Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:6]2[C:11]([F:12])=[C:10]([NH:13][NH2:14])[N:9]=[C:8]([CH3:15])[N:7]=2)[CH2:5][CH:4]=[CH:3][CH2:2]1.[CH:16]1([CH2:21][C@H:22]([CH2:26][N:27]([CH:35]=[O:36])[O:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][O:30]2)[C:23](O)=[O:24])[CH2:20][CH2:19][CH2:18][CH2:17]1.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.C(Cl)CCl>CN(C=O)C>[CH:16]1([CH2:21][C@@H:22]([C:23]([NH:14][NH:13][C:10]2[C:11]([F:12])=[C:6]([N:1]3[CH2:2][CH:3]=[CH:4][CH2:5]3)[N:7]=[C:8]([CH3:15])[N:9]=2)=[O:24])[CH2:26][N:27]([O:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][O:30]2)[CH:35]=[O:36])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OC1CCCCO1
Reactant: Cc1nc(NN)c(F)c(N2CC=CC2)n1
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OC2CCCCO2)c(F)c(N2CC=CC2)n1
Yield: 42 %

Procedure:
4-(2,5-Dihydro-1H-pyrrol-1-yl)-5-fluoro-6-hydrazino-2-methylpyrimidine (142 mg, 0.68 mmol), (2R)-3-cyclopentyl-2-{[formyl(tetrahydro-2H-pyran-2-yloxy)amino]methyl}propanoic acid (242 mg, 0.81 mmol), and HOAt (110 mg, 0.81 mmol) were dissolved in 4 mL of DMF. NMM (370 μL, 3.4 mmol) was added, followed by EDC (155 mg, 0.81 mmol). When the starting materials were consumed, the reaction mixture was purified by RP-HPLC to provide ((2R)-2-(cyclopentylmethyl)-3-{2-[6-(2,5-dihydro-1H-pyrrol-1-yl)-5-fluoro-2-methyl-4-pyrimidinyl]hydrazino}-3-oxopropyl)(tetrahydro-2H-pyran-2-yloxy)formamide (140 mg, 55%).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([O:11][C:12]([N:14]1[CH2:17][CH:16]([CH:18]=O)[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].[C:20]([O:23][CH2:24][CH3:25])(=[O:22])[CH3:21].Cl>O1CCCC1>[C:7]([O:11][C:12]([N:14]1[CH2:15][CH:16](/[CH:18]=[CH:21]/[C:20]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17]1)=[O:13])([CH3:8])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CC(C=O)C1
Reactant: CCOC(C)=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/C1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Triethyl phosphonoacetate (1.9 mL; 9.72 mmol) was dissolved in tetrahydrofuran (30 mL). Potassium tert-butoxide (1.1 g; 9.72 mmol) was added portionwise. 3-Formylazetidine-1-car-boxylic acid tert-butyl ester (1.0 g; 5.40 mmol) was dissolved in tetrahydrofuran (6 mL) and added to the reaction mixture. The reaction mixture was stirred for 1 hour at room temperature. Ethyl acetate (100 mL) and hydrochloric acid (100 mL; 1N) were added and the phases were separated. The aqueous phase was extracted with ethyl acetate (2×50 mL) and the combined organic phases were washed with saturated sodium hydrogen carbonate (100 mL), dried (magnesium sulfate) and evaporated in vacuo. The residue was chromatographed on silica (3×30 cm) using ethyl acetate/heptane (1:1) as eluent to afford 1.0 g of 3-((E)-2-ethoxycarbonylvinyl)azetidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [C:1]1([C:7](=O)[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]([O:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([N+:28]([O-:30])=[O:29])[C:26]=1[OH:27])[CH:22]=O)[CH3:17].[CH3:31][NH:32][C:33]([NH2:35])=[O:34].Cl>CCO.CO.CCOC(C)=O>[CH2:16]([O:18][C:19]1[CH:20]=[C:21]([CH:22]2[C:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:32]([CH3:31])[C:33](=[O:34])[NH:35]2)[CH:24]=[C:25]([N+:28]([O-:30])=[O:29])[C:26]=1[OH:27])[CH3:17]
