Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[Br:9][C:10]1[N:14]2[CH:15]=[C:16](I)[CH:17]=[CH:18][C:13]2=[N:12][CH:11]=1.C(O)CO.[NH2:24][C@H:25]1[CH2:30][CH2:29][C@H:28]([OH:31])[CH2:27][CH2:26]1>C(O)(C)C.[Cu]I>[Br:9][C:10]1[N:14]2[CH:15]=[C:16]([NH:24][CH:25]3[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27][CH2:26]3)[CH:17]=[CH:18][C:13]2=[N:12][CH:11]=1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: Brc1cnc2ccc(I)cn12
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CC(C)O
Product: OC1CCC(Nc2ccc3ncc(Br)n3c2)CC1
Temperature: 80 °C

Procedure:
Copper (I) iodide (0.1 eq, 1.45 g, 7.68 mmol) and potassium phosphate tribasic (2 eq, 0.153 mol, 32.5 g) are stirred at RT under an atmosphere of argon during the addition of 3-bromo-6-iodo-imidazo[1,2-a]pyridine (Intermediate F) (25 g, 77 mmol, 1 eq) in isopropyl alcohol (200 ml), ethylene glycol (2 eq, 0.153 mol, 8.5 ml) and finally trans-4-aminocyclohexanol (2 eq, 17.5 g, 153 mmol) The reaction is heated at 80° C. for 40 hours. The majority of the solvent is removed in vacuo and the residue is diluted with water (500 ml) and extracted with EtOAc (3×500 ml). The combined organic portions are dried (MgSO4) and concentrated in vacuo. Purification by flash chromatography on silica eluting with 0-15% MeOH in EtOAc gives 4-(3-bromo-imidazo[1,2-a]pyridin-6-ylamino)-cyclohexanol; [M+H]+=310 (312)
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[C:15]([C:17]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)#[N:16].[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].CO>C(OCC)(=O)C>[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:20]3[CH2:21][CH2:22][C:17]([C:15]#[N:16])([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:18][CH2:19]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: N#CC1(c2ccccc2)CCNCC1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: N#CC1(c2ccccc2)CCN(C[C@H](O)COc2cccc3[nH]ccc23)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-cyano-4-phenylpiperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 57% overall yield. FDMS m/e=375 (M+ of free base). α[D]589 =-12.76 (c=0.48, methanol).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SC)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[CH3:34][O:35][CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[F:32][C:2]([F:1])([F:33])[C:3]1[CH:27]=[C:26]([C:28]([F:30])([F:31])[F:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:41]4[CH2:42][CH2:43][N:38]([CH2:37][CH2:36][O:35][CH3:34])[CH2:39][CH2:40]4)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Reactant: COCCN1CCNCC1
Product: COCCN1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)CC1

Procedure:
5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2-methoxy-ethyl)-piperazin-1-yl]-thiazol-4-one was prepared from 5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and 1-(2-methoxy-ethyl)-piperazine following General Procedure C.
Reaction SMILES: ClC(OCC(C)C)=O.[O:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]#[C:17][C:18]([OH:20])=O)[CH2:11][CH2:10]1.CN1CCOCC1.N#N.[NH2:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[N:37]=[CH:36][C:35]([C:41]#[N:42])=[C:34]2[NH:43][C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([Br:50])[CH:45]=1>N1C=CC=CC=1>[Br:50][C:46]1[CH:45]=[C:44]([NH:43][C:34]2[C:33]3[C:38](=[CH:39][CH:40]=[C:31]([NH:30][C:18](=[O:20])[C:17]#[C:16][CH2:15][N:12]4[CH2:11][CH2:10][O:9][CH2:14][CH2:13]4)[CH:32]=3)[N:37]=[CH:36][C:35]=2[C:41]#[N:42])[CH:49]=[CH:48][CH:47]=1
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Br)c1
Reactant: O=C(O)C#CCN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: N#N
Solvent: c1ccncc1
Solvent: CN1CCOCC1
Product: N#Cc1cnc2ccc(NC(=O)C#CCN3CCOCC3)cc2c1Nc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 26.5 %

