Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][N:9]([CH:12]([C:14]3[CH:15]=[N:16][C:17]([N:21]4[CH:25]=[CH:24][CH:23]=[N:22]4)=[C:18]([CH3:20])[CH:19]=3)[CH3:13])[C:10](=[O:11])[C:6]=2[CH:5]=[CH:4][N:3]=1.[CH:26]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:27]>>[CH3:20][C:18]1[CH:19]=[C:14]([CH:12]([N:9]2[C:10](=[O:11])[C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:26]([O:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:27])[C:7]=3[CH2:8]2)[CH3:13])[CH:15]=[N:16][C:17]=1[N:21]1[CH:25]=[CH:24][CH:23]=[N:22]1
Reactant: O=COc1ccccc1
Reactant: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)cnc1-n1cccn1
Product: Cc1cc(C(C)N2Cc3c(ccnc3C(=O)Oc3ccccc3)C2=O)cnc1-n1cccn1
Yield: 56 %

Procedure:
The title compound is prepared in 56% yield (154 mg, brown solid) from 4-chloro-2-(1-(5-methyl-6-(1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (220 mg, 0.62 mmol, Intermediate-85, single enantiomer) and phenyl formate (150 mg, 1.2 mmol) in a similar manner to Intermediate-91.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]([CH:14]3[CH2:19][CH2:18][CH:17]([CH2:20][NH2:21])[CH2:16][CH2:15]3)[NH:12][CH:13]=2)[CH:6]=[CH:7][CH:8]=1.[C:24](Cl)(=[O:26])[CH3:25]>C(Cl)Cl.C1COCC1>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]([CH:14]3[CH2:15][CH2:16][CH:17]([CH2:20][NH:21][C:24](=[O:26])[CH3:25])[CH2:18][CH2:19]3)[NH:12][CH:13]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CC(=O)Cl
Reactant: NCC1CCC(c2nc(-c3cccc(C(F)(F)F)c3)c[nH]2)CC1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)NCC1CCC(c2nc(-c3cccc(C(F)(F)F)c3)c[nH]2)CC1
Reaction time: 2 h

Procedure:
C-{4-[4-(3-trifluoromethyl-phenyl)-1H-imidazole-2-yl]-cyclohexyl}-methylamine (326 mg, 1.0 mmol, from Example 1C) and TEA (102 mg, 1.0 mmol) were dissolved in CH2Cl2/THF (1:1) and brought to 0° C. with an ice bath. Acetyl chloride (79 mg, 1.0 mmol) was added to the reaction mixture slowly and the ice bath was removed. After 2 hours, the solution was diluted with CH2Cl2, added to a separatory funnel and washed with 10% NaOH (3×). The solution was dried (Na2SO4), concentrated under reduced pressure, and the residue purified using flash chromatography (5%→10% MeOH/CH2Cl2) to give (N-{4-[4-(3-Trifluoromethyl-phenyl)-1H-imidazol-2-yl]-cyclohexylmethyl}-acetamide.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:24][N:25](C)[C:26](=O)OC(C)(C)C)=[CH:4][N:5]([S:14]([C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.C(OCC)(=O)C.Cl>C(OCC)(=O)C.CC(O)C>[F:1][C:2]1[C:3]([CH2:24][NH:25][CH3:26])=[CH:4][N:5]([S:14]([C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: Cc1cccnc1S(=O)(=O)n1cc(CN(C)C(=O)OC(C)(C)C)c(F)c1-c1cccnc1F
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CNCc1cn(S(=O)(=O)c2ncccc2C)c(-c2cccnc2F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.2 %

