Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[CH:2]1.[NH2:9][C@H:10]([CH3:26])[CH2:11][N:12]1[CH:16]=[CH:15][C:14]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([Cl:25])[CH:18]=2)=[N:13]1>>[Cl:25][C:19]1[CH:18]=[C:17]([C:14]2[CH:15]=[CH:16][N:12]([CH2:11][C@H:10]([NH:9][C:6]([C:4]3[N:3]=[CH:2][O:1][CH:5]=3)=[O:8])[CH3:26])[N:13]=2)[CH:24]=[CH:23][C:20]=1[C:21]#[N:22]
Reactant: O=C(O)c1cocn1
Reactant: C[C@@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: C[C@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cocn1
Yield: 45.5 %

Procedure:
(R)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)oxazole-4-carboxamide was prepared using the method of Example 34(d) starting from 4-oxazolecarboxylic acid (0.202 g, 1.749 mmol) and (R)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.4 g, 1.457 mmol). The product was triturated using diethyl ether. Yield 45.5%. 1H-NMR (400 MHz; DMSO-d6): δ 1.11 (d, 3H), 4.31 (dd, 1H), 4.38 (dd, 1H), 4.41-4.48 (m, 1H), 6.95 (d, 1H), 7.84 (d, 1H), 7.96-8.01 (m, 2H), 8.15 (dd, 1H), 8.50 (d, 1H), 8.54 (d, 1H), 8.58 (d, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:6][O:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:18]=[CH:17][C:16]([C:19](OC)=[O:20])=[CH:15][CH:14]=2)=[N:3]1.[H-].[Li+].[Al+3].[H-].[H-].[H-].O>O1CCCC1>[CH3:1][C:2]1([CH3:23])[CH2:6][O:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:14]=[CH:15][C:16]([CH2:19][OH:20])=[CH:17][CH:18]=2)=[N:3]1
Reactant: COC(=O)c1ccc(-c2ccccc2C2=NC(C)(C)CO2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)COC(c2ccccc2-c2ccc(CO)cc2)=N1
Yield: 92.7 %

Procedure:
2.0 g (6.48 mmol) of 4,4-dimethyl-2-(4'-methoxycarbonylbiphenyl-2-yl)oxazoline was dissolved in tetrahydrofuran (20 ml). 0.49 g (12.9 mmol) of aluminum lithium hydride was gradually added thereto under cooling with ice, followed by the stirring for 2 hours as such. Water (50 ml) was added thereto to conduct hydrolysis, followed by the extraction with chloroform. After washing with water and drying, vacuum concentration was conducted. The residue was purified by silica gel column chromatography (a n-hexane/ethyl acetate system) to give 1.69 g of the title compound (yield 93%).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3](=[CH2:7])[C:4]([OH:6])=[O:5].[CH2:10]([N:17]([CH2:21][Si](C)(C)C)[CH2:18]OC)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:10]([N:17]1[CH2:18][CH2:7][C:3]([C:2]([F:9])([F:8])[F:1])([C:4]([OH:6])=[O:5])[CH2:21]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: C=C(C(=O)O)C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C1(C(F)(F)F)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.9 %

Procedure:
2-(Trifluoromethyl)acrylic acid (2.48 g, 20 mmol) was dissolved in 30 mL of dry methylene chloride, a solution of 4.75 g (20 mmol) of N-benzyl-N-(methoxymethyl)-trimethylsilylmethylamine in 20 mL of dry methylene chloride was added dropwise under N2 at 0° C. To this solution was added 2 mL of TFA, and the solution was stirred for 2 hours at room temperature. The white precipitate was collected, washed and dried to give 3.22 g of the title compound.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[Na].Br[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].O>C(O)C>[CH2:11]([O:2][C:1]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4])[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: Oc1ccccc1O
Reactant: CCCCCBr
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CCCCCOc1ccccc1O
Reaction time: 1 h
Yield: 87.1 %

