Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:31])OC2C=CC=CC=2)=[CH:18][CH:17]=1)#[N:2].[NH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1.O>CS(C)=O>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)=[O:31])=[CH:18][CH:17]=1)#[N:2]
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)Oc4ccccc4)cc3)c2cc1C#N
Reactant: Nc1ccccn1
Solvent: O
Solvent: CS(C)=O
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccccn4)cc3)c2cc1C#N
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 54.7 %

Procedure:
Phenyl N-(4-(6-cyano-7-methoxy-4-quinolyl)oxyphenyl)carbamate (150 mg) and 2-aminopyridine (69 mg) were dissolved in 1 ml of dimethylsulfoxide, and the solution was heated and stirred at 80° C. for 1.5 hours. After cooling, water was added, and the precipitated solid was filtered out and washed with ethyl acetate to obtain 82 mg of the title compound as light brown crystals (54% yield).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][O:9][C:10](=[O:13])[CH:11]=[CH2:12].C(N(CC)CC)C>C(#N)C>[C:10]([O:9][CH3:8])(=[O:13])/[CH:11]=[CH:12]/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC(=O)OC
Reactant: Ic1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)/C=C/c1ccccc1
Temperature: 100 °C
Reaction time: 12 h
Yield: 35 %

Procedure:
To a solution of iodobenzene (102 mg), methylacrylate (1.25 eq.) and triethylamine (1.25 eq.) in acetonitrile (3.00 ml) was added the catalyst substrate (5×5) obtained in Example 2. The mixture was stirred at 100° C. for 12 h under an argon atmosphere. The organic layers were then washed with brine and dried over sodium sulfate. The solvents were removed under reduced pressure and the resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1). The intended product, trans-methyl cinnamate was obtained with yield of 35%. The recycled substrate was subjected to the above reaction conditions in a 2nd run and the intended product methyl cinnamate was obtained with yield of 13%. Further conducted the 3rd run and the intended methyl cinnamate was obtained with yield of 9%.
Reaction SMILES: C(OC([N:8]([CH2:25][C@H:26]1[CH2:35][CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([C:36]3[CH:45]=[CH:44][CH:43]=[CH:42][C:37]=3[C:38]([O:40][CH3:41])=[O:39])[CH:32]=2)[O:27]1)[CH2:9][C@H:10]([O:17][Si](C(C)(C)C)(C)C)[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=O)(C)(C)C.Cl>CO.O1CCOCC1>[OH:17][C@H:10]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[CH2:9][NH:8][CH2:25][C@H:26]1[CH2:35][CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([C:36]3[CH:45]=[CH:44][CH:43]=[CH:42][C:37]=3[C:38]([O:40][CH3:41])=[O:39])[CH:32]=2)[O:27]1
Reactant: COC(=O)c1ccccc1-c1ccc2c(c1)CC[C@H](CN(C[C@H](O[Si](C)(C)C(C)(C)C)c1cccnc1)C(=O)OC(C)(C)C)O2
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)c1ccccc1-c1ccc2c(c1)CC[C@H](CNC[C@H](O)c1cccnc1)O2
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.2 %

Procedure:
A stirred solution of methyl 2-[(2R)-2-({(tert-butoxycarbonyl)[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoate (Example 82, 61 mg, 0.096 mmol) in MeOH (0.50 mL) was treated with HCl in dioxane (1 mL of a 4N solution in dioxane, Aldrich Chemical Co.) at room temperature and stirring continued for 60 minutes. The mixture was concentrated in vacuo and purified on silica gel using a gradient of 5-10% MeOH/EtOAc to provide 31 mg of product as colorless oil (77%); 1H NMR (DMSO-d6, δ): 1.65-2.04 (m, 2H), 2.50-3.10 (m, 6H), 3.65 (s, 3H), 4.10 (dd, 1H), 4.80 (d, 1H), 6.80 (d, 1H), 7.00 (bs, 2H), 7.25-7.40 (m, 3H), 7.42-7.52 (m, 1H), 7.78-7.80 (m, 2H), 8.52 (s, 1H), 8.60 (s, 1H); MS: m/z=419.3 [M+H]+.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3B(O)O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[C:27]1[C:28]([CH3:33])=[N:29][O:30][C:31]=1[CH3:32]>>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:27]3[C:28]([CH3:33])=[N:29][O:30][C:31]=3[CH3:32])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccccc1C=C1c2ccccc2CCc2ccccc21
Reactant: Cc1noc(C)c1Br
Product: Cc1noc(C)c1-c1ccccc1C=C1c2ccccc2CCc2ccccc21
Yield: 2 %

