Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:6][CH2:5][C:4]([CH3:8])([CH3:7])[C:3]1=[O:9].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C>O1CCCC1>[CH3:1][C:2]1([CH3:10])[CH2:6][CH2:5][C:4]([CH3:8])([CH3:7])[CH:3]1[OH:9]
Reactant: CC1(C)CCC(C)(C)C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)C1O
Yield: 81.5 %

Procedure:
To a magnetically stirred solution of 10 g (0.071 mol) 2,2,5,5-tetramethylcyclopentanone in 75 ml of dry tetrahydrofuran at 0° C. under argon is added 2.69 g (0.071 mol) of lithium aluminum hydride. When the reduction was complete, ethyl acetate was introduced dropwise to destroy unreacted lithium aluminum hydride. 25 mls of water is then added, followed by 300 mls of diethyl ether. The organic phase is washed with 100 mls of water, and dried over MgSO4. Filtration followed by evaporation afforded 8.23 g of 2,2,5,5-tetramethylcyclopentanol.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].Br[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1/[C:11](=[CH:19]/[C:20]1[NH:21][CH:22]=[CH:23][C:24]=1[O:25][CH3:26])/[C:12](=[O:18])[NH:13]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC>[OH:7][CH2:1][CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1/[C:11](=[CH:19]/[C:20]1[NH:21][CH:22]=[CH:23][C:24]=1[O:25][CH3:26])/[C:12](=[O:18])[NH:13]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Reactant: C#CCCCCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CCCCCO)c21

Procedure:
Using general Method D above, 5-hexyn-1-ol (56 mg, 0.57 mmol) (Aldrich) was coupled with (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (110 mg, 0.38 mmol) (Starting Material 1 supra) using (Ph3P)2PdCl2 (13 mg) (Aldrich) and CuI (7 mg) (Aldrich) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 70° C. for 14 h to yield (Z)-1,3-dihydro-4-(6-hydroxy-1-hexynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][CH2:20][CH2:21][O:22]C2CCCCO2)[CH:13]=1.Cl.C(OCC)(=O)C>C(O)C>[OH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][CH2:20][CH2:21][OH:22])[CH:13]=1
Reactant: c1cc(CCCCOC2CCCCO2)cc(CCCCOC2CCCCO2)c1
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: OCCCCc1cccc(CCCCO)c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 56.4 %

Procedure:
To a solution of, 822 mg of 1,3-bis[4-(2-tetrahydropyranyloxy)butyl]benzene in 3 ml of ethanol was added 1.5 ml of 6N hydrochloric acid, and after stirring at a room temperature for 7 hours, 30 ml of ethyl acetate and 10 ml of ice water were added. The separated organic layer was washed with 5% sodium bicarbonate aqueous solution, water and a saturated sodium chloride, dried over magnesium sulfate, and evaporated under a reduced pressure to remove the solvent. The resulting oily residue was applied to a silica gel column and eluted with chloroform/methanol (100:1) to obtain 264 mg of the title compound as a colorless liquid.
Reaction SMILES: [Cl-].[In+3].[Cl-].[Cl-].[C:5]([O:10][CH2:11][CH3:12])(=[O:9])[C:6]([CH3:8])=O.C(#N)C.[CH:16](=[N:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O>[CH2:11]([O:10][C:5]([C:6]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([OH:30])[CH:28]=2)[N:23]=[C:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:8]=1)=[O:9])[CH3:12]
Reactant: Oc1ccc(N=Cc2ccccc2)cc1
Reactant: CCOC(=O)C(C)=O
Agent: [Cl-]
Agent: [In+3]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1cc(-c2ccccc2)nc2ccc(O)cc12
Temperature: 90 °C
Reaction time: 0.45 h
Yield: 20 %