Procedure:
110 g (1 mole) of catechol was added to a solution of 23 g (1 mole) of metallic sodium in 1 liter of absolute ethanol and the mixture was stirred under nitrogen for 1 hour. Then, 166 g ((1.1 mole) of 1-bromopentane were added dropwise to the mixture over 15 minutes and the mixture was refluxed with stirring for 3 hours, was cooled and poured into 3 liters of water. The mixture was extracted with 1000 ml of ether and the ether extracts were washed with 20% sodium carbonate solution and then water, dried over magnesium sulfate and evporated to dryness under reduced pressure to obtain 157 g of 2-(n-pentyloxy)-phenol as a yellow oil. IR spectrum showed OH at 3540cm-1.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1.CS(O[CH:15]1[CH2:18][N:17]([C:19]([C:21]2[O:22][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:24][N:25]=2)=[O:20])[CH2:16]1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+].C(OCC)(=O)C>CN(C=O)C>[OH:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([S:1][CH:15]2[CH2:16][N:17]([C:19]([C:21]3[O:22][C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[N:24][N:25]=3)=[O:20])[CH2:18]2)=[CH:3][CH:4]=1
Reactant: CS(=O)(=O)OC1CN(C(=O)c2nnc(-c3ccccc3)o2)C1
Reactant: OCc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(c1nnc(-c2ccccc2)o1)N1CC(Sc2ccc(CO)cc2)C1
Temperature: 90 °C
Reaction time: 8 h
Yield: 61.5 %

Procedure:
(4-Mercaptophenyl)methanol (2.38 g, 17.0 mmol) and 1C (5.00 g, 15.5 mmol) were mixed in DMF (80 mL). Cs2CO3 (6.05 g, 18.56 mmol) was added. The mixture was stirred at 90° C. overnight and then cooled room temperature. Ethyl acetate (150 mL) was added and the mixture was washed with water (50 mL). The aqueous layer was extracted with ethyl acetate (100 mL). The organic phases were combined, dried (MgSO4) and evaporated to dryness. The residue was purified by column chromatography eluting with ethyl acetate/heptane (20:80, 40:60 and then 60:40). There was obtained 3.5 g (61%) of 5A as a solid. 1H NMR (500 MHz, CDCl3): δ 4.19 (m, 2H), 4.64 (m, 2H), 4.69 (s, 2H), 5.10 (m, 1H), 7.34 (m, 4H), 7.53 (t, 2H), 7.59 (t, 1H), 8.15 (d, 2H), MS (APCI+) m/z 368 [M−H]−.
Reaction SMILES: [CH3:1][C:2]([CH3:16])([CH2:14][CH3:15])[CH2:3][C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11](=[S:13])[NH2:12])[NH:7][CH:8]=1.Br[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[C:23]([F:28])[CH:22]=1)=O>C(O)C.O1CCOCC1>[F:28][C:23]1[CH:22]=[C:21]([C:19]2[N:12]=[C:11]([CH2:10][CH2:9][C:6]3[NH:5][C:4]([CH2:3][C:2]([CH3:16])([CH3:1])[CH2:14][CH3:15])=[CH:8][N:7]=3)[S:13][CH:18]=2)[CH:26]=[CH:25][C:24]=1[F:27]
Reactant: O=C(CBr)c1ccc(F)c(F)c1
Reactant: CCC(C)(C)Cc1c[nH]c(CCC(N)=S)n1
Solvent: C1COCCO1
Solvent: CCO
Product: CCC(C)(C)Cc1cnc(CCc2nc(-c3ccc(F)c(F)c3)cs2)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-[4-(2,2-Dimethylbutyl)-1H -imidazol-2-yl]propanethioamide (58 mg, 0.24 mmol) in ethanol (1 mL) was added to 2-bromo-1-(3,4-difluorophenyl)ethanone (56 mg, 0.24 mmol) in anhydrous 1,4-dioxane (4 mL). After stirring at rt overnight, the reaction mixture was concentrated to give a residue, which was purified by reverse phase HPLC (KR100-5C18 100×21.2 mm column; 10-100% MeCN/H2O over 12 min) to afford the title compound. LC-MS: m/e 376 (M+H).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[O:28]=[S:29]1(=[O:44])[CH2:34][CH2:33][N:32]([C:35]2[CH:43]=[CH:42][C:38]([C:39](O)=[O:40])=[CH:37][CH:36]=2)[CH2:31][CH2:30]1>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:39](=[O:40])[C:38]5[CH:42]=[CH:43][C:35]([N:32]6[CH2:31][CH2:30][S:29](=[O:44])(=[O:28])[CH2:34][CH2:33]6)=[CH:36][CH:37]=5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: O=C(O)c1ccc(N2CCS(=O)(=O)CC2)cc1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1)c1ccc(N2CCS(=O)(=O)CC2)cc1

