Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][O:6][C:7]1[C:8]([C:15]([NH:17][C@H:18]2[CH2:26][O:25][C:24](=[O:27])[C@H:23]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C@@H:22]([OH:35])[C@H:21]([CH3:36])[O:20][C:19]2=[O:37])=[O:16])=[N:9][CH:10]=[CH:11][C:12]=1[O:13][CH3:14])(=[O:3])[CH3:2].[CH:38]1[CH:43]=CC(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)=C[CH:39]=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:4][CH2:5][O:6][C:7]1[C:8]([C:15]([NH:17][C@H:18]2[CH2:26][O:25][C:24](=[O:27])[C@H:23]([CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C@@H:22]([O:35][CH2:43][CH:38]=[CH2:39])[C@H:21]([CH3:36])[O:20][C:19]2=[O:37])=[O:16])=[N:9][CH:10]=[CH:11][C:12]=1[O:13][CH3:14])(=[O:3])[CH3:2]
Reactant: c1ccc(P(CCCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Reactant: COc1ccnc(C(=O)N[C@H]2COC(=O)[C@H](Cc3ccccc3)[C@@H](O)[C@H](C)OC2=O)c1OCOC(C)=O
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: C=CCO[C@H]1[C@H](C)OC(=O)[C@@H](NC(=O)c2nccc(OC)c2OCOC(C)=O)COC(=O)[C@@H]1Cc1ccccc1
Yield: 68 %

Procedure:
Compound 8 was prepared in 68% yield using Compound 3 (150 mg, 0.29 mmol) with dppb (12 mg, 0.03 mmol), Pd2dba3 (5.30 mg, 0.006 mmol) and ethyl methallylcarbonate (41 mg, 0.31 mmol). Purification by flash column chromatography on silica gel eluting with a mixture of hexane-acetone (1:1) gave a white foam: MS: (M+1)+=557, (M−1)+=555. Spectral data were consistent with the assigned structure.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[CH2:5][N:6]1[CH:10]([C:11]2[O:12][C:13]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:15]=2)[CH2:9][CH2:8][C:7]1=[O:28].Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[CH2:37]([O:36][C:34]([CH2:33][O:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[CH2:5][N:6]1[CH:10]([C:11]2[O:12][C:13]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:15]=2)[CH2:9][CH2:8][C:7]1=[O:28])=[O:35])[CH3:38]
Reactant: O=C1CCC(c2nc(-c3ccccc3)c(-c3ccccc3)o2)N1Cc1cccc(O)c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)COc1cccc(CN2C(=O)CCC2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Yield: 101.7 %

Procedure:
A solution of 1-(3-hydroxybenzyl)-5-(4,5-diphenyloxazol-2-yl)pyrrolidin-2-one (0.13 g), ethyl bromoacetate (0.21 g), potassium carbonate (99 mg) and potassium iodide (catalytic amount) in acetonitrile (10 ml) was refluxed for 9 hours. The reaction mixture was partitioned between ethyl acetate and brine. The organic layer was washed with brine. The dried solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel to give 1-(3-ethoxycarbonylmethoxybenzyl)-5-(4,5-diphenyloxazol-2-yl)pyrrolidin-2-one (0.16 g).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15].C([O:18][C:19](=[O:49])[CH2:20][CH2:21][C:22]1[CH:27]=[C:26]([C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH2:36][C:37]([O:39]CC)=[O:38])=[O:29])[CH:25]=[CH:24][C:23]=1[O:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47]Br)C>CCCCCC.C(OCC)(=O)C>[C:37]([CH2:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[C:28]([C:26]1[CH:25]=[CH:24][C:23]([O:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][O:1][C:2]2[CH:12]=[CH:11][C:5]3[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=3[C:3]=2[CH2:13][CH2:14][CH3:15])=[C:22]([CH2:21][CH2:20][C:19]([OH:49])=[O:18])[CH:27]=1)=[O:29])([OH:39])=[O:38]
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Reactant: CCOC(=O)CCc1cc(C(=O)c2ccccc2CC(=O)OCC)ccc1OCCCCCBr
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCc1c(OCCCCCOc2ccc(C(=O)c3ccccc3CC(=O)O)cc2CCC(=O)O)ccc2c1OCCC2=O
Yield: 23.1 %

