Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:9]([C@H:18]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:8]([CH3:29])=[CH:7][C:5]=2[N:6]=1.[Cl:30][C:31]1[CH:36]=[C:35](B(O)O)[CH:34]=[CH:33][N:32]=1.C([O-])([O-])=O.[K+].[K+]>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>[C:25]([O:24][C@@H:18]([C:9]1[C:8]([CH3:29])=[CH:7][C:5]2[N:6]=[C:2]([C:35]3[CH:34]=[CH:33][N:32]=[C:31]([Cl:30])[CH:36]=3)[S:3][C:4]=2[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])([CH3:28])([CH3:27])[CH3:26]
Reactant: OB(O)c1ccnc(Cl)c1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
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: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(Cl)c3)sc2c1-c1ccc(Cl)cc1
Temperature: 90 °C

Procedure:
To a solution of (S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (858 mg, 1.733 mmol) and 2-chloropyridine-4-boronic acid (327 mg, 2.080 mmol) in dioxane (14.6 mL) was added Pd(PPh3)4 (160 mg, 0.139 mmol) and 2N K2CO3 (3.6 mL, 7.280 mmol). The reaction was degassed for 5 minutes with N2 and then heated at 90° C. for 6 h. After cooling, the reaction mixture was diluted with EtOAc, extracted with H2O, brine, dried over Na2SO4, filtered and concentrated and purified by flash column chromatography (silica gel, 0 to 100% ethyl acetate/hexanes) to give the desired product. LCMS-ESI+ (m/z): [M+H]+ calcd for C27H27Cl2N2O3S: 529.1; found: 529.2.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][CH:6]=1)=O.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1.C(=O)([O-])O.[Na+]>C(O)C>[I:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:12]=[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]3[CH:2]=2)=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccc(I)cc1
Reactant: Nc1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Ic1ccc(-c2cn3ccccc3n2)cc1
Yield: 79 %

Procedure:
Dissolving 27 g (83 mmol) of crude 2-bromo-4′-iodo acetophenone thus obtained and 8.0 g (85 mmol) of 2-aminopyridine into 200 milliliter of ethanol, adding 10 g of sodium hydrogen carbonate, the resultant suspension was refluxed under heating for 6 hours. After completion of the reaction, separation with filtration was carried out and resultant crystals were washed with water and ethanol, thereby obtaining 21 g of 2-(4-iodophenyl)-imidazo [1,2-a] pyridine (yield: 82%).
Reaction SMILES: [CH2:1]([SH:4])[CH:2]=[CH2:3].[CH:5]([NH:7][C:8]1[S:9][CH:10]=[C:11]([C:13](=[N:19][O:20][CH2:21][CH2:22]Br)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:12]=1)=[O:6].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:1]([S:4][CH2:22][CH2:21][O:20][N:19]=[C:13]([C:11]1[N:12]=[C:8]([NH:7][CH:5]=[O:6])[S:9][CH:10]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:2]=[CH2:3]
Reactant: C=CCS
Reactant: CCOC(=O)C(=NOCCBr)c1csc(NC=O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCSCCON=C(C(=O)OCC)c1csc(NC=O)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 81.6 %

Procedure:
Allyl mercaptan (2.12 g.) was added dropwise to a stirred suspension of ethyl 2-(2-formamidothiazol-4-yl)-2-(2-bromoethoxyimino)acetate (syn isomer, 5 g.) and potassium carbonate (3.95 g.) in N,N dimethylformamide (50 ml.) under ice cooling and stirred at the same temperature for 10 minutes and further at room temperature for 5 hours. After adding water (300 ml.) to the resultant solution, the mixture was extracted with ethyl acetate three times. The extracts were washed twice with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The oily residue was subjected to column chromatography on silica gel and eluted with chloroform. The eluate was concentrated in vacuo to give ethyl 2-(2-allylthioethoxyimino)-2-(2-formamidothiazol-4-yl)acetate (syn isomer, 4.0 g.), mp. 62° to 64° C.
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([CH2:15][CH3:16])([CH3:14])[CH3:13])[C:7]=1[OH:17])([CH2:4][CH3:5])([CH3:3])[CH3:2].[C:18]([OH:22])(=[O:21])[CH:19]=O.Cl>C(O)(=O)C>[C:12]([C:8]1[C:7](=[O:17])[C:6]([C:1]([CH2:4][CH3:5])([CH3:3])[CH3:2])=[CH:11][C:10](=[CH:19][C:18]([OH:22])=[O:21])[CH:9]=1)([CH2:15][CH3:16])([CH3:14])[CH3:13]
Reactant: CCC(C)(C)c1cccc(C(C)(C)CC)c1O
Reactant: O=CC(=O)O
Agent: Cl
Solvent: CC(=O)O
Product: CCC(C)(C)C1=CC(=CC(=O)O)C=C(C(C)(C)CC)C1=O
Temperature: 0 °C
Yield: 35 %