Procedure:
The title compound, white solid (126 mg, 89%), MS (ISP) m/z=568.5 [(M+H)+], mp 260.5° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and 4-(1,1-dioxo-1λ6-thiomor-pholin-4-yl)-benzoic acid.
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[F:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1.[Cl-].[Al+3].[Cl-].[Cl-]>[N+](CC)([O-])=O.[N+](C)([O-])=O>[F:8][C:9]1[CH:15]=[CH:14][C:12]2[NH:13][C:6](=[O:7])[NH:5][S:2](=[O:4])(=[O:3])[C:11]=2[CH:10]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Nc1ccc(F)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: CC[N+](=O)[O-]
Product: O=C1Nc2ccc(F)cc2S(=O)(=O)N1
Temperature: -80 °C
Reaction time: 0.17 h

Procedure:
After dissolving chlorosulfonyl isocyanate (3.29 mL, 37.8 mmol) in nitroethane (45 mL), the mixture was cooled to −80° C. A solution of 4-fluoroaniline (3.50 g, 31.5 mmol) in nitromethane (5 mL) was then added dropwise thereto over a period of 10 minutes. The reaction mixture was raised to 0° C., and aluminum chloride (5.33 g, 40.0 mmol) was added. After heating to reflux for 30 minutes, the reaction mixture was cooled to room temperature and poured into ice water (120 mL). The precipitated crystals were filtered out and dried to obtain 7-fluoro-2H,4H-benzo[e]1,2,4-thiadiazine-1,1,3-trione.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]#[N:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C1C(=O)N([Br:20])C(=O)C1>CC#N.CCOC(C)=O>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:11]#[N:12])[CH2:9][CH2:10]2)=[CH:6][C:7]=1[Br:20]
Reactant: N#CC1(c2ccc(N)cc2)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: CCOC(C)=O
Product: N#CC1(c2ccc(N)c(Br)c2)CC1
Reaction time: 8 h
Yield: 80.1 %

Procedure:
To a solution of 1-(4-amino-phenyl)-cyclopropanecarbonitrile (96 mg, 0.60 mmol) in MeCN (3 mL) at 0° C. was added NBS (108 mg, 0.60 mmol) and the reaction was allowed to stir overnight. The reaction was diluted with EtOAc (25 mL) and was then washed with saturated aqueous NaHCO3 (1×25 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo to give 114 mg (80%) of 1-(4-amino-3-bromo-phenyl)-cyclopropanecarbonitrile. The crude product was used without further purification.
Reaction SMILES: [C:1]([NH2:9])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]1([C:16]([CH:18](Cl)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)(C)C>[C:10]1([C:16]2[S:8][C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[N:9][C:18]=2[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(c1ccccc1)C(Cl)c1ccccc1
Reactant: NC(=S)c1ccccc1
Solvent: CC(C)O
Product: c1ccc(-c2nc(-c3ccccc3)c(-c3ccccc3)s2)cc1