Reactant: O=C(Cc1ccccc1)c1ccccc1
Reactant: CNC(N)=O
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CO
Product: CCOc1cc(C2NC(=O)N(C)C(c3ccccc3)=C2c2ccccc2)cc([N+](=O)[O-])c1O
Yield: 15.2 %

Procedure:
A mixture of 1,2-diphenylethanone (400 mg, 2.04 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (430 mg, 2.04 mmol), and 1-methylurea (454 mg, 6.12 mmol) in anhydrous EtOH was added concentrated HCl (204 mg, 2.04 mmol), and the reaction mixture was refluxed for 3 days. When TLC (EtOAc:MeOH=10:1) showed that the starting materials were consumed, the reaction mixture was concentrated, and purified by preparative HPLC to afford Compound 11 as a yellow solid (138 mg, yield: 15.2%). 1H NMR (DMSO-d6 400 MHz TMS): δ 10.25 (s, 1H), 7.68 (d, J=2.8 Hz, 1H), 7.45 (s, 1H), 7.20-7.28 (m, 3H), 7.15-7.20 (m, 3H), 6.85-6.95 (m, 3H), 6.70 (d, J=6.4 Hz, 1H), 5.00 (d, J=2.4 Hz, 1H), 4.02 (m, 2H), 2.60 (s, 3H), 1.30 (t, J=7.0 Hz, 3H); MS (ESI): m/z 446.2 [M+1]+.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13]Br)=[N:5]1)(=[O:3])[CH3:2].Cl.[CH2:16]([CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCN(C(C)C)C(C)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13][N:27]2[CH2:28][CH2:29][CH:24]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:25][CH2:26]2)=[N:5]1)(=[O:3])[CH3:2]
Reactant: c1ccc(CCC2CCNCC2)cc1
Reactant: CC(=O)n1nc(CBr)c2ccccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)n1nc(CN2CCC(CCc3ccccc3)CC2)c2ccccc21
Temperature: 20 °C
Reaction time: 16 h
Yield: 13.7 %

Procedure:
1-Acetyl-3-bromomethyl-1H-indazole (0.50 g, 1.98 mmol) in CH2Cl2 (25 mL) was treated with 4-phenethylpiperidine hydrochloride (0.893 g, 3.96 mmol) and Hunig's base (0.78 g, 5.94 mmol) and the mixture stirred at 20° C. for 16 h. The mixture was poured into saturated aqueous sodium bicarbonate solution (25 mL) and extracted with CH2Cl2 (3×25 mL). The combined organic extracts were dried (MgSO4), concentrated and the residue purified by flash chromatography (0%→10% EtOAc in hexane) to give 1-acetyl-3-(4-phenethylpiperidin-1-ylmethyl)-1H-indazole as a colourless oil (98 mg, 14%). This was dissolved in CH2Cl2 /methanol (1:1, 10 mL), treated with NaOMe (2 mg) and stirred for 15 min at 20° C. The mixture was poured into saturated aqueous sodium bicarbonate solution (25 mL) and extracted with CH2Cl2 (3×25 mL). The combined organic extracts were dried (MgSO4), concentrated and the residue recrystallised from EtOAc/hexane to give the title compound (55 mg, 69%) as colourless crystals; mp 153°-155° C. (from EtOAc/hexane); 1H NMR (360 MHz, d6 -DMSO) δ 12.75 (bs, 1H, NH), 7.84 (d, J=8.1 Hz, 1H, indazole), 7.46 (d, J=8.4 Hz, 1H, indazole), 7.31 (t, J=6.7 Hz, 1H, indazole), 7.27-7.12 (m, 5H, Ph), 7.07 (t, J=7.1 Hz, 1H, indazole), 3.78 (s, 2 H, Ar--CH2N), 2.85 (m, 2 H, aliphatic), 2.56 (m, 2 H, aliphatic), 1.94 (m, 2H, aliphatic), 1.65 (m, 2H, aliphatic), 1.47 (m, 2H, aliphatic), 1.16 (m, 3H, aliphatic); MS (CI+) m/e 320 (M+H+); Anal. calcd for C21H25N3 : C, 78.96; H, 7.89; N, 13.15. Found: C, 78.94; H, 7.96; N, 12.89.
