Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.CCCCCC.C(OC([N:17]1[C:21]([C:22]2[CH:27]=[CH:26][C:25]([S:28][CH3:29])=[CH:24][CH:23]=2)=[C:20]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[N:19]=[CH:18]1)C)C.CN(C)CCN(C)C.C[Si](C)(C)[N:47]=[C:48]([C:53]([F:56])([F:55])[F:54])[C:49]([F:52])([F:51])[F:50].C(=O)(O)[O-].[Na+]>O1CCCC1>[F:36][C:33]1[CH:32]=[CH:31][C:30]([C:20]2[N:19]=[C:18]([C:48]([C:53]([F:56])([F:55])[F:54])([C:49]([F:52])([F:51])[F:50])[NH2:47])[NH:17][C:21]=2[C:22]2[CH:27]=[CH:26][C:25]([S:28][CH3:29])=[CH:24][CH:23]=2)=[CH:35][CH:34]=1
Reactant: C[Si](C)(C)N=C(C(F)(F)F)C(F)(F)F
Reactant: CCOC(C)n1cnc(-c2ccc(F)cc2)c1-c1ccc(SC)cc1
Agent: CN(C)CCN(C)C
Agent: O=C([O-])O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CSc1ccc(-c2[nH]c(C(N)(C(F)(F)F)C(F)(F)F)nc2-c2ccc(F)cc2)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 28.6 %

Procedure:
Under an atmosphere of nitrogen, 1.6M n-butyl lithium in hexane (30 ml, 0.048 mole) was added dropwise to a solution of 1-(1-ethoxyethyl)-4-(4-fluorophenyl)-5-(4-methylthiophenyl)-1H-imidazole (10.0 g, 0.028 mole) and N,N,N',N'-tetramethylethylenediamine (3.9 g, 0.0336 mole) in tetrahydrofuran (150 ml) at -78° C. The mixture was stirred for 15 minutes at -78° C. and then N-(trimethylsilyl)hexafluoroacetone imine (11.0 g, 0.046 mole) was added dropwise at -78° C. The mixture was stirred for one hour at -78° C. and then allowed to warm to 0° C. A saturated aqueous solution of sodium bicarbonate (100 ml) was added dropwise while allowing the reaction mixture to warm to room temperature. The organic phase was separated and solvent removed in vacuo. Hydrochloric acid (2N; 100 ml) and ethanol (200 ml) were added to the residue and the mixture stirred overnight at room temperature. Ethanol was then removed under vacuum and the aqueous residue extracted with ether. The ether extracts were washed with water and then dried over magnesium sulfate. The ether solution was concentrated under reduced pressure and the residual oil placed on a column of dry silica gel; the product was eluted with hexane/ethyl acetate (1:1). Solvent was removed by evaporation in vacuo and the residue crystallized from 1-chlorobutane to afford 3.6 g (28%) of 4-(4-fluorophenyl)-5-(4-methylthiophenyl)-α,α-bis(trifluoromethyl)imidazole-2-methylamine, as colorless crystals, m.p. 150°-152°. IR: 3300 cm-1 (NH2). NMR: δ2.2 (s, 3H, CH3); 3.0 (s, 2H, NH2); 6.8-7.7 (m, 8H, aromatic).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][C:17]2[C:20](I)=[N:21][N:22](C3CCCCO3)[C:16]=2[CH2:15]1)=[O:13].[F:30][C:31]1[CH:32]=[CH:33][C:34](B2OC(C)(C)C(C)(C)O2)=[N:35][CH:36]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>CN(C=O)C.O.C(=O)([O-])[O-].[Na+].[Na+].[Cu](Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[Cl:1][C:2]1[C:7]([C:8]([F:10])([F:11])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][C:17]2=[C:20]([C:34]3[CH:33]=[CH:32][C:31]([F:30])=[CH:36][N:35]=3)[NH:21][N:22]=[C:16]2[CH2:15]1)=[O:13]
Reactant: CC1(C)OB(c2ccc(F)cn2)OC1(C)C
Reactant: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCc2c(I)nn(C3CCCCO3)c2C1
Agent: Cl[Cu]Cl
Agent: [Fe+2]
Agent: [Pd+2]
Solvent: O
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCc2c(n[nH]c2-c2ccc(F)cn2)C1
Temperature: 85 °C
Reaction time: 8 h
Yield: 6 %