Procedure:
Thiobenzamide (13.7 g, 0.10 mole) and desyl chloride (23.1 g, 0.10 mole) are heated under reflux in isopropyl alcohol (100 ml) for three hours. When the reaction mixture is cooled, the white solid precipitate formed is filtered off, washed twice with isopropyl alcohol, and dried. The yield of triphenylthiazole, m.p. 84°-85.5° C., is 21.5 g or 69%.
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[C:9]([OH:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[Sn](Cl)(Cl)(Cl)Cl.[Br:28][C:29]1[CH:42]=[CH:41][C:32]([CH2:33][C:34]2[O:35][C:36]([CH3:40])=[C:37]([CH3:39])[CH:38]=2)=[CH:31][CH:30]=1>CN(C)C=O>[Br:28][C:29]1[CH:42]=[CH:41][C:32]([CH2:33][C:34]2[O:35][C:36]([CH3:40])=[C:37]([CH3:39])[C:38]=2[C:9]([C:8]2[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH:7]=2)=[O:11])=[CH:31][CH:30]=1
Reactant: Cc1cc(Cc2ccc(Br)cc2)oc1C
Reactant: COc1ccc(C(=O)O)cc1C1CCCC1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)c2c(Cc3ccc(Br)cc3)oc(C)c2C)cc1C1CCCC1
Yield: 78.5 %

