Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([N:17]2[CH2:22][CH2:21][C@@:20]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)([CH2:23][CH2:24][OH:25])[O:19][C:18]2=[O:33])[CH3:16])=[CH:11][CH:10]=1.CCN(CC)CC.[CH3:41][S:42](Cl)(=[O:44])=[O:43].O>C(Cl)Cl>[CH3:41][S:42]([O:25][CH2:24][CH2:23][C@@:20]1([C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[O:19][C:18](=[O:33])[N:17]([C@H:15]([C:12]2[CH:13]=[CH:14][C:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])=[CH:10][CH:11]=2)[CH3:16])[CH2:22][CH2:21]1)(=[O:44])=[O:43]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCO)(c2ccc(F)cc2)OC1=O
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCOS(C)(=O)=O)(c2ccc(F)cc2)OC1=O
Temperature: 25 °C
Yield: 98.8 %

Procedure:
To a solution of (S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one (50 mg, 0.11 mmol) in dry CH2Cl2 (2 mL) was added Et3N (33 mg, 0.33 mmol) at 0˜−5° C. Then a solution of MsCl (12 mg, 0.13 mmol) in dry CH2Cl2 (1 mL) was added dropwise at the same temperature. After addition, the mixture was allowed to warm to rt gradually. When the reaction was over, water (10 mL) was added. The layers were separated, and the aqueous layer was extracted with CH2Cl2 (3×10 mL). The combined organic layers was washed with 10% citric acid, aqueous NaHCO3 and brine respectively, dried over Na2SO4, filtered and concentrated to give 2-((S)-3-((S)-1-(2′,4′-difluorobi-phenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethyl methanesulfonate (58 mg, crude), which was used for the next step without purification.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([S:12]([O-:15])(=O)=[O:13])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[K+].P(Cl)(Cl)([Cl:19])=O>O>[CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([S:12]([Cl:19])(=[O:15])=[O:13])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCCc1ccc(S(=O)(=O)[O-])cc1
Agent: [K+]
Solvent: O
Product: CCCCCc1ccc(S(=O)(=O)Cl)cc1
Temperature: 170 °C
Reaction time: 1 h
Yield: 86.4 %

Procedure:
A mixture of potassium 4-n-pentylbenzene sulfonate (65 g, 0.243 m) and phosphoryl chloride (75 g, 0.492 m) was heated to approximately 170° C. with stirring until the reaction mixture became less viscous. Heating continued for approximately one hour. The hot reaction mixture was poured into cold water (1600 ml) and the reaction product was extracted with chloroform (2×600 ml). The extract was washed with water until it was neutralized and dried over anhydrous sodium sulfate. The solvent (chloroform) was evaporated and the extract was vacuum-distilled to give 4-n-pentylbenzenesulfonyl chloride (52 g, 87%, boiling point 132°-134° C./0.3 mm).
Reaction SMILES: [Li][CH2:2]CCC.C(N(C(C)C)C(C)C)(C)C.[CH:16]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17]1.IC>C1COCC1.O>[CH3:2][C:16]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CCOC(=O)C1CCCC1
Reactant: [Li]CCCC
Agent: CC(C)N(C(C)C)C(C)C
Solvent: CI
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C1(C)CCCC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
A solution of nBuLi in hexanes (242 mL, 387 mmol) was added to a −78° C. solution of thisopropylamine (39.1 g, 387 mmol) in anhydrous THF (300 mL) and the resultant mixture was stirred for 30 min at −78° C. A solution of ethyl cyclopentanecarboxylate (50 g, 352 mmol) in anhydrous THF (150 mL) was added dropwise into the mixture and the reaction mixture was stirred at −78° C. for 1 h. Iodomethane (79.2 g, 558 mmol) was added dropwise and the resulting mixture was warmed to RT and stirred overnight The mixture was poured into water and extracted with ethyl ether. The combined extracts were washed with brine, dried (MgSO4) and concentrated in vacuo to give ethyl 1-methylcyclopentanecarboxylate (47 g, 85%). 1H NMR (300 MHz, DMSO-d6): δ 4.03 (q, J=7.2 Hz, 2 H), 1.37-2.03 (m, 8 H), 1.15-1.12 (m, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][CH:10]=[C:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[N:3]=1.F[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1.O>CN1CCCC1=O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][CH:10]=[C:11]2[CH2:12][CH2:13][N:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:15][CH2:16]2)[N:3]=1
Reactant: Fc1ccccn1
Reactant: Cc1cccc(C#CC=C2CCNCC2)n1
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cccc(C#CC=C2CCN(c3ccccn3)CC2)n1
Yield: 14.7 %

