C

Procedure:
A mixture of 10 grams salicylic acid, 7 ml of thionyl chloride, and 0.02 gram of aluminum chloride was heated at 40 to 45°C. for 11/2 hours. The excess thionyl chloride was removed in vacuum and the salicylyl chloride reaction product can be used without further purification.