Reaction SMILES: [N:1]#[C:2][NH2:3].[Na].[F:5][C:6]1[CH:16]=[CH:15][C:9]([O:10][CH2:11][CH:12]2[CH2:14][O:13]2)=[CH:8][CH:7]=1>CO>[F:5][C:6]1[CH:16]=[CH:15][C:9]([O:10][CH2:11][CH:12]2[O:13][C:2]([NH2:3])=[N:1][CH2:14]2)=[CH:8][CH:7]=1
Reactant: N#CN
Reactant: Fc1ccc(OCC2CO2)cc1
Agent: [Na]
Solvent: CO
Product: NC1=NCC(COc2ccc(F)cc2)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.6 %

Procedure:
To a vigorously stirred solution of sodium hydrogen cyanamide (0.64 g, 10.0 mmol) in methanol (10 mL) was added dropwise 2-(4-fluoro-phenoxymethyl)-oxirane (1.68 g, 10 mmol) after which the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated to remove methanol. Anhydrous diethyl ether (50 mL) was added after which the resulting white precipitate was removed by filtration through celite and the filtrate concentrated. The residue was purified by flash chromatography (silica, 7N NH3 in methanol/methylene chloride) to give 0.77 g (37%) of 5-(4-fluorophenoxymethyl)-(4,5-dihydro-oxazol-2-yl)amine.
Reaction SMILES: Cl.[C:2]12([CH2:12][CH2:13][NH2:14])[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2.[Cl:15][C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19]>>[Cl:15][C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([NH:14][CH2:13][CH2:12][C:2]12[CH2:9][CH:8]3[CH2:7][CH:6]([CH2:5][CH:4]([CH2:10]3)[CH2:3]1)[CH2:11]2)=[O:19]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: NCCC12CC3CC(CC(C3)C1)C2
Agent: Cl
Product: O=C(NCCC12CC3CC(CC(C3)C1)C2)c1ccccc1Cl

Procedure:
Prepared according, to the method of Example 1 from 1-adamantaneethylamine hydrochloride (0.055 g) and 2-chlorobenzoyl chloride (0.033 ml) to give the title compound as a white solid (0.074 g).
Reaction SMILES: N[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](O)([C:13]([F:16])([F:15])[F:14])[CH2:5][C:6](=[O:12])[NH:7]2.N([O-])=[O:19].[Na+]>OS(O)(=O)=O.O>[OH:19][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([C:13]([F:16])([F:15])[F:14])=[CH:5][C:6](=[O:12])[NH:7]2
Reactant: O=N[O-]
Reactant: Nc1cccc2c1C(O)(C(F)(F)F)CC(=O)N2
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=c1cc(C(F)(F)F)c2c(O)cccc2[nH]1
Temperature: 145 °C
Yield: 83.6 %

Procedure:
To a solution of 5-amino-3,4-dihydro-4-hydroxy-4-(trifluoromethyl)-1H-quinolin-2-one (6.0 g, 24 mmol) in 100 mL 4.8 M H2SO4 was added a solution of NaNO2 (1.85 g, 26.8 mmol) in 6 mL water at 0° C. The reaction mixture became deep red. This solution was transferred to 120 mL 10M H2SO4 preheated to 145° C. The mixture was heated at 145° C. for 0.5 h, then poured into 400 g of ice water. The crude solid was adsorbed onto silica gel and eluted with 9:1 CH2Cl2:MeOH to afford 4.6 g (82%) of 5-hydroxy-4-(trifluoromethyl)-1H-quinolin-2-one, an off-white solid. 1H NMR (400 MHz, acetone-d6) δ 11.0 (broad s, 1H), 9.64 (s, 1H), 7.42 (t, 1H, J=8.1), 6.99 (d, 1H, J=8.1), 6.90 (s, 1H), 6.79 (d, 1H, J=8.1).