Procedure:
A solution of the Compound of Example 3 (100 mg, 0.47 mmol), 2-fluoropyridine (45.5 μL, 0.52 mmol), TEA (102 μL) in N-methylpyrrolidone was heated in a microwave oven at 160° C. for 20 min. Afterwards, the reaction mixture was cooled, poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried on Na2SO4 and evaporated to dryness in vacuo to afford a residue, which was purified by flash chromatography (EtOAc—Petroleum Ether gradient from 7:93 to 40:60) affording the title product (0.02 g).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl>O1CCOCC1>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc2cc[nH]c2c1
Agent: Cl
Solvent: C1COCCO1
Product: Fc1ccc2c(c1)NCC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 104.9 %

Procedure:
To a stirred solution of 6-fluoro-1H-indole (21.0 g, 0.155 mol) in dioxane (210 mL) was added BH3-NEt3 (92 mL, 0.620 mol) and a 12 M solution of HCl (27 mL, 0.326 mol) dropwise. The reaction mixture was stirred at room temperature for 10 min then at reflux for 2.5 h. The mixture was cooled to room temperature, and 6 M HCl (210 mL) was added. The mixture stirred at room temperature for 10 min and then at reflux for 1.5 h. The dioxane was removed under reduced pressure, and the residue diluted with water (500 mL) and washed with diethyl ether (1×250 mL). The aqueous fraction was basified with 10% NaOH and extracted with diethyl ether (3×250 mL). The combined organic layers were washed with water (2×100 mL) and brine (100 mL), dried (Na2SO4) and concentrated under reduced pressure, giving 22.3 g of the title compound.
Reaction SMILES: [OH:1][C:2]1([C:9]2[S:13][N:12]=[C:11]([CH3:14])[CH:10]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:15]1[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)=[O:21])[CH2:16]1>>[OH:1][C:2]1([C:9]2[S:13][N:12]=[C:11]([CH3:14])[CH:10]=2)[CH2:7][CH2:6][CH:5]([N:15]2[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[CH:26]=3)=[O:21])[CH2:16]2)[CH2:4][CH2:3]1
Reactant: Cc1cc(C2(O)CCC(=O)CC2)sn1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: Cc1cc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)sn1

Procedure:
The title compounds were prepared as white solids from reductive amination of 4-hydroxy-4-(3-methyl-isothiazol-5-yl)-cyclohexanone, as prepared in the previous step, and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step E of Example 1.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:25]=[CH:24][C:9]2[N:10]=[C:11]([NH:14][C@H:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)[O:12][CH2:13][C:8]=2[CH:7]=1)=[O:4].[CH3:26][O:27][CH:28](N)[CH3:29].C(#[N:33])C>>[C@H:15]1([NH:14][C:11]2[O:12][CH2:13][C:8]3[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][NH:33][CH2:29][CH2:28][O:27][CH3:26])[CH:25]=[CH:24][C:9]=3[N:10]=2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16]1
Reactant: O=C(CCl)Nc1ccc2c(c1)COC(N[C@@H]1CCc3ccccc31)=N2
Reactant: CC#N
Reactant: COC(C)N
Product: COCCNCC(=O)Nc1ccc2c(c1)COC(N[C@@H]1CCc3ccccc31)=N2
Yield: 63 %

Procedure:
Prepared from 2-chloro-N-[2-((R)-indan-1-ylamino)-4H-benzo[d][1,3]oxazin-6-yl]-acetamide (Example 3 step A) (100 mg, 0.281 mmol) and 1-methoxyethylamine (0.12 ml, 1.405 mmol) in acetonitrile (1 ml) according to the procedure described for Example 3 step B. Obtained the title compound as a white solid (70 mg, 63%), MS (ISP) m/e=395.2 [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([NH:10][CH3:11])[C:3]=1[CH3:12]>ClCCl.[O-2].[Mn+2]>[Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([NH:10][CH3:11])[C:5]([CH:8]=[O:9])=[CH:6][N:7]=1
Reactant: CNc1c(CO)cnc(Cl)c1C
Agent: [Mn+2]
Agent: [O-2]
Solvent: ClCCl
Product: CNc1c(C=O)cnc(Cl)c1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.2 %

