Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([N:6]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[N:8]=[CH:7]1)([CH3:5])[CH:3]=O.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>>[CH3:1][C:2]([N:6]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[N:8]=[CH:7]1)([CH3:5])[CH2:3][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: C1COCCN1
Reactant: CC(C)(C=O)n1cnc([N+](=O)[O-])c1
Product: CC(C)(CN1CCOCC1)n1cnc([N+](=O)[O-])c1

Procedure:
2-Methyl-2-(4-nitro-imidazol-1-yl)-propionaldehyde was reacted with morpholine to provide the title compound: MS m/z 255.1 (M+1)
Reaction SMILES: S(Cl)(Cl)=O.CN(C=O)C.[CH2:10]1[C:18]2[C:13](=[CH:14][C:15]([NH:19][C:20](=[O:30])[CH:21]=[CH:22][S:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:16][CH:17]=2)[CH2:12][CH2:11]1>C1(C)C=CC=CC=1>[CH2:10]1[C:18]2[C:13](=[CH:14][C:15]([N:19]=[C:20]([O:30][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:21]=[CH:22][S:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:16][CH:17]=2)[CH2:12][CH2:11]1
Reactant: O=C(C=CSc1ccccc1)Nc1ccc2c(c1)CCC2
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: C(=CC(=Nc1ccc2c(c1)CCC2)Oc1ccccc1)Sc1ccccc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 164.8 %

Procedure:
Thionyl chloride (1.53 mL) and DMF (catalytic amount) were added to a solution of N-(5-indanyl)-3-(phenylthio)acrylamide (2.47 g) in toluene (80 mL), and the mixture was stirred at 70° C. for 1 hour. The reaction mixture was concentrated under reduced pressure. To the residue was added anhydrous THF (40 mL). To a solution of phenol (1.18 g) in anhydrous THF (20 mL) was added sodium hydride (60%) (0.769 g) under a nitrogen atmosphere under ice-cooling, and then stirred at room temperature under a nitrogen atmosphere for 30 minutes. The reaction mixture was added to the above-described reaction mixture under ice-cooling, and the mixture was stirred at room temperature for 2.5 hours. To the reaction mixture was added ethyl acetate (200 mL), which was washed with a 1N aqueous sodium hydroxide solution, water and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was isolated and purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to obtain phenyl N-(5-indanyl)-3-(phenylthio)acrylimidate (2.56 g) as a orange oil.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]2([C:17]3[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=3[CH2:15][O:14]2)[CH2:10][CH2:9]1)C1C=CC=CC=1>C(O)C.[Pd]>[F:22][C:19]1[CH:20]=[CH:21][C:16]2[CH2:15][O:14][C:11]3([CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[C:17]=2[CH:18]=1
Reactant: Fc1ccc2c(c1)C1(CCN(Cc3ccccc3)CC1)OC2
Agent: [Pd]
Solvent: CCO
Product: Fc1ccc2c(c1)C1(CCNCC1)OC2
Temperature: 25 °C
Yield: 95.1 %

Procedure:
To a solution of 1′-benzyl-6-fluoro-3H-spiro[2-benzofuran-1,4′-piperidine] (1 g, 3.4 mmol) in ethanol (10 ml) was added Pd/C 10% (100 mg, 0.09 mmol). The mixture was refluxed under an hydrogen atmosphere for 8 hours then cooled to room temperature and purged with argon. The catalyst was filtered and the filtrate was concentrated in vacuo to yield 0.67 g (96%) 6-fluoro-3H-spiro[2-benzofuran-1,4′-piperidine] as a white solid. MS m/e: 208 (M+H+).
Reaction SMILES: O[C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:54][CH2:55][CH2:56][CH2:57][NH:58][C:59](=[O:65])[O:60][C:61]([CH3:64])([CH3:63])[CH3:62].CCOC(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1>C1COCC1>[C:61]([O:60][C:59]([NH:58][CH2:57][CH2:56][CH2:55][O:54][N:5]1[CH2:4][C:3]2[C:7](=[C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)[CH:9]=[CH:10][CH:2]=2)[C:6]1=[O:34])=[O:65])([CH3:64])([CH3:63])[CH3:62]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: CC(C)(C)OC(=O)NCCCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCCCON1Cc2cccc(-c3cc4cc(CN5CCCCC5)ccc4n3C(=O)OC(C)(C)C)c2C1=O
Yield: 87.6 %