Procedure:
15.0 g (0.064 Mol) of 2,6-di-tert-amylphenol and 11.4 g (0.077 mol) of 50% aqueous glyoxylic acid are dissolved in 100 ml of acetic acid. The solution is then saturated at 15°-25° C. with hydrogen chloride gas and stirred at room temperature for additional four hours. The mixture is then poured in 400 ml of ice-water and extracted with 200 ml of ethyl acetate. The ethyl acetate layer is washed several times with water, dryed over anhydrous sodium sulfate, and evaporated in vacuo. The oily residue is then chromatographed on silica gel with ethyl acetate:hexane (1:20→1:3). The pure fractions are recrystallized from hexane to give 6.5 g of the title compound as orange needles, melting at 109°-110° C.
Reaction SMILES: NCOC(=O)CCC1C=CC=CC=1.[OH:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=[O:19].[Br:23]Br>>[Br:23][C:20]1[CH:21]=[CH:22][C:15]([OH:14])=[CH:16][C:17]=1[CH:18]=[O:19]
Reactant: O=Cc1cccc(O)c1
Reactant: BrBr
Agent: NCOC(=O)CCc1ccccc1
Product: O=Cc1cc(O)ccc1Br

Procedure:
Reaction Scheme 9 shows the synthetic route to prepare aminomethyldihydrocinnamate headpiece. 3-Hydroxybenzaldehyde (29) is reacted with bromine to give 2-bromo-5-hydroxybenzaldehyde (30), which is then coupled to t-butylacrylate to give the compound (31). Compound (31) is treated with NH2OH to give oxime (32), which undergoes hydrogenation to give aminomethyldihydrocinnamate (33). Various functional groups (Z2) can be introduced at the aminomethyl portion of compound (33) to afford compound (34).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[Br-]>O>[C:1]1([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(Sc2ccccc2)cc1
Temperature: 20 °C

Procedure:
2.2 g of thiophenol and 2.8 g of potassium carbonate were added to 50 ml of dimethylformamide and, with stirring at about 20° C., 13.0 g of polyprenyl bromide of general formula (II) in which n=15 and A=Br were added dropwise. After the addition, the mixture was stirred overnight at room temperature. The reaction mixture was poured into about 100 ml of water and extracted with hexane. The hexane layer was washed with a 10% aqueous solution of sodium hydroxide and water, and then dried over anhydrous magnesium sulfate. The hexane was distilled off to give a yellow liquid. The yellow liquid was purified by silica gel column chromatography using methylene chloride as the eluent to give 8.6 g of a slightly yellow liquid. NMR analysis of this liquid showed that a signal (doublet, δ=3.91) assignable to --CH2Br of the starting polyprenyl bromide had disappeared and a signal (doublet, δ=3.47) assignable to --CH2S-- and a signal (multiplet, δ=7.05- 7.32) assignable to --SC6H5 had newly appeared. FD-MASS analysis gave m/e=1334.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]#[N:16])=[CH:10][CH:9]=2)=O)C.[NH3:17].CO>>[C:15]([C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:4]([NH2:17])=[O:3])=[CH:14]2)#[N:16]
Reactant: CCOC(=O)c1cc2cc(C#N)ccc2[nH]1
Reactant: N
Solvent: CO
Product: N#Cc1ccc2[nH]c(C(N)=O)cc2c1
Yield: 83.3 %