Procedure:
A mixture of (6-chloro-5-methyl-4-(methylamino)pyridin-3-yl)methanol (1.4 g, 8.0 mmol) and manganese oxide (2.8 g, 32 mmol) in dichloromethane (100 mL) was stirred at RT for 4 h. LCMS monitored the reaction was completed. The solid was filtered off, and the filtrate was concentrated to get the title compound (1.2 g, crude) as a yellow oil. MS (ES+) C8H9ClN2O requires: 184, 186. Found: 185, 187 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].O1CCCC1.B.[Na]>CO>[CH2:17]([O:16][C:13]1[CH:14]=[CH:15][C:10]([C:7]2[CH:6]=[CH:5][C:4]([CH:1]([OH:3])[CH3:2])=[CH:9][CH:8]=2)=[CH:11][CH:12]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(=O)c1ccc(-c2ccc(OCc3ccccc3)cc2)cc1
Agent: B
Agent: [Na]
Solvent: C1CCOC1
Solvent: CO
Product: CC(O)c1ccc(-c2ccc(OCc3ccccc3)cc2)cc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 90.3 %

Procedure:
12.09 g (0.04 mol) of 4'-acetyl-4-benzyloxybiphenyl (VII-23), 40 ml of tetrahydrofuran and 10 ml of methanol were supplied into a four-necked flask provided with a stirrer and a thermometer. Then 1.51 g (0.4 mol) of sodium boron hydride was added at 15°-25° C. over a period of 2 hours. The mixture was kept at the same temperature for 5 hours, then poured into ice-water and extracted with 50 ml of chloroform. The organic layer was concentrated under reduced pressure to give 11.0 g (95% yield) of 4-benzyloxy-4'-(1-hydroxyethyl)biphenyl (VI-23).
Reaction SMILES: [CH2:1](I)[CH:2]=[CH2:3].[NH2:5][C:6]1[N:10]([C:11]2[C:16]([Cl:17])=[CH:15][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:13][C:12]=2[Br:22])[N:9]=[C:8]([C:23](=[S:25])[NH2:24])[C:7]=1[S:26]([CH3:28])=[O:27]>>[CH2:1]([S:25][C:23]([C:8]1[C:7]([S:26]([CH3:28])=[O:27])=[C:6]([NH2:5])[N:10]([C:11]2[C:16]([Cl:17])=[CH:15][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:13][C:12]=2[Br:22])[N:9]=1)=[NH:24])[CH:2]=[CH2:3]
Reactant: C=CCI
Reactant: CS(=O)c1c(C(N)=S)nn(-c2c(Cl)cc(C(F)(F)F)cc2Br)c1N
Product: C=CCSC(=N)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Br)c(N)c1S(C)=O

Procedure:
In a manner similar to that described in EXAMPLE 2, allyl iodide was reacted with 5-amino-1-[2-bromo-6-chloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carbothioamide (Compound 6, prepared as described in applicants' concurrently filed, copending application referenced in EXAMPLE 2 above) to give 5-amino-1-[2-bromo-6-chloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carboximidothioic acid 2-propenyl ester having a melting point of about 91° C. This compound is referred to hereinafter as Compound 3.
Reaction SMILES: [CH2:1]([Si:19]([CH3:22])([CH3:21])O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].CN(C)C=O.C(Cl)([Cl:30])=O>ClCCCl>[CH2:1]([Si:19]([CH3:22])([CH3:21])[Cl:30])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC[Si](C)(C)O
Reactant: O=C(Cl)Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCC[Si](C)(C)Cl
Yield: 87 %