Procedure:
The title compound was prepared according to the procedure in Example 5, step 2 using 3-cyclopentyl-p-anisic acid (2.04 g, 9.24 mmol, RN-59216-82-9), oxalyl chloride (0.887 mL, 10.2 mmol), N,N-dimethylformamide (2 drops), tin (IV) chloride (1.19 mL, 10.2 mmol) and 2-(4-bromo-benzyl)-4,5-dimethyl-furan (2.45 g, 9.24 mmol) in CH2C2. Purification on Biotage KP-Sil eluting with 4% EtOAc/pet. ether gave 3.39 g (78%) of the title compound. 1H NMR (DMSO-d6) δ1.38-1.47 (m, 2 H), 1.60-1.73 (m, 4 H), 1.79 (s, 3 H), 1.90-1.94 (m, 2 H), 2.18 (s, 3 H), 3.21 (quintet, 1 H) 3.82 (s, 2 H), 3.88 (s, 3 H), 7.02-7.08 (m, 3 H), 7.44 (d, 2 H), 7.55-7.61 (m , 2 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH:10]([C:13]([OH:15])=[O:14])[C:9]2=[O:16])=[CH:4][CH:3]=1.CO.[CH2:19]1COCC1.[N+](=C[Si](C)(C)C)=[N-]>CCOCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][CH2:11][CH:10]([C:13]([O:15][CH3:19])=[O:14])[C:9]2=[O:16])=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: O=C(O)C1CCN(c2ccc(F)cc2)C1=O
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCOCC
Solvent: CO
Product: COC(=O)C1CCN(c2ccc(F)cc2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To a solution of 1-(4-fluorophenyl)-2-oxopyrrolidine-3-carboxylic acid (0.20 g, 0.90 mmol) in a mixture of Et2O (6 mL), MeOH (2 mL), and THF (2 mL) was added (diazomethyl)trimethylsilane (1.1 mL, 2.0 M) at 0° C. The resulting mixture was stirred for 30 minutes at room temperature, quenched with AcOH, and diluted with EtOAc. The organic layer was washed with water, NaHCO3 solution (2×), and brine, dried over MgSO4, and concentrated under reduced pressure to give the desired product (0.206 g, 98%). LRMS (ESI pos) m/e 238.0 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[N:7]([CH3:12])[N:6]=[CH:5]2.[Li]CCCC.[Cl:18][C:19]1[CH:20]=[CH:21][C:22]2[N:23]([C:25]([C:28](=[O:30])[CH3:29])=[CH:26][N:27]=2)[N:24]=1>C1COCC1>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]2[N:23]([C:25]([C:28]([C:2]3[CH:3]=[C:4]4[C:8](=[CH:9][C:10]=3[F:11])[N:7]([CH3:12])[N:6]=[CH:5]4)([OH:30])[CH3:29])=[CH:26][N:27]=2)[N:24]=1
Reactant: Cn1ncc2cc(Br)c(F)cc21
Reactant: CC(=O)c1cnc2ccc(Cl)nn12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1ncc2cc(C(C)(O)c3cnc4ccc(Cl)nn34)c(F)cc21
Temperature: -100 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
To a solution of 5-bromo-6-fluoro-1-methyl-1H-indazole (intermediate L) (1.800 g, 7.86 mmol) in THF (79 mL) at −100° C. was added n-BuLi (5.40 mL, 8.64 mmol) dropwise. After stirring for 1 h at −100° C., a solution of 1-(6-chloroimidazo[1,2-b]pyridazin-3-yl)ethanone (intermediate M) (1.691 g, 8.64 mmol) in THF (20 mL) was added dropwise. The reaction solution was stirred for additional 2 h and quenched with NH4Cl (aq). The resulting mixture was extracted with EtOAc. The combined organic layers were washed with NH4Cl (aq), dried over Na2SO4 and concentrated in vacuo to afford the crude product which was purified by column chromatography (hexanes:EtOAc) to give the title compound in 34% yield. LCMS (method B): [MH]+=346, tR=2.14 min.
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[N+:9]([O-])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].P(Cl)(Cl)([Cl:18])=O.O.[OH-].[Li+]>O1CCCC1>[Cl:18][C:8]1[N:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[C:2]([F:1])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(O)c1cc[n+]([O-])c(C(F)(F)F)c1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(Cl)nc(C(F)(F)F)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-fluoro-2-(trifluoromethyl)isonicotinic acid 1-oxide (1.0 g, 4.4 mmol from Step A) in phosphoryl chloride (4 mL, 40 mmol) was heated to 110° C. for 2 hours, then was left to stir at ambient temperature overnight. The POCl3 was evaporated, the residue was treated with sodium bicarbonate solution, which was stirred for 1 hour. To this mixture was added tetrahydrofuran (20 mL) and lithium hydroxide monohydrate (0.24 g, 5.7 mmol). This was stirred for 3 hours. The pH of the mixture was then adjusted to the range of pH 4-5 by the addition of c.HCl. The product was extracted with three portions of ethyl acetate. The combined extracts were dried over sodium sulfate, filtered and concentrated. Yield: 0.54 g (50%); LC-MS: 244.1/245.9 (M+H)+. 1H NMR (300 MHz, CDCl3): δ 8.07 (d, 1H).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:16]([NH:18][C@H:19]([C@@H:27](O)[CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31])[CH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:17])[CH2:10][C:11]1[N:15]=[CH:14][NH:13][CH:12]=1)=O)(C)(C)C.FC(F)(F)C(O)=[O:37]>C(OCC)(=O)C>[NH2:8][C@H:9]([C:16]([NH:18][C@@H:19]([CH2:27][CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31])[C@@H:20]([OH:37])[CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:17])[CH2:10][C:11]1[N:15]=[CH:14][NH:13][CH:12]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)CC[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Product: CC(C)CCC[C@H](NC(=O)[C@@H](N)Cc1c[nH]cn1)[C@@H](O)C1CCCCC1