Procedure:
Starting with 0.153 g (0.74 mmol) of 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one, and 0.394 g (0.74 mmol) of 2-[(5-bromopentyl)oxy]-5-[[2-(2-ethoxy-2-oxoethyl)phenyl]carbonyl]benzenepropanoic acid ethyl ester, the title compound (0.103 g, 26.7% overall yield) was obtained as a white solid, mp 105°-108.5° C. (recrystallized from hexane-ethyl acetate), using the procedure of example 22.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[CH:7]=[CH:6]2)#[N:2].[Br:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](O)=O>>[Br:21][C:22]1[CH:23]=[C:24]([C:25]2[O:15][N:14]=[C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:17]([F:19])([F:20])[F:18])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[CH:7]3)[N:16]=2)[CH:28]=[CH:29][CH:30]=1
Reactant: O=C(O)c1cccc(Br)c1
Reactant: N#Cc1ccc2c(ccn2CC(=N)NO)c1C(F)(F)F
Product: N#Cc1ccc2c(ccn2Cc2noc(-c3cccc(Br)c3)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 72 from 2-[5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide and 3-bromobenzoic acid: MS (ESI): m/z 449 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([O:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)[CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18]([O:20]CC)=[O:19])=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCCC1.C(O)C.[OH-].[Na+]>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([O:23][C:24]2[CH:25]=[CH:26][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][CH:29]=2)[CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18]([OH:20])=[O:19])=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(OCc3ccccc3)c2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(Oc2cc(OCc3ccccc3)c3[nH]c(C(=O)O)cc3c2)cc1
Temperature: 50 °C
Reaction time: 0.75 h
Yield: 89.6 %

Procedure:
Ethyl 7-(benzyloxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylate (1.9 g) was dissolved in a mixed solvent of tetrahydrofuran (10 mL)-ethanol (10 mL), 1M aqueous sodium hydroxide solution (10 mL) was added, and the mixture was stirred at 50° C. for 45 min. The reaction solution was allowed to cool to room temperature, and concentrated under reduced pressure. Water was added to the residue, and the mixture was neutralized with 1M hydrochloric acid. The obtained crystals were collected by filtration, and washed successively with water and diethyl ether to give the title compound (1.6 g, yield 89%) as a pale-orange solid. The pale-orange solid was recrystallized from ethanol-hexane to give pale-orange crystals. melting point 232-233° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:10]1[C:11]([Cl:18])=[N:12][C:13]([S:16][CH3:17])=[N:14][CH:15]=1)[OH:9]>C1(C)C=CC=CC=1.[O-2].[Mn+4].[O-2]>[Cl:18][C:11]1[C:10]([C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[O:9])=[CH:15][N:14]=[C:13]([S:16][CH3:17])[N:12]=1
Reactant: CSc1ncc(C(O)c2ccccc2Cl)c(Cl)n1
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: CSc1ncc(C(=O)c2ccccc2Cl)c(Cl)n1
Reaction time: 2.5 h

Procedure:
To a solution of (2-chlorophenyl)-(4-chloro-2-methylsulfanylpyrimidin-5-yl)methanol (10.8 g, 35.75 mmol) in toluene (150 mL) was added manganese (IV) oxide (Aldrich) (31.2 g, 10 eq). The resulting mixture was heated to reflux with stirring for a total of 2.5 hours. The reaction was then filtered hot through a 3.5 cm pad of Celite. The pad of Celite was rinsed with hot ethyl acetate, and the filtrate was concentrated to give a crude oil. Purification by Flash Column Chromatography on Silica Gel eluting with a gradient of 2%-10% ethyl acetate in hexanes gave the title compound as a yellow viscous semi-solid (5.3 g, (M+H)+=299.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[C:5]([C:7]1[C:16]2[C:11](=[C:12]([CH3:21])[CH:13]=[C:14]([N:18]=[C:19]=[S:20])[C:15]=2[CH3:17])[N:10]=[CH:9][CH:8]=1)#[N:6]>C1(C)C=CC=CC=1>[NH2:3][CH2:2][CH2:1][NH:4][C:19](=[S:20])[NH:18][C:14]1[C:15]([CH3:17])=[C:16]2[C:11](=[C:12]([CH3:21])[CH:13]=1)[N:10]=[CH:9][CH:8]=[C:7]2[C:5]#[N:6]
Reactant: NCCN
Reactant: Cc1cc(N=C=S)c(C)c2c(C#N)ccnc12
Solvent: Cc1ccccc1
Product: Cc1cc(NC(=S)NCCN)c(C)c2c(C#N)ccnc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethylenediamine (2.93 mL) in toluene (30 mL) is slowly added a solution of 4-cyano-5,8-dimethyl-6-isothiocyanatoquinoline (2.1 g, 8.78 mmol) in toluene (100 mL). The reaction mixture is stirred at room temperature overnight. The solid which forms is filtered, washed well with toluene, and dried to afford 6-[N'-(2-aminoethyl)thioureido]-4-cyano-5,8-dimethylquinoline.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([F:19])[CH:12]=2)=[O:9])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[NH3:21]>O1CCOCC1>[NH2:21][C:6]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([F:19])[CH:12]=2)=[O:9])=[C:2]([Cl:1])[N:3]=[CH:4][N:5]=1
Reactant: N
Reactant: COc1ccc(NC(=O)c2c(Cl)ncnc2Cl)cc1F
Solvent: C1COCCO1
Product: COc1ccc(NC(=O)c2c(N)ncnc2Cl)cc1F
Temperature: 0 °C
Reaction time: 8 h