Procedure:
Treat 5-cyano-1H-indole-2-carboxylic acid ethyl ester, 3a (m=0, 1.0 g, 4.67 mmol) with 7 N NH3/MeOH as described in General Procedure IV to afford the title compound as an ivory colored solid (720 mg, 83.3%): mp>300° C.; 1H NMR (DMSO-d6) δ 12.0 (brs, 1H), 8.21 (s, 1H), 8.14 (brs, 1H), 7.51 (m, 3H), 7.25 (s, 1H); tlc (10% MeOH/CH2Cl2) Rf=0.40, m/z obs=186 (M+1).
Reaction SMILES: CN([C:4]([O:8][N:9]1N=NC2C=CC=N[C:10]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([O:29][C:30]([N:32]1[CH2:36][CH2:35][CH:34]([C:37]([OH:39])=O)[CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].Cl.CNOC.C(N(CC)CC)C>C(Cl)Cl>[CH3:4][O:8][N:9]([CH3:10])[C:37]([CH:34]1[CH2:35][CH2:36][N:32]([C:30]([O:29][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:31])[CH2:33]1)=[O:39]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)C1
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
HATU (4.56 g, 12.0 mmol) was added to 1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (2.15 g, 10.0 mmol), N,O-dimethylhydroxylamine hydrochloride (1.17 g, 12.0 mmol), and triethylamine (30.0 mmol) in DCM (50.0 mL), and the resulting mixture was allowed to stir at rt. After 12 h, the reaction mixture was diluted with DCM, and the combined organics were washed with water and brine, dried (sodium sulfate) and concentrated in vacuo to afford the title compound i-19a. m/z (ES) 259 (MH)+.
Reaction SMILES: [OH:1][N:2]=[CH:3][C@H:4]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)[CH:19]=2)=[CH:12][CH:11]=1)[CH2:5][C:6]([O:8][CH3:9])=[O:7].N1C=C[CH:37]=[CH:36][CH:35]=1.C1C(=O)N(Cl)C(=O)C1.CC#C>C(Cl)Cl>[F:33][C:30]([F:32])([F:31])[C:27]1[CH:26]=[CH:25][C:24]([C:20]2[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=2)[CH2:17][O:16][C:13]2[CH:12]=[CH:11][C:10]([C@@H:4]([C:3]3[CH:35]=[C:36]([CH3:37])[O:1][N:2]=3)[CH2:5][C:6]([O:8][CH3:9])=[O:7])=[CH:15][CH:14]=2)=[CH:29][CH:28]=1
Reactant: COC(=O)C[C@H](C=NO)c1ccc(OCc2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1
Reactant: c1ccncc1
Agent: C#CC
Agent: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: COC(=O)C[C@@H](c1ccc(OCc2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1)c1cc(C)on1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Compound 39.2 (100 mg, 0.22 mmol) was dissolved in DCM, and pyridine (0.05 mL) and NCS (30 mg, 0.22 mmol) were added. The resulting mixture was stirred at room temperature for 3 hours. Additional NCS (60 mg) was added, and the mixture was left at room temperature overnight. Then TEA (0.4 mL) was added to the mixture, and a stream of methylacetylene was passed through the reaction mixture for 20 minutes. LCMS detected the desired product. The solvent was removed, and the residue was purified by CombiFlash to give 39.3.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:10][CH2:11][CH2:12][CH2:13][NH:14]C(=O)OC(C)(C)C)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[ClH:22].C(OC(C)C)(C)C>O1CCOCC1.O>[N+:1]([C:4]1[C:5]([NH:10][CH2:11][CH2:12][CH2:13][NH2:14])=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[ClH:22]
Reactant: CC(C)(C)OC(=O)NCCCNc1ncccc1[N+](=O)[O-]
Agent: Cl
Solvent: O
Solvent: CC(C)OC(C)C
Solvent: C1COCCO1
Product: NCCCNc1ncccc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
To tert-butyl (3-((3-nitropyridin-2-yl)amino)propyl)carbamate (C42, 53 mg), a 4.0 mol/L solution of hydrochloric acid in dioxane (2 mL) and water (100 μL) were added at room temperature, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture, diisopropyl ether were added, the solvent was removed by decantation, and then the residue was dried under reduced pressure to obtain N1-(3-nitropyridin-2-yl)propane-1,3-diamine (C43) hydrochloride (113 mg).
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH2:7][CH2:8][O:9][CH3:10])[N:5]=[CH:4][C:3]=1[N+:11]([O-])=O.C(O)(=O)C>O.[Fe]>[Cl:1][C:2]1[N:6]([CH2:7][CH2:8][O:9][CH3:10])[N:5]=[CH:4][C:3]=1[NH2:11]
Reactant: COCCn1ncc([N+](=O)[O-])c1Cl
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: COCCn1ncc(N)c1Cl
Temperature: 90 °C
Yield: 69 %