Procedure:
To a solution of tert-butyl ({4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(3-methylpyridin-2-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (107 mg) in ethyl acetate (2 mL) and 2-propanol (1 mL) were added 4 mol/L hydrogen chloride-ethyl acetate solution (3 mL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. Combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent:hexane-ethyl acetate=4:1→1:1) to give 1-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(3-methylpyridin-2-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamine as a pale-yellow oil (yield 45 mg, 54%). A solution of the obtained 1-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(3-methylpyridin-2-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamine in ethyl acetate (2 mL) was added dropwise to a solution of fumaric acid (14 mg) in ethanol (2 mL) and the mixture was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-ethanol to give the title compound as a white solid (yield 51 mg, 88%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[N:5]=[C:4]([C:15]2[O:16][C:17]([CH2:20][OH:21])=[CH:18][CH:19]=2)[CH:3]=1.Cl.[N:23](OCC)=[O:24].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[NH2:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[N:5]=[C:4]([C:15]2[O:16][C:17]([CH2:20][OH:21])=[CH:18][CH:19]=2)[C:3]=1[N:23]=[O:24]
Reactant: Nc1cc(-c2ccc(CO)o2)nn1Cc1ccccc1F
Reactant: CCON=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Nc1c(N=O)c(-c2ccc(CO)o2)nn1Cc1ccccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10 g (34.8 mmol) of 5-amino-1-(2-fluorobenzyl)-3-(5-hydroxymethyl-2-furyl)-pyrazole are initially introduced in a mixture of 66 ml of ethanol and 26.7 ml of 5% strength aqueous hydrochloric acid, treated in the course of 5 minutes with 26.4 ml of a 15% strength ethanolic solution of ethyl nitrite and stirred at room temperature for 1 h. The deep violet reaction solution is added to aqueous potassium carbonate solution and extracted with ethyl acetate. After evaporating the organic phase in vacuo, 8 g of the residue are obtained, which can be immediately reacted further. (Rf=0.17, T1E1, SiO2).
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[N:8]=2)[CH:6]=1.C([Mg]Cl)(C)C.[Li+].[Cl-].[Sn:34](Cl)([CH2:43][CH2:44][CH2:45][CH3:46])([CH2:39][CH2:40][CH2:41][CH3:42])[CH2:35][CH2:36][CH2:37][CH3:38]>C1COCC1>[CH2:43]([Sn:34]([CH2:35][CH2:36][CH2:37][CH3:38])([CH2:39][CH2:40][CH2:41][CH3:42])[C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[N:8]=2)[CH:6]=1)[CH2:44][CH2:45][CH3:46]
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)cc(-n3cnc(I)c3)n2)cc1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cn(-c2cc(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)n2)cn1
Temperature: 23 °C
Reaction time: 14 h

Procedure:
To a solution of 2-(4-iodo-imidazol-1-yl)-4-trifluoromethyl-6-(4-trifluoromethylphenyl)-pyridine (example E.23) (4.83 g, 10 mmol) in THF (50 mL) at 0° C. was quickly added added i-PrMgCl.LiCl (1 M in THF, 11 mL, 11 mmol) and the mixture was stirred at 0° C. for 15 min. Then Bu3SnCl (3.25 mL, 12 mmol) was added, the cooling bath was removed and the mixture was stirred at 23° C. for 14 h. Poured into sat. NH4Cl-sol., extracted with EtOAc, washed with brine and dried over Na2SO4. Removal of the solvent in vacuum left a brown oil, which was purified by quick silica gel column chromatography with heptane/EtOAc 4:1 gave a yellow oil (4.42 g, 62%, ca. 90% pure). MS (ISP) 647.3 [(M+H)+].
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5][C:6]=1[C:7](OCC)=[O:8].[CH:17]([NH2:19])=O.CN(C=O)C>C(O)=O>[CH2:15]([O:14][C:12]([C:4]1[NH:3][C:2]2[N:1]=[CH:17][N:19]=[C:7]([OH:8])[C:6]=2[CH:5]=1)=[O:13])[CH3:16]
Reactant: CCOC(=O)c1cc(C(=O)OCC)c(N)[nH]1
Reactant: NC=O
Solvent: O=CO
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(O)ncnc2[nH]1
Temperature: 2.5 °C

