Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[Cl:14][C:15]1[N:20]=[C:19](Cl)[CH:18]=[CH:17][N:16]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O.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>[Cl:14][C:15]1[N:20]=[C:19]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=2)[CH:18]=[CH:17][N:16]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: OB(O)c1ccc(C(F)(F)F)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: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccc(-c2ccnc(Cl)n2)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 27.6 %

Procedure:
4-(trifluoromethyl)phenylboronic acid (319 mg, 1.68 mmol), 2,4-dichloropyrimidine (250 mg, 1.68 mmol), Na2CO3 (445 mg, 4.20 mmol) and Pd(PPh3)4 (97.0 mg, 0.0839 mmol) were combined in a 5 mL reaction vial and diluted with toluene (3 mL) and water (300 μL). The reaction was purged with argon, heated to 60° C. and stirred overnight. The reaction was loaded directly onto silica gel and eluted with 5% ethyl acetate/hexanes to 60% ethyl acetate/hexanes to yield the desired compound (120 mg, 0.464 mmol, 27.6% yield).
Reaction SMILES: CN1CCOCC1.C(OC(Cl)=O)C(C)C.[C:16]([NH:26][C:27]([CH3:32])([C:29]([OH:31])=O)[CH3:28])([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].Cl.[CH3:34][NH:35][O:36][CH3:37].Cl>C(Cl)Cl>[CH3:37][O:36][N:35]([CH3:34])[C:29](=[O:31])[C:27]([NH:26][C:16](=[O:17])[O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)([CH3:28])[CH3:32]
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Reactant: CNOC
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CON(C)C(=O)C(C)(C)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
N-Methylmorpholine (682 mg, 741 μL, 6.74 mmol) and isobutylchloroformate (460 mg, 441 μL, 3.37 mmol) were added successively to a stirred solution of N-carbobenzyloxy-2-methylalanine (0.64 g, 2.69 mmol) in dry CH2Cl2 at 0° C. under N2. The resulting cloudy mixture was stirred at 0° C. for 90 min. N,O-Dimethylhydroxylamine hydrochloride (316 mg, 3.24 mmol) was added portionwise and the mixture was warmed to room temperature and stirred for 3 h. The mixture was poured into 1N HCl (30 mL) and extracted with CH2Cl2 (3×40 mL). The combined extracts were washed with 1N HCl (30 mL), dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 40×160 mm, 0-80% EtOAc in hexanes gradient) to afford benzyl {2-[methoxy(methyl)amino]-1,1-dimethyl-2-oxoethyl}carbamate. Rf=0.47 (50% EtOAc in hexanes). LCMS calc.=303.1; found=303.2 (M+Na)+. 1H NMR (500 MHz, CDCl3) δ 7.37-7.29 (m, 5H), 5.82 (s, 1H), 5.09 (s, 2H), 3.60 (s, 3H), 3.18 (s, 3H), 1.60 (s, 6H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH2:13][CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:2]=1.[CH:14](O)=O.C=O>O>[CH3:14][N:10]1[CH2:11][CH2:12][CH2:13][N:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH2:8][CH2:9]1
Reactant: O=CO
Reactant: c1cncc(N2CCCNCC2)c1
Agent: C=O
Solvent: O
Product: CN1CCCN(c2cccnc2)CC1

Procedure:
A solution of 1-(3-pyridyl)-homopiperazine (0.42 g, 2.4 mmol), formic acid (3.3 g, 71.7 mmol), formaldehyde (2.1 g, 37%) and water (10 ml) was stirred at reflux for 15 h. The mixture was evaporated and sodium hydroxide (15 ml, 4 M) was added and the product was extracted two times with ethyl acetate (15 ml). The product was obtained as an oil. Yield 0.46 g,100%.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([F:22])[CH:3]=1.Br[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:26].[H-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[C:7]([O:8][CH2:24][C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:26])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:17])[F:19])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([F:22])[CH:3]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(O)c(Cl)cc2F)c1=O
Reactant: O=C(CBr)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(OCC(=O)c3ccccc3)c(Cl)cc2F)c1=O