Procedure:
Indium chloride (0.4977 g, 2.25 mmol) and ethyl pyruvate (1.3064 g, 11.3 mmol) were added to an acetonitrile (15.0 mL) solution of 4-benzylideneaminophenol (0.8875 g, 4.50 mmol), and the mixture was heated with stirring at 90° C. for 27 minutes with microwave irradiation. To the reaction solution, water and saturated saline were added. The mixture was subjected to extraction with dichloromethane and dried over anhydrous sodium sulfate, and then, the solvent was distilled off. The obtained residue was purified by silica gel column chromatography, and the solvent was distilled off to obtain 6-hydroxy-2-phenyl-4-quinolinecarboxylic acid ethyl ester (0.264 g, 0.900 mmol) as a pale yellow powder.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15].[N+:16]([C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[C:22](O)=[O:23])([O-:18])=[O:17]>>[CH3:1][N:2]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])[C:22](=[O:23])[C:21]1[CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=[C:19]([N+:16]([O-:18])=[O:17])[CH:20]=1
Reactant: CNc1cnccc1-c1ccccc1C
Reactant: O=C(O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Product: Cc1ccccc1-c1ccncc1N(C)C(=O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 90, from N-methyl-4-o-tolylpyridin-3-amine (example 1, intermediate a) and 3-nitro-5-trifluoromethyl-benzoic acid (CAS RN 328-80-3) after a reaction time of 48 hours. The compound was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 0:80). The product-containing fractions were pooled and concentrated under vacuum. The residue was dissolved in 30 mL 1M aqueous HCl and 30 mL EtOAc and the layers were separated. The aqueous layer was extracted a second time with 30 mL EtOAc. The organic layers were washed twice with 30 mL 1M aqueous HCl and with 30 mL brine, dried over MgSO4, filtered and concentrated under vacuum. Light yellow solid (66%). MS (ESI): m/z=416.121 [M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:19][CH2:18][C@@H:17]([NH:20][C:21]2[CH:40]=[CH:39][C:38]([C:41]#[N:42])=[CH:37][C:22]=2[C:23]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=2)=[O:24])[CH2:16]1)=O)(C)(C)C>C(Cl)(Cl)Cl>[C:41]([C:38]1[CH:39]=[CH:40][C:21]([NH:20][C@@H:17]2[CH2:18][CH2:19][NH:15][CH2:16]2)=[C:22]([CH:37]=1)[C:23]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=1)=[O:24])#[N:42]
Reactant: COc1ccc(CNC(=O)c2cc(C#N)ccc2N[C@@H]2CCN(C(=O)OC(C)(C)C)C2)cc1OC
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CNC(=O)c2cc(C#N)ccc2N[C@@H]2CCNC2)cc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.9 %

Procedure:
Trifluoroacetic acid (5 mL) was added to a solution of (R)-2-[1-(tert-butoxycarbonyl)pyrrolidin-3-ylamino]-5-cyano-N-(3,4-dimethoxybenzyl)benzamide (918 mg) in chloroform (5 mL). The mixture was stirred for 4 hours at ambient temperature and concentrated in vacuo. The residue was partitioned between chloroform and an aqueous saturated sodium bicarbonate solution. The organic layer was dried over magnesium sulfate and concentrated in vacuo to give (R)-5-cyano-N-(3,4-dimethoxybenzyl)-2-(3-pyrrolidinylamino)benzamide (610 mg) as amorphous powders.
Reaction SMILES: [C:1]([OH:18])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH2:19](O)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].O>C1(C)C=CC=C(C)C=1.C1(C)C(S(O)(=O)=O)=CC=CC=1>[C:1]([O:18][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH3:19])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCC(=O)O
Reactant: CCCCCCCCCCCCCCCCCCO
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: O
Solvent: Cc1cccc(C)c1
Product: CCCCCCCCCCCCCCCCCCOC(=O)CCCCCCCCCCCCCCC
Yield: 129.3 %