Procedure:
To a suspension of 5-chloro-1-(2-methoxyethyl)-4-nitro-1H-pyrazole (1 equiv) and iron dust (3 equiv) in water (0.51 M) was added acetic acid (2.6 equiv). The mixture was heated to 90° C. for 1.5 h, then cooled to room temperature. The reaction was quenched by addition of solid sodium bicarbonate and treated with ethyl acetate with continuous stirring. The mixture was filtered and the solid was rinsed with ethyl acetate. The combined filtrate was dried over sodium sulfate and concentrated. The crude product was purified by silica gel chromatography (1.5% MeOH in DCM) to provide the desired product (69% yield) as a brown oil. MS (ESI) m/z 176 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]#[N:8])=[N:5][N:4]([CH3:9])[N:3]=1.[H-].[Na+].F[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[N+:20]([O-:22])=[O:21]>O1CCCC1>[CH3:9][N:4]1[N:3]=[C:2]([NH:1][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[N+:20]([O-:22])=[O:21])[C:6]([C:7]#[N:8])=[N:5]1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Reactant: Cn1nc(N)c(C#N)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1nc(C#N)c(Nc2ccc(F)cc2[N+](=O)[O-])n1
Reaction time: 0.25 h

Procedure:
To a solution of 4-amino-2-methyl-1,2,3-triazole-5-carbonitrile (1.7 g) in tetrahydrofuran (35 ml) under nitrogen, was added sodium hydride (1.0 g; 50% oil dispersion) at room temperature. After 15 minutes, 2,5-difluoronitrobenzene (2.22 g) was added to the mixture, which was stirred overnight under nitrogen. The deep red solution was then quenched in ice/water/HCl and filtered to give an orange solid. The solid was chromatographed on a magnesium silicate column using dichloromethane; the purified product recrystallised from ethyl acetate-ethanol to give an orange crystalline solid, melting point 159°-160° C.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[C:2]#[CH:3].C([Li])CCC.[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1.[Cl-].[NH4+]>O1CCCC1>[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]([OH:18])[C:3]#[C:2][C:1]([O:5][CH3:6])=[O:4])=[CH:15][CH:14]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: C#CC(=O)OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)C#CC(O)c1ccc(Cl)cc1
Reaction time: 0.17 h

Procedure:
A solution of 8.36 ml (0.1 mol) of methyl propiolate in 100 ml of tetrahydrofuran was treated at -78° under argon with 68.8 ml of n-butyllithium (1.6M in hexane). The mixture was stirred at -78° for 10 minutes and then a solution of 14.06 g (0.1 mol) of 4-chlorobenzaldehyde in 100 ml of tetrahydrofuran was added within 40 minutes. The reaction mixture is stirred at -78° for a further 20 minutes, then brought to room temperature and treated with 100 ml of saturated ammonium chloride solution. The aqueous phase was extracted twice with ether. The combined organic phases were washed in succession with saturated sodium chloride solution and with water, dried over sodium sulphate and concentrated. The residue was purified by flash chromatography on 1000 g of silica gel (elution agent methylene chloride/ethyl acetate 9:1). There was obtained methyl 4-(4-chlorophenyl)-4-hydroxy-2-butynoate as a red oil.
Reaction SMILES: F[C:2]1[CH:7]=[C:6](F)[C:5]([F:9])=[CH:4][C:3]=1[N:10]1[C:19]2[C:14](=[CH:15][C:16]([F:26])=[C:17]([N:20]3[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21]3)[CH:18]=2)[C:13](=[O:27])[N:12]([OH:28])[C:11]1=[O:29].F[C:31](F)(F)C([O-])=O>>[F:9][C:5]1[CH:4]=[C:3]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:26])=[C:17]([N:20]4[CH2:21][CH2:22][N:25]([CH3:31])[CH2:23][CH2:24]4)[CH:18]=3)[C:13](=[O:27])[N:12]([OH:28])[C:11]2=[O:29])[CH:2]=[CH:7][CH:6]=1
Reactant: NC1CCN(c2cc3c(cc2F)c(=O)n(O)c(=O)n3-c2cc(F)c(F)cc2F)C1
Reactant: O=C([O-])C(F)(F)F
Product: CN1CCN(c2cc3c(cc2F)c(=O)n(O)c(=O)n3-c2cccc(F)c2)CC1