Procedure:
To a solution of 6-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine (a mixture of regioisomers) (81 mg, 0.15 mmol) in DMF (1 mL) was added 5-fluoropyridine-2-boronic acid pinacol ester (84 mg, 0.38 mmol), cesium carbonate (198 mg, 0.600 mmol), copper chloride (15 mg, 0.15 mmol), palladium acetate (2 mg, 0.008 mmol) and 1,1′-bis(diphenylphosphino)ferrocene (8 mg, 0.150 mmol). The reaction was stirred at 85° C. overnight under an atmosphere of N2. The reaction was diluted with water and aqueous sodium carbonate (5%) and extracted with EtOAc three times. The organic layers were combined, dried over anhydrous MgSO4, filtered and concentrated. The residue was purified by HPLC (Agilent prep system, Waters XBridge, C18, 5 μm, 30×100 mm column, 5-99% MeOH/20 nM NH4OH over 18 min at 30 mL/min). The product fractions were concentrated in vacuo and then dissolved in CH2Cl2 (1 mL). (THP deprotection) To the solution, triethylsilane (0.011 mL, 0.0737 mmol) and TFA (0.236 mL, 0.059 mmol) were added. The reaction was stirred at rt for 1 h then concentrated in vacuo. Chromatography on silica gel (0-100% ethyl acetatehexanes) provided the desired product as a colorless oil (4 mg, 6%). MS (ESI) mass calcd. C19H13ClF4N4O, 424.1. m/z found, 425.1 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.50-8.47 (m, 1H), 7.81-7.74 (m, 1H), 7.56-7.42 (m, 4H), 5.13 (d, J=16.5 Hz, 0.5H), 4.93 (d, J=16.5 Hz, 0.5H), 4.51 (d, J=15.8 Hz, 0.5H), 4.40 (d, J=15.9 Hz, 0.5H), 4.34-4.25 (m, 0.5H), 4.07-3.98 (m, 0.5H), 3.61-3.49 (m, 1H), 3.08-3.03 (m, 1H), 3.01-2.94 (m, 0.5H), 2.88-2.78 (m, 0.5H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]1[C:21]1[CH:26]=[C:25](Br)[CH:24]=[CH:23][C:22]=1[O:28][CH2:29][C:30]([O:32]CC)=[O:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCOCC.[CH3:40][N:41](C=O)C>[C-]#N.[Zn+2].[C-]#N.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]1[C:21]1[CH:26]=[C:25]([C:40]#[N:41])[CH:24]=[CH:23][C:22]=1[O:28][CH2:29][C:30]([OH:32])=[O:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: CCOC(=O)COc1ccc(Br)cc1C1c2ccccc2CCN1C(=O)OCc1ccccc1
Agent: [Pd]
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOCC
Product: N#Cc1ccc(OCC(=O)O)c(C2c3ccccc3CCN2C(=O)OCc2ccccc2)c1
Temperature: 110 °C
Reaction time: 18 h

Procedure:
To a solution of (±)-1-(5-bromo-2-ethoxycarbonylmethoxy-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (105 mg, 0.20 mmol, 1.0 eq.) in DMF (10 mL) were added zinc cyanide (23 mg, 0.20 mmol, 1.0 eq.) and tetrakis(triphenylphosphine) palladium (0) (23 mg, 0.02 mmol, 0.1 eq.). The resulting suspension was stirred at 110° C. for 18 hours. After cooling, Et2O (100 mL) was added and the solution was washed with sat. aq. NaCl soln. (2×120 mL). The organic layer was dried over MgSO4, filtered, and the solvent was removed under vacuum. To a solution of the crude product in DMF (0.9 mL) 1M aq. NaOH soln. (0.25 mL) was added. The solution was stirred at r.t. for 18 hours. The solution was acidified with 1M aq. HCl soln.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:12][C:11]([CH2:35][C:36]#[N:37])([N:13]2[CH:17]=[C:16]([C:18]3[C:19]4[CH:26]=[CH:25][N:24](COCC[Si](C)(C)C)[C:20]=4[N:21]=[CH:22][N:23]=3)[CH:15]=[N:14]2)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C(N)CN>>[CH2:1]([O:8][CH:9]1[CH2:12][C:11]([CH2:35][C:36]#[N:37])([N:13]2[CH:17]=[C:16]([C:18]3[C:19]4[CH:26]=[CH:25][NH:24][C:20]=4[N:21]=[CH:22][N:23]=3)[CH:15]=[N:14]2)[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CC(OCc5ccccc5)C4)c3)ncnc21
Solvent: NCCN
Solvent: O=C(O)C(F)(F)F
Product: N#CCC1(n2cc(-c3ncnc4[nH]ccc34)cn2)CC(OCc2ccccc2)C1