Procedure:
128 grams (0.5 mole) of purified palmitic acid (melting point 63° C.) and 203 grams (0.75 mole) of 1-octadecanol were added to 11 grams of toluenesulfonic acid in 130 ml of m-xylene and charged into a Dean-Stark equipped 1-liter round bottom flask. After 6 hours of reflux under nitrogen at a pot temperature of 190° C., 13 ml of water was collected. The solvent and any excess alcohol were stripped under 29 inches of mercury vacuum at 130° C. to give 329 grams of a solid having a melting point of 55° C. The acid number of the product was 0. Infrared spectroscopic analysis showed formation of the ester function.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[CH2:9]([C:12]1[C:13]([OH:24])=[C:14]([CH:19]=[C:20]([Cl:23])[C:21]=1[NH2:22])[C:15]([O:17][CH3:18])=[O:16])[CH:10]=[CH2:11]>CC(C)=O>[CH2:9]([C:12]1[C:13]([O:24][CH3:1])=[C:14]([CH:19]=[C:20]([Cl:23])[C:21]=1[NH2:22])[C:15]([O:17][CH3:18])=[O:16])[CH:10]=[CH2:11]
Reactant: C=CCc1c(N)c(Cl)cc(C(=O)OC)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: C=CCc1c(N)c(Cl)cc(C(=O)OC)c1OC

Procedure:
A mixture of potassium carbonate (19 g), methyl iodide (8 g) and the phenolic compound of step 2 above (3.4 g) in acetone (100 ml) is stirred under reflux for about 6.4 hours. The mixture is partitioned between CH2Cl2 and H2O, and the organic layer is separated and washed with 10% aqueous HCl, dried (MgSO4) and evaporated affording an oil which chromatographed on silica gel affording the desired product which is used in the next step.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([NH:13][C:14]2[NH:15][C:16]3[C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)=[O:12])[N:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:59]([O:63][C:64]([N:66]1[CH2:71][CH2:70][C:69]2[N:72]=[C:73]([NH2:75])[S:74][C:68]=2[CH2:67]1)=[O:65])([CH3:62])([CH3:61])[CH3:60]>CN(C=O)C>[C:59]([O:63][C:64]([N:66]1[CH2:71][CH2:70][C:69]2[N:72]=[C:73]([NH:75][C:23]([C:22]3[C:16]4[NH:15][C:14]([NH:13][C:11]([C:3]5[N:2]=[CH:1][C:10]6[C:5]([CH:4]=5)=[CH:6][CH:7]=[CH:8][CH:9]=6)=[O:12])=[N:18][C:17]=4[CH:19]=[CH:20][CH:21]=3)=[O:24])[S:74][C:68]=2[CH2:67]1)=[O:65])([CH3:62])([CH3:60])[CH3:61]
Reactant: O=C(Nc1nc2cccc(C(=O)O)c2[nH]1)c1cc2ccccc2cn1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(N)sc2C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCc2nc(NC(=O)c3cccc4nc(NC(=O)c5cc6ccccc6cn5)[nH]c34)sc2C1
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 49.8 %

Procedure:
To a solution of 0.25 g (0.75 mmol) of 2-[(isoquinoline-3-carbonyl)-amino]-3H-benzoimidazole-4-carboxylic acid in DMF (4 mL) was added 0.4 g (1.05 mmol) of HBTU and DIEA (1 mL). The mixture was stirred for 5 min and then 0.18 g (0.7 μmmol) of 2-amino-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid tert-butyl ester was added. The resulting reaction mixture was heated at 80° C. for 2 h. After usual workup, the residue was purified by column chromatography to afford the 0.2 g (55%) of 2-({2-[(isoquinoline-3-carbonyl)-amino]-3H-benzoimidazole-4-carbonyl}-amino)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid tert-butyl ester. LCMS: 570 (M+1)+. 1H NMR (DMSO-d6, 400 MHz): δ 9.56 (s, 1H), 8.84 (s, 1H), 8.35 (m, 2H), 7.96 (m, 4H), 7.84 (d, 1H), 7.35 (t, 1H), 4.58 (bs, 2H), 3.70 (t, 2H), 2.73 (t, 2H), 1.44 (s, 9H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([CH2:18][CH3:19])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[CH2:10][N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH:27]([CH2:33][CH3:34])[C:28]([O:30][CH2:31][CH3:32])=[O:29]>C(=O)(OCC)OCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([CH2:18][CH3:19])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[C:10]([CH2:34][CH2:33][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])([C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(Br)CC
Reactant: CCc1cc2c(s1)-n1c(C)nnc1CN=C2c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(=O)OCC
Product: CCOC(=O)CCCC1(C(=O)OCC)N=C(c2ccc(Cl)cc2)c2cc(CC)sc2-n2c(C)nnc21
Temperature: 25 °C