Procedure:
With the exclusion of air, 51.5 g (227 mmol) of 2-amino-3,5-bis(ethoxycarbonyl)-1H-pyrrole, 455 ml of formamide, 227 ml of DMF and 113 ml of formic acid are stirred at 140° C. for 27 hours. The resulting yellow suspension is cooled to 0-5° C. Filtering and washing with isopropanol and hexane yield the title compound; 1H-NMR (DMSO-d6): 13-12 (2 HX), 7.99 and 7.11 (2s, 2H), 4.31 (q, J=7, 2H), 1.32 (t, J=7, 3H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([O:8][CH2:9][C:10]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:11]=2[C:12]([O:14]C)=[O:13])[CH2:3]1.[Cl:21][C:22]1[CH:23]=[C:24]([C:28]2[O:29][C:30]([CH3:35])=[C:31]([CH2:33]I)[N:32]=2)[CH:25]=[CH:26][CH:27]=1>>[Cl:21][C:22]1[CH:23]=[C:24]([C:28]2[O:29][C:30]([CH3:35])=[C:31]([CH2:33][O:1][CH:2]3[CH2:7][CH2:6][CH2:5][CH:4]([O:8][CH2:9][C:10]4[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:11]=4[C:12]([OH:14])=[O:13])[CH2:3]3)[N:32]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: Cc1oc(-c2cccc(Cl)c2)nc1CI
Reactant: COC(=O)c1c(C)cccc1COC1CCCC(O)C1
Product: Cc1cccc(COC2CCCC(OCc3nc(-c4cccc(Cl)c4)oc3C)C2)c1C(=O)O

Procedure:
Using methyl 2-(3-hydroxycyclohexyloxymethyl)-6-methylbenzoate and 2-(3-chlorophenyl)-4-iodomethyl-5-methyloxazole as starting materials in the procedure of Example XXXI, gave the product 57 of molecular weight 469.97 (C26H28CINO5), MS(ESI): 470.43 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1F.[Cl:12][C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([Cl:12])[CH:14]=1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: Oc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(Oc2cccc(Cl)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
According to Scheme 3 Step 1, Method A: 2-Chloro-1-fluoro-4-nitrobenzene (1.12 mmol, 0.20 g) was added to a suspension of 3-chlorophenol (1.02 mmol, 0.10 mL), Cs2CO3 (1.25 mmol, 407 mg) in DMF/ACN (40:60, 3.6 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with water. The aqueous phase was extracted with AcOEt. The organic phase was washed with brine, was dried over MgSO4, was filtered and was concentrated under reduced pressure. The crude product was used without further purification to obtain 2-chloro-1-(3-chlorophenoxy)-4-nitrobenzene (1.02 mmol, 288 mg, 100%) as an orange solid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:9][CH3:10])=[N:7][CH:8]=1.[CH2:11]([O:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH2:21][CH2:22][CH2:23][CH:24]2[C:29]([NH:31][C:32]1[CH:33]=[N:34][C:35]([CH:38]([CH3:40])[CH3:39])=[CH:36][CH:37]=1)=[O:30])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([O:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH2:21][CH2:22][CH2:23][CH:24]2[C:29]([N:31]([C:32]1[CH:33]=[N:34][C:35]([CH:38]([CH3:40])[CH3:39])=[CH:36][CH:37]=1)[CH2:2][C:3]1[CH:8]=[N:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1)=[O:30])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COc1ccc(CCl)cn1
Reactant: CC(C)c1ccc(NC(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Product: COc1ccc(CN(C(=O)C2CCCc3c(OCc4ccccc4)cccc32)c2ccc(C(C)C)nc2)cn1
Yield: 108.5 %

Procedure:
By the reaction and treatment in the same manner as in Example 132 using 5-chloromethyl-2-methoxypyridine (0.63 g) and 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.87 g) as starting materials, 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(6-methoxypyridin-3-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.23 g) was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8](Cl)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(=O)(O)[O-].[Na+].O>O1CCOCC1.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>[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:8]2[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[N:9]=2)=[CH:14][CH:13]=1
Reactant: Nc1ccc(B(O)O)cc1
Reactant: N#Cc1ccc(Cl)nc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1ccc(-c2ccc(N)cc2)nc1Cl
Temperature: 100 °C
Reaction time: 0.08 h