Procedure:
Isobutyl chloroformate (0.161 g, 1.18 mmol) was dropwise added into an ice cold solution of 4-morpholino-2-butynoic acid (0.25 g, 1.48 mmol) and N-methylmorpholine (0.15 g, 1.48 mmol) in 8 mL of tetrahydrofuan under N2. After stirring for 30 min, a solution of 025 g (0.74 mmol) of 6-amino-4-[(3-bromophenyl)amino]-3-quinolinecarbonitrile in 6 mL of pyridine was added dropwise and the mixture was stirred at 0° C. for 2 hr. The reaction was quenched with ice water, poured into saturated sodium bicarbonate and brine, and extracted with ethyl acetate. The ethyl acetate layer was concentrated and purified by thin-layer chromatography eluted with 15% methanol in ethyl acetate. The product was collected, and dried in vacuo to give 0.096 g (27%) of yellow solid; :mass spectrum (electrospray, m/e,) 490.1, 492.1 (M+H+); mp 145-148° C.
Reaction SMILES: [Cl:1]C1C=C(N)C=C(Cl)C=1OC1C=[N:11]C2C(C=1)=CC=CC=2.Cl[C:22]1[CH:27]=[C:26](Cl)[CH:25]=[CH:24][C:23]=1[S:29](Cl)(=[O:31])=[O:30].Cl>>[ClH:1].[C:23]1([S:29]([NH2:11])(=[O:31])=[O:30])[CH:24]=[CH:25][CH:26]=[CH:27][CH:22]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Reactant: Nc1cc(Cl)c(Oc2cnc3ccccc3c2)c(Cl)c1
Agent: Cl
Product: NS(=O)(=O)c1ccccc1
Yield: 99 %

Procedure:
3,5-dichloro-4-(quinolin-3-yloxy)-phenylamine (5) was then reacted with 2,4-dichlorobenzenesulfonylchloride, followed by treatment with hydrochloric acid, to give 2,4-dichloro-N-[3,5-dichloro-4-quinolin-3-yloxy)phenyl]-benzenesulfonamide HCl (1; the hydrochloride salt of compound 101) in 99% yield.
Reaction SMILES: [CH3:1][N:2]([CH:4]([CH:7]1[CH2:16][CH2:15][C:10]2([O:14][CH2:13][CH2:12][O:11]2)[CH2:9][CH2:8]1)[C:5]#N)[CH3:3].C1COCC1.[F:22][C:23]1[CH:28]=[CH:27]C([Mg]Br)=[CH:25][CH:24]=1.[Cl-].[NH4+]>O>[O:14]1[C:10]2([CH2:15][CH2:16][CH:7]([CH:4]([N:2]([CH3:3])[CH3:1])[C:5]3[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=3)[CH2:8][CH2:9]2)[O:11][CH2:12][CH2:13]1
Reactant: CN(C)C(C#N)C1CCC2(CC1)OCCO2
Reactant: Fc1ccc([Mg]Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(c1ccc(F)cc1)C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of the aminonitrile 4 (19.89 g, 88 mmol) in absol. THF (160 ml) was added dropwise to a 1 M solution of 4-fluorophenylmagnesium bromide in THF (220 ml, 220 mmol) under argon and while cooling with ice and the mixture was stirred at RT for 20 h. The reaction mixture was worked up by adding saturated ammonium chloride solution (100 ml) and water (100 ml) while cooling with ice, and extracting the mixture with diethyl ether (3×100 ml). The organic phase was washed with water and saturated sodium chloride solution, dried (Na2SO4) and concentrated.
Reaction SMILES: [CH3:1][C:2]1[C:10]([NH2:11])=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:12][CH2:13][C:14](=O)[CH2:15][CH3:16].[BH3-]C#N.[Na+].C(O)(=O)C>CO>[CH2:13]([CH:14]([NH:11][C:10]1[C:2]([CH3:1])=[N:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12)[CH2:15][CH3:16])[CH3:12]
Reactant: CCC(=O)CC
Reactant: Cc1nn2ccccc2c1N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCC(CC)Nc1c(C)nn2ccccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.3 %

