Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:31]([F:34])([F:33])[F:32])[O:13][N:12]=[C:11]([C:14]3[CH:29]=[CH:28][C:17]([C:18]([NH:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)=[O:19])=[C:16](I)[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.O.N.O.C[C:39]([N:41](C)C)=O>[C-]#N.[Zn+2].[C-]#N.[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:39]([C:16]1[CH:15]=[C:14]([C:11]2[CH2:10][C:9]([C:4]3[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=3)([C:31]([F:34])([F:33])[F:32])[O:13][N:12]=2)[CH:29]=[CH:28][C:17]=1[C:18]([NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)=[O:19])#[N:41]
Reactant: CC(=O)N(C)C
Reactant: O=C(NCc1ccccn1)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1I
Agent: [Fe+2]
Agent: [Pd]
Agent: N
Solvent: O
Product: N#Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCc1ccccn1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
In a solution of 0.19 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-iodo-N-(2-pyridylmethyl)benzoic acid amide (Compound of the present invention No. 5-065) synthesized similarly to Synthetic Example 4 in 10 ml of dimethylacetamide, 36.0 mg of zinc cyanide, 4.8 mg of zinc, 11.0 mg of tris(dibenzylideneacetone)dipalladium and 13.5 mg of 1,1′-bis(diphenylphosphino)ferrocene were added, and stirred under nitrogen atmosphere at 80 to 120° C. for 5 hours. After the completion of the reaction, 30 ml of ammonia water and 20 ml of water were added in the reaction mixture, and extracted with ethyl acetate (50 ml×1). The organic phase was washed with 30 ml of water, dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethylacetate-hexane (2:1), and 0.05 g of the aimed product was obtained as brown resinous substance.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([NH2:13])[CH:7]=1.C([O:17][C:18](=O)[CH:19]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[C:20](=O)[CH3:21])C>O>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:7]=1[C:18](=[O:17])[C:19]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=1)=[C:20]([CH3:21])[NH:13]2
Reactant: CCOC(=O)C(Cc1ccc(Cl)cc1)C(C)=O
Reactant: COC(=O)COc1ccc(F)c(N)c1
Solvent: O
Product: COC(=O)COc1ccc(F)c2[nH]c(C)c(Cc3ccc(Cl)cc3)c(=O)c12
Temperature: 130 °C

Procedure:
A mixture of (3-amino-4-fluorophenoxy)acetic acid methyl ester (0.50 g), 2-(4-chlorobenzyl)-3-oxobutyric acid ethyl ester (7.4 g) and polyphosphoric acid (1.1 g) was heated at 130° C. for 2 hours. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined extracts were washed with water and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (19:1 by volume) to afford title compound, 0.29 g.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[N:13]1[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]1)[CH:8]=O.C([N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][C:23]1=[O:28])(=O)C.O>C1COCC1.CN(C=O)C>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[N:13]1[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]1)/[CH:8]=[C:24]1/[C:23](=[O:28])[NH:22][CH2:27][CH2:26][CH2:25]/1
Reactant: COc1cc(C=O)ccc1-n1cnc(C)c1
Reactant: CC(=O)N1CCCCC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(/C=C2\CCCNC2=O)ccc1-n1cnc(C)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 36.4 %