Procedure:
3-(Benzyloxy)-1-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutylacetonitrile (0.024 g, 0.000046 mol) was treated with trifluoroacetic acid (0.5 mL, 0.006 mol) at rt for 30 min, then evaporated to dry. The residue was dissolved in MeOH (1 mL) and treated with ethylenediamine (0.2 mL, 0.003 mol) at rt for 2 h. The reaction mixture was concentrated in vacuo and the resulting residue purified on prep. HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.15% NH4OH) to give 2 isomers of the desired products. First peak retention time 1.406 min; LCMS calculated for C22H21N6O(M+H)+: 385.2; Found: 385.3. 1H NMR (400 MHz, DMSO-d6): δ 12.10 (1H, br s), 8.71 (1H, s), 8.67 (1H, s), 8.38 (1H, s), 7.58 (1H, d, J=3.6 Hz), 7.33 (4H, m), 7.29 (1H, m), 7.05 (1H, d, J=3.6 Hz), 4.43 (2H, s), 4.23 (1H, m), 3.43 (2H, s), 2.78 (2H, m), 2.74 (2H, m) ppm. Second peak retention time 1.474 min, LCMS calculated for C22H21N6)(M+H)+: 385.2; Found: 385.3. 1H NMR (400 MHz, DMSO-d6): δ 12.10 (1H, br s), 8.79 (1H, s), 8.67 (1H, s), 8.39 (1H, s), 7.59 (1H, d, J=3.6 Hz), 7.34 (4H, m), 7.29 (1H, m), 7.06 (1H, d, J=3.6 Hz), 4.44 (2H, s), 4.14 (1H, m), 3.44 (2H, s), 3.16 (2H, m), 2.44 (2H, m) ppm.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:32]=[CH:33][C:34]=1[N+:35]([O-])=O)[C:12]([N:14]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:17](=[O:31])[CH2:16][CH2:15]1)=[O:13])C1C=CC=CC=1.[H][H]>[Pd].C(O)C.O1CCOCC1>[NH2:35][C:34]1[CH:33]=[CH:32][C:11]([C:12]([N:14]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[N:18]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:17](=[O:31])[CH2:16][CH2:15]2)=[O:13])=[CH:10][C:9]=1[OH:8]
Reactant: CCOC(=O)CN1C(=O)CCN(C(=O)c2ccc([N+](=O)[O-])c(OCc3ccccc3)c2)c2ccccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CCO
Product: CCOC(=O)CN1C(=O)CCN(C(=O)c2ccc(N)c(O)c2)c2ccccc21
Yield: 89.5 %

Procedure:
A solution of 5-(3-benzyloxy-4-nitrobenzoyl)-1-ethoxycarbonylmethyl-1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one (2.2 g), 10% palladium on carbon (220 mg) in ethanol (30 ml) and 1,4-dioxane (15 ml) was stirred under 4 atmospheric pressure of hydrogen at ambient temperature for 7 hours. The reaction mixture was filtered through a bed of celite, concentrated and purified by silica gel column chromatography (SiO2 60 g, ethyl acetate:n-hexane =2:1) to give 5-(4-amino-3-hydroxybenzoyl)-1-ethoxycarbonylmethyl-1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one (1.5 g).
Reaction SMILES: [C:1]([C:5]1[CH:34]=[CH:33][C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)=[CH:12][C:11]=2/[CH:27]=[CH:28]\[C:29]([O:31]C)=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CO.[OH-].[Na+].Cl>O1CCCC1>[C:1]([C:5]1[CH:34]=[CH:33][C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:24])([F:25])[F:26])=[CH:18][CH:17]=3)=[CH:12][C:11]=2/[CH:27]=[CH:28]\[C:29]([OH:31])=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)/C=C\c1cc(-c2ccc(OC(F)(F)F)cc2)ccc1Oc1ccc(C(C)(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)c1ccc(Oc2ccc(-c3ccc(OC(F)(F)F)cc3)cc2/C=C\C(=O)O)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
A mixture of methyl (Z)-3-{4-[4-(tert-butyl)phenoxy]-4′-(trifluoromethoxy)biphenyl-3-yl}propenoate (590 mg, 1.293 mmol), methanol (1 ml), tetrahydrofuran (4 ml) and 2N aqueous sodium hydroxide (1.94 ml) was stirred at 60° C. for 1 hour. The reaction mixture was cooled to room temperature, acidified by addition of 2N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (550 mg, 93.2%) as a pale yellow oil.
Reaction SMILES: C(N(CC)CC)C.[C:8](=[S:10])=S.[CH3:11][C:12]1[CH:28]=[CH:27][C:15]([O:16][C:17]2[S:18][C:19]3[CH:25]=[C:24]([NH2:26])[CH:23]=[CH:22][C:20]=3[N:21]=2)=[CH:14][CH:13]=1.P(Cl)(Cl)(Cl)=O>C(OCC)C>[CH3:11][C:12]1[CH:28]=[CH:27][C:15]([O:16][C:17]2[S:18][C:19]3[CH:25]=[C:24]([N:26]=[C:8]=[S:10])[CH:23]=[CH:22][C:20]=3[N:21]=2)=[CH:14][CH:13]=1
Reactant: Cc1ccc(Oc2nc3ccc(N)cc3s2)cc1
Reactant: S=C=S
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc(Oc2nc3ccc(N=C=S)cc3s2)cc1
Reaction time: 12 h