Procedure:
A solution of 2(S)-(N-t-butoxycarbonyl-L-histidyl)amino-1-cyclohexyl-3(S)-hydroxy-6-methylheptane (383 mg) in trifluoroacetic acid (10 ml) was stirred at 0° C. for 30 minutes. After concentration of the mixture in vacuo, the residue was dissolved in ethyl acetate (20 ml). The solution was washed with saturated sodium bicarbonate solution, dried over magnesium sulfate, and concentrated in vacuo to give 2(S)-(L-histidyl)amino-1-cyclohexyl-(S)-hydroxy-6-methylheptane (275 mg) as an amorphous powder.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C@H:14]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]#[C:21][CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:15]1=[O:28].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:48]([C:51]1[CH:59]=[CH:58][C:54]([C:55](O)=[O:56])=[CH:53][CH:52]=1)([O-:50])=[O:49]>O1CCCC1>[N+:48]([C:51]1[CH:52]=[CH:53][C:54]([C:55]([O:13][C@@H:14]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]#[C:21][CH2:22][N:23]3[CH2:24][CH2:25][CH2:26][CH2:27]3)[C:15]2=[O:28])=[O:56])=[CH:58][CH:59]=1)([O-:50])=[O:49]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: O=C1[C@@H](O)CCN1CC#CCN1CCCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(O[C@@H]1CCN(CC#CCN2CCCC2)C1=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 8 h
Yield: 79.8 %

Procedure:
A solution of 0.9 g of diethyl azodicarboxylate in 5 ml of tetrahydrofuran was added dropwise to a solution of 0.9 g of (S)-3-hydroxy-1-[4-(1-pyrrolidinyl)-2-butynyl]-2-pyrrolidinone, 1.1 g of triphenylphosphine and 0.9 g of 4-nitrobenzoic acid in 30 ml of dry tetrahydrofuran. The mixture was stirred overnight and the solvent was removed in vacuo. The residue was purified by chromatography (silica gel), giving 1.2 g of the desired product as off white crystals, [α]D26° =+41°-(dichloromethane); mp 89°-90° C.
Reaction SMILES: Br[CH:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl:9][C:10]1[N:11]=[C:12]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)[C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>ClCCl>[Cl:9][C:10]1[N:11]=[C:12]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:23][CH:22]=2)[C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: Oc1ccc(Nc2nc(Cl)cc3ccccc23)cc1
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Oc1ccc(Nc2nc(Cl)cc3ccccc23)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 70.6 %

Procedure:
A mixture of ethyl 2-bromopropionate (1.33 g), 4-[N-(3-chloroisoquinolin-1-yl)amino]phenol (1.80 g), anhydrous potassium carbonate (1.01 g) and dimethyl formamide was heated, with stirring, at a temperature of 100° C. for a period of 1 hour. The mixture was cooled and poured into dichloromethane and the resulting mixture was repeatedly washed with water. The organic phase was dried over anhydrous magnesium sulfate and the solvent was removed by distillation under reduced pressure. The residue was purified by chromatography over silica gel (eluant dichloromethane) to give ethyl 2-{4-[N-(3-chloroisoquinolin-1-yl)amino]phenoxy}propionate (1.74 g) as a yellow oil. The assigned structure was confirmed by proton magnetic resonance spectroscopy and mass spectrometry. Proton magnetic resonance spectrum (CDCl3 ; δ ppm); 1.20 (3H, t); 1.50 (3H, d); 4.12 (2H, q); 4.60 (1H, q); 6.60-8.20 (10H, m).
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.CCOCC.[C:12]1([Mg]Cl)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>C1COCC1>[C:12]1([C:2]2[CH:6]=[CH:5][S:4][CH:3]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Brc1ccsc1
Reactant: Cl[Mg]c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: c1ccc(-c2ccsc2)cc1
Temperature: 0 °C
Yield: 34.1 %