Procedure:
To a sodium hydride suspension (40% mineral oil content, 2.77 g) in THF (50 mL) and DMF (200 mL), a solution of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (10 g) obtained in Example 1 and 1-acetylpiperidin-2-one (7.17 g) in THF (50 mL) and DMF (200 mL) were added dropwise over 20 minutes at 5° C. This reaction solution was agitated at 0° C. for 2 hours. The reaction solution was added to iced water and the reaction solution was extracted with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, and concentrated under reduced pressure after dried over anhydrous magnesium sulfate. The deposited solids were separated by filtering and 5.0 g of the title compound was obtained by washing with diethyl ether. The physical properties of the compound are as follows.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1.[C:15]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])#[N:16].N1CCCCC1>CCO>[C:15](/[C:17](=[CH:11]/[C:10]1[CH:13]=[CH:14][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:8][CH:9]=1)/[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])#[N:16]
Reactant: CC(C)(C)OC(=O)CC#N
Reactant: O=Cc1ccc(-c2ccccn2)cc1
Solvent: C1CCNCC1
Solvent: CCO
Product: CC(C)(C)OC(=O)/C(C#N)=C\c1ccc(-c2ccccn2)cc1
Temperature: 73 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
To a solution of 4-(pyridin-2-yl)-benzaldehyde (300 mg, 1.638 mmol) in EtOH (5 ml) at room temperature was added tert-butyl 2-cyanoacetate (0.281 ml, 1.965 mmol) followed by piperidine (0.016 ml, 0.164 mmol). The mixture was stirred at 73° C. overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. To the obtained mixture was added water and then extracted with DCM. The combined organic layer was washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by flash chromatography (silica gel, 15 to 30% EtOAc/Heptane) and gave the title compound: 350 mg (yield: 70%). LCMS (condition B): 307.2 (M+1); retention time=1.30 min.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])[CH3:2].[C:11]([OH:15])(=[O:14])[CH:12]=[O:13].[OH-].[Na+]>O>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([CH:12]([OH:13])[C:11]([OH:15])=[O:14])[CH:7]=[CH:6][C:5]=1[OH:10])[CH3:2]
Reactant: O=CC(=O)O
Reactant: CCOc1ccccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOc1cc(C(O)C(=O)O)ccc1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.6 %

Procedure:
2-Ethoxyphenol (56.6, 0.401 mol, 1 eq.), glyoxylic acid (50% aqueous solution) (41.0 mL, 0.396 mol, 0.99 eq.), and distilled water (110 mL) were combined. The mixture was cooled in an ice bath, and a solution of 10% NaOH (32.2 g NaOH in 300 mL distilled water, 0.805 mol, 2 eq.) was slowly added via addition funnel. The reaction was allowed to slowly warm to room temperature, and after ˜18 hours, the solution was washed with ethyl acetate (4×250 mL), then acidified with 6N HCl until pH ˜3. NaCl was added and the product was then extracted into ethyl acetate (4×200 mL). The organic phase was washed with brine, dried over magnesium sulfate, and solvent was removed under vacuum, giving 51.8 g of intermediate 2 as a light pink solid.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[O:18][C:17]3[CH:19]=[C:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[CH2:27]([NH2:30])[CH2:28][CH3:29]>C(#N)C>[CH3:26][S:23]([C:20]1[CH:21]=[CH:22][C:16]2[O:15][CH2:14][CH:13]([CH2:12][NH:30][CH2:27][CH2:28][CH3:29])[O:18][C:17]=2[CH:19]=1)(=[O:24])=[O:25]
Reactant: CCCN
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3ccc(S(C)(=O)=O)cc3O2)cc1
Solvent: CC#N
Product: CCCNCC1COc2ccc(S(C)(=O)=O)cc2O1
Temperature: 120 °C

Procedure:
A mixture of [7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.4 g, 0.90 mmol), propan-1-amine (1 ml) and ACN (3 ml) was heated under microwave radiation at 120° C. for 30 min. Purification on SCX-3 column (TEA/MeOH) and on a small silica plug (DCM/MeOH). Yield: 0.2 g, 90%. The amine was converted to the hydrochloric acid salt and crystallized from MeOH/Et2O. M.p. 223° C. MS m/z (rel. intensity, 70 eV) 285 (M+, 5), 256 (4), 207 (5), 73 (5), 72 (bp).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][C:11]([C:12](O)=[O:13])=[C:10]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[N:38]1[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][N:39]=1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CN(C)C=O>[N:1]1([CH2:7][C:8]2[C:16]([C:17]([F:19])([F:18])[F:20])=[CH:15][C:11]([C:12]([NH:44][C:41]3[CH:42]=[CH:43][N:38]=[N:39][CH:40]=3)=[O:13])=[C:10]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:9]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1cc(C(F)(F)F)c(CN2CCOCC2)cc1OCc1ccccc1
Reactant: Nc1ccnnc1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccnnc1)c1cc(C(F)(F)F)c(CN2CCOCC2)cc1OCc1ccccc1
Reaction time: 3 h