Procedure:
using 3-(4-chloro-2-fluoro-5-hydroxyphenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione with α-bromoacetophenone and sodium hydride in dimethylformamide there is obtained 3-[4-chloro-2-fluoro-5-(phenacyloxy)-phenyl]-1-methyl-6 -trifluoromethyl-2,4(1H,3H)-pyrimidinedione, m.p. 152°-153° C.;
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH2:4].[C:10](OC(=O)C)(=[O:12])[CH3:11]>C1C=CC=CC=1>[CH3:11][C:10]([NH:4][C:3]1[CH:5]=[C:6]([F:9])[CH:7]=[CH:8][C:2]=1[F:1])=[O:12]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc(F)ccc1F
Solvent: c1ccccc1
Product: CC(=O)Nc1cc(F)ccc1F
Yield: 94.2 %

Procedure:
20.5 g of 2,5-difluoroaniline was dissolved in 68 ml of benzene, and 17.8 g of acetic anhydride was dropwise added. Fifteen hours later, benzene was distilled off, and the residue was washed with ethyl ether to obtain 25.6 g of 2,5-difluoroacetanilide as white crystals. Then, this compound was dissolved in 98% sulfuric acid, and 60% nitric acid was dropwise added at a temperature of not higher than 0° C. After the dropwise addition, the mixture was stirred for three hours at room temperature, and poured on ice. Precipitated crystals were collected by filtration and dried to obtain 25.9 g of the above-identified compound as yellow crystals.
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[C:9](=[O:10])[N:8]([CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[C:7]2[CH:21]=[CH:22][CH:23]=[CH:24][C:6]=2[S:5][C:4]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[OH:31]O>C(O)(=O)C>[ClH:2].[ClH:1].[Cl:2][C:3]1[C:9](=[O:10])[N:8]([CH2:11][CH2:12][CH2:13][N:14]2[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]2)[C:7]2[CH:21]=[CH:22][CH:23]=[CH:24][C:6]=2[S:5](=[O:31])[C:4]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: OO
Reactant: CN1CCN(CCCN2C(=O)C(Cl)=C(c3ccccc3)Sc3ccccc32)CC1
Agent: Cl
Solvent: CC(=O)O
Product: CN1CCN(CCCN2C(=O)C(Cl)=C(c3ccccc3)S(=O)c3ccccc32)CC1
Reaction time: 16 h

Procedure:
3-Chloro-5-[3-(4-methyl-1-piperazinyl)propyl]-2-phenyl-1,5-benzothiazepin-4(5H)-one, hydrochloride (prepared as described in Example 1) is treated with one equivalent of hydrogen peroxide in dilute acetic acid, and allowed to stand for about 16 hours. Solvent removal yields the title compound.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:22])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15](=[O:21])[N:16]([CH3:20])[CH:17]=[CH:18][CH:19]=2)=[CH:10][CH:9]=1)[NH2:6].[Br:23][C:24]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:25]=1[C:26](O)=[O:27].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:2][O:3][C:4](=[O:22])[C@H:5]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:15](=[O:21])[N:16]([CH3:20])[CH:17]=[CH:18][CH:19]=2)=[CH:12][CH:13]=1)[NH:6][C:26]([C:25]1[CH:29]=[C:30]([O:33][CH3:34])[CH:31]=[CH:32][C:24]=1[Br:23])=[O:27]
Reactant: COc1ccc(Br)c(C(=O)O)c1
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2cccn(C)c2=O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(-c2cccn(C)c2=O)cc1)NC(=O)c1cc(OC)ccc1Br
Yield: 67.6 %