Procedure:
Additions are made dropwise, at -10° to -5°, firstly of 31 ml of triethylamine and then of 4.3 ml of carbon disulphide to 18.4 g of 2-(4'-methylphenoxy)-6-aminobenzothiazole in 360 ml of absolute diethyl ether. Stirring is continued for ca. 12 hours at room temperature; the mixture is cooled to 0°, and an addition made at this temperature, within 30 minutes, of 6.7 ml of phosphorus oxychloride in 80 ml of absolute diethyl ether. After 10 hours' stirring at room temperature, filtration is performed; the filter residue is washed firstly with diethyl ether and then with water and dried. the product is afterwards chromatographed through aluminium oxide, with methylene chloride as the eluant, to obtain 2-(4'-methylphenoxy)-6-isothiocyanobenzothiazole, M.P. 121° - 123°.
Reaction SMILES: [C:1]([O:21][CH3:22])(=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][C@@H:12]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[OH:13].COC(=O)C(C)CCCCCC/C=C\C[C@@H](CCCCCC)O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:22][O:21][C:1](=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12](=[O:13])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCC[C@@H](O)C/C=C\CCCCCCCC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCCCC[C@@H](O)C/C=C\CCCCCCC(C)C(=O)OC
Product: CCCCCCC(=O)CCCCCCCCCCC(=O)OC
Temperature: 120 °C

Procedure:
1.52 g Aliquat 100 (tetrabutyl ammonium bromide, TBAB) and 8.3 mg Pd(OAc)2 were placed in a 5 mL vial with crimp cap. This mixture was heated to 120° C. under vacuum for 2.5 hours. The vial was put under N2-atmosphere and 312 mg (1 mmol) methyl ricinoleate was added. This mixture was heated to 120° C. for 94 hours. The product was extracted from the TBAB with heptane. After concentration 172 mg was obtained. The reaction products were analyzed by GC (FIG. 11): 8 area % methyl ricinoleic acid methyl ester, 15 area % at 2.54′, 21 area % at 11.8′, 20 area % at 12.77′ and 33 area % at 13.69′. No 12-oxostearate methyl ester was formed.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=3)=[C:17]([Cl:29])[CH:16]=2)[NH:7][N:6]=1.[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[Cl:29][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][N:34]4[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]4)[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][C:22]1[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCCl)c34)cc2Cl)cn1
Reactant: CN1CCNCC1
Product: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCN5CCN(C)CC5)c34)cc2Cl)cn1
Yield: 42 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-{3-chloro-4-[(6-methylpyridin-3-yl)oxy]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine and N-methylpiperazine to give the title compound in 42% yield; NMR Spectrum: 2.11 (s, 3H), 2.28 (br s, 4H), 2.45 (s, 3H), 2.50 (hidden by DMSO, 4H), 2.80 (t, 2H), 4.44 (t, 2H), 7.20 (d, 1H), 7.26 (br s, 2H), 7.72 (d, 1H), 8.11 (s, 1H), 8.20 (s, 1H), 8.36 (s, 1H), 8.59 (br s, 1H); Mass Spectrum: 495 (MH+).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#[N:9])=O.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[C:21](=[S:23])[NH2:22]>>[F:24][C:14]([F:13])([F:25])[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[C:21]1[S:23][CH:2]=[C:3]([C:5]2[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=2)[C:8]#[N:9])[N:22]=1
Reactant: N#Cc1cccc(C(=O)CBr)c1
Reactant: NC(=S)c1cnccc1C(F)(F)F
Product: N#Cc1cccc(-c2csc(-c3cnccc3C(F)(F)F)n2)c1
Yield: 76.3 %