Procedure:
Following procedures essentially as described in Example 225 and using 2-(10,11-dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-phenylboronic acid (100 mg, 307 mmol) and 4-bromo-3,5-dimethylisoxazole (81 mg, 0.460 mmol), provides the title compound in 2% yield. MS (ES) 378 (M+H); HPLC shows 94% purity.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([OH:9])=[O:8].Cl.[C:11]([CH:15]1[CH2:20][CH2:19][CH:18]([O:21][C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[CH:28]=[C:27]([CH:32]=O)[CH:26]=[CH:25]3)[CH2:17][CH2:16]1)([CH3:14])([CH3:13])[CH3:12].ClCCCl.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[C:11]([CH:15]1[CH2:20][CH2:19][CH:18]([O:21][C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[CH:28]=[C:27]([CH2:32][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]2[C:7]([OH:9])=[O:8])[CH:26]=[CH:25]3)[CH2:17][CH2:16]1)([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C(O)C1CCCCN1
Reactant: CC(C)(C)C1CCC(Oc2ccc3cc(C=O)ccc3c2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)C1CCC(Oc2ccc3cc(CN4CCCCC4C(=O)O)ccc3c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.9 %

Procedure:
Piperidine-2-carboxylic acid (0.125 g, 0.967 mmol) as HCl salt was combined with 6-(4-tert-Butyl-cyclohexyloxy)-naphthalene-2-carbaldehyde (0.250 g, 0.805 mmol) in 1,2-dichloroethane (5 mL, 60 mmol) and acetic acid (0.500 mL, 8.79 mmol). The mixture was heated to reflux while stirring overnight. Reaction cooled to room temperature and then sodium triacetoxyborohydride (546 mg, 2.58 mmol) was added in small portions. The reaction was then left stirring overnight. Reaction was then purified directly via reverse phase chromatography (5-95% CH3CN/Water (0.1% TFA), C18, 150 mm). The product was then lyophilized to dryness to give 3 mg 1-[6-(4-tert-Butyl-cyclohexyloxy)-naphthalen-2-ylmethyl]-piperidine-2-carboxylic acid as a yellow solid (0.8%). ESI-LCMS (424 M+H). 1H NMR (DMSO-d6, 400 MHz): δ (ppm) 12.34-12.58 (m, 1H), 11.20-11.53 (m, 1H), 8.01 (s, 1H), 7.68-7.93 (m, 3H), 7.41 (s, 1H), 7.02-7.22 (m, 1H), 4.35 (br. s., 3H), 3.23-3.43 (m, 2H), 2.86-3.09 (m, 2H), 1.74-2.30 (m, 8H), 1.00-1.52 (m, 5H), 0.87 (s, 9H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([N:13]([CH3:21])[C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[N:5][CH:4]=1.Cl[C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[N:25][N:24]=1>>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([N:13]([CH3:21])[C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:23]4[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[C:26]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)=[N:25][N:24]=4)=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[N:5][CH:4]=1
Reactant: Clc1nnc(-c2ccccc2)c2ccccc12
Reactant: COc1cnc2c(N(C)c3ccc(N)cc3)ccnc2c1
Product: COc1cnc2c(N(C)c3ccc(Nc4nnc(-c5ccccc5)c5ccccc45)cc3)ccnc2c1
Temperature: 100 °C