Procedure:
To a suspension of 2-methyl-3-amino-pyrazolo[1,5-a]pyridine (0.158 g, 1.07 mmol) and 3-pentanone (0.11 g, 0.14 mL, 1.29 mmol) in methanol (5.0 mL) was added NaCNBH3 (0.095 g, 1.5 mmol) and a drop of acetic acid. The mixture was stirred at room temperature for 18 h. The reaction was partitioned between CH2Cl2 and H2O. The layers were separated and the aqueous layer was extracted with CH2Cl2 (2×). The organic layers were combined and dried over MgSO4 and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography (15% ethyl acetate/hexane) to give 0.196 g (85%) of a yellow oil as the title compound: 1H NMR (400 MHz, CDCl3) δ 8.25 (d, J=7.0 Hz, 1H), 7.37 (d, J=8.9 Hz, 1H), 6.99–6.95 (m, 1H), 6.59 (t, J=6.8 Hz, 1H), 2.87 (quintet, J=5.9 Hz, 1H), 2.44 (s, 3H), 1.57–1.47 (m, 4H), 1.01 (t, J=7.4 Hz, 6H); HRMS (FAB) calcd for C13H19N3+H 218.1657. found 218.1647.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:13][C:14]([C:17]3[C:18]([O:27][CH3:28])=[C:19]([CH2:24][CH:25]=O)[CH:20]=[C:21]([F:23])[CH:22]=3)=[CH:15][N:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].C(O)(=O)C.C([O-])(=O)C.[Na+].[NH:38]1[CH2:41][CH:40]([C:42]([O:44][CH3:45])=[O:43])[CH2:39]1>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:13][C:14]([C:17]3[C:18]([O:27][CH3:28])=[C:19]([CH2:24][CH2:25][N:38]4[CH2:41][CH:40]([C:42]([O:44][CH3:45])=[O:43])[CH2:39]4)[CH:20]=[C:21]([F:23])[CH:22]=3)=[CH:15][N:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: COc1c(CC=O)cc(F)cc1-c1cnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Reactant: COC(=O)C1CNC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: COC(=O)C1CN(CCc2cc(F)cc(-c3cnc(-c4ccc(OC(C)C)c(Cl)c4)s3)c2OC)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.2 %

Procedure:
To a solution of [3-(2-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazol-5-yl)-5-fluoro-2-(methyloxy)phenyl]acetaldehyde (D80) (95 mg), acetic acid (0.044 mL) and sodium acetate (113 mg) in ethanol (20.00 mL) stirred under nitrogen at room temperature was added methyl 3-azetidinecarboxylate (106 mg) in one charge. The reaction mixture was stirred at room temperature for 1 h, then the solvent was evaporated in vacuo. The residue was dissolved in dichloromethane (DCM) (20 mL), sodium triacetoxyborohydride (195 mg) was added to the mixture. The reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate (100 mL) and saturated brine (30 mL). The organic phase was dried over sodium sulphate and evaporated in vacuo to give the crude product methyl 1-{2-[3-(2-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazol-5-yl)-5-fluoro-2-(methyloxy)phenyl]ethyl}-3-azetidinecarboxylate (D82) (100 mg). The crude product was used for next step without further purification. MS (ES): C26H28ClFN2O4S requires 518. found 519.2 (M+H+).
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.Cl.[CH2:14]([O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][C:23]=1[O:30][CH3:31])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][CH:42]([C:45](O)=[O:46])[CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33].C(N(CC)CC)C>C(Cl)Cl>[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][CH:42]([C:45](=[O:46])[NH:27][CH2:26][C:25]2[CH:28]=[CH:29][C:22]([O:21][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:23]([O:30][CH3:31])[CH:24]=2)[CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33]
Reactant: COc1cc(CN)ccc1OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(CNC(=O)C2CCN(C(=O)OC(C)(C)C)CC2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 71.7 %