Procedure:
4-(4-Chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine (6 g) is dissolved in diethyl carbonate (100 ml) under a nitrogen stream, and 60% sodium hydride (1.2 g) is added with stirring at room temperature. The mixture is refluxed under heating for 1 hour and cooled to 50° C. with ice water. Ethyl bromobutyrate (4.3 ml) is added. After stirring at 100° C. for 2 hours, the reaction mixture is poured into ice water (1 l) and extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (ethyl acetate:methanol=100:l) and crystallized from isopropyl ether to give 3.9 g of (±)-ethyl 4-(4-(4-chlorophenyl)-6-ethoxycarbonyl-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)butyrate as white powdery crystals. (±)-Ethyl 4-(4-(4-chlorophenyl)-6-ethoxycarbonyl-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]-triazolo[4,3-a][1,4]diazepin-6-yl)butyrate (3.5 g) is dissolved in a mixture of ethanol (180 ml) and water (60 ml), and barium hydroxide 8 hydrate (8.4 g) is added. The mixture is refluxed under heating for 4 hours. After the completion of the reaction, ethanol is distilled away under reduced pressure and adjusted to pH 1 with 1N hydrochloric acid. The mixture is stirred for 30 minutes and adjusted to pH 4 with a saturated aqueous solution of sodium hydrogencarbonate to give 1.1 g of (±)-4-(4-(4-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)butyric acid as white powdery crystals, melting point 185°-187° C.
Reaction SMILES: C([NH:3][C:4]1[N:9]=[C:8]([C:10](=[N:14][O:15][CH3:16])[C:11]([OH:13])=[O:12])[CH:7]=[CH:6][CH:5]=1)=O.[ClH:17]>CO>[ClH:17].[NH2:3][C:4]1[N:9]=[C:8]([C:10](=[N:14][O:15][CH3:16])[C:11]([OH:13])=[O:12])[CH:7]=[CH:6][CH:5]=1
Reactant: CON=C(C(=O)O)c1cccc(NC=O)n1
Agent: Cl
Solvent: CO
Product: CON=C(C(=O)O)c1cccc(N)n1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 104.7 %

Procedure:
A suspension of 2-(6-formamidopyridin-2-yl)-2-methoxyiminoacetic acid (1.5 g.) and conc. hydrochloric acid (0.77 g.) in methanol (30 ml.) was stirred at room temperature for 45 minutes. After concentrating the resultant solution under reduced pressure, the residue was washed with diethyl ether. The precipitates were collected by filtration to give 2-(6-aminopyridin-2-yl)-2-methoxyiminoacetic acid hydrochloride (1.63 g.), mp 100° to 105° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[C:10](=[O:16])[CH2:11][CH2:12][C:13]=2[O:14][CH3:15])=[C:4]([CH3:17])[CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:28]1[CH:33]([CH:34]=[O:35])[CH2:32][CH2:31][O:30][CH2:29]1>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH3:17])[C:5]([C:9]2[C:10](=[O:16])[CH:11]([CH:34]([OH:35])[CH:33]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH2:12][C:13]=2[O:14][CH3:15])=[C:6]([CH3:8])[CH:7]=1
Reactant: COC1=C(c2c(C)cc(Br)cc2C)C(=O)CC1
Reactant: O=CC1CCOCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC1=C(c2c(C)cc(Br)cc2C)C(=O)C(C(O)C2CCOCC2)C1
Temperature: -75 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(4-bromo-2,6-dimethylphenyl)-3-methoxycyclopent-2-enone (7.5 g, 26.0 mmol) in anhydrous tetrahydrofuran (70 ml) under a nitrogen atmosphere is added lithium bis(trimethylsilyl)amide (44.6 ml, 31.0 mmol, 0.7M in tetrahydrofuran) dropwise at −75°C. After stirring for 40 minutes at this temperature a second solution of tetrahydropyranyl-4-carboxaldehyde (5.90 g, 52.0 mmol) in tetrahydrofuran (70 ml) is added over 20 minutes, and the resulting solution is stirred at −75°C. for 2 hours. After warming to room temperature the mixture is stirred for a further 2 hours, then is quenched with ice cold water (100 ml) and extracted with ethyl acetate (3×150 ml). Organics are combined, dried over sodium sulphate, filtered and the filtrate is concentrated in vacuo to afford 2-(4-bromo-2,6-dimethylphenyl)-5-[hydroxy(tetrahydropyran-4-yl)methyl]-3-methoxycyclopent-2-enone. This material is used directly in the next step without further purification.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(CC#N)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: N#CCc1cccc(O)c1
Temperature: 25 °C