Procedure:
A mixture of N1-(7-methoxy-1,5-naphthyridin-4-yl)-N1-methylbenzene-1,4-diamine (0.061 g, 0.22 mmol) and 1-chloro-4-phenylphthalazine (0.052 g, 0.22 mmol) was heated at 100° C. for 48 h. The solvent was removed in vacuo and the residue was purified by silica gel chromatography using 1-10% MeOH:CH2Cl2 containing 1% NH4OH to afford N1-(7-methoxy-1,5-naphthyridin-4-yl)-N1-methyl-N4-(4-phenylphthalazin-1-yl)benzene-1,4-diamine as a yellow solid.
Reaction SMILES: [CH:1](/[C:9]1[CH:18]=[C:17]([NH:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1)=[CH:2]\[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[ClH:25].CCOCC.[H][H]>CO.[Pd]>[ClH:25].[CH2:1]([C:9]1[CH:18]=[C:17]([NH:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1)[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: OCC(O)CNc1cc(/C=C/c2ccccc2)nc2ccccc12
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: OCC(O)CNc1cc(CCc2ccccc2)nc2ccccc12
Temperature: 25 °C
Yield: 29 %

Procedure:
(E)-(RS)-3-(2-Styryl-quinolin-4-ylamino)-propane-1,2-diol (0.23 g, 0.718 mmol) was dissolved in MeOH (25 ml) and acidified with HCl/Et2O. The reaction mixture was refluxed for 2 hours in the presence of 10% Pd/C (0.02 g) under an atmospheric pressure of hydrogen. The mixture was cooled to room temperature, the catalyst was filtered, and the filtrate was concentrated. Addition of EtOH provided (RS)-3-(2-phenethyl-quinolin-4-ylamino)-propane-1,2-diol hydrochloride (0.075 g, 29%) as a light yellow solid, m. p. 143-145° C., MS: m/e=323.3 (M+H+).
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[C:11]([O:13][CH2:14][O:15][CH3:16])[CH:10]=[C:9]([Br:17])[CH:8]=1.CN([CH:21]=[O:22])C.O>CCOCC>[Br:17][C:9]1[CH:8]=[C:7]([CH:12]=[C:11]([O:13][CH2:14][O:15][CH3:16])[CH:10]=1)[CH:21]=[O:22]
Reactant: CN(C)C=O
Reactant: COCOc1cc(Br)cc(Br)c1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: COCOc1cc(Br)cc(C=O)c1
Temperature: 25 °C
Yield: 73.3 %

Procedure:
n-BuLi (8.34 mL of a 1.6 M solution in Et2O, 13.34 mmol) was added dropwise to a solution cooled to −78° C. of 1,3-dibromo-5-methoxymethoxy-benzene (3.59 g, 12.13 mmol) in anhydrous Et2O (40 mL) under a nitrogen atmosphere. The solution was aged at −78° C. for 45 m, anhydrous DMF (1.03 mL, 13.34 mmol) was added, and the reaction mixture was slowly warmed to RT. The mixture was poured into H2O (50 mL), and the aqueous phase was extracted with Et2O (2×75 mL). The combined organic fractions were washed with brine (50 mL) and dried over anhydrous MgSO4. The solvents were evaporated, and the remaining oil was purified by flash chromatography over silica gel (0% to 10% EtOAc/hexanes) to afford 2.18 g (74%) of 3-bromo-5-methoxymethoxy-benzaldehyde (113b).
Reaction SMILES: [C:1]([N:4]1[CH2:10][CH2:9][CH2:8][C:7]2[CH:11]=[CH:12][S:13][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].[Cl:14][CH2:15][CH2:16][CH2:17][C:18](Cl)=[O:19].[Cl-].[Al+3].[Cl-].[Cl-].O>ClCCl>[C:1]([N:4]1[CH2:10][CH2:9][CH2:8][C:7]2[CH:11]=[C:12]([C:18](=[O:19])[CH2:17][CH2:16][CH2:15][Cl:14])[S:13][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCCc2ccsc2C1
Reactant: O=C(Cl)CCCCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CC(=O)N1CCCc2cc(C(=O)CCCCl)sc2C1
Reaction time: 0.5 h
Yield: 75.6 %