Reaction SMILES: C(OC([NH:8][CH:9]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[S:22][C:23]3[C:28]([N:29]=2)=[CH:27][CH:26]=[C:25]([C:30]2([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH2:32][CH2:31]2)[N:24]=3)=[C:17]([F:39])[CH:16]=1)[C:10]([OH:12])=[O:11])=O)(C)(C)C.C(OC(C(CCC1C=CC(C2SC3C(N=2)=CC=C(C2(C4C=CC=CC=4)CC2)N=3)=C(F)C=1)C(O)=O)=O)(C)(C)C.[F:78][C:79]([F:84])([F:83])[C:80]([OH:82])=[O:81]>C(Cl)Cl>[F:78][C:79]([F:84])([F:83])[C:80]([OH:82])=[O:81].[NH2:8][C@H:9]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[S:22][C:23]3[C:28]([N:29]=2)=[CH:27][CH:26]=[C:25]([C:30]2([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH2:32][CH2:31]2)[N:24]=3)=[C:17]([F:39])[CH:16]=1)[C:10]([OH:12])=[O:11].[F:78][C:79]([F:84])([F:83])[C:80]([OH:82])=[O:81].[NH2:8][C@@H:9]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[S:22][C:23]3[C:28]([N:29]=2)=[CH:27][CH:26]=[C:25]([C:30]2([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH2:32][CH2:31]2)[N:24]=3)=[C:17]([F:39])[CH:16]=1)[C:10]([OH:12])=[O:11]
Reactant: CC(C)(C)OC(=O)NC(CCc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1)C(=O)O
Agent: CC(C)(C)OC(=O)C(CCc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1)C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H](CCc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1)C(=O)O
Product: N[C@H](CCc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1)C(=O)O
Reaction time: 0.08 h

Procedure:
Separately, the enantiomers of 2-(tert-butoxycarbonylamino)-4-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)butanoic acid were processed by the following procedure: 2-(tert-butoxycarbonyl)-4-(3-fluoro-4-(5-(1-phenylcyclopropyl)-thiazolo[5,4-b]pyridin-2-yl)phenyl)butanoic acid (0.047 g, 0.086 mmol) in DCM (2.0 mL) was added trifluoroacetic acid (1.0 mL, 13 mmol). After 5 min, the solvent was removed, the solid rinsed with water and diethyl ether to give both (R)-2-amino-4-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)butanoic acid trifluoroacetic acid salt and (S)-2-amino-4-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)butanoic acid trifluoroacetic acid salt. MS (ESI) m/z: calculated: 447.1; Observed: 448.1 (M++1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([OH:13])=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:14](OC(=O)C)(=O)C>N1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11](=[O:13])[CH3:14])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(O)Cc1cccc([N+](=O)[O-])c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Cc1cccc([N+](=O)[O-])c1

Procedure:
A mixture of 3-nitrophenyl acetic acid (20 g), pyridine (44 g) and acetic anhydride (106 g) was refluxed for four hours. Complete disappearance of starting material was observed by tlc (silica gel eluted with 1:1 parts by volume diethyl ether:hexane), and the brown solution was then evaporated to dryness in vacuo at 40°. The resulting residue was refluxed in the presence of concentrated HCl (7.5 ml) and ethanol (78 ml) for one hour; and to the hydrolysis product was added ice water (400 ml) and the precipitating 3-nitrophenyl acetone was filtered and washed with water. Additional product was obtained by extracting the filtrate with methylene chloride, drying over sodium sulfate, and evaporating the organic solvents. The crude products were combined and dissolved in a minimum amount of methanol:methylene chloride (1:1 parts by volume). Silica gel (30-50 g, flash chromatography, EM 230-400 mesh) was added and the solvent evaporated. The dried silica gel was placed on a column (3in.×6 in.) containing the same silica gel and eluted with 4:6 parts by volume ethyl acetate:hexane. The solution containing the desired product was evaporated to give the title compound. NMR for this product (in CDCl3) shows a 3 proton singlet at 2.34 ppm; a 2 proton singlet at 3.63 ppm; a 2 proton multiplet at 7.5 ppm; and a 2 proton multiplet at 8.0 ppm.