Procedure:
2.89 mmol (500 mg) of 2,6-dichloronicotinonitrile and 3.18 mmol (551 mg, 1.1 eq.) of 4-aminophenylboronic acid are dissolved under an inert atmosphere in 33.3 ml of dioxane. 680 mg (8.09 mmol, 2.8 eq.) of sodium bicarbonate and then 8.3 ml of water are subsequently added. The mixture is stirred for 5 minutes under an inert atmosphere and then 334 mg (0.29 mmol, 0.1 eq.) of tetrakis(triphenylphosphine)palladium are added. The reaction mixture is brought to reflux (100° C.) for 2 hours and is then cooled to ambient temperature. The reaction medium is filtered and then extracted four times with ethyl acetate. The organic phases are combined, washed twice with a saturated aqueous sodium chloride solution, dried with magnesium sulphate, and concentrated. A yellow solid is then obtained. This crude is purified on a column of 90 g of silica, with an eluent gradient of 20% to 50% of ethyl acetate in heptane. The expected product is obtained in the form of a yellow solid (531 mg).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]([OH:9])=[O:8].Cl.[CH3:11]O>O1CCOCC1>[NH2:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]([O:9][CH3:11])=[O:8]
Reactant: CO
Reactant: N[C@H]1CCC[C@H]1C(=O)O
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)[C@@H]1CCC[C@@H]1N

Procedure:
To a solution of (1R,2S)-2-aminocyclopentanecarboxylic acid (0.15 g, 0.9 mmol) in methanol (5 mL) was added 4N HCl in dioxane (1 mL) and the reaction mixture was stirred at reflux overnight. The reaction mixture was concentrated in vacuo to afford an oil which was used directly for the next step.
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([F:15])[CH:9]=2)[C:3]1=[O:16].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C@@H:25]2[CH2:30][CH2:29][NH:28][CH2:27][C@H:26]2[OH:31])=[CH:21][CH:20]=1.C(N(CC)CC)C>C(#N)C.[Cl-].[NH4+]>[F:15][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][C:11]=1[CH3:14])[CH2:7][N:4]1[CH2:5][CH2:6][CH:2]([N:28]2[CH2:29][CH2:30][C@@H:25]([C:22]3[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=3)[C@H:26]([OH:31])[CH2:27]2)[C:3]1=[O:16]
Reactant: COc1ccc([C@@H]2CCNC[C@H]2O)cc1
Reactant: Cc1ccc(CN2CCC(Br)C2=O)cc1F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc([C@@H]2CCN(C3CCN(Cc4ccc(C)c(F)c4)C3=O)C[C@H]2O)cc1
Temperature: 100 °C
Yield: 72.9 %

Procedure:
To a solution of 3-bromo-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one (Intermediate 6, 200 mg, 0.7 mmol) and (±)-rel-(3S,4S)-4-(4-methoxyphenyl)piperidin-3-ol (145 mg, 0.7 mmol, from Example 46, step B) in acetonitrile (15 mL) was added triethylamine (0.1 mL, 0.7 mmol) and the resulting mixture was heated in the microwave at 100° C. for 1 h. The cooled reaction mixture was diluted with a saturated ammonium chloride solution and extracted with ethyl acetate (100 mL). The organic layer was separated, dried over Na2SO4, filtered, and evaporated under reduced pressure to give (±)-rel-1-(3-fluoro-4-methylbenzyl)-3-((3S,4S)-3-hydroxy-4-(4-methoxyphenyl)piperidin-1-yl)pyrrolidin-2-one (280 mg, 0.51 mmol, 73% yield, mixture of 4 diaseteroisomers), which was used directly in the next step. LCMS (Method F) RT 1.99 min m/z 413.2 (M+H+).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[C:17]([C:25]2[NH:29][C:28](=[O:30])[NH:27][N:26]=2)[N:16]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[C:17]([C:25]2[NH:29][C:28](=[O:30])[NH:27][N:26]=2)[N:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CNc1nc(-c2n[nH]c(=O)[nH]2)cc2ccccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1[nH]nc(-c2cc3ccccc3c(NC[C@@H]3CCCN3)n2)[nH]1
Reaction time: 2 h