Procedure:
To a solution of 2.5 g of 7-acetyl-5,6,7,8-tetrahydro-4H-thieno-[2,3-c]azepine and 2.7 g of 4-chlorobutyryl chloride in 25 ml of dichloromethane was added 6.0 g of aluminum chloride under ice-cooling. The mixture was stirred for 30 minutes, poured into water and extracted with chloroform. The extract was washed with water, dried over magnesium sulfate and concentrated. The residue was purified by column chromatography on a silica gel to give 2.9 g of 7-acetyl-2-(4-chlorobutyryl)-5,6,7,8-tetrahydro-4H-thieno[2,3-c]azepine as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11]([CH:12]([CH3:26])[N:13]([C:16](=[O:25])[C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([O:23]C)[CH:18]=4)[C:14]=2[CH:15]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3.ClC1C=CC(C2C=CC=CC=2C(NC(=O)C2C=CC=C(OC)C=2)C)=C(F)C=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11]([CH:12]([CH3:26])[N:13]([C:16]([C:17]4[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=4)=[O:25])[C:14]=2[CH:15]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: COc1cccc(C(=O)N2c3cc(Cl)ccc3-c3ccccc3C2C)c1
Agent: COc1cccc(C(=O)NC(C)c2ccccc2-c2ccc(Cl)cc2F)c1
Solvent: C1CCOC1
Product: CC1c2ccccc2-c2ccc(Cl)cc2N1C(=O)c1cccc(O)c1
Temperature: 70 °C
Yield: 56.9 %

Procedure:
3-chloro-5-(3-methoxybenzoyl)-6-methyl-5,6-dihydrophenanthridine—N-[1-(4′-Chloro-2′-fluoro-biphenyl-2-yl)-ethyl]-3-methoxy-benzamide (1.04 g, 2.7 mmol) was dissolved in anhydrous THF (10 mL) and the vial was capped and purged with an inert atmosphere. Lithium bis(trimethylsilyl)amide (4.1 mL, 1M in THF) was added to the solution and the mixture heated (70° C). The reaction progress was monitored by LCMS and heating was discontinued upon the expense of the starting material. The THF was removed and the resulting residue was purified by flash column chromatography (Biotage® 40 Mi, 30-50% methyl tert-butylether in hexane) affording 537 mg (54%) of the desired product. MS [(ES+), m/z]: 364/366 [M+H]+, 1 Cl pattern.
Reaction SMILES: Cl[C:2]([S:4]Cl)=[O:3].[CH3:6][O:7][CH2:8][C:9]([NH2:11])=[O:10]>C1(C)C=CC=CC=1>[CH3:6][O:7][CH2:8][C:9]1[O:10][C:2](=[O:3])[S:4][N:11]=1
Reactant: O=C(Cl)SCl
Reactant: COCC(N)=O
Solvent: Cc1ccccc1
Product: COCc1nsc(=O)o1
Yield: 79.9 %

Procedure:
Chlorocarbonylsulfenyl chloride (7.35 g) was added to a suspension of methoxyacetamide (5 g) in toluene (30 cm3). The reaction mixture was stirred and heated at 90°-100° C. for 5 hours, then cooled. The solvent was removed by evaporation under reduced pressure to give a brown gum (6.6 g). M+ =147; 1H NMR (DMSO-d6): δ 3.30(3H,s); 4.30(2H,s) which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].Cl[CH2:10][C:11](=O)[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>CO>[S:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1]/[C:11](=[CH:12]/[C:13]([O:15][CH2:16][CH3:17])=[O:14])/[CH2:10]1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: Nc1ccccc1S
Solvent: CO
Product: CCOC(=O)/C=C1\CSc2ccccc2N1
Yield: 55.9 %