Procedure:
To a solution of 4-(4-morpholinylmethyl)-2-[(phenylmethyl)oxy]-5-(trifluoromethyl)benzoic acid (may be prepared as described in Description 50; 120 mg, 0.30 mmol) in N,N-dimethylformamide (5 ml) was added diisopropylethylamine (0.11 ml, 0.61 mmol), 4-pyridazinamine (43.3 mg, 0.46 mmol), 1-hydroxy-7-azabenzotriazole (53.7 mg, 0.40 mmol) and EDC (116 mg, 0.61 mmol). The reaction was stirred for 3 hours and the solvent was removed in vacuo to give yellow oil. Purification by MDAP gave the title compound as a white solid. 72 mg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][N:8]2[N:12]=[N:11][C:10]([C:13]3[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=3)[C:16](O)=[O:17])=[N:9]2)=[CH:5][CH:4]=1.C(Cl)(=O)C([Cl:27])=O.CN(C=O)C>ClCCl>[CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][N:8]2[N:12]=[N:11][C:10]([C:13]3[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=3)[C:16]([Cl:27])=[O:17])=[N:9]2)=[CH:5][CH:4]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc(Cn2nnc(-c3cccc(C(=O)O)c3)n2)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(Cn2nnc(-c3cccc(C(=O)Cl)c3)n2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.3 %

Procedure:
The carboxylic acid intermediate (10 g, 0.032 mol) from Step (c) was suspended in dichloromethane followed by the addition of oxalyl chloride (20.4 g, 0.16 mol) and catalytic DMF. The reaction mixture was stirred at room temperature for 3 hours, at which time dissolution was nearly complete. The reaction mixture was filtered and concentrated in vacuo. The residue was triturated with petroleum ether and collected by filtration to give the title compound (9.5 g, 90%) as a white solid. 1H NMR (CDCl3) δ 8.9 (s, 1H), 8.5 (d, 1H), 8.2 (d, 1H), 8.6 (t, 1H), 7.4 (d, 2H), 6.9 (d, 2H), 3.8 (s, 3H) ppm. Mp 122–124° C.
Reaction SMILES: [CH2:1]([C@@H:4]([NH:14][C:15]([NH2:17])=[O:16])[C:5]1[CH:10]=[CH:9][C:8]2[O:11][CH2:12][O:13][C:7]=2[CH:6]=1)[CH:2]=[CH2:3]>C(O)C.[Pd]>[CH2:1]([C@@H:4]([NH:14][C:15]([NH2:17])=[O:16])[C:5]1[CH:10]=[CH:9][C:8]2[O:11][CH2:12][O:13][C:7]=2[CH:6]=1)[CH2:2][CH3:3]
Reactant: C=CC[C@@H](NC(N)=O)c1ccc2c(c1)OCO2
Agent: [Pd]
Solvent: CCO
Product: CCC[C@@H](NC(N)=O)c1ccc2c(c1)OCO2
Yield: 99 %

Procedure:
A solution of N-[(R)-α-allyl-(3,4-methylenedioxy)benzyl] urea (7) in ethanol (5 mL) was hydrogenated at 40 p.s.i. over 10% Palladium on Carbon (40 mg) for 30 minutes. The reaction was filtered and evaporated to dryness to afford 350 mg (99%) of the title compound as a white solid. NMR (CDCl3): δ 0.91 (t, J=8 Hz, 3 H), 1.1-1.5 (m, 2 H), 1.5-1.9 (m, 2 H), 3.8-5.0 (v b s, 2 H), 4.46 (v br q, J=8 Hz, 1 H), 4.96 (b d, 1 H), 5.95 (s, 2 H), 6.76 (s, 2 H), 6.79 (s, 1 H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:7][CH2:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[CH:12]=[O:13])[S:5][CH:6]=1.Br[C:18]1[CH:19]=[C:20](S)[S:21][CH:22]=1.BrCC1C=C(C=CC=1)C=O.C([Sn](CCCC)(CCCC)C1C=CSC=1)CCC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[S:21]1[CH:22]=[CH:18][C:19]([C:2]2[CH:3]=[C:4]([S:7][CH2:8][C:9]3[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=3)[CH:12]=[O:13])[S:5][CH:6]=2)=[CH:20]1
Reactant: O=Cc1cccc(CSc2cc(Br)cs2)c1
Reactant: Sc1cc(Br)cs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[Sn](CCCC)(CCCC)c1ccsc1
Agent: O=Cc1cccc(CBr)c1
Product: O=Cc1cccc(CSc2cc(-c3ccsc3)cs2)c1