Procedure:
A solution of 4-(1-methyl-2-oxo-3-pyridinyl)-L-phenylalanine methyl ester hydrochloride (52 mg, 0.16 mmol), 2-bromo-5-methoxybenzoic acid (45 mg, 0.19 mmol), DIEA (140 μL, 0.80 mmol) and HBTU (85 mg, 0.22 mmol) in DMF (3 mL) was stirred at room temperature for 18 hr. The mixture was concentrated, the residue was dissolved in ethyl acetate (15 mL), was washed with 0.5 N HCl (1×5 mL), sat. NaHCO3 (1×5 mL), brine (1×5 mL) and was dried (MgSO4). The residue obtained upon evaporation (85 mg) was chromatographed on 25 g of silica gel, eluting with ethyl acetate to give N-[(2-bromo-5-methoxyphenyl)carbonyl]-4-(1-methyl-2-oxo-3-pyridinyl)-L-phenylalanine methyl ester (54 mg, 68%). HRMS: Obs. Mass 499.0872. Calcd. Mass 499.0869 (M+H)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:9])[CH:8]=1)[NH2:5].C[Si](Cl)(C)C.C([Li])CCC.CN(C)[CH:22]=[O:23].Cl>C1COCC1.CCCCCC>[NH2:5][C:4]1[CH:3]=[C:2]([F:1])[C:8]([CH:22]=[O:23])=[C:7]([F:9])[CH:6]=1
Reactant: Nc1cc(F)cc(F)c1
Reactant: CN(C)C=O
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Nc1cc(F)c(C=O)c(F)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 3,5-difluoroaniline (12.9 g, 0.1 mol) in anhydrous THF (400 mL) was cooled at −78° C. and treated with nbutyllithium (2.5 M in hexane, 84 mL, 0.21 mol, 2.1 equv.) dropwise over 25 min. After stirring at −78° C. for 30 min, trimethylsilyl chloride (1.0 M in THF, 210 mL, 0.21 mol, 2.1 equiv.) was added dropwise over 30 min. The temperature was allowed to rise to 23° C. and stirred overnight. After re-cooling to −78° C., additional n-butyllithium (2.5 M in hexane, 44 mL, 0.11 mol, 1.1 equiv.) was added dropwise over 20 min, and the reaction mixture was stirred at that temperature for 5 hours to form the anion. Then dimethylformamide (11.6 ml, 0.15 mol, 1.5 equiv.) was added dropwise over 20 min. The temperature was allowed to rise to 23° C. and stirred overnight. The mixture was cooled in an ice-bah and acidified to pH=1 by slow addition of aqueous HCl (1.0 M, 220 mL, 0.22 mol). After stirring 15 min, the mixture was extracted with ethyl acetate (3×200 mL). The combined organic layers were washed (brine), dried (Na2SO4), filtered and evaporated to dry. The residue was purified by chromatography on a silica gel column, eluting with a gradient increasing in polarity from 0 to 50% ethyl acetate in hexane. Relevant fractions were combined to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[CH2:7][N:8]1[C:13](=[O:14])[CH:12]=[CH:11][C:10]([C:15]([O:17]CC2C=CC=CC=2)=[O:16])=[CH:9]1)([CH3:4])([CH3:3])[CH3:2]>CCOC(C)=O.CCO.[Pd]>[C:1]([O:5][C:6](=[O:25])[CH2:7][N:8]1[C:13](=[O:14])[CH:12]=[CH:11][C:10]([C:15]([OH:17])=[O:16])=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Cn1cc(C(=O)OCc2ccccc2)ccc1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)Cn1cc(C(=O)O)ccc1=O
Temperature: 23 °C
Reaction time: 0.75 h

Procedure:
A solution of benzyl 1-(2-(tert-butoxy)-2-oxoethyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (924 mg, 2.69 mmol) in EtOAc (20 mL) and EtOH (5 mL) was treated with palladium 10 wt. % on activated carbon (143 mg, 0.135 mmol) under nitrogen. The reaction vessel was purged through 3 vacuum-hydrogen cycles, and was stirred under a hydrogen balloon at 23° C. After 45 min, the reaction was filtered through Celite® brand filter agent, the filter cake washed with MeOH (100 mL), the filtrates were combined and concentrated, affording the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.02-13.68 (br. s., 1H), 8.49 (br. s., 1H), 7.83 (d, J=9.39 Hz, 1H), 6.44 (d, J=9.19 Hz, 1H), 4.68 (br. s., 2H), 1.41 (s, 9H). MS (ESI, positive ion) m/z: 276.0 (M+H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([C:12]1[CH:33]=[CH:32][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[N:24]=[CH:25][C:18]=23)=[CH:14][CH:13]=1)(=[O:11])=[O:10].[CH:34]1([C:39](Cl)=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35]1>>[CH:34]1([C:39]([N:29]2[CH2:28][CH2:27][CH:26]([N:23]3[C:19]4=[N:20][CH:21]=[N:22][C:17]([O:16][C:15]5[CH:14]=[CH:13][C:12]([S:9]([CH3:8])(=[O:11])=[O:10])=[CH:33][CH:32]=5)=[C:18]4[CH:25]=[N:24]3)[CH2:31][CH2:30]2)=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: O=C(Cl)C1CCCC1
Reactant: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCNCC2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCN(C(=O)C3CCCC3)CC2)cc1