Procedure:
To the same reactor as used in Example 1 were added 82.2 g (0.25 mole) of octadecyldimethylsilanol, 330 g of 1,2-dichloroethane and 1.83 g (0.025 mole) of N,N-dimethylformamide, and 27.2 g (0.275 mole) of phosgene was introduced into the resulting mixture at a temperature of from 40° to 45° C. over 2 hours with stirring. After completion of the introduction, the same procedure as in Example 7 was carried out to obtain 75.5 g of octadecyldimethylchlorosilane.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([CH:13]2[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[Cl:20][C:21]1[C:22](F)=[N:23][CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1.C(N(CC)CC)C>C(O)(C)(C)C>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([CH:13]2[CH2:18][CH2:17][CH2:16][N:15]([C:22]3[C:21]([Cl:20])=[CH:26][C:25]([C:27]([F:30])([F:28])[F:29])=[CH:24][N:23]=3)[CH2:14]2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1ncc(C(F)(F)F)cc1Cl
Reactant: CC(C)(C)c1cc(NC(=O)C2CCCNC2)no1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)(C)O
Product: CC(C)(C)c1cc(NC(=O)C2CCCN(c3ncc(C(F)(F)F)cc3Cl)C2)no1
Temperature: 175 °C
Reaction time: 8 h

Procedure:
A microwave reaction vial is charged with piperidine-3-carboxylic acid (5-tert-butyl-isoxazol-3-yl)-amide; hydrochloride (94 mg; 0.327 mmol), 3-chloro-2-fluoro-5-trifluoromethylpyridine (0.043 mL; 0.33 mmol), triethylamine (0.092 mL; 0.66 mmol) and t-butanol (0.5 mL). The vial is heated in microwave at 175° C. for 1 hour then left standing at room temperature overnight. The reaction mixture is concentrated in vacuo. Purification by flash chromatography on silica using methanol/methylene chloride then recrystallization from hot methanol provides the title compound, m/z 431 [M+H+].
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1.[N+:11]([O-])([OH:13])=[O:12].N([O-])=O.[Na+]>CO>[Br:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=[N+]([O-])O
Reactant: Brc1coc2ccccc12
Agent: O=N[O-]
Agent: [Na+]
Solvent: CO
Product: O=[N+]([O-])c1oc2ccccc2c1Br
Reaction time: 0.25 h

Procedure:
A 5.0 g. sample of powdered 3-bromobenzofuran on a glass dish is placed next to a container of nitric acid. Sodium nitrite is added periodically to the nitric acid, and the entire experiment is covered with a bell jar. After about 15 minutes the powder becomes an oil. After 12 hours the product is dissolved in hot methanol and slowly crystallized by cooling. Recrystallization from methanol provides yellow crystals of 3-bromo-2-nitrobenzofuran, m.p. 130°-132° C. (lit. 132° C.).
Reaction SMILES: [CH:1]([O-])([O-])OC.[C:6]([NH:12][C:13]1[CH:14]=[C:15]([CH:23]=[CH:24][CH:25]=1)[NH:16][C:17](=[O:22])[CH2:18][C:19](=[O:21])[CH3:20])(=[O:11])[CH2:7][CH2:8][CH2:9][CH3:10].C1(C)C=CC=CC=1.N1C2C(=CC=CC=2)C=CC=1>CO.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:6]([NH:12][C:13]1[CH:14]=[C:15]([CH:23]=[CH:24][CH:25]=1)[NH:16][C:17](=[O:22])/[CH:18]=[C:19](\[O:21][CH3:1])/[CH3:20])(=[O:11])[CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCC(=O)Nc1cccc(NC(=O)CC(C)=O)c1
Reactant: COC([O-])[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: c1ccc2ncccc2c1
Solvent: Cc1ccccc1
Product: CCCCC(=O)Nc1cccc(NC(=O)/C=C(/C)OC)c1
Temperature: 20 °C
Reaction time: 72 h
Yield: 69 %

Procedure:
16.5 g of methyl orthoformate were added to a solution of 27.6 g of m-valeramido-acetylacetanilide in 50 ml of methanol and after the addition of 0.5 g of p-toluene sulfonic acid, the mixture was stirred for 72 hours at 20° C. 200 ml of toluene and 1 ml of quinoline were added and the mixture was heated at 140° C. for 1 hour while distilling a methanol-toluene azeotrope. The mixture was evaporated to dryness under reduced pressure and the residue was chromatographed over silica gel. Elution with an 8- 2 methylene chloride-acetone mixture yielded 20 g of m-valeramido-3-methoxy-crotonanilide melting at 115° C. and after crystallization from ethyl acetate melted at 116° C.
Reaction SMILES: [F:1][C:2]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12](I)[S:13][C:6]=12.Br[C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][N:24]=1>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>[F:1][C:2]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:23]3[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][N:24]=3)[S:13][C:6]=12
Reactant: O=Cc1ccc(Br)nc1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: O=Cc1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)nc1
Yield: 52.1 %