Procedure:
Using 3-(4-bromothienylthiomethyl)benzaldehyde [obtained by performing the same reaction as in Referential Example 56 using 4-bromo-2-thiophenethiol [Chem. Abst., 56, 4277 (1962)] and 3-bromomethylbenzaldehyde as starting materials], tributyl(3-thienyl)stannane and tetrakis(triphenylphosphine)palladium, the same reaction as in Referential Example 37 is carried out to give the captioned compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])=O.[CH3:19][O:20][CH:21]([O:27]C)[CH2:22][C:23](OC)=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[Cl:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:4]1[C:3]2[C:2](=[C:16]([CH3:17])[CH:15]=[C:14]([CH3:18])[CH:13]=2)[N:1]=[CH:23][C:22]=1[C:21]([O:20][CH3:19])=[O:27]
Reactant: Cc1cc(C)c(N)c(C(=O)c2ccccc2Cl)c1
Reactant: COC(=O)CC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: COC(=O)c1cnc2c(C)cc(C)cc2c1-c1ccccc1Cl
Yield: 58.5 %

Procedure:
A mixture of 2-amino-2'-chloro-3,5-dimethylbenzophenone (2.59 g), methyl 3,3-dimethoxypropionate (3.7 g), p-toluenesulfonic acid hydrate (0.19 g) and benzene (30 ml) was refluxed for 16 hrs., with removal of water by a Dien-Stark apparatus. The mixture was distilled to remove the solvent, and the residue was purified by a column chromatography on silica gel to give methyl 4-(2-chlorophenyl)-6,8-dimethyl-3-quinolinecarboxylate as crystals (1.90 g, 58.5%), which was recrystallized from isopropyl ether as colorless prisms. m.p. 117°-118° C.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([C@:10]23[CH2:19][CH2:18][O:17][CH2:16][CH:15]2[CH2:14][S:13][C:12]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[N:11]3)[CH:7]=[CH:8][CH:9]=1)=[N+]=[N-]>[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]([C@:10]23[CH2:19][CH2:18][O:17][CH2:16][CH:15]2[CH2:14][S:13][C:12]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[N:11]3)[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cccc(N=[N+]=[N-])c3)CCOCC2CS1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cccc(N)c3)CCOCC2CS1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.4 %