Procedure:
1-(2,4,5-Trifluorophenyl)-6-fluoro-3-hydroxy-7-(3-aminopyrrolidin-1-yl)-1H-quinazoline-2,4-dione, trifluoroacetate;
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=O)[O:24]C3C=CC=CC=3)=[CH:16][CH:15]=2)[N:3]=1.[F:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=1[S:40]([NH2:43])(=[O:42])=[O:41]>>[CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:43][S:40]([C:34]3[CH:35]=[CH:36][C:37]([F:39])=[CH:38][C:33]=3[F:32])(=[O:41])=[O:42])=[O:24])=[CH:16][CH:15]=2)[N:3]=1
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)c(C)c1-c1ccccc1
Reactant: NS(=O)(=O)c1ccc(F)cc1F
Product: Cc1nn(-c2ccc(CCNC(=O)NS(=O)(=O)c3ccc(F)cc3F)cc2)c(C)c1-c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 42 from phenyl 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethylcarbamate (step 1 of Example 22) and 2,4-difluorobenzenesulfonamide: 1H-NMR (CDCl3) δ 7.98-7.90 (1H, m), 7.47-7.41 (2H, m), 7.35-7.22 (7H, m), 7.07-6.92 (2H, m), 6.16 (1H, br.s), 3.50-3.43 (2H, m), 2.84 (2H, t, J=6.6 Hz), 2.33 (3H, s), 2.23 (3H, s).
Reaction SMILES: C(OC(C1C=CC(C2C=CC(O)=CC=2)=CC=1)=O)C.[OH-].[K+].CC(OS(C1C(C)=CC=CC=1)(=O)=O)CCCCCC.C([O:42][C:43]([C:45]1[CH:50]=[CH:49][C:48]([C:51]2[CH:56]=[CH:55][C:54]([O:57][CH:58]([CH3:65])[CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH3:64])=[CH:53][CH:52]=2)=[CH:47][CH:46]=1)=[O:44])C.[OH-].[Na+]>C(O)C.O.C1(C)C=CC=CC=1>[CH3:65][CH:58]([O:57][C:54]1[CH:55]=[CH:56][C:51]([C:48]2[CH:47]=[CH:46][C:45]([C:43]([OH:44])=[O:42])=[CH:50][CH:49]=2)=[CH:52][CH:53]=1)[CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH3:64]
Reactant: CCCCCCC(C)Oc1ccc(-c2ccc(C(=O)OCC)cc2)cc1
Agent: CCCCCCC(C)OS(=O)(=O)c1ccccc1C
Agent: CCOC(=O)c1ccc(-c2ccc(O)cc2)cc1
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCCCCC(C)Oc1ccc(-c2ccc(C(=O)O)cc2)cc1
Yield: 65.8 %

Procedure:
On the other hand, 4-hydroxy-4'-biphenylcarboxylic acid ethyl ester (IV) (38.7 g, 0.160 mol) was dissolved in ethanol (200 ml), and KOH (9 g, 0.160 mol) was added to and dissolved in the solution, followed by adding optically active toluenesulfonic acid 1-methyl-heptyl ester (50 g, 0.176 mol) obtained above, keeping the mixture under reflux for 4 hours, then cooling, adding toluene (200 ml) and 6N--HCl (50 ml), washing the resulting toluene layer with 2N--NaOH aqueous solution and further with water till the washing water became neutral, and distilling off toluene to obtain as a residue, optically active 4'-(1-methyl-heptyloxy)-4-biphenylcarboxylic acid ethyl ester (V) (38.6 g). This product (38.6 g, 0.109 mol) was dissolved in ethanol (6 ml), NaOH (5.3 g, 0.130 mol) and water (26 ml), followed by heating the solution under reflux for 10 minutes to deposit crystals, cooling, adding 6N--HCl (20 ml) to filter off crystals and further recrystallizing from acetic acid to obtain optically active 4'-(1-methyl-heptyloxy)-4-biphenylcarboxylic acid (VI) (23.4 g). This product exhibited liquid crystal phases and the phase transition points were as follows: C-SC* point 160° C., SC*-Ch point 177° C. and Ch-I point 196° C.
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.C(Cl)Cl.C(N(CC)CC)C.[C:34]1([CH:40]([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[CH2:41][N:42]([CH3:60])[C:43](=[O:59])[CH:44]([NH:51][CH2:52][CH2:53][C:54]2[N:55]=[CH:56][NH:57][CH:58]=2)[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CN(C)C=O>[C:1]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([N:51]([CH:44]([C:43](=[O:59])[N:42]([CH2:41][CH:40]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=1)[CH3:60])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH2:52][CH2:53][C:54]1[N:55]=[CH:56][NH:57][CH:58]=1)=[O:13])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccccc1C(=O)c1ccccc1
Reactant: CN(CC(c1ccccc1)c1ccccc1)C(=O)C(NCCc1c[nH]cn1)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CC(c1ccccc1)c1ccccc1)C(=O)C(c1ccccc1)N(CCc1c[nH]cn1)C(=O)c1ccccc1C(=O)c1ccccc1
Reaction time: 8 h
Yield: 70.5 %