Procedure:
To a mixture of 1.0 mL (10.6 mmol) of 3-bromothiophene, 20 mL of anhydrous ether, 60 mg (0.11 mmol) of 1,3-[Bis(diphenylphosphino)-propane]dichloronickel(II)[NiCl2 (dppp)] under N2 with stirring at 0° C. was slowly added 7.0 mL (14 mmol) of 2.0 M PhMgCl in THF. The reaction was slowly warmed to room temperature. Note that a vigorous exothermic reaction may occur if the Grignard reagent is added too fast or if the reaction is allowed to warm to room temperature to rapidly. After stirring for 3 h, the mixture was warmed to reflux for 2 h, poured into 20 mL of 5% HCl solution, and extracted with 2×20 mL of ether. The combined organic phases were washed with 15 mL of H2O and 15 mL of brine, dried (MgSO4) and concentrated. Crystallization from hexanes provided 0.58 g (34% yield) of 3-phenylthiophene.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH3:13][C@H:14]([CH2:17][C:18]([F:21])([F:20])[F:19])[CH2:15]O.[C:22]1(=[O:32])[NH:26][C:25](=[O:27])[C:24]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(OCC)C.O1CCCC1>[CH3:13][C@H:14]([CH2:17][C:18]([F:21])([F:20])[F:19])[CH2:15][N:26]1[C:22](=[O:32])[C:23]2[C:24](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:25]1=[O:27]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C[C@@H](CO)CC(F)(F)F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[C@@H](CN1C(=O)c2ccccc2C1=O)CC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.7 %

Procedure:
Diethyl azodicarboxylate (15.4 ml) was added to a 20 C., stirred slurry of (R)-2-methyl-4,4,4-trifluorobutan-1-ol (about 12.0 g), phthalimide (13.4 g), and triphenylphosphine (23.7 g) in diethyl ether (about 6.5 g, see above) and dry tetrahydrofuran (110 ml), warmed to room temperature overnight, and stirred an additional 8 h. The mixture was evaporated, methylene chloride was added to the residue, and the slurry was filtered. The filtrate was purified by flash chromatography, eluting with 1:1 methylene chloride:hexanes, to give (R)-2-(2-methyl-4,4,4-trifluorobutyl)-1H-isoindol-1,3(2H)-dione (17.1 g, 75%) as a white solid; m.p. 45°-47° C.; partial NMR (400 MHz, CDCl3): 1.08 (d, 3H, CH3), 1.94-2.07 (m, 1H, CF3CH2), 2.14-2.31 (m, 1H, CF3CH2), 2.36-2.50 (m, 1H, CHCH3), 3.58 (dd, 1 H, CH2N), 3.64 (dd, 1H, CH2N).
Reaction SMILES: [F:1][CH2:2][C:3]1([CH2:20][F:21])[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[C:6]2[CH:15]=[C:16]([I:19])[CH:17]=[CH:18][C:5]=2[O:4]1.ClC1C=CC=C(C(OO)=[O:30])C=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[F:21][CH2:20][C:3]1([CH2:2][F:1])[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N+:10]=2[O-:30])[C:6]2[CH:15]=[C:16]([I:19])[CH:17]=[CH:18][C:5]=2[O:4]1
Reactant: FCC1(CF)C=C(c2ccccn2)c2cc(I)ccc2O1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: [O-][n+]1ccccc1C1=CC(CF)(CF)Oc2ccc(I)cc21
Yield: 23.1 %

Procedure:
To a mixture of 1.04 g of 2,2-bisfluoromethyl-6-iodo-4-(2-pyridyl)-2H-1-benzopyran and 20 ml of methylene chloride was added 0.78 g of m-chloroperbenzoic acid (70%) with stirring under ice-cooling. The mixture was stirred under ice-cooling for 1 hour and then stirred at room temperature for 25 hours. Potassium carbonate solution was added thereto and the mixture was extracted with methylene chloride. The organic layer was washed with water and dried. The solvent was distilled off and the resultant residue was purified using silica gel column chromatography (developing solution, MeOH:CH2Cl2 =1:99) to obtain 0.25 g of oily 2-(2,2-bisfluoromethyl-6-iodo-2H-1-benzopyran-4-yl)pyridine N-oxide represented by the following formula.