Procedure:
4,6-Dichloro-N-(3-fluoro-4-methoxyphenyl)pyrimidine-5-carboxamide (720 mg, 2.28 mmol) was dissolved in dioxane (10 ml) and cooled in an ice bath. Ammonia solution (1.63 mL, 7N in MeOH) was added dropwise and the mixture was stirred at 0° C. for 6 h and overnight at room temperature. After evaporation of the solvent under reduced pressure, the residue (675 mg, 100%) was used in the next synthetic step without further purification.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([C:9]([OH:13])(O)[C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([NH:24][C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]>OS(O)(=O)=O>[OH:13][C:9]1([C:19]2[CH:20]=[C:21]([O:22][CH3:23])[C:16]([O:15][CH3:14])=[CH:17][C:18]=2[NH:24][C:25](=[O:29])[CH:26]([CH3:27])[CH3:28])[C:10](=[O:11])[C:4]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[C:7]1=[O:8]
Reactant: COc1ccc(NC(=O)C(C)C)cc1OC
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Agent: O=S(=O)(O)O
Product: COc1cc(NC(=O)C(C)C)c(C2(O)C(=O)c3ccccc3C2=O)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.8 %

Procedure:
Ninhydrin (1.00 g, 5.6 mmol) was dissolved in conc.H2SO4 (10 ml). This solution was added with N-(3,4-dimethoxyphenyl)isobutyramide (1.25 g, 5.62 mmol) at 0° C. and stirred for 30 min under room temperature. Ice water was added with the reaction mixture, and then washed with ice water and ethylacetate. After drying and filtrating, the ethylacetate layer was purified using column chromatography (ethylacetate:hexane=1:4) to afford the title compound (1.37 g, 63%).
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6]/[C:7](=[CH:9]/[CH2:10][OH:11])/[CH3:8])[CH3:3].[H][H]>CO>[CH3:1][C:2](=[CH:4][CH2:5][CH2:6][CH:7]([CH2:9][CH2:10][OH:11])[CH3:8])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)=CCC/C(C)=C/CO
Solvent: CO
Product: CC(C)=CCCC(C)CCO
Reaction time: 5 h
Yield: 97775.1 %

Procedure:
Into a 200-ml stainless steel-made autoclave were placed 16.1 g (0.104 mmole) of geraniol, 17.7 mg (0.0208 mmole) of Ru(OAc)2 ((-)-OcH-BINAP) as obtained in Example 7, and 18 ml of methanol. This mixture was stirred at a hydrogen pressure of 100 kg/cm2 and a temperature of 25° C. for 5 hours. After completion of the reaction, the solvent was removed by evaporation, and the residual crude product was subjected to vacuum distillation using a Claisen distillation flask, thereby obtaining 15.89 g of citronellol. The percent yield was 98%, and the optical purity of the citronellol was 98.3% ee.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].[I:12]Cl>C(Cl)(Cl)Cl>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([I:12])=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:9])=[O:10]
Reactant: Nc1ccccc1S(N)(=O)=O
Reactant: ClI
Solvent: ClC(Cl)Cl
Product: Nc1ccc(I)cc1S(N)(=O)=O
Temperature: 25 °C
Yield: 54.1 %