Procedure:
step 1—To a solution of 2-aminothiophenol (4.96 g, 39.6 mmol) in MeOH (200 mL) was added the ethyl 4-chloroacetoacetate (6.2 g, 38 mmol). After stirring at room temperature for 2 h the MeOH was removed under reduced pressure. The residue was dissolved in Et2O and washed with HCl (1N), saturated NaHCO3, and brine. The organic phase was dried over MgSO4, filtered and the solvent was removed under reduced pressure. The product was obtained from a minimum of EtOH to afford 5.0 g (54%) of 8: LCMS RT 3.7 min, M+H.
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]1[O:15][CH2:14][CH2:13][N:12]([CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:21]=[CH:22][C:23]3[C:24]4[N:25]([CH2:41][CH2:42][N:43]=4)[C:26]([NH:32][C:33](=[O:40])[C:34]4[CH:39]=[CH:38][CH:37]=[N:36][CH:35]=4)=[N:27][C:28]=3[C:29]=2[O:30][CH3:31])[CH2:11]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.O>[OH:8][CH2:9][CH:10]1[O:15][CH2:14][CH2:13][N:12]([CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:21]=[CH:22][C:23]3[C:24]4[N:25]([CH2:41][CH2:42][N:43]=4)[C:26]([NH:32][C:33](=[O:40])[C:34]4[CH:39]=[CH:38][CH:37]=[N:36][CH:35]=4)=[N:27][C:28]=3[C:29]=2[O:30][CH3:31])[CH2:11]1
Reactant: COc1c(OCCCN2CCOC(CO[Si](C)(C)C(C)(C)C)C2)ccc2c1N=C(NC(=O)c1cccnc1)N1CCN=C21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COc1c(OCCCN2CCOC(CO)C2)ccc2c1N=C(NC(=O)c1cccnc1)N1CCN=C21
Temperature: 25 °C
Reaction time: 4 h
Yield: 47 %

Procedure:
N-(8-{3-[2-({[tert-butyl(dimethyl)silyl]oxy}methyl)morpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide (260 mg, 0.43 mmol) was suspended in THF (2 mL) and treated with a solution of tetra-n-butylammonium fluoride (1N, 0.64 mL, 0.64 mmol) in THF. The resulting mixture was stirred at rt for 4 h and was then diluted with water and extracted with 20% isopropanol/80% chloroform, dried (MgSO4) and concentrated under reduced pressure. The residue was then triturated with methanol and filtered to give the product as a solid (100 mg, 47%): HPLC MS RT=0.19 min, MH+=495.2; 1H NMR (DMSO-d6) δ: 12.7 (1H, s), 9.33 (1H, dd), 8.73 (1H, dd), 8.46 (1H, dt), 7.60 (1H, d), 7.54-7.49 (1H, m), 7.06 (1H, d) 4.66 (1H, t), 4.20-4.09 (4H, m), 4.07-3.98 (2H, m) 3.93 (3H, s), 3.76 (1H, br d), 3.48 (1H, td), 3.42-3.26 (4H, m), 2.83 (1H, d), 2.70 (1H, d), 2.47 (2H, t), 2.03-1.91 (3H, m).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[NH:10][N:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:24][CH2:25][CH2:26]Br>C(#N)C>[Br:24][CH2:25][CH2:26][N:10]1[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:12][C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[N:9]1
Reactant: BrCCBr
Reactant: CCOC(=O)c1cc(-c2ccc(F)cc2)n[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cc(-c2ccc(F)cc2)nn1CCBr
Yield: 45.8 %