Procedure:
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (12.5 g) was added to a mixture of 4-benzyloxy-3-methoxy benzylamine hydrochloride (14.0 g), 1-(t-butoxycarbonyl)-piperidine-4-carboxylic acid (11.5 g), triethylamine (14.0 ml) and methylene chloride (300 ml). After stirring the reaction mixture at room temperature for 20 hours, the mixture was washed with saturated ammonium chloride aqueous solution and then saturated brine, the organic layer was dried over sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: hexane/ethyl acetate=100/0 to 0/100 gradient) to obtain 16.3 g of t-butyl-4-(4-benzyloxy-3-methoxybenzylcarbamoyl)-piperidine-1-carboxylate.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:31])=[C:8]2[C:13](=[CH:14][C:15]=1[CH3:16])[N:12]=[C:11]([CH2:17][OH:18])[N:10]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](=[O:29])(=[O:28])[NH:26][CH3:27])[C:9]2=[O:30])=[O:5])[CH3:2].[CH2:32](OC(C1C(C)=C2C(=CC=1C)N=C(COCC1C=CC=CC=1)N(C1C=CC=CC=1S(=O)(=O)NC)C2=O)=O)[CH3:33].C(OCC)C>C1COCC1.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:31])=[C:8]2[C:13](=[CH:14][C:15]=1[CH3:16])[N:12]=[C:11]([CH2:17][OH:18])[N:10]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](=[O:29])(=[O:28])[NH:26][CH3:27])[C:9]2=[O:30])=[O:5])[CH2:2][CH2:32][CH3:33]
Reactant: CCOC(=O)c1c(C)cc2nc(COCc3ccccc3)n(-c3ccccc3S(=O)(=O)NC)c(=O)c2c1C
Reactant: CCOC(=O)c1c(C)cc2nc(CO)n(-c3ccccc3S(=O)(=O)NC)c(=O)c2c1C
Agent: [Pd]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCOC(=O)c1c(C)cc2nc(CO)n(-c3ccccc3S(=O)(=O)NC)c(=O)c2c1C
Reaction time: 8 h

Procedure:
Preparation of 2-Hydroxymethyl-5,7-dimethyl-3-(2-methylsulfamoyl-phenyl)-4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid ethyl ester: A solution of 2-Benzyloxymethyl-5,7-dimethyl-3-(2-methylsulfamoyl-phenyl)-4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid ethyl ester (15 g, 0.028 mol) in anhydrous THF (270 mL) is degassed under house vacuum. Palladium on activated charcoal (Acros, 10% Pd, 930 mg) is added and the suspension is flushed with hydrogen (balloon). The suspension is stirred under hydrogen overnight. TLC and LCMS analysis indicates that starting material remained. The reaction mixture is filtered through Celite, and the catalyst is washed sequentially with methanol, DCM and methanol. The filtrate is evaporated to give a cream solid. Trituration with diethyl ether provides a white solid which is removed by filtration and dried under high vacuum to provide the title compound. The ethereal filtrate, which contains un-reacted starting material, is evaporated in vacuo and the residue is subjected to a second cycle of hydrogenation (Pd—C, 920 mg): after stirring overnight under hydrogen TLC/LCMS indicated absence of starting material. The reaction mixture is worked-up as above to provide the title compound as a white solid.
Reaction SMILES: [C:1]1([C:7]2[S:8][C:9]([C:16]([OH:18])=O)=[C:10]([C:12]([F:15])([F:14])[F:13])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[F:52][C:53]([F:65])([F:64])[O:54][C:55]1[CH:56]=[C:57]([CH:61]([NH2:63])[CH3:62])[CH:58]=[CH:59][CH:60]=1.CCN(CC)CC>CN(C=O)C.CN(C1C=CN=CC=1)C>[F:52][C:53]([F:64])([F:65])[O:54][C:55]1[CH:56]=[C:57]([CH:61]([NH:63][C:16]([C:9]2[S:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:11][C:10]=2[C:12]([F:13])([F:14])[F:15])=[O:18])[CH3:62])[CH:58]=[CH:59][CH:60]=1
Reactant: CC(N)c1cccc(OC(F)(F)F)c1
Reactant: O=C(O)c1sc(-c2ccccc2)nc1C(F)(F)F
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(NC(=O)c1sc(-c2ccccc2)nc1C(F)(F)F)c1cccc(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 42.3 %