Procedure:
A solution of 399 (1 g, 2.40 mmol) and 6-bromonicotinaldehyde (450 mg, 2.40 mmol) in 1,4-dioxane (10 mL) was treated sequentially with bis-trimethyl tin (500 μL, 787 mg, 2.40 mmol) and Pd(PPh3)4 (270 mg, 0.24 mmol). The reaction mixture was then heated to reflux under nitrogen overnight, cooled, and concentrated. The crude product was purified by flash chromatography using the gradient 5%-10% MeOH in DCM and subsequent trituration by MeOH, providing pure 400 (494 mg, 52% yield). 1H NMR (400 MHz, DMSO-d6) δ(ppm): 10.11 (s, 1H), 9.10 (m, 1H), 8.65 (d, 1H, J=5.2 Hz), 8.62 (s, 1H), 8.51 (d, 1H, J=8.8 Hz), 8.48 (dd, 1H, J=2.8 Hz, J=10.4 Hz), 8.38 (dd, 1H, J=2.1 Hz, J=8.2 Hz), 8.20 (m, 1H), 7.73 (t, 1H, J=9.0 Hz), 7.01 (d, 1H, J=5.5 Hz). MS (m/z): (M+1) 395.9.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([O:16][C:17]1[CH:22]=[C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:20]([Cl:31])=[CH:19][C:18]=1[C:32]1[CH:36]=[CH:35][NH:34][N:33]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O>ClCCl>[CH2:9]([O:16][C:17]1[CH:22]=[C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:20]([Cl:31])=[CH:19][C:18]=1[C:32]1[C:36]([Br:1])=[CH:35][NH:34][N:33]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Clc1cc(-c2cc[nH]n2)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: ClCCl
Product: Clc1cc(-c2n[nH]cc2Br)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.6 %

Procedure:
N-Bromosuccinimide (4.70 g, 26 mmol) was added in portions over 5 minutes to a stirred solution of 3-(2,4-Bis-benzyloxy-5-chloro-phenyl)-1H-pyrazole (10.29 g 26 mmol) in dichloromethane (200 ml). The reaction mixture was stirred at ambient temperature for 2 hours then water (200 ml) was added and vigorous stirring continued for 10 minutes. The phases were separated and the organic phase was washed with water (3×100 ml), saturated aqueous sodium chloride solution (2×100mi) and dried over sodium sulphate. The mixture was filtered and filtrate solvents were removed in vacuo to afford an off-white solid, which was triturated with ethyl acetate/hexane (1:20) mixture to give 3-(2,4-Bis-benzyloxy-5-chloro-phenyl)-4-bromo-1H-pyrazole (11.80 g, 97%) as off-white solid.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([CH2:14][NH:15][C:16]([C@H:18]3[CH2:22][CH2:21][CH2:20][N:19]3[C:23]([C@@H:25]3[CH2:29][C@@H:28](OS(C)(=O)=O)[CH2:27][N:26]3[C:35](=[O:56])[CH2:36][C:37]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:24])=[O:17])[CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N-:57]=[N+:58]=[N-:59].[Na+]>CN(C)C=O.C(OCC)(=O)C>[N:57]([C@@H:28]1[CH2:27][N:26]([C:35](=[O:56])[CH2:36][C:37]([C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C@H:25]([C:23]([N:19]2[CH2:20][CH2:21][CH2:22][CH:18]2[C:16]([NH:15][CH2:14][C@H:10]2[CH2:11][CH2:12][CH2:13][N:8]([CH2:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH2:9]2)=[O:17])=[O:24])[CH2:29]1)=[N+:58]=[N-:59]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](C(=O)N2CCC[C@@H]2C(=O)NC[C@H]2CCCN(CC3CCCCC3)C2)N(C(=O)CC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: [N-]=[N+]=N[C@H]1C[C@@H](C(=O)N2CCCC2C(=O)NC[C@H]2CCCN(CC3CCCCC3)C2)N(C(=O)CC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: 85 °C
Reaction time: 10 h
Yield: 81.3 %