Procedure:
By the reaction in the same manner as in Example 25-iii) using 3-(bromoacetyl)benzonitrile (913 mg) and 4-trifluoromethylpyridine-3-thiocarboxamide (840 mg), the title compound (1.03 g) was obtained as colorless powder crystals.
Reaction SMILES: CO[C:3]([C:5]1[C:10]([NH:11][C:12](=[O:21])[CH2:13][C:14]2[S:18][C:17]([Cl:19])=[N:16][C:15]=2[CH3:20])=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Cl:19][C:17]1[S:18][C:14]([C:13]2[C:12](=[O:21])[NH:11][C:10]3=[N:9][CH:8]=[CH:7][N:6]=[C:5]3[C:3]=2[OH:4])=[C:15]([CH3:20])[N:16]=1
Reactant: COC(=O)c1nccnc1NC(=O)Cc1sc(Cl)nc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(Cl)sc1-c1c(O)c2nccnc2[nH]c1=O
Temperature: 25 °C

Procedure:
3-[2-(2-Chloro-4-methyl-thiazol-5-yl)-acetylamino]-pyrazine-2-carboxylic acid methyl ester (Example 2.2) (1.020 g) was heated to 110° C. with potassium carbonate (1.08 g) in dry N,N-dimethylformamide (30 ml) for 3 hours. The reaction mixture was allowed to cool to ambient temperature, diluted with water and the mixture extracted with ethyl acetate. The aqueous fraction was acidified to pH 3 by addition of concentrated hydrochloric acid (36% by weight in water) and then extracted again with ethyl acetate. The organic fraction was washed with water, dried over magnesium sulfate, and concentrated to give Compound No. B1 of Table B (0.61 g).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.N([O-])=O.[Na+].[I-:25].[Na+].C([O-])(=O)C.[Na+]>O.C(O)(=O)C>[I:25][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: Nc1ccc(-c2cccnc2)cc1
Agent: CC(=O)[O-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CC(=O)O
Product: Ic1ccc(-c2cccnc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1.7 g (10 mmol) of 3-(4-aminophenyl)-pyridine [F. S. Tanaka et al.. J. Agric. Food Chem. 30, 957 (1982)], 17 ml of glacial acetic acid and 1.5 ml of trifluoroacetic acid was cooled in ice-water. Sodium nitrite. 0.8 g (11.4 mmol) was added in portions. After stirring for 15 minutes in ice-water and 15 minutes without cooling, 5 g of sodium iodide and 3 g of sodium acetate was added slowly with water cooling. The reaction mixture was diluted with 30 ml of water and stirred for 30 minutes. It was then partitioned between methylene chloride and 10% aqueous sodium carbonate solution. The organic phase was dried and evaporated and the residue was chromatographed over 20 g of silica gel using 10% (V/V) of ethyl acetate in methylene chloride. Crystallization from hexane yielded off-white crystals with m.p. 112°-115°.
Reaction SMILES: [F:1][C:2]([F:15])=[CH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14].[C:16]1([N:22]=[C:23]=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CCCCCCC.C([O-])(=O)C.C([O-])(=O)C.C([Sn+2]CCCC)CCC>[C:16]1([NH:22][C:23](=[O:24])[O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[C:2]([F:15])[F:1])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OCCCCCCCCCCC=C(F)F
Reactant: O=C=Nc1ccccc1
Agent: CC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: CCCCCCC
Product: O=C(Nc1ccccc1)OCCCCCCCCCCC=C(F)F
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a stirred solution of 2.0 grams (0.0091 mole) of 12,12-difluoro-11-dodecen-1-ol (prepared in Example 5) in 15 ml of heptane was added two drops of dibutyltin diacetate, and then 1.2 grams (0.0100 mole) of phenyl isocyanate was added dropwise. Upon completion of addition, the reaction mixture was warmed to 80° C. where it stirred for 30 minutes. The reaction mixture was allowed to cool to ambient temperature where it stirred for 18 hours. After this time the reaction mixture was cooled in a freezer, and a precipitate was collected by filtration. The filter cake was washed with cold pentane and dried yielding 2.47 grams of 12,12-difluoro-11-dodecenyl N-phenylcarbamate; m.p. 54°-56° C. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([N:11]1[CH2:15][CH2:14][C@H:13]([N:16]([C:24](=[O:33])[C:25]([CH3:32])([CH3:31])[CH2:26][O:27][C:28](=[O:30])[CH3:29])[CH:17]2[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]2)[CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[BH4-].[Na+]>C1COCC1>[C:1]([N:11]1[CH2:15][CH2:14][C@H:13]([N:16]([C:24](=[O:33])[C:25]([CH3:32])([CH3:31])[CH2:26][O:27][C:28](=[O:30])[CH3:29])[CH:17]2[CH2:18][CH2:19][CH:20]([OH:23])[CH2:21][CH2:22]2)[CH2:12]1)([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: CC(=O)OCC(C)(C)C(=O)N(C1CCC(=O)CC1)[C@H]1CCN(C(=O)OCc2ccccc2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)OCC(C)(C)C(=O)N(C1CCC(O)CC1)[C@H]1CCN(C(=O)OCc2ccccc2)C1
Reaction time: 12 h
Yield: 0.1 %