Procedure:
To a solution of 2-phenyl-4-trifluoromethyl-thiazole-5-carboxylic acid (35 mg, 0.128 mmol) in DMF (1 mL) was added PyBOP (73 mg, 0.141 mmol) and DMAP (16 mg, 0.128 mmol). A solution of 1-(3-trifluoromethoxyphenyl)-ethylamine (27 mg, 0.128 mmol) in DMF (0.5 mL) was then added, followed by Et3N (36 μL, 0.256 mmol). This mixture was stirred at 25° C. for 18 h. The reaction mixture was applied directly to a preparatory HPLC column for purification (C18, 10-100% methanol/water/0.1% trifluoroacetic acid) which gave the amide as a white solid (24.9 mg, 42%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:26][C:27]([F:37])([F:36])[C:28]([NH:30][CH:31]1[CH2:35][CH2:34][NH:33][CH2:32]1)=[O:29].C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:33]1[CH2:34][CH2:35][CH:31]([NH:30][C:28](=[O:29])[C:27]([F:37])([F:36])[F:26])[CH2:32]1)=[O:6])[C:11]([NH:13][CH:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: O=C(NC1CCNC1)C(F)(F)F
Agent: ClCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(NC(=O)c1ccc(C(=O)N2CCC(NC(=O)C(F)(F)F)C2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, 3-(2,2,2-trifluoroacetylamino)pyrrolidine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 4.34 minutes; C23H20Cl2F3N5O3 (542.34); mass spectrum: (M−H)−=541/543/545 (chlorine isotope).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:15](Br)[CH:16]([CH3:18])[CH3:17]>CC(C)=O.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)COc1ccc(Br)cc1
Yield: 60.2 %

Procedure:
4-Bromo-phenol (2 g, 11.6 mmol) is dissolved in acetone (40 mL). Potassium carbonate (8 g, 38.4 mmol) is then added followed by isobutyl bromide (4 g, 29.2 mmol). The reaction is heated to reflux for four days, refilling solvent as necessary. The reaction mixture is diluted with water and extracted with ether, the organic layer is separated and concentrated in vacuo. The residue is dissolved in hexane dried with magnesium sulfate, and filtered through a plug of silica gel. The solvent is removed in vacuo to afford 1.6 g (60% yield) of the title compound as a colorless non-viscous oil. 1H NMR (CDCl3) 1.01 (d, 6H, J=6.56 Hz), 2.05-2.08 (m, 1H), 3.67 (d, 2H, J=6.57 Hz), 6.77 (d, 2H, J=9.09 Hz), 7.36 (d, 2H, J=9.09 Hz).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[CH:11]=[CH:12]/[C@H:13]2[CH2:18][CH2:17][C@H:16]([S:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[CH2:15][CH2:14]2)=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:38])C=1.S([O-])([O-])=O.[Na+].[Na+].C(OCC)(=O)C>C(Cl)Cl>[F:29][C:2]([F:1])([F:28])[C:3]1[CH:4]=[CH:5][C:6](/[CH:9]=[CH:10]/[CH:11]=[CH:12]/[C@H:13]2[CH2:14][CH2:15][C@H:16]([S:19]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=3)=[O:38])[CH2:17][CH2:18]2)=[CH:7][CH:8]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: FC(F)(F)c1ccc(/C=C/C=C/[C@H]2CC[C@H](SCc3ccc(Cl)cc3)CC2)cc1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=S(Cc1ccc(Cl)cc1)[C@H]1CC[C@H](/C=C/C=C/c2ccc(C(F)(F)F)cc2)CC1
Reaction time: 0.08 h

Procedure:
In 20 ml of methylene chloride were dissolved 211 mg (0.48 mmol) of 4-chlorobenzyl trans-4-[(1E,3E)-4-[4-(trifluoromethyl)phenyl]-1,3-butadienyl]cyclohexyl sulfide, and 104 mg (0.48 mmol) of m-chloroperbenzoic acid (purity: 80%) were added to the solution at 0° C. followed by stirring of the resulting mixture for 5 minutes. An aqueous sodium sulfite solution and ethyl acetate were added to the reaction mixture and the organic layer was washed with an aqueous sodium hydrogencarbonate solution and an aqueous NaCl solution. After the mixture was dried, the crude product obtained by evaporation of the solvent was recrystallized from a mixed solvent of ethyl acetate-hexane to obtain 168 mg (yield: 77%) of the title compound having a melting point of 212 to 214° C.
Reaction SMILES: [N:1]1[C:11]2[CH2:10][CH2:9][CH2:8][C:7](=[O:12])[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Li][CH2:14]CCC.CI.[NH4+].[Cl-]>C1COCC1>[CH3:14][N:6]1[C:7](=[O:12])[CH2:8][CH2:9][CH2:10][C:11]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]1=2
Reactant: O=C1CCCc2ncccc2N1
Reactant: [Li]CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Product: CN1C(=O)CCCc2ncccc21
Temperature: 0 °C
Reaction time: 17 h