Procedure:
A mixture of tert-butyl (8aS)-8a-(3-azidophenyl)-4,4a,5,7,8,8a-hexahydropyrano[4,3-d][1,3]thiazin-2-ylcarbamate (0.398 g, 1.02 mmol) and palladium on carbon −10% by weight (0.200 g) in ethanol (25 mL) is purged with nitrogen then hydrogen. The reaction is stirred at room temperature under hydrogen (30 psi) for 2 h. Na2SO4 is added to the reaction mixture and it is filtered through diatomaceous earth, using methanol to rinse the filter cake. The solvent is removed under reduced pressure to give the title compound (0.361 g, 97%). ES/MS m/e: 364 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][CH:14]=O)[C:11](=[O:16])[N:10]([CH2:17][C:18]([NH:20][C:21]([CH3:33])([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)[CH3:22])=[O:19])[N:9]=2)=[CH:4][CH:3]=1.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCl.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][CH2:14][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[C:11](=[O:16])[N:10]([CH2:17][C:18]([NH:20][C:21]([CH3:22])([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[CH:24]=3)[CH3:33])=[O:19])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(NC(=O)Cn1nc(-c2ccc(Cl)cc2)n(CC=O)c1=O)c1cccc(C(F)(F)F)c1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(NC(=O)Cn1nc(-c2ccc(Cl)cc2)n(CCN2CCOCC2)c1=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
0.10 g (0.21 mmol) of 2-[3-(4-chlorophenyl)-4-(2-oxoethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-{1-methyl-1-[3-(trifluoromethyl)phenyl]ethyl}-acetamide from Example 401 are dissolved in 30 ml of dichloromethane and 0.4 ml of DMF and stirred with 22 mg (0.2 mmol) of morpholine for 1 hr at RT. Next, 66 mg (0.31 mmol) of sodium triacetoxyborohydride are added and the mixture is stirred for 18 hrs at RT. The reaction mixture is treated with 10 ml of saturated sodium hydrogen carbonate solution and extracted three times with 10 ml ethyl acetate each time. The combined organic phases are dried over sodium sulphate, filtered and concentrated in vacuo. The crude product is purified by preparative HPLC [Method 10]. 11.0 mg (10% of theory) of the target compound are obtained.
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][C@@H:7]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=1)[O:8]C1CCCCO1)(=[O:4])=[O:3].Cl>CO>[CH3:1][S:2]([O:5][CH2:6][C@@H:7]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=1)[OH:8])(=[O:3])=[O:4]
Reactant: CS(=O)(=O)OC[C@H](OC1CCCCO1)c1cccc(Cl)c1
Agent: Cl
Solvent: CO
Product: CS(=O)(=O)OC[C@H](O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Into methanol (10 ml) were added (R)-2-(3-chlorophenyl)-2-(3,4,5,6-tetrahydro-[2H]-pyran-2-yloxy)ethyl methanesulfonate (3.0 g) and hydrochloric acid (0.11 g), and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was neutralized, concentrated, and ethyl acetate and water were added to the resulting residue. The organic layer was collected by layer separation, washed with a saturated aqueous sodium chloride solution and dried with anhydrous magnesium sulfate. The desiccant was filtered off, and the solvent was distilled off under reduced pressure to obtain a colorless oily compound mentioned above (2.1 g, 93.5%).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][N:10]([CH:13]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)[CH2:9][CH2:8]2)[CH:5]2[CH2:26][CH2:27][CH2:28][CH2:29][CH:4]2[NH:3]1>Cl.O1CCOCC1.O>[NH:16]1[CH2:17][CH2:18][CH:13]([N:10]2[CH2:9][CH2:8][CH:7]([N:6]3[C@H:5]4[CH2:26][CH2:27][CH2:28][CH2:29][C@@H:4]4[NH:3][C:2]3=[O:1])[CH2:12][CH2:11]2)[CH2:14][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCC(N3C(=O)NC4CCCCC43)CC2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: O=C1N[C@H]2CCCC[C@@H]2N1C1CCN(C2CCNCC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.4 %

Procedure:
tert-butyl 4-(2-oxooctahydro-1H-benzimidazol-1-yl)-1,4′-bipiperidine-1′-carboxylate (1.2 g, 2.95 mmol) was dissolved in a mixture of 4M HCl in dioxane (15 mL) and water (5 mL). The mixture was stirred at rt for 1 hour then concentrated in vacuo to provide the title compound as a white solid (0.7 g). 1H NMR (400 MHz, CHLOROFORM-D) free base: δ ppm 1.22-1.53 (m, 5H), 1.49-1.69 (m, 1H), 1.69-1.88 (m, 7H), 1.94 (m, 1H), 2.04-2.52 (m, 6H), 2.60 (t, J=11.33 Hz, 2H), 2.82-3.09 (m, 4H), 3.17 (d, J=12.89 Hz, 2H), 3.59-3.88 (m, 1H), 4.47-4.68 (m, 1H). MS (M+1): 307.3.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([OH:8])=O)(=[O:3])[CH3:2].Cl.[NH2:10][CH2:11][C:12]1[C:17]([Cl:18])=[N:16][CH:15]=[CH:14][N:13]=1>>[C:1]([O:4][CH2:5][C:6]([NH:10][CH2:11][C:12]1[C:17]([Cl:18])=[N:16][CH:15]=[CH:14][N:13]=1)=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(=O)O
Reactant: NCc1nccnc1Cl
Agent: Cl
Product: CC(=O)OCC(=O)NCc1nccnc1Cl
Yield: 90.3 %