Procedure:
The product of Step A of Intermediate 126, (3S)-1-cbz-3-[acetyloxypivaloyl (4-oxo-cyclohexyl)amino]pyrrolidine (1.60 g, 3.49 mmol) was dissolved in THF (15 mL), and NaBH4 (172 mg, 4.19 mmol) was added at rt. After being stirred for 12 h, the reaction mixture was quenched with water, and the organic material was extracted with EtOAc. The extracts were dried over MgSO4 and concentrated in vacuo, and the residue was purified by column chomatography (EtOAc/Hex=1/1) to give the title compound (1.481 mg, 92.1%).
Reaction SMILES: CO[Na].[CH2:4]([O:6][C:7](=[O:12])[CH2:8][C:9](=[O:11])[CH3:10])C.C([O:15][C:16](=O)[CH:17]=[CH:18][CH3:19])C>CO>[CH3:4][O:6][C:7]([C:8]1[CH:18]([CH3:19])[CH2:17][C:16](=[O:15])[CH2:10][C:9]=1[OH:11])=[O:12]
Reactant: CC=CC(=O)OCC
Reactant: CCOC(=O)CC(C)=O
Agent: CO[Na]
Solvent: CO
Product: COC(=O)C1=C(O)CC(=O)CC1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 45.7 %

Procedure:
To a freshly prepared solution of MeONa (432 g, 7.99 mol) in MeOH (2 L) is added 3-oxo-butyric acid ethyl ester (1.04 kg, 7.99 mol) over 15 min and the mixture is stirred on an ice bath for an additional 15 min. But-2-enoic acid ethyl ester (912 g, 7.99 mol) is added dropwise at RT and the mixture stirred at RT for 1 h and then the reaction mixture is refluxed for 2 h. After cooling to RT, the precipitated solids are filtered off, dissolved in cold water (1.5 L), acidified with HCl (3 M) to pH to 7 and the resulting mixture is extracted with EtOAc (4×800 mL). The combined organic phase is dried over anhydrous Na2SO4, the solvents are evaporated in vacuo and the residue recrystallized from hexane to give 2-hydroxy-6-methyl-4-oxo-cyclohex-1-enecarboxylic acid methyl ester (672 g, 42% yield).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]#[C:6][C:7]([O:9][CH3:10])=[O:8])=[O:4].[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)CCl>[C:12]1([NH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:3]([O:2][CH3:1])=[O:4])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)C#CC(=O)OC
Reactant: Nc1ccccc1
Solvent: ClCCCl
Product: COC(=O)C=C(Nc1ccccc1)C(=O)OC
Reaction time: 1 h

Procedure:
To a stirred solution of dimethylacetylenedicarboxylate (DMAD, 0.10 mol) in 50 mL of ethylene dichloride (EDC), is slowly added a solution of aniline (0.10 mol) in 15 mL of EDC. The temperature of the reaction mixture is maintained below 30° C. and stirring is continued for about one hour until the reaction is essentially complete. The EDC is then removed under vacuum to afford the dimethyl 3-phenylaminobut-2-ene-dioate.