Procedure:
To a solution of 2-(3-Methoxyphenyl)acetonitrile (3.6 g, 25.4 mmol) in dry methylene chloride (20 ml) was added BBr3 (55 ml, 1M in CH2Cl2, 55 mmol) at −78° C. under argon atmosphere. The reaction mixture was warmed to ambient temperature for 48 hours, quenched by crushed ice, and extracted with methylene chloride. The organic layer was dried over Na2SO4, filtered, concentrated and purified by flash chromatography on a silica gel column (CH2Cl2: ethyl acetate 4:1) to give the title compound as oil.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:15]1[N:19]([CH3:20])[N:18]=[N:17][N:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]([F:14])([F:13])[F:12])[CH:5]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+].Cl.Cl[CH2:31][C:32]1[N:33]=[C:34]([NH2:37])[S:35][CH:36]=1>C(#N)C>[CH3:20][N:19]1[C:15]([C:3](=[N:2][O:1][CH2:31][C:32]2[N:33]=[C:34]([NH2:37])[S:35][CH:36]=2)[C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]([F:13])([F:14])[F:12])[CH:5]=2)=[N:16][N:17]=[N:18]1
Reactant: Nc1nc(CCl)cs1
Reactant: Cn1nnnc1C(=NO)c1cccc(OC(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Cn1nnnc1C(=NOCc1csc(N)n1)c1cccc(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 79 %

Procedure:
To a stirred solution of N-hydroxy-1-(1-methyl-1H-tetrazol-5-yl)-1-[3-(trifluoromethoxy)phenyl]methanimine (220 mg, 0.73 mmol) in acetonitrile (10 mL) were added cesium carbonate (498 mg, 1.53 mmol), potassium iodide (60 mg, 0.36 mmol) and 4-(chloromethyl)-1,3-thiazol-2-amine hydrochloride (156 mg, 0.80 mmol). After stirring for 18 h at room temperature, the mixture was filtered, the filtrate concentrated in vacuo. Purification of the residue on silica gel afforded 4-{[({(1-methyl-1H-tetrazol-5-yl)[3-(trifluoromethoxy)phenyl]methylene}amino)oxy]methyl}-1,3-thiazol-2-amine as an oil [230 mg, yield 79%; HPLC/MS:m/z=400 (M+H); log P(HCOOH)=2.10].
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH3:9][C:10]1[CH:11]=[C:12]([NH:21][C:22]2[N:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][N:23]=2)[CH:13]=[C:14]([C:16]2[S:20][CH:19]=[N:18][CH:17]=2)[CH:15]=1.[C:32]([C@H:35]1[CH2:40][CH2:39][C@H:38]([C:41]([O:43][CH2:44][CH2:45][CH2:46][CH3:47])=[O:42])[CH2:37][CH2:36]1)(=[O:34])[CH3:33]>C1COCC1.O.C(OCC)(=O)C>[OH:34][C:32]([C@H:35]1[CH2:40][CH2:39][C@H:38]([C:41]([O:43][CH2:44][CH2:45][CH2:46][CH3:47])=[O:42])[CH2:37][CH2:36]1)([C:19]1[S:20][C:16]([C:14]2[CH:13]=[C:12]([NH:21][C:22]3[N:27]=[C:26]([C:28]([F:29])([F:31])[F:30])[CH:25]=[CH:24][N:23]=3)[CH:11]=[C:10]([CH3:9])[CH:15]=2)=[CH:17][N:18]=1)[CH3:33]
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cncs2)c1
Reactant: CCCCOC(=O)[C@H]1CC[C@H](C(C)=O)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCOC(=O)[C@H]1CC[C@H](C(C)(O)c2ncc(-c3cc(C)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC1
Temperature: -78 °C