Procedure:
In a similar manner to Step 1 of Example 149, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (60.0 mg, 0.130 mmol) was dissolved in THF (3.6 mL), and the solution was treated with triphenylphosphine (136 mg, 0.78 mmol), tert-butyl N-(3-hydroxypropyl)carbamate (92 mg, 0.52 mmol) and 40% DEAD-toluene solution (0.236 mL), followed by purification by preparative thin-layer chromatography (chloroform/methanol=4/1) to obtain 4-[(3-(tert-butoxycarbonylamino)propoxy]-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (70.5 mg, yield 88%).
Reaction SMILES: [N+:1]([CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([O:12][C:13](=[O:15])[CH3:14])[CH:9]=[CH:10][CH:11]=1)([O-:3])=[O:2].[CH:16]([C@H:18]1[CH2:22][O:21][C:20]([CH3:24])([CH3:23])[N:19]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[O:17].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:28]([O:27][C:25]([N:19]1[C@@H:18]([C@@H:16]([OH:17])[C@@H:4]([N+:1]([O-:3])=[O:2])[CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13](=[O:15])[CH3:14])[CH:7]=2)[CH2:22][O:21][C:20]1([CH3:24])[CH3:23])=[O:26])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(=O)Oc1cccc(CC[N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)N1[C@@H](C=O)COC1(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(=O)Oc1cccc(C[C@@H]([C@H](O)[C@H]2COC(C)(C)N2C(=O)OC(C)(C)C)[N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 42.9 %

Procedure:
Dissolve acetic acid 3-(2-nitroethyl)-phenyl ester (25.53 g, 121.6 mmol) and tert-butyl (R)-(+)-4-formyl-2,2-dimethyl-3-oxazolidinecarboxylate (Gardner's aldehyde) (22.38 g, 97.61 mmol) in dry tetrahydrofuran (200 mL). Cool in ice bath and add tetrabutylammonium fluoride (98 mL, 98 mmol, 1.0 M in tetrahydrofuran) and stir for 15 minutes. Pour into ice water (2.7 L), wash with 1 N hydrochloric acid (200 mL), saturated aqueous sodium chloride, dry (magnesium sulfate), filter through a pad of silica gel and concentrate. Purify using silica gel chromatography, eluting with 5:95 ethyl acetate:dichloromethane, followed by 2 separate crystallizations using hexanes/dichloromethane to give the desired compound (18.372 g, 43% total yield).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])[C:8]([NH2:11])=[N:9][CH:10]=1.Cl[C:21]1[N:26]=[C:25]([NH2:27])[C:24]([N+:28]([O-:30])=[O:29])=[CH:23][CH:22]=1>>[NH2:27][C:25]1[N:26]=[C:21]([NH:1][CH2:2][CH2:3][NH:4][C:5]2[N:6]=[C:7]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[C:8]([NH2:11])=[N:9][CH:10]=2)[CH:22]=[CH:23][C:24]=1[N+:28]([O-:30])=[O:29]
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: NCCNc1cnc(N)c(-c2ccc(Cl)cc2Cl)n1
Product: Nc1nc(NCCNc2cnc(N)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]

Procedure:
The compound was prepared from N5-(2-aminoethyl)-3-(2,4-dichlorophenyl)pyrazine-2,5-diamine and 6-chloro-3-nitro-2-pyridylamine in accordance to the procedure described for Example 6.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[F:22])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16](=[O:18])[CH3:17])[N:14]=2)[N:11]=1.[CH3:23][N:24]1[C:28]([C:29](Cl)=[O:30])=[CH:27][C:26]([CH3:32])=[N:25]1.O>CN(C)C(=O)C>[C:16]([NH:15][C:13]1[N:14]=[C:9]2[CH:8]=[CH:7][C:6]([O:5][C:4]3[CH:19]=[CH:20][C:21]([F:22])=[C:2]([NH:1][C:29]([C:28]4[N:24]([CH3:23])[N:25]=[C:26]([CH3:32])[CH:27]=4)=[O:30])[CH:3]=3)=[N:11][N:10]2[CH:12]=1)(=[O:18])[CH3:17]
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Reactant: CC(=O)Nc1cn2nc(Oc3ccc(F)c(N)c3)ccc2n1
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(=O)Nc1cn2nc(Oc3ccc(F)c(NC(=O)c4cc(C)nn4C)c3)ccc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.5 %

Procedure:
To a solution of N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]acetamide (5.6 g, 18.6 mmol) in N,N-dimethylacetamide (44.8 mL) was added 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (3.25 g, 20.4 mmol). After stirring at room temperature for 2 hr, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate/tetrahydrofuran, washed with saturated brine, dried over anhydrous magnesium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was washed with ethyl acetate/ethanol to give the title compound (6.1 g, 78%) as a white powder.
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[N:8]=[CH:9][C:10]2[NH:11][C:12]3[C:17]([C:18]=2[C:19]=1[CH2:20][CH3:21])=[CH:16][C:15]([NH:22][C:23](=O)[CH3:24])=[CH:14][CH:13]=3)=[O:6])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1.C(OCC)(=O)C>O1CCOCC1>[CH:1]([O:4][C:5]([C:7]1[N:8]=[CH:9][C:10]2[NH:11][C:12]3[C:17]([C:18]=2[C:19]=1[CH2:20][CH3:21])=[CH:16][C:15]([NH:22][C:23](=[S:35])[CH3:24])=[CH:14][CH:13]=3)=[O:6])([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCc1c(C(=O)OC(C)C)ncc2[nH]c3ccc(NC(C)=O)cc3c12
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCc1c(C(=O)OC(C)C)ncc2[nH]c3ccc(NC(C)=S)cc3c12
Yield: 53.7 %