Procedure:
To crude (S)-tert-butyl-2-(((3-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)isoquinolin-1-yl)amino)methyl)pyrrolidine-1-carboxylate (653 mg) suspended in DCM (3 mL) was added TFA (2 mL). The mixture was stirred for 2 hours and then concentrated. The product was purified by preparative HPLC eluting with a gradient of 5-30% ACN in water (acid mode) to give the title compound.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH2:16])=[CH:4][C:5]([CH3:13])=[C:6]2[C:10]=1[C:9](=[N:11]O)[CH2:8][CH2:7]2.[H][H].[ClH:25]>C(O)(=O)C.C(O)C.[Pt]=O>[ClH:25].[NH2:11][CH:9]1[C:10]2[C:6](=[C:5]([CH3:13])[CH:4]=[C:3]([CH:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:15][CH3:16])[C:2]=2[OH:1])[CH2:7][CH2:8]1
Reactant: [H][H]
Reactant: C=CC(c1ccccc1)c1cc(C)c2c(c1O)C(=NO)CC2
Agent: O=[Pt]
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Product: CCC(c1ccccc1)c1cc(C)c2c(c1O)C(N)CC2

Procedure:
2.93 Grams of 2,3-dihydro-7-hydroxy-4-methyl-6-(1-phenyl-2-propenyl)-1H-inden-1-one oxime and 0.293 g of platinum oxide were suspended in 200 ml of acetic acid, then the suspension was reduced at room temperature under 3 atmospheric hydrogen pressure for 8 hours. After the completion of hydrogenation, the catalyst was removed by filtration, and the filtrate thus obtain was concentrated to dryness under a reduced pressure. The residue thus obtained was dissolved in 100 ml of ethanol and the pH of the solution was adjusted to about pH=1 by adding an ethanol solution saturated with hydrogen chloride gas, then this solution was again concentrated to dryness under a reduced pressure. The residue thus obtained was recrystallized from ethanoldiethyl ether to obtain 0.88 g of 1-amino-2,3-dihydro-7-hydroxy-4-methyl-6-(1-phenylpropyl)-1H-indene hydrochloride. Colorless powdery crystals. Melting point: 187.5°-189.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=O.C1C[O:17][CH2:16][CH2:15]1>C(OCC)C.O.[Zn+2].[Br-].[Br-].[Cl-].[Cl-].[Zn+2]>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=[CH:15][CH:16]=[O:17]
Reactant: C1CCOC1
Reactant: O=Cc1cc(C(F)(F)F)ccc1Cl
Agent: [Br-]
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Solvent: CCOCC
Product: O=CC=Cc1cc(C(F)(F)F)ccc1Cl
Temperature: 10 °C
Reaction time: 8 h