Procedure:
2-Benzoylbenzoic acid (0.341 g, 1.51 mmol) was taken up in a 2M solution of oxalyl chloride in methylene chloride (1.5 mL, 3.0 mmol). One drop of N,N-dimethylformamide was added and the frothy mixture was stirred overnight and concentrated. A solution of the crude 2-benzoylbenzoyl chloride in methylene chloride (4 mL) followed by triethylamine (0.25 mL, 1.8 mmol) was added to the product of step 2 (0.220 g, 0.502 mmol). The mixture was heated at reflux for 2 hours and concentrated. The residue was taken up in 5:1 methanol/1 N aqueous lithium hydroxide (12 mL) and stirred for 1 hour. The reaction was again concentrated and the residue was partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The organic layer was dried (sodium sulfate) and concentrated to afford a foamy amber solid. Flash chromatography over silica (methylene chloride/methanol) provided 0.229 g (71%) of product as a foamy pale amber solid: 1H NMR (CDCl3) δ 7.91–6.92 (m, 26H), 6.54–6.39 (m, 1H), 6.34–6.06 (m, 1H), 4.83–4.31 (m, 2H), 3.97–2.82 (m, 3H), 2.70–2.39 (m, 3H), 2.35–2.09 (m, 2H) ppm. MS (ESI) m/z 648 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][NH:11][CH:12]=2)=[CH:4][CH:3]=1.C(OCC)C.C(O[CH:21](OCC)[N:22]([CH3:24])[CH3:23])C>>[CH3:21][N:22]([CH3:24])[CH:23]=[N:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[CH:10][NH:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: CCOC(OCC)N(C)C
Reactant: Nc1ccc(-c2c[nH]cn2)cc1
Solvent: CCOCC
Product: CN(C)C=Nc1ccc(-c2c[nH]cn2)cc1

Procedure:
A solution of 3.18 gm of 4-(4-aminophenyl)-1-H-imidazole in 8.82 gm of N,N-dimethyl-formamide diethyl acetal was stirred at room temperature for two days. Addition of diethyl ether resulted in precipitation of the formamidine, which was collected by filtration.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([CH:16]2[C:20]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[F:30])([C:21]#[N:22])[CH:19]([CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[NH:18][CH:17]2[C:36](O)=[O:37])[CH:12]=[CH:13][C:14]=1[F:15].CC1(C)[O:44][C@@H:43]([CH2:45][CH2:46][NH2:47])[CH2:42][O:41]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl>C(Cl)Cl.O1CCCC1>[OH:44][C@H:43]([CH2:42][OH:41])[CH2:45][CH2:46][NH:47][C:36]([CH:17]1[CH:16]([C:11]2[CH:12]=[CH:13][C:14]([F:15])=[C:9]([Cl:8])[CH:10]=2)[C:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[F:30])([C:21]#[N:22])[CH:19]([CH2:31][C:32]([CH3:35])([CH3:33])[CH3:34])[NH:18]1)=[O:37]
Reactant: CC1(C)OC[C@H](CCN)O1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2ccc(F)c(Cl)c2)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)NCC[C@H](O)CO)C(c2ccc(F)c(Cl)c2)C1(C#N)c1ccc(Cl)cc1F
Yield: 67.6 %

Procedure:
In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3R,4R,5S)-3-(3-chloro-4-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 69c (0.28 g, 0.48 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine (0.21 g, 1.44 mmol), HATU (0.33 g, 0.87 mmol) and iPr2NEt (0.42 mL, 2.4 mmol) in CH2Cl2 at room temperature for 20 h, then reacted with aqueous HCl solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3R,4R,5S)-3-(3-chloro-4-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.18 g, 77%).