Procedure:
A solution of 2-aminobenzenesulfonamide (25.0 g, 145.2 mmol) in chloroform (275 mL) at 0° C. was treated with a solution of iodine monochloride (24.75 g, 152.4 mmol) in chloroform (50 mL) dropwise over 1 h. After addition, the solution was allowed to slowly warm to 25° C. over 18 h. The precipitate was collected by filtration and washed with chloroform (3×), saturated sodium bicarbonate solution (1×), and water (4×). After air drying, these procedures afforded the title compound (23.4 g, 55%) as a red solid. 1H NMR (300 MHz, DMSO-d6): δ 6.65 (d, J=8.46 Hz, 1 H) 7.35 (s, 2 H) 7.48 (dd, J=8.82, 2.21 Hz, 1 H) 7.76 (d, J=2.21 Hz, 1 H).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[CH2:25]([Mg]Br)[CH3:26]>>[F:24][C:2]([F:1])([F:23])[O:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:22]=[CH:21][C:18]([CH:19]([OH:20])[CH2:25][CH3:26])=[CH:17][CH:16]=3)=[N:11]2)=[CH:8][CH:9]=1
Reactant: O=Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: CC[Mg]Br
Product: CCC(O)c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1

Procedure:
The title compound was prepared as described in Example 24 from 4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzaldehyde and ethylmagnesium bromide and isolated as a yellow oil (5.00 g, 100%): 1H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 8.20-8.12 (m, 2H), 7.85-7.76 (m, 2H), 7.50-7.44 (m, 2H), 7.39 (dq, J=8.0, 1.0 Hz, 2H), 4.68 (t, J=6.5 Hz, 1H), 1.93-1.75 (m, 2H), 1.59 (s, 1H), 0.95 (t, J=7.4 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −58.03; ESIMS m/z 364 ([M+H]+).
Reaction SMILES: [C:1]1([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:49])[O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]([C:20](=[O:48])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]2[S:28][C:29]([C:33](=[O:47])[N:34]([CH2:36][CH2:37][N:38](C(OC(C)(C)C)=O)[CH3:39])[CH3:35])=[C:30]([CH3:32])[CH:31]=2)[CH3:19])[CH2:12][CH2:11]1.Cl.CO>C1(C)C=CC=CC=1>[C:1]1([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:49])[O:9][CH:10]1[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][N:18]([CH3:19])[C:20](=[O:48])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]2[S:28][C:29]([C:33](=[O:47])[N:34]([CH3:35])[CH2:36][CH2:37][NH:38][CH3:39])=[C:30]([CH3:32])[CH:31]=2)[CH2:14][CH2:15]1
Reactant: Cc1cc(NCCCCCC(=O)N(C)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)sc1C(=O)N(C)CCN(C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CO
Product: CNCCN(C)C(=O)c1sc(NCCCCCC(=O)N(C)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.7 %

Procedure:
The compound (153 mg, 0.201 mmol) obtained in Example 89d was dissolved in 2 N hydrochloric acid-methanol (2.01 mL, 4.01 mmol), and the mixture was stirred at room temperature for 2 hours. Toluene was added to the reaction mixture, the solvent was evaporated under reduced pressure, the resulting residue was dissolved in ethyl acetate, and the mixture was adjusted to pH 10 with a 1 N aqueous sodium hydroxide solution. The mixture was extracted with ethyl acetate (×2) and dried with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=100:0→methylene chloride:methanol=10:1, v/v) to give the title compound (122 mg; yield, 92%) as a white solid.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]=[C:16]([NH:50]C(OC(C)(C)C)=O)[NH:17][C@@H:18]([CH2:22][S:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][C:34]([C:37]3[C:42]4[O:43][C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=5[C:41]=4[CH:40]=[CH:39][CH:38]=3)=[CH:33][CH:32]=2)=[CH:27][CH:26]=1)[C:19]([OH:21])=[O:20])=O)(C)(C)C>ClCCl>[CH:40]1[C:41]2[C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=3[O:43][C:42]=2[C:37]([C:34]2[CH:33]=[CH:32][C:31]([C:28]3[CH:29]=[CH:30][C:25]([CH2:24][S:23][CH2:22][C@H:18]([NH:17][C:16]([NH2:50])=[NH:15])[C:19]([OH:21])=[O:20])=[CH:26][CH:27]=3)=[CH:36][CH:35]=2)=[CH:38][CH:39]=1
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N[C@@H](CSCc1ccc(-c2ccc(-c3cccc4c3oc3ccccc34)cc2)cc1)C(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)N[C@@H](CSCc1ccc(-c2ccc(-c3cccc4c3oc3ccccc34)cc2)cc1)C(=O)O
Reaction time: 4 h
Yield: 98.1 %