Reaction SMILES: N1C=CC=CC=1.[OH:7][N:8]=[C:9]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)[C:10]#[N:11].[C:17]([O:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)(=[O:19])[CH3:18].C(OCC)C>CN(C)C1C=CN=CC=1.O1CCCC1>[C:17]([O:20][C:21]1[CH:22]=[CH:23][C:24]([S:27]([O:7][N:8]=[C:9]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[C:10]#[N:11])(=[O:29])=[O:28])=[CH:25][CH:26]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)Oc1ccc(S(=O)(=O)Cl)cc1
Reactant: N#CC(=NO)c1cccs1
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(S(=O)(=O)ON=C(C#N)c2cccs2)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 53.5 %

Procedure:
200 mg of 4-dimethylaminopyridine and 6.2 g (0.08 mole) of pyridine are added to a solution of 12 g (0.08 mole) of α-hydroxyiminothien-2-ylacetonitrile (3b) in 75 ml of tetrahydrofuran. With cooling to 0° C., a solution of 18.5 g (0.08 mole) of 4-acetoxybenzenesulfonyl chloride (3a) in 30 ml of tetrahydrofuran is added dropwise. The reaction mixture is stirred for 16 hours at room temperature, and 100 ml of diethyl ether are subsequently added. The precipitated salts are removed by filtration and the solution is concentrated by evaporation. The residual crude product is recrystallised from hexane/ethyl acetate, affording 15 g of crystals with a melting point of 114°-115° C.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][C@H:11]([CH2:13][CH:14]=[CH2:15])[CH3:12])[CH:3]=1.[CH3:16][Mg]I>C(OCC)C.O>[CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([OH:7])[CH3:16])=[C:4]([O:10][C@H:11]([CH2:13][CH:14]=[CH2:15])[CH3:12])[CH:3]=1
Reactant: C[Mg]I
Reactant: C=CC[C@H](C)Oc1cc(C)ccc1C=O
Solvent: O
Solvent: CCOCC
Product: C=CC[C@H](C)Oc1cc(C)ccc1C(C)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
To a mixture of (S)-4-methyl-2-(pent-4-en-2-yloxy)benzaldehyde (50 mg, 0.245 mmol) in diethyl ether (2 mL) was added methylmagnesium iodide (0.245 mL, 0.734 mmol) and the mixture was stirred at rt for 1 h. It was then diluted with water, extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by biotage, eluting with 25% EtOAc/hexane to obtain 1-(4-methyl-2-((S)-pent-4-en-2-yloxy)phenyl)ethanol (50 mg, 93%) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.19 (dd, J=7.7, 3.8 Hz, 1H), 6.76 (d, J=7.8 Hz, 1H), 6.71 (s, 1H), 5.88 (ddtd, J=17.2, 10.3, 7.0, 3.5 Hz, 1H), 5.22-5.10 (m, 2H), 5.10-4.96 (m, 1H), 4.62-4.47 (m, 1H), 2.94 (dd, J=18.8, 5.4 Hz, 1H), 2.64-2.38 (m, 2H), 2.34 (s, 3H), 1.51 (d, J=6.6 Hz, 3H), 1.37 (dd, J=6.0, 4.0 Hz, 3H).