Procedure:
According to the procedure described in example 13 step 13a acetoxyacetic acid (0.667 g) and 2-aminomethyl-3-chloropyrazine hydrochloride (content 77%; 0.81 g) gave 2-((3-chloropyrazin-2-yl)methylamino)-2-oxoethyl acetate (0.99 g) after purification by column chromatography (silica gel; gradient of dichloromethane to dichloromethane/ethyl acetate 1/1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C@H:4]([NH:10][C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([F:18])=[C:13]([CH3:19])[CH:12]=1)[CH2:5][CH2:6][CH2:7][CH2:8][NH2:9].[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][C:23]=1[CH3:30].C(N(CC)CC)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[F:18][C:14]1[C:15]([CH3:17])=[CH:16][C:11]([NH:10][C@H:4]([CH2:5][CH2:6][CH2:7][CH2:8][NH:9][CH2:26][C:25]2[CH:28]=[CH:29][C:22]([F:21])=[C:23]([CH3:30])[CH:24]=2)[C:3]([O:2][CH3:1])=[O:20])=[CH:12][C:13]=1[CH3:19]
Reactant: Cc1cc(C=O)ccc1F
Reactant: COC(=O)[C@@H](CCCCN)Nc1cc(C)c(F)c(C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](CCCCNCc1ccc(F)c(C)c1)Nc1cc(C)c(F)c(C)c1
Temperature: 25 °C
Reaction time: 63 h
Yield: 87.5 %

Procedure:
To a solution of (R)-6-amino-2-(4-fluoro-3,5-dimethyl-phenylamino)-hexanoic acid methyl ester (0.400 g, 1.009 mmol), 4-fluoro-3-methylbenzaldehyde (0.139 g, 1.009 mmol), and triethylamine (0.204 g, 2.018 mmol) in 10 mL of dichloroethane, was added NaBH(OAc)3 (0.299 g, 1.413 mmol). After stirring at room temperature for 63 h, the reaction was quenched with 30 mL of saturated NaHCO3 solution and the reaction mixture was extracted with ethyl acetate (30 mL×3). The combined organic extracts dried (Na2SO4), filtered, and concentrated under reduced pressure. The product was isolated by Flash column chromatography (silica gel column) eluting with 0-10% methanol/dichloromethane to give the title compound as brown oil (0.357 g, 87% yield). GC-MS: tR=7.5 min; m/z 404 (M+).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[C:12]([O:16][C:17]([NH:19][C@@:20]([CH3:32])([CH2:23][O:24][C:25](=[O:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:21][OH:22])=[O:18])([CH3:15])([CH3:14])[CH3:13].CCOCC>C(Cl)Cl>[C:12]([O:16][C:17]([NH:19][C@@:20]([CH3:32])([CH2:23][O:24][C:25](=[O:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:21]=[O:22])=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CCCCCC(=O)OC[C@@](C)(CO)NC(=O)OC(C)(C)C
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCCC(=O)OC[C@@](C)(C=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.6 %

Procedure:
Molecular sieve 4A (220 g) and pyridinium chlorochromate (43.6 g, 0.202 mol) were added to a solution of (2R)-2-t-butoxycarbonylamino-3-n-hexanoyloxy-2-methyl-1-propanol (30.7 g, 0.101 mol) obtained in Reference example 1 (1a) in methylene chloride (600 mL) under ice-cooling and the mixture was stirred at room temperature for 2 hours. Ether was added to the reaction mixture, the mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate, 10:1-5:1) to obtain the title compound (28.8 g, yield: 95%).
Reaction SMILES: [S:1]1[C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[CH:3]=[CH:2]1.Br[CH2:11][CH2:12][CH2:13][CH2:14][C:15]12[CH2:26][CH2:25][CH2:24][C:22]3[C:23]1=[C:18]([CH:19]=[CH:20][CH:21]=3)[NH:17][C:16]2=[O:27]>>[S:1]1[C:9]2[CH2:8][CH2:7][N:6]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]34[CH2:26][CH2:25][CH2:24][C:22]5[C:23]3=[C:18]([CH:19]=[CH:20][CH:21]=5)[NH:17][C:16]4=[O:27])[CH2:5][C:4]=2[CH:3]=[CH:2]1
Reactant: c1cc2c(s1)CCNC2
Reactant: O=C1Nc2cccc3c2C1(CCCCBr)CCC3
Product: O=C1Nc2cccc3c2C1(CCCCN1CCc2sccc2C1)CCC3

Procedure:
This was synthesized by the same method of Synthesis Example 14c, except that 4,5,6,7-tetrahydro-thieno[3,2-c]pyridine was used instead of 1,2,3,4-tetrahydroisoquinoline and 2a-(4-bromobutyl)-2a,3,4,5-tetrahydro-1H-benz[cd]indol-2-one was used instead of 2a-(4-bromobutyl)-1-methyl-2a,3,4,5-tetrahydro-1H-benz[cd]indol-2-one (yield, 84%).