Procedure:
Trifluoroacetic acid (2 mL) was added to a stirred solution of (2R)-2-[2,3-bis-(tert-butoxycarbonyl)guanidino]-3-(4′-dibenzofuran-4-yl-biphenyl-4-ylmethylsulfanyl)-propionic acid (250 mg, 0.36 mmol) in anhydrous dichloromethane (10 mL). The reaction was stirred for 4 hours (HPLC control) and then concentrated in vacuo. The resultant brown oil was reconstituted and concentrated from methanol (3×10 mL) and then from dichloromethane (2×10 mL) to give the title compound as an off-white solid (175 mg, 99%): Rf=0.20 (10% methanol in dichloromethane). 1H NMR (DMSO-d6, 300 MHz): δ 8.19 (1H, d, J=8 Hz, Ar—H), 8.13 (1H, d, J=9 Hz, Ar—H), 8.02 (2H, d, J=9 Hz, Ar—H), 7.84 (3H, m, Ar—H), 7.74 (4H, m, 2×Ar—H, 2×NH), 7.53 (3H, m, Ar—H), 7.42 (3H, m, Ar—H), 7.26 (1H, d, J=9 Hz, NH), 7.10 (1H, br s, NH), 4.58 (1H, m, CHN), 3.86 (2H, s, PhCH2S), 2.92 (1H, dd, J=15, 5 Hz, CHHCHN), 2.75 (1H, dd, J=15, 7 Hz, CHHCHN); ESI-LCMS e/z calcd for C29H25N3O3S 495.600, found 496 (M+H)+.
Reaction SMILES: [F:1][C:2]1([F:25])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:24])([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[C:8]([O:10][CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[O:9])[CH2:3]1.[CH:26](=O)[CH3:27].C([BH3-])#N.[Na+]>CO.C(Cl)(Cl)Cl>[F:25][C:2]1([F:1])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:24])([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[C:8]([O:10][CH:11]2[CH2:12][CH2:13][N:14]([CH2:26][CH3:27])[CH2:15][CH2:16]2)=[O:9])[CH2:3]1
Reactant: O=C(OC1CCNCC1)[C@](O)(c1ccc(Cl)cc1)[C@@H]1CCC(F)(F)C1
Reactant: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCN1CCC(OC(=O)[C@](O)(c2ccc(Cl)cc2)[C@@H]2CCC(F)(F)C2)CC1
Reaction time: 2 h

Procedure:
To a solution of 25 mg of piperidin-4-yl (2R)-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-chlorophenyl)ethanoate in 1 ml of methanol, 50 mg of acetaldehyde and 10 mg of sodium cyanoborohydride were added at room temperature, followed by two hours' stirring at the same temperature. The reaction liquid was diluted with chloroform, washed successively with saturated sodium hydrogencarbonate solution and with saturated brine, and dried over anhydrous sodium sulfate. Distilling the solvent off under reduced pressure, the residue was purified on preparative thin layer chromatography (Kieselgel™60F254, Art5744 (Merck), chloroform/methanol=10/1) to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:33]([Cl:34])=[CH:32][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][C:18]([N:20]3[CH2:29][CH2:28][C:23]4(OCC[O:24]4)[CH2:22][CH2:21]3)=[O:19])[CH2:11][C@H:10]2[O:30][CH3:31])=[O:7])=[C:4]([O:35][CH3:36])[CH:3]=1.S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O>[NH2:1][C:2]1[C:33]([Cl:34])=[CH:32][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][C:18](=[O:19])[N:20]3[CH2:21][CH2:22][C:23](=[O:24])[CH2:28][CH2:29]3)[CH2:11][C@H:10]2[O:30][CH3:31])=[O:7])=[C:4]([O:35][CH3:36])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCCC(=O)N2CCC3(CC2)OCCO3)C[C@H]1OC
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCCC(=O)N2CCC(=O)CC2)C[C@H]1OC
Reaction time: 2 h
Yield: 51.9 %