Reaction SMILES: [F:1][CH:2]([F:23])[C:3]([NH:5][CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17]C)[CH:15]=2)[NH:10][C:9]=1[C:19]([NH:21][CH3:22])=[O:20])=[O:4].ClCCl.B(Br)(Br)Br>CO>[F:23][CH:2]([F:1])[C:3]([NH:5][CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[NH:10][C:9]=1[C:19]([NH:21][CH3:22])=[O:20])=[O:4]
Reactant: CNC(=O)c1[nH]c2ccc(OC)cc2c1CCNC(=O)C(F)F
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: CNC(=O)c1[nH]c2ccc(O)cc2c1CCNC(=O)C(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.3 %

Procedure:
To a mixture of 3-{2-[(difluoroacetyl)amino]ethyl}-5-methoxy-N-methyl-1H-indole-2-carboxamide (2.52 g) and dichloromethane (50.0 mL) was added boron tribromide (1.0 M dichloromethane solution, 23.3 mL) under ice-cooling, followed by slowly warming to room temperature, and then stirring at room temperature overnight. The reaction mixture was cooled to −15° C. and methanol (5.00 mL) was added thereto, followed by warming to room temperature. The reaction mixture was concentrated under reduced pressure and then the residue was purified by silica gel column chromatography (chloroform:methanol=100:0 to 5:1) to obtain 3-{2-[(difluoroacetyl)amino]ethyl}-5-hydroxy-N-methyl-1H-indole-2-carboxamide (2.37 g) as a yellow solid.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].CO[C:7](=[O:15])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Br:14])[CH:9]=1.[Cl-].[NH4+].O1CC[CH2:20][CH2:19]1>>[Br:14][C:10]1[CH:9]=[C:8]([C:7]([OH:15])([CH2:1][CH3:2])[CH2:19][CH3:20])[CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)c1cccc(Br)c1
Reactant: C1CCOC1
Reactant: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Product: CCC(O)(CC)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethylmagnesium bromide (3 mol/l solution in diethyl ether, 34.1 mL, 102.3 mmol) was added to a solution of 3-bromobenzoic acid methyl ester (10 g, 46.51 mmol) in tetrahydrofuran (100 mL) in a nitrogen atmosphere at −78° C. The mixture was stirred at the same temperature for one hour and then heated to room temperature. The reaction mixture was poured into a saturated aqueous ammonium chloride solution, followed by extraction with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and filtered, and the solvent was distilled off under reduced pressure to give crude 3-(3-bromo-phenyl)-pentan-3-ol.
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:5]([C@H:14]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:4]1)=O.[OH:31][C:32]1([CH2:38][CH2:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.Cl.CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[OH:31][C:32]1([CH2:38][CH2:39][CH2:40][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH2:37][CH2:36][N:35]([CH2:1][C@@H:3]2[C@@H:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:6][N:5]([C@H:14]([CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:4]2)[CH2:34][CH2:33]1
Reactant: O=C[C@H]1CN([C@@H](C(=O)OCc2ccccc2)C2CCCCC2)C[C@@H]1c1ccccc1
Reactant: OC1(CCCc2ccccc2)CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCc1ccccc1)[C@@H](C1CCCCC1)N1C[C@H](CN2CCC(O)(CCCc3ccccc3)CC2)[C@@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