Procedure:
A solution of 1.0 eq of 96 in 30 mL of dry THF was cooled to −78° C. While stirring, 1.1 eq of n-BuLi (2.5 M in hexanes) was added dropwise. The reaction solution was warmed to 0° C. and stirred for 1 hr. The solution was then cooled to −78° C. and 1.2 eq of methyl iodide was slowly added. The mixture was stirred, as the solution warmed to rt. After 17 hrs, 50 mL of saturated NH4Cl was added and extracted with EtOAc (3×50 mL). The combined organic extracts were dried over MgSO4 and vacuum filtered. The filtrate was rotary evaporated and dried under vacuum to afford a dark orange colored solid as 97.
Reaction SMILES: [Na].C[O-].[CH3:4][C:5]1[N:10]=[CH:9][C:8]([CH2:11][C:12]#[N:13])=[CH:7][CH:6]=1.[CH3:14][C:15]1[CH:16]=[CH:17][C:18]([N+:23]([O-:25])=[O:24])=[C:19]([CH:22]=1)[CH:20]=O>CO.O>[CH3:14][C:15]1[CH:16]=[CH:17][C:18]([N+:23]([O-:25])=[O:24])=[C:19](/[CH:20]=[C:11](\[C:8]2[CH:9]=[N:10][C:5]([CH3:4])=[CH:6][CH:7]=2)/[C:12]#[N:13])[CH:22]=1
Reactant: Cc1ccc(CC#N)cn1
Reactant: Cc1ccc([N+](=O)[O-])c(C=O)c1
Agent: C[O-]
Agent: [Na]
Solvent: CO
Solvent: O
Product: Cc1ccc([N+](=O)[O-])c(/C=C(/C#N)c2ccc(C)nc2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 54.9 %

Procedure:
Sodium metal (1.9 g, 0.0848 mol) was dissolved in MeOH (180 mL), and the resulting methoxide solution was cooled to 0° C. To this was added 2-(6-methylpyridin-3-yl)acetonitrile (11.19 g, 0.0848 mol), and the reaction mixture was stirred for 30 min. at 0° C. 5-Methyl-2-nitrobenzaldehyde (7.0 g, 0.0424 mol) was added at 0° C., and the mixture was further stirred for 1 h at 0° C. After completion of reaction (monitored by TLC), the mixture was diluted with water (100 mL), and extracted with EtOAc (3×150 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by column chromatography (20% EtOAc:hexane in silica 100-200 mesh, diameter of column—5.0 cm, height of silica—approx. 5 inch) to give the desired compound as a yellow colored solid (6.5 g, 59% yield).
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]1[S:10][C:9]([C:11]([OH:13])=O)=[CH:8][CH:7]=1)(=[O:4])=[O:3].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:47][C@@H:48]([CH2:62][C:63]1[CH:68]=[C:67]([F:69])[CH:66]=[C:65]([F:70])[CH:64]=1)[C@H:49]([OH:61])[CH2:50][NH:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[C:55]([CH2:59][CH3:60])[CH:54]=1>C(Cl)Cl>[F:69][C:67]1[CH:68]=[C:63]([CH:64]=[C:65]([F:70])[CH:66]=1)[CH2:62][C@H:48]([NH:47][C:11]([C:9]1[S:10][C:6]([CH2:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:7][CH:8]=1)=[O:13])[C@H:49]([OH:61])[CH2:50][NH:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[C:55]([CH2:59][CH3:60])[CH:54]=1
Reactant: CS(=O)(=O)Cc1ccc(C(=O)O)s1
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1cccc(CNC[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2ccc(CS(C)(=O)=O)s2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 16.1 %

Procedure:
To a solution of acid from step 5 (115 mg, 0.52 mmol) and N,N-diisopropylethylamine (540 μL, 3.12 mmol) in methylene chloride (6.5 mL) was added HBTU (200 mg, 0.52 mmol) and the reaction mixture was stirred for 0.5 h. (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol (211 mg, 0.52 mmol) was added in one portion and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with methylene chloride and washed with saturated sodium bicarbonate, and saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash chromatography (silica, 1-5% methanol in chloroform) gave the title compound (45 mg): mp 128-131° C.; ESI MS m/z 537 [M+H]+.