Procedure:
To a solution of Intermediate 1B (135 g, 576 mmol) and potassium carbonate (159 g, 1153 mmol) in acetonitrile (1400 mL) was added 1,2-dibromoethane (59.6 mL, 692 mmol) and the resulting reaction mixture was refluxed for 4 h. Acetonitrile was removed under reduced pressure and the residue was diluted with water. The aqueous layer was extracted with DCM (2×500 mL) The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by ISCO using 880 g REDISEP® column and 1% methanol in chloroform as eluent. Combined fractions were concentrated to afford Intermediate 1C (90 g, 45%). MS(ES): m/z=343 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 7.91-7.97 (m, 2H), 7.41 (s, 1H), 7.24-7.30 (m, 2H), 4.96 (t, J=6.34 Hz, 2H), 4.36 (q, J=7.11 Hz, 2H), 3.90 (t, J=6.34 Hz, 2H), 1.35 (t, J=7.12 Hz, 3H).
Reaction SMILES: C([O:8][C:9](=O)[CH2:10][C@H:11]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]I)C1C=CC=CC=1.[BH4-].[Li+].C1COCC1>C(OCC)C>[C:18]([O:17][C:15](=[O:16])[NH:14][C@H:11]([CH3:12])[CH2:10][CH2:9][OH:8])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N[C@H](CI)CC(=O)OCc1ccccc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[C@H](CCO)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of (S)-3-tert-butoxycarbonylamino-4-iodo-butyric acid benzyl ester (0.2 g, 0.477 mmol) in dry diethylether (3 ml) cooled to 0° C. under argon, is treated with a 2.0 M solution of lithium borohydride in THF (0.95 ml, 1.9 mmol). The reaction mixture is allowed to warm to ambient temperature with stirring for 18 hours. The reaction is quenched by addition of water and partitioned between ethylacetate and 10% citric acid solution. The organic phase is washed with brine, dried over magnesium sulphate and evaporated. The crude product is purified by flash silica chromatography using 1% methanol in DCM as eluent to afford ((R)-3-hydroxy-1-methyl-propyl)-carbamic acid tert-butyl ester.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:11]([CH3:20])([CH3:19])[CH2:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.[N:21]1[CH:26]=[C:25](B(O)O)[CH:24]=[N:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>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.CO.COCCOC.CN(C=O)C>[F:15][C:14]([F:17])([F:16])[C:13](=[O:18])[CH2:12][C:11]([CH3:20])([C:4]1[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=[C:2]([C:25]2[CH:26]=[N:21][CH:22]=[N:23][CH:24]=2)[CH:3]=1)[CH3:19]
Reactant: CC(C)(CC(=O)C(F)(F)F)c1cc(Br)cc2c1OCC2
Reactant: OB(O)c1cncnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COCCOC
Solvent: CO
Product: CC(C)(CC(=O)C(F)(F)F)c1cc(-c2cncnc2)cc2c1OCC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 63.2 %

Procedure:
To a mixture of 4-(5-bromo-2,3-dihydrobenzofuran-7-yl)-1, 1,1-trifluoro-4-methylpentan-2-one (1.00 g, 2.8 mmol), pyrimidine-5-boronic acid (529 mg, 4.3 mmol) and potassium carbonate (787 mg) in a sealed tube was added 20 mL of MeOH-DME-DMF (3:2:1). After stirring at room temperature for 10 minutes, tetrakis(triphenylphosphine)palladium(0) (329 mg) was added and the reaction mixture was heated at 120° C. for 40 minutes. After cooling to room temperature, the crude mixture was filtered through a cotton plug with the aid of ethyl acetate. The filtrate was concentrated in vacuo to remove most of the methanol, redissolved in 160 mL of ethyl acetate, and washed with 80 mL of aqueous 1 N sodium hydroxide solution, 80 mL of water, and 80 mL of brine respectively. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification by column chromatography with 20% to 30% ethyl acetate-hexanes afforded 620 mg (62% yield) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[C:24]3[NH:23][C:22](=[O:25])[O:21][C:20]([CH3:27])([CH3:26])[C:19]=3[CH:18]=[CH:17][CH:16]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[OH:28]O>>[CH3:1][C:2]1[CH:3]=[C:4]([S:9]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[C:24]3[NH:23][C:22](=[O:25])[O:21][C:20]([CH3:27])([CH3:26])[C:19]=3[CH:18]=[CH:17][CH:16]=2)=[O:28])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: OO
Reactant: Cc1ccc(SCCCCOc2cccc3c2NC(=O)OC3(C)C)cc1C
Product: Cc1ccc(S(=O)CCCCOc2cccc3c2NC(=O)OC3(C)C)cc1C