Procedure:
Cyclopentyl-{4-[4-(4-methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidin-1-yl}-methanone was prepared according to General Procedure I by the reaction of 4-(4-methanesulfonyl-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoroacetate salt (Intermediate 27) with cyclopentanecarbonyl chloride (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA). 1H NMR (400 MHz, DMSO-d6) δ 1.54-1.79 (m, 8H), 1.93-2.10 (m, 4H), 2.82-2.87 (m, 1H), 3.02-3.08 (m, 1H), 3.30 (methyl sulfonyl and water peak), 4.14-4.17 (m, 1H), 4.53-4.56 (m, 1H), 5.07-5.12 (m, 1H), 7.63-7.65 (m, 2H), 8.05-8.07 (m, 2H), 8.38 (s, 1H), 8.57 (s, 1H). Mass spectrum MH+=470.
Reaction SMILES: [N:1]1([CH2:10][CH2:11][C:12](=O)[CH3:13])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH3:15]>[Ni].C(OCC)(=O)C>[NH2:15][CH:12]([CH3:13])[CH2:11][CH2:10][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CC(=O)CCn1cnc2ccccc21
Reactant: N
Agent: [Ni]
Solvent: CCOC(C)=O
Product: CC(N)CCn1cnc2ccccc21

Procedure:
Benzimidazole (VIII) (1 mole), condensed with methylvinylketone in slight excess (1-1.1 mole), in the presence of a catalytic amount of Triton B (benzyltrimethylammonium hydroxide), gives 1-[1-benzimidazolyl]-3-oxo butane (IX). This reaction is conducted in a non-polar neutral solvent, such as an aromatic hydrocarbon (for example toluene) or, preferably, ethyl acetate. The ketone (IX) is converted, by known process, into its oxime ((X). The latter, by catalytic hydrogenation, in an alcoholic medium, in the presence of ammonia and Raney nickel, under pressure (20-80 bars) and heat (50° to 100° C.), results in the amine (III). ##STR6##
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][CH:3]=1.[I:10]I>FC(F)(F)C([O-])=O.[Ag+].ClCCCl>[NH2:1][C:2]1[C:3]([I:10])=[CH:4][C:5]([C:8]#[N:9])=[CH:6][N:7]=1
Reactant: N#Cc1ccc(N)nc1
Reactant: II
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCCl
Product: N#Cc1cnc(N)c(I)c1
Yield: 33.3 %

Procedure:
6-Amino-3-pyridinecarbonitrile (10.0 g, 0.081 mol), silver trifluoroacetate (25.5 g, 0.115 mol) and 160 ml of 1,2-dichloroethane are combined in a flask and heated under reflux for 5 h. Iodine (29.5 g, 0.116 mol) is added, and the mixture is heated for a further 18 h. After cooling, the mixture is filtered and partitioned between water and dichloroethane. Organic and aqueous phase are filtered through Celite. The aqueous phase is extracted to exhaustion, and the combined organic phases are combined, dried and evaporated. The residue is dissolved in ethyl acetate and washed with sodium thiosulfate solution. Removal of the solvent gives 6.6 g of yellowish crystals product. These are reacted further without further purification; HPLC: 2.57 min; LCMS: 246 [M+H]+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[CH:8]=[CH:7][C:6]=1[NH2:17])(=[O:4])=[O:3].N1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>ClCCl>[CH3:1][S:2]([C:5]1[CH:10]=[C:9]([C:11]2[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=2)[CH:8]=[CH:7][C:6]=1[NH:17][S:2]([C:19]1[CH:9]=[CH:10][C:5]2[C:21](=[CH:22][CH:23]=[CH:7][CH:6]=2)[CH:20]=1)(=[O:4])=[O:3])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1cc(-c2ccncc2)ccc1N
Reactant: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)c1cc(-c2ccncc2)ccc1NS(=O)(=O)c1ccc2ccccc2c1
Temperature: 70 °C
Reaction time: 6 h