Procedure:
A flask containing THF (78 mL) was cooled to −78° C. LDA (1.8 M in THF/heptane/ethylbenzene, 21.7 mL, 39.1 mmol) was added followed by a solution of N-[3-methyl-5-(1,3-thiazol-5-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (2.63 g, 7.82 mmol) in THF (25 mL). The resulting solution was allowed to stir at −78° C. for thirty minutes. A solution of butyl trans-4-acetylcyclohexanecarboxylate (2.65 g, 11.73 mmol) in THF (10 mL) was added in one portion and the solution was stirred for 1 hour at −78° C. The reaction was then diluted with water and allowed to warm to room temperature. The mixture was then diluted with water and ethyl acetate. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel to afford racemic butyl trans-4-{1-hydroxy-1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}-phenyl)-1,3-thiazol-2-yl]ethyl}cyclohexanecarboxylate. MS ESI calc'd. for C28H34F3N4O3S [M+H]+ 563. found 563. 1H NMR (500 MHz, DMSO-d6) δ 10.24 (s, 1H), 8.83 (d, J=4.9, 1H), 7.98-7.91 (m, 2H), 7.45 (s, 1H), 7.27 (d, J=4.9, 1H), 7.14 (s, 1H), 5.84 (s, 1H), 3.96 (t, J=6.5, 2H), 2.31 (s, 3H), 2.16-2.06 (m, 1H), 1.99-1.79 (m, 2H), 1.64 (s, 1H), 1.58-1.44 (m, 6H), 1.32-1.18 (m, 6H), 1.04 (d, J=13.1, 1H), 0.85 (t, J=7.4, 3H). rhSyk=+++
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8]([O:10]C)=[O:9])=[CH:5][C:4]=1[C:12]1[N:16]([CH3:17])[N:15]=[CH:14][CH:13]=1)[CH3:2].[Cl:18]N1C(=O)CCC1=O.[OH-].[Na+]>O1CCCC1>[Cl:18][C:13]1[CH:14]=[N:15][N:16]([CH3:17])[C:12]=1[C:4]1[CH:5]=[C:6]([C:8]([OH:10])=[O:9])[S:7][C:3]=1[CH2:1][CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCc1sc(C(=O)OC)cc1-c1ccnn1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCc1sc(C(=O)O)cc1-c1c(Cl)cnn1C
Reaction time: 1 h
Yield: 100 %

Procedure:
A solution of methyl 5-ethyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (300 mg, 1.2 mmol) [Prepared in Example 98] and N-chlorosuccinimide (160 mg, 1.2 mmol) in tetrahydrofuran (6 ml) was stirred in a sealed tube for 1 h at 70° C. 6N sodium hydroxide (1 ml, 5.99 mmol) was added in one portion and the solution stirred an additional 1 h. The reaction mixture was then partitioned between H2O-DCM and the pH of the aqueous phase was adjusted to 4 and washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated then purified via column chromatography (silica, 20% EtOAC in hexanes) yielding 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxylic acid (325 mg, 1.20 mmol, 100% yield) as a yellow oil: LCMS (ES) m/e 271, 273 (M, M+2)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[O:12]C(=O)[NH:10][CH:9]1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1.[OH-].[Na+]>C(O)C>[NH2:10][CH:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=1)[CH:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])[OH:12]
Reactant: O=C1NC(Cc2ccc(C(F)(F)F)cc2)C(c2ccccc2F)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccccc1F
Yield: 96.1 %

Procedure:
To a solution of (4RS,5SR)-5-(2-fluorophenyl)-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidin-2-one (7.0 g, 20.6 mmol) in ethanol (100 ml) was added 8N aqueous sodium hydroxide solution (12.9 ml, 103 mmol) and the mixture was heated under reflux for 6 hrs. The reaction solution was concentrated, diluted with water (300 ml) and extracted with ethyl acetate (300 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give (1RS,2SR)-2-amino-1-(2-fluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (6.2 g, 96%) as a colorless oil.