A solution of 87 mg (0.21 mmol) of 2-(R)-(3-(R)-formyl-4-(S)-phenylpyrrolidin-1-yl)-2-(cyclohexyl)acetic acid, benzyl ester (from EXAMPLE 1, Step I) and 69 mg (0.26 mmol) of 4hydroxy-4-(3-phenylpropyl)-piperidine.HCl in 5 mL of CH2Cl2 at rt was treated with 0.045 mL (0.25 mmol) of DIEA and 86 mg (0.40 mmol) of sodium triacetoxyborohydride and stirred at rt for 1 h. The reaction was diluted with 25 mL of CH2Cl2 and washed with 25 mL of 1.0 N NaHCO3. The layers were separated and the aqueous layer was extracted with 25 mL of CH2Cl2. The combined organic phases were washed with 50 mL of sat'd NaCl, dried over Na2SO4 and concentrated. Flash chromatography on silica gel using 50:1 v/v CH2Cl2/MeOH as the eluant afforded 110 mg (83%) of the title compound: RF: 0.46 (20:1 v/v CH2Cl2/MeOH); 1H NMR (300 MHz) δ 0.91-2.85 (m, 32H), 3.16-3.27 (m, 3H), 5.15 (ABq, J=12.2 Hz, 2H), 7.15-7.41 (m, 15H); NH3-CI-MS 609 (M+H).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]1[NH:14][C:13]2[CH:15]=[CH:16][C:17]([C:19](O)=[O:20])=[CH:18][C:12]=2[N:11]=1.[NH2:24][C:25]1[CH:33]=[CH:32][C:28]2[N:29]=[CH:30][S:31][C:27]=2[CH:26]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[S:31]1[C:27]2[CH:26]=[C:25]([NH:24][C:19]([C:17]3[CH:16]=[CH:15][C:13]4[NH:14][C:10]([NH:9][C:4]5[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=5[C:2]([F:22])([F:23])[F:1])=[N:11][C:12]=4[CH:18]=3)=[O:20])[CH:33]=[CH:32][C:28]=2[N:29]=[CH:30]1
Reactant: Nc1ccc2ncsc2c1
Reactant: O=C(O)c1ccc2[nH]c(Nc3ccccc3C(F)(F)F)nc2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(Nc1ccc2ncsc2c1)c1ccc2[nH]c(Nc3ccccc3C(F)(F)F)nc2c1

Procedure:
The carboxylic acid obtained as above (0.25 mmol) was coupled with 6-aminobenzothiazole (0.25 mmol) using HBTU employing general procedure D. The product, 2-(2-Trifluoromethylphenylamino)-1H-benzoimidazole-5-carboxylic acid benzothiazol-6-ylamide, was obtained as a light brown solid after purification by silica gel chromatography using DCM/methanol as eluent. MS: m/z 454 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.Br[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CS(C)=O>[C:16]1([CH2:15][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)CCc1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)CCc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A reaction mixture of methyl 3-(4-hydroxyphenyl)propanoate (commercially available, from Aldrich) (4.0 g, 22 mmol), 1-(bromomethyl)benzene (3.8 g, 22 mmol (commercially available from Aldrich)) and cesium carbonate (14.30 g, 44 mmol) in DMSO (20.0 mL) was stirred at room temperature for 2.5 hours. The reaction mixture was poured into water (50.0 mL) and extracted with EtOAc (100.0 mL), and the organic layer was washed with water (3×30 mL) and brine (30 mL), and dried with MgSO4. The crude product was recrystallized with hexane/EtOAc (98/2) to the title compound 23.1. 1H NMR (500 MHz, CDCl3) δ ppm 2.65 (t, J=7.83 Hz, 2H) 2.94 (t, J=7.83 Hz, 2H) 3.71 (s, 3H) 5.08 (s, 2H) 6.95 (d, J=8.56 Hz, 2H) 7.16 (d, J=8.56 Hz, 2H) 7.34-7.50 (m, 5H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14]([C:16]2[CH:17]=[N:18][C:19]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[N:20][CH:21]=2)=[O:15])[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)([O-])=O.[OH:27][CH2:28][CH2:29][O:30][C:31]1[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=1>>[OH:27][CH2:28][CH2:29][O:30][C:31]1[CH:38]=[CH:37][C:34]([C:35]2[NH:10][C:9]3[CH:8]=[CH:7][C:6]([NH:13][C:14]([C:16]4[CH:17]=[N:18][C:19]([N:22]5[CH2:26][CH2:25][CH2:24][CH2:23]5)=[N:20][CH:21]=4)=[O:15])=[CH:5][C:4]=3[N:1]=2)=[CH:33][CH:32]=1
Reactant: O=C(Nc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)c1cnc(N2CCCC2)nc1
Reactant: O=Cc1ccc(OCCO)cc1
Product: O=C(Nc1ccc2[nH]c(-c3ccc(OCCO)cc3)nc2c1)c1cnc(N2CCCC2)nc1

Procedure:
Compound 243 was prepared according to the procedure similar to that described in Scheme III from N-(3,4-dinitrophenyl)-2-(pyrrolidin-1-yl)pyrimidine-5-carboxamide and 4-(2-hydroxyethoxy)benzaldehyde. [M+H]+ calcd for C24H24N6O3: 445.20; found: 444.87.