Procedure:
To a solution of 2-methanesulfonyl-4-pyridin-4-yl-phenylamine (cf. Example 20c, 0.046 g) in pyridine (0.5 ml) was added naphthalene-2-sulfochloride (0.051 g). The reaction mixture was stirred at 70° C. for 6 h, diluted with dichloromethane and chromatographed on silica gel using dichloromethane/methanol/ammonia to obtain the title compound (0.025 g) as an off-white solid. MS (ISP): 439.1 (M+H)+
Reaction SMILES: [OH:1][CH2:2][C@H:3]([N:5]1[C:13]2[C:8](=[C:9]([C:16]([F:19])([F:18])[F:17])[C:10]([C:14]#[N:15])=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH3:20])[CH3:4].O[C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:31])[CH3:30])=[CH:24][CH:23]=1>>[C:14]([C:10]1[C:9]([C:16]([F:19])([F:17])[F:18])=[C:8]2[C:13](=[CH:12][CH:11]=1)[N:5]([C@H:3]([CH3:4])[CH2:2][O:1][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:31])[CH3:30])=[CH:24][CH:23]=1)[C:6]([CH3:20])=[CH:7]2)#[N:15]
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1[C@H](C)CO
Product: CC(=O)Nc1ccc(OC[C@@H](C)n2c(C)cc3c(C(F)(F)F)c(C#N)ccc32)cc1

Procedure:
Synthesized as described in Example 139C using 1-[(1R)-2-hydroxy-1-methylethyl]-2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 329) and N-(4-hydroxyphenyl)acetamide: 1H NMR (400 MHz, CDCl3) δ 7.55 (d, J=8.5 Hz, 1H), 7.49 (d, J=8.5 Hz, 1H), 7.25 (d, J=8.8 Hz, 2H), 7.13 (s, 1H), 6.55 (m, 3H), 4.57 (m, 1H), 4.36 (m, 1H), 4.27 (m, 1H), 2.53 (s, 3H), 2.11 (s, 3H), 1.38 (d, J=6.1 Hz, 3H); MS (ES) m/z 414 (M−1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:13])=[C:6]2[C:11]=1[CH:10]=[N:9][C:8]([NH2:12])=[CH:7]2.[C:14](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:15]>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:13])=[C:6]2[C:11]=1[CH:10]=[N:9][C:8]([N:12]=[C:14]=[S:15])=[CH:7]2
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: Nc1cc2c(F)ccc(Br)c2cn1
Solvent: ClCCl
Product: Fc1ccc(Br)c2cnc(N=C=S)cc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 8-bromo-5-fluoroisoquinolin-3-amine (0.30 g, 1.245 mmol) and dichloromethane (5 mL) was added 1,1′-thiocarbonyldipyridin-2(1H)-one (0.318 g, 1.369 mmol). The resulting mixture was stirred at rt for 3 hours. The product was directly purified on a 40 g Thompson silica cartridge (3% to 100% EtOAc in Hexanes, 1200 mL). The desired product was obtained as a off-white solid (0.23 g, 0.812 mmol, 65.3% yield). LC/MS (2.098 min, MH+: 284.93). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.38 (1H, s), 8.04 (1H, dd, J=8.31, 4.78 Hz), 7.96 (1H, s), 7.67 (1H, dd, J=9.82, 8.31 Hz). 19F NMR (376 MHz, DMSO-d6) δ ppm −122.13 (1F, s).
Reaction SMILES: [CH:1]([N:4]1[CH2:8][CH2:7][C@H:6]([O:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14]([C:19]([OH:21])=O)=[CH:13]3)[CH2:5]1)([CH3:3])[CH3:2].Cl.[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:1]([N:4]1[CH2:8][CH2:7][C@H:6]([O:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14]([C:19]([N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:21])=[CH:13]3)[CH2:5]1)([CH3:2])[CH3:3]
Reactant: CC(C)N1CC[C@H](Oc2ccc3[nH]c(C(=O)O)cc3c2)C1
Reactant: C1CCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)N1CC[C@H](Oc2ccc3[nH]c(C(=O)N4CCCC4)cc3c2)C1

Procedure:
According to the procedure described for the synthesis of Example 1 the title compound was synthesized from 5-((S)-1-isopropyl-pyrrolidin-3-yloxy)-1H-indole-2-carboxylic acid 1:1 hydrochloride and pyrrolidine under coupling conditions employing TBTU and DIPEA in DMF. The crude product was purified over silica eluting with a gradient formed from DCM/MeOH(2 N NH3) 98/2 to 94/6. The product fractions were evaporated to yield the title compound as off-white solid. (m/e): 342.3 (MH+, 100%).
Reaction SMILES: CO[C:3](=[O:23])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[CH3:24][NH:25][C:26]([NH2:28])=[O:27].C[O-].[Mg+2].C[O-].CO>>[CH:6]1([CH2:5][CH:4]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[CH:13][CH:12]=2)[C:3]([NH:28][C:26]([NH:25][CH3:24])=[O:27])=[O:23])[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: CNC(N)=O
Reactant: COC(=O)C(CC1CCCC1)c1ccc(N2CCOCC2)cc1
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: CNC(=O)NC(=O)C(CC1CCCC1)c1ccc(N2CCOCC2)cc1
Temperature: 25 °C
Yield: 10.5 %