Procedure:
To a solution of 2-chloro-5-trifluoromethylbenzaldehyde (300 mg) in 5 mL THF was added 40 mg of ZnBr2. With stirring, 360 mg of α,α-bis(trimethylsilyl)-t-butylacetaldimine (7) was added, and stirring was continued overnight. The solution was cooled to 10° C., then hydrolyzed by the addition of a solution of ZnCl2 (40 mg) in diethyl ether/water (3 mL each), followed by stirring at room temperature for 1 h. The solids were removed by filtration through Celite and the filtrate extracted with diethyl ether (2×). The combined ether extracts were washed with water and brine, dried over magnesium sulfate, filtered and concentrated to provide the title compound as a light brown oil (220 mg): 1H NMR (CDCl3) δ 6.09 (s, 2H), 6.14 (s, 1H), 6.86-6.98 (m, 4H), 7.43 (d, 1H, J=9.6 Hz), 9.69 (d, 1H, J=4.5 Hz).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:8]([O:10]CC1C=CC=CC=1)=[O:9])[CH2:3][CH2:4][C:5](=O)[OH:6].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:40]1[C:45]([S:46]([OH:49])(=[O:48])=[O:47])=[C:44]([OH:50])[C:43]([NH2:51])=[CH:42][C:41]=1Cl.C1COCC1>C(Cl)Cl>[OH:50][C:44]1[C:45]([S:46]([OH:49])(=[O:48])=[O:47])=[CH:40][CH:41]=[CH:42][C:43]=1[NH:51][C:5](=[O:6])[CH2:4][CH2:3][C@@H:2]([C:8]([OH:10])=[O:9])[NH2:1]
Reactant: O=C(O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reactant: Nc1cc(Cl)cc(S(=O)(=O)O)c1O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: N[C@@H](CCC(=O)Nc1cccc(S(=O)(=O)O)c1O)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
Z-Glu-OBn (371 mg, 1 mmol) was dissolved in methylene chloride (1 mL), and CDI (180 mg, 1.1 mmol) was added thereto and stirred at room temperature for 30 minutes. Then, 2-amino-4-chlorophenol-6-sulfonic acid (223 mg, 1 mmol) and THF (1 mL) were added thereto and stirred overnight at room temperature. After removing a solvent, purification was conducted in accordance with the purification process A. The obtained intermediate was dissolved in a mixed solvent of methanol and water. Pd/C in catalyst quantity was added thereto and stirred under hydrogen atmosphere overnight at room temperature. After filtering out the catalyst and removing a solvent, purification was conducted in accordance with the purification process A to obtain a title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N:15]([CH3:25])[S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)(=[O:18])=[O:17])[CH:14]=1)[NH:11][C:10]([C:26]([OH:28])=O)=[CH:9]2.Cl.[CH3:30][O:31][C:32](=[O:56])[C@@H:33]([CH2:35][S:36][C:37]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[NH2:34].N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(N(CC)CC)C>[CH3:30][O:31][C:32](=[O:56])[C@@H:33]([CH2:35][S:36][C:37]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[NH:34][C:26]([C:10]1[NH:11][C:12]2[C:8]([CH:9]=1)=[CH:7][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:14][C:13]=2[N:15]([CH3:25])[S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)(=[O:18])=[O:17])=[O:28]
Reactant: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C(=O)O)cc2c1
Reactant: COC(=O)[C@H](N)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C(=O)N[C@H](CSC(c3ccccc3)(c3ccccc3)c3ccccc3)C(=O)OC)cc2c1
Temperature: 25 °C
Reaction time: 64 h
Yield: 70.7 %

Procedure:
A mixture of 5-(2-methoxyethoxy)-7-[methyl(pyridin-2-ylsulfonyl)amino]-1H-indole-2-carboxylic acid (0.45 g), S-trityl-D-cysteine methyl ester hydrochloride (0.46 g), 1H-1,2,3-benzotriazol-1-ol (0.26 g), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.32 g), triethylamine (0.19 mL) and N,N-dimethylformamide (5 mL) was stirred at room temperature for 64 hr. The reaction mixture was concentrated, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (4:1-1:4, volume ratio) to give the title compound (0.60 g, yield 72%) as a colorless amorphous solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([O:19][CH2:18]1)[C:10]([F:17])([F:16])[S:11][CH2:12][CH2:13][O:14][CH3:15].[NH:20]1[CH:24]=[N:23][CH:22]=[N:21]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.CCOCC>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:19])([CH2:18][N:20]1[CH:24]=[N:23][CH:22]=[N:21]1)[C:10]([F:17])([F:16])[S:11][CH2:12][CH2:13][O:14][CH3:15]
Reactant: COCCSC(F)(F)C1(c2ccc(F)cc2F)CO1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: COCCSC(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 50 °C
Reaction time: 1 h
Yield: 12.4 %

Procedure:
To a solution of 2-(2,4-difluorophenyl)-1,1-difluoro-1-[(2-methoxyethyl)thio]-2,3-epoxypropane (13.0 g, 0.044 mol) in DMSO (100 ml), 1,2,4-triazole (7.6 g, 0.11 mol) and potassium carbonate (15.2 g, 0.11 mol) were added and the resulting mixture was stirred at room temperature for 12 hours and at an external temperature of 50° C. for one hour. After the completion of the reaction, the reaction mixture was diluted with ether and insoluble matter was filtered off. The ether solution was washed with water, dried over magnesium sulfate and distilled off under reduced pressure. The residue was recrystallized from isopropyl ether-ethyl acetate, whereby 2-(2,4-difluorophenyl)-1,1-difluoro-1-[(2-methoxyethyl)thio]-3-(1H-1,2,4-triazol-1-yl)-2-propanol (2.0 g, yield: 12.0%) was obtained as colorless crystals.