Procedure:
To a solution of 33 mg of (2R)-N-{((3R)-1-cyclohexylmethyl-3-piperidyl)methyl}-1-{(2S,4R)-4-(methylsulfonyloxy)-1-(3,3,3-triphenylpropanoyl)pyrrolidin-2-yl}carbonylpyrrolidine-2-carboxamide in 1 ml of N,N-dimethylformamide, 8.3 mg of sodium azide was added at room temperature, followed by 10 hours' stirring at 85° C. under heating. The reaction liquid was diluted with ethyl acetate, washed with water and dried over anhydrous sodium sulfate. Distilling the solvent off under reduced pressure, the resultant residue was purified by means of a preparative thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (Merck), chloroform/methanol/28% aqueous ammonia=100/10/1) to provide 25 mg of the title compound.
Reaction SMILES: [C:1]([S:9][CH2:10][CH2:11][C:12]([N:14]1[C@H:18]([C:19]([OH:21])=O)[CH2:17][S:16][C@@H:15]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[OH:28])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.C(Cl)(=O)OCC(C)C.Cl.[CH2:45]([O:47][C:48](=[O:51])[CH2:49][NH2:50])[CH3:46]>C1COCC1.O>[CH2:45]([O:47][C:48](=[O:51])[CH2:49][NH:50][C:19]([C@@H:18]1[CH2:17][S:16][C@H:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[OH:28])[N:14]1[C:12](=[O:13])[CH2:11][CH2:10][S:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:21])[CH3:46]
Reactant: CCOC(=O)CN
Reactant: O=C(SCCC(=O)N1[C@@H](c2ccccc2O)SC[C@H]1C(=O)O)c1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CCOC(=O)CNC(=O)[C@@H]1CS[C@H](c2ccccc2O)N1C(=O)CCSC(=O)c1ccccc1
Reaction time: 0.25 h
Yield: 96.6 %

Procedure:
To the solution of 2.09 g of (2R,4R)-3-(S-benzoyl-3-mercaptopropanoyl)-2-(2-hydroxyphenyl)-4-thiazolidinecarboxylic acid dissolved in 30 ml of dry THF, 0.51 g of N-methylmorpholine is added. To the mixture 0.68 g of isobutyl chlorocarbonate is added at a temperature of -15° to -10° C. After stirring it for 15 minutes, the solution of 0.7 g of glycine ethyl ester hydrochloride and 0.51 g of N-methylmorpholine dissolved in 5 ml of THF and 15 ml of water is added to it. After stirring it for 1 hour while being back to the room temperature gradually, and then removing THF in vacuo, the mixture is extracted with ethyl acetate. The organic layer is washed with N--HCl, water, saturated aqueous sodium chloride solution, in order, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue is crystallized from ethyl acetate-benzene to give 2.43 g (82%) of the titled compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:10]2[C:5](=[CH:6][C:7]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:8][CH:9]=2)[NH:4][CH2:3]1.CN(C=O)C.[H-].[Na+].Cl[C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]=[C:28]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:27]=1[CH3:42].N1C2C(=CC=CC=2)C=CC=1>CCOC(C)=O.C(=O)(O)[O-].[Na+]>[CH3:1][C:2]1([CH3:17])[C:10]2[C:5](=[CH:6][C:7]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:8][CH:9]=2)[N:4]([C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:29]=[C:28]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:27]=2[CH3:42])[CH2:3]1
Reactant: Cc1c(-c2ccccc2)nc2ccccc2c1Cl
Reactant: CC1(C)CNc2cc(N3CCOCC3)ccc21
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: c1ccc2ncccc2c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c(-c2ccccc2)nc2ccccc2c1N1CC(C)(C)c2ccc(N3CCOCC3)cc21
Temperature: 25 °C
Reaction time: 0.2 h

Procedure:
Under a N2 atmosphere, 3,3-dimethyl-6-morpholinoindoline (0.100 g, 0.430 mmol) was dissolved in DMF (2.00 mL, 26.0 mmol). Sodium hydride (0.0227 g, 0.947 mmol) was added and the reaction was stirred at rt for 12 minutes. The reaction was treated with 4-chloro-3-methyl-2-phenylquinoline (0.218 g, 0.861 mmol) and placed in a preheated oil bath at 140° C. for 2 h. LCMS showed no starting quinoline remained. The reaction was diluted with EtOAc and 2% sodium bicarbonate. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography eluting with 20% to 50% EtOAc in hexane, and then purified again by preparative reverse phase chromatography to give 4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-indol-1-yl)-3-methyl-2-phenylquinoline. Mass Spectrum (ESI) m/e=450.2 (M+1)