Procedure:
A mixture of 3-cyclopentyl-2-(4-morpholin-4-yl-phenyl)-propionic acid methyl ester (364.0 mg, 1.15 mmol) and methyl urea (254.8 mg, 3.44 mmol) was treated with a solution of magnesium methoxide in methanol (7.4 wt. %, 6.6 mL, 4.59 mmol). The resulting reaction mixture was heated under reflux for 3 d. The reaction mixture was allowed to cool to 25° C. and then filtered through a pad of celite. The pad of celite was washed well with ethyl acetate until the washings showed the absence of product by thin layer chromatography. The filtrate was then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 3/1 hexanes/ethyl acetate then 1/1 hexanes/ethyl acetate) afforded 1-[3-cyclopentyl-2-(4-morpholin-4-yl-phenyl)-propionyl]-3-methyl-urea (43.5 mg, 11%) as a white solid: mp 206-207° C.; FAB-HRMS m/e calcd for C20H29N3O3 (M+) 359.2209, found 359.2206.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[F:12][CH:13]([F:16])[CH2:14][OH:15]>N1C=CC=CC=1>[F:12][CH:13]([F:16])[CH2:14][O:15][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: OCC(F)F
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC(F)F)cc1
Reaction time: 72 h

Procedure:
Combine p-toluenesulfonyl chloride (12.9 g, 67.4 mmol) in pyridine (15 mL) at room temperature and treat dropwise with 2,2-difluoroethanol (5.0 g, 60.9 mmol) via syringe. Stir the reaction mixture under nitrogen for 72 hours, partition between water (20 mL) and dichloromethane (20 mL). Separate the aqueous phase and extract with additional dichloromethane (2×40 mL). Combine the organic extracts and wash sequentially with 1 N hydrochloric acid (2×50 mL), sodium bicarbonate (2×50 mL), and brine (2×50 mL). Dry the organic layer over sodium sulfate and concentrate in vacuo to give the title compound as a yellowish oil: 1H NMR (300 MHz, CDCl3): 7.82 (d, 2H, J=9.0 Hz), 7.40 (d, 2H, J=9.0 Hz), 5.92 (tt, 1H, J=55.0, 0.4 Hz), 4.19 (td, 2H, J=12.6, 4.0 Hz), 2.48 (s, 3H).
Reaction SMILES: [Si]([O:8][C@@H:9]1[CH2:13][O:12][C@@H:11]2/[C:14](=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])/[CH2:15][O:16][C@H:10]12)(C(C)(C)C)(C)C.[BH4-].[Na+]>O.O.O.O.O.O.[Ni](Cl)Cl.C(O)C>[OH:8][C@H:9]1[C@H:10]2[O:16][CH2:15][CH:14]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C@H:11]2[O:12][CH2:13]1
Reactant: CCOC(=O)/C=C1\CO[C@H]2[C@@H]1OC[C@H]2O[Si](C)(C)C(C)(C)C
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CC1CO[C@@H]2[C@H](O)CO[C@H]12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 20 mL vessel was charged ethyl(2E)-2-[(3R,3aS,6aR)-3-[tert-butyl(dimethyl)silyl]oxy-2,3,3a,6a-tetrahydrofuro[3,2-b]furan-6-ylidene]acetate (45 mg, 0.137 mmol), nickel chloride hexahydrate (32.6 mg, 0.137 mmol) and ethanol (1 mL). Sodium borohydride (51.8 mg, 1.37 mmol) was added slowly and the mixture was stirred at room temperature for 1 h. The reaction was quenched with water (0.5 mL) and partitioned between water (4 mL) and ethyl acetate (10 mL). The aqueous layer was extracted with ethyl acetate (3×5 mL). The combined organic phases were dried over MgSO4, filtered and concentrated to afford the title compound. LC-MS: calculated for C1OH16O5, [M+Na]+Calc: 239.1. Found: 239.1, Rt=0.22 min (4 min run).