Procedure:
Prepared analogously to Example 2 from 8-[4-(3,4-dimethyl-phenylmercapto)-butoxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [C:1]([O:20][CH3:21])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[SH2:22]>CCCCCC>[SH:22][CH: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][CH2:16][CH2:17][CH3:18])[C:1]([O:20][CH3:21])=[O:19]
Reactant: S
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OC
Solvent: CCCCCC
Product: CCCCCCCCCCCCCCCCC(S)C(=O)OC
Yield: 57 %

Procedure:
The reaction of methyl oleate with hydrogen sulfide in hexane at -70° for 4 hours and +25° C. for 7 hours results in the formation of 89% and 57% methyl mercaptostearate, respectively, when catalyzed by boron trifluoride. Methyl linoleate reacts with hydrogen sulfide under the same conditions to form a mixture of the cyclic sufides in yield of 83.8% and 64.5%, respectively. Temperature programmed gas-liquid chromatography (GLC) of the above reaction products reveals that essentially all components are eluted at temperatures below 250° C.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH3:7][N:8]([CH2:10][CH2:11][CH2:12][CH2:13]CC(O)=O)[CH3:9].C(=O)=O>>[ClH:4].[CH3:7][N:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:1][C:2]([Cl:4])=[O:3])[CH3:9]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CN(C)CCCCCC(=O)O
Agent: O=C=O
Product: CN(C)CCCCCC(=O)Cl
Product: Cl
Temperature: 40 °C
Reaction time: 2 h

Procedure:
Into a 500 ml three-necked round-bottomed flask equipped with a reflux condenser, internal thermometer, mechanical stirrer, and argon inlet, is placed oxalyl chloride (398.67 g, 3.14 mol). Acid 2 (100 g, 0.63 mol) is added over 30 min while maintaining the reaction temperature at 40° C. As reaction takes place, CO2 and CO are swept away from the mixture with argon. After addition is complete, the mixture is stirred for 2 h while the reaction flask cools to room temperature. Excess oxalyl chloride is removed by rotary evaporation at 50° C. and then by Kugelrohr distillation at 50° C. (0.1 mm Hg) for 2 h. Isolated is 3, 118.98 g (88.5%) as an oil that solidifies on standing.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][C:8]([CH2:11][OH:12])=[CH:9][N:10]=1.O[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][CH2:23][N:24]2[CH:28]=[CH:27][N:26]=[CH:25]2)=[CH:16][CH:15]=1>>[N:24]1([CH2:23][CH2:22][CH2:21][CH2:20][C:17]2[CH:18]=[CH:19][C:14]([O:12][CH2:11][C:8]3[S:7][C:6]([C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)=[N:10][CH:9]=3)=[CH:15][CH:16]=2)[CH:28]=[CH:27][N:26]=[CH:25]1
Reactant: Oc1ccc(CCCCn2ccnc2)cc1
Reactant: OCc1cnc(-c2cccs2)s1
Product: c1csc(-c2ncc(COc3ccc(CCCCn4ccnc4)cc3)s2)c1
Yield: 86 %

Procedure:
In substantially the same manner as in Working Example 159, 2-(2-thienyl)-5-thiazolylmethanol was chlorinated and then reacted with 1-[4-(4-hydroxyphenyl)butyl]imidazole to obtain 5-[4-[4-(1-imidazolyl)butyl]phenoxymethyl]-2-(2-thienyl)thiazole. The yield was 86%. Recrystallization from ethyl acetate-hexane gave pale yellow prisms, mp 128-129° C.