Procedure:
A mixture of 2.1 parts of cis-4-amino-5-chloro-N-[1-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-4-oxobutyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide, 0.74 parts of sulfuric acid and 40 parts of water was stirred for 2 hours at reflux temperature. After cooling, the reaction mixture was made alkaline with sodium carbonate while cooling. The product was extracted with trichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried in vacuo at 60° C., yielding 1 part (51.9%) of cis-4-amino-5-chloro-2-methoxy-N-[3-methoxy-1-[4-oxo-4-(4-oxo-1-piperidinyl)butyl]-4-piperidinyl]benzamide; mp. 156.9° C. (compound 109).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]2[C:18]#[N:19])=[O:7])=[CH:4][CH:3]=1.C(=O)(O)[O-:23].[Na+].OO>CC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]2[C:18]([NH2:19])=[O:23])=[O:7])=[CH:20][CH:21]=1
Reactant: O=C([O-])O
Reactant: N#CC1C=Cc2ccccc2N1C(=O)c1ccc(F)cc1
Agent: OO
Agent: [Na+]
Solvent: CC(C)=O
Product: NC(=O)C1C=Cc2ccccc2N1C(=O)c1ccc(F)cc1
Reaction time: 0.17 h

Procedure:
1-(4-Fluorobenzoyl)-1,2-dihydro-quinoline-2-carbonitrile (24.0 g) was dissolved in acetone (500 mL). Solid sodium bicarbonate (15 g) was added. The mixture was stirred for 10 minutes. 30% Hydrogen peroxide solution (300 mL of a 30% solution) was added drop-wise. Stirring was continued for 30 minutes. The mixture was then warmed slowly until a solution formed, then stirred at ambient temperature for 2 hours. The acetone was evaporated under vacuum. The aqueous residue was diluted with water (100 mL), and acidified with 1N HCl. The mixture was extracted with ethyl acetate (500 mL). The organic extract was washed with water (300 mL), dried over anhydrous sodium sulfate, then concentrated. Hexane was added to the precipitation point. The solid was collected and dried to give the title compound as a white solid, m. p. 149-151° C.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:17])[N:4]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])[C:5](=[O:8])[NH:6][N:7]=1.C(N(CC)CC)C.[CH:25]([CH:27]=[CH2:28])=[O:26]>CN(C)C=O>[Br:1][C:2]1[C:3](=[O:17])[N:4]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])[C:5](=[O:8])[N:6]([CH2:28][CH2:27][CH:25]=[O:26])[N:7]=1
Reactant: O=C(c1ccccc1)n1c(=O)[nH]nc(Br)c1=O
Reactant: C=CC=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=CCCn1nc(Br)c(=O)n(C(=O)c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 103.7 %

Procedure:
To a stirring solution of 6-bromo-4-(phenylcarbonyl)-1,2,4-triazine-3,5(2H,4H)-dione (1.46 g, 4.93 mmol) in dry N,N-Dimethylformamide (DMF) (64.9 ml), TRIETHYLAMINE (0.825 ml, 5.92 mmol) was added and the mixture was stirred at room temperature for 15 minutes. Acrolein (0.366 ml, 4.93 mmol) was then added and the mixture was left stirring at room temperature for 3 hours. It was then quenched with NH4Cl saturated solution and diluted with AcOEt. Phases were separated, organic phase was washed with cold water, dried over sodium sulphate, filtered and concentrated under reduced pressure affording 3-[6-bromo-3,5-dioxo-4-(phenylcarbonyl)-4,5-dihydro-1,2,4-triazin-2(3H)-yl]propanal (1.8 g, 5.11 mmol). The compound was used for next step without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[C:19]2[C:14](=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:16]=[CH:17][CH:18]=2)[NH:13][N:12]=1.[H-].[Na+].I[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[C:19]2[C:14](=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:16]=[CH:17][CH:18]=2)[N:13]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[N:12]=1
Reactant: COc1ccc(-c2n[nH]c3c(C(F)(F)F)cccc23)c(OC)c1
Reactant: CCCCCI
Agent: [H-]
Agent: [Na+]
Product: CCCCCn1nc(-c2ccc(OC)cc2OC)c2cccc(C(F)(F)F)c21
Yield: 35.9 %

Procedure:
Prepared according to Method D step B from 3-(2,4-dimethoxyphenyl)-7-(trifluoromethyl)-1H-indazole (0.150 g, 0.49 mmol), sodium hydride (60% in oil, 0.025 g, 1.04 mmol) and 1-iodopentane (0.07 mL, 0.7 mmol) to give the title compound (0.069 g) as a white solid.