Procedure:
2741 mg of 6-acetylamino-4-ethyl-β-carboline-3-carboxylic acid isopropyl ester is heated to 70° C. in 110 ml of dioxane with 3915 mg of Lawesson's reagent while being stirred. After cooling, it is mixed with 100 ml of ethyl acetate and washed with saturated sodium chloride solution. The organic phases are dried and concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel with toluene+methanol=8+2. 1541 mg of 4-ethyl-6-thioacetylamino-β-carboline-3-carboxylic acid isopropyl ester with a melting point of 158-160° C. is obtained from the desired fractions.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([S:8](Cl)(=[O:10])=[O:9])=[C:5]([CH3:7])[N:6]=1.[NH3:12]>CO>[CH3:1][C:2]1[S:3][C:4]([S:8]([NH2:12])(=[O:10])=[O:9])=[C:5]([CH3:7])[N:6]=1
Reactant: N
Reactant: Cc1nc(C)c(S(=O)(=O)Cl)s1
Solvent: CO
Product: Cc1nc(C)c(S(N)(=O)=O)s1
Yield: 34 %

Procedure:
According to Reference Example 9-7, by use of 2,4-dimethylthiazole-5-sulfonyl chloride (250 mg, 1.1 mmol) and a 7 mol/L solution of ammonia in methanol (2 mL), the mixture was stirred and reacted at room temperature for 2 hours. Then, purification by silica gel column chromatography (chloroform/methanol=1/0 to 20/1) was performed to give 2,4-dimethylthiazole-5-sulfonamide (Compound FL) (60 mg, yield: 34%).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:10]1[NH:11][C:12]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:13]=2[N:14]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:22][CH:23]([CH3:25])[CH3:24]>CC(N(C)C)=O>[CH2:3]([C:10]1[N:14]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:13]2[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:12]=2[N:11]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)CBr
Reactant: COc1ccc2nc(Cc3ccccc3)[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1ccc2c(c1)nc(Cc1ccccc1)n2CC(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (18.31 mmole, 0.44 g, 60% in mineral oil) is added in small amounts under nitrogen to an ice cooled solution of 2-benzyl-5-methoxybenzimidazole (16.64 mmole, 3.96 g) in dry DMA (9 ml). The mixture is stirred at the same temperature for 30 minutes. 1-Bromo-2-methylpropane (18.31 mmole, 2.51 g) in DMA (4 ml) is added in several portions, and the mixture is allowed to stir at room temperature over night. The reaction mixture is added dropwise onto ice. The precipitate is collected and dissolved in dichloromethane. The organic solution is washed several times with water, is dried with Na2SO4, is filtered and is evaporated to give the title compound (R1=2-methylpropyl, R2=benzyl, R3=OCH3, n=1).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:16]=[CH:15][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.Br[CH:20]([CH:25](Br)[CH3:26])[CH2:21][C:22]([OH:24])=[O:23].C(=O)([O-])[O-].[K+].[K+].Cl>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.O.C1(C)C=CC=CC=1>[F:1][C:2]([F:17])([F:18])[C:3]1[CH:16]=[CH:15][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]([O:14][CH:25]([CH3:26])[CH:20]=[CH:21][C:22]([OH:24])=[O:23])=[CH:12][CH:13]=2)=[CH:5][CH:4]=1
Reactant: CC(Br)C(Br)CC(=O)O
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C=CC(=O)O)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Yield: 84 %

Procedure:
In a reactor, 15 g of toluene and 15 g of water was charged in a reactor and then, 12.7 g (0.05 mole) of 4-(4-trifluoromethylphenoxy)phenol, 14.3 g (0.055 mole) of 3,4-dibromopentanoic acid, 16.6 g (0.12 mole) of potassium carbonate and 0.23 g (0.001 mole) of triethylbenzylammonium chloride were added. They were refluxed for 6 hours to react them and then, conc. hydrochloric acid was added to the reaction mixture with stirring to be acidic and then, the water phase was separated and the organic phase was washed with water and then, toluene and low boiling by-products were distilled off at 100° C. under a reduced pressure (0.02-0.05 mmHg) to obtain 14.8 g of 4-[4-(4-trifluoromethylphenoxy)phenoxy]-2-pentenoic acid (nD20 1.5284). The yield was 84.2%.
Reaction SMILES: [OH:1][CH:2]([C:6](=[CH2:10])[CH2:7][CH2:8][CH3:9])[CH2:3][C:4]#[CH:5].N1C=CN=C1.CN(C)C=O.[CH2:21]([Si:23]([CH2:27][CH3:28])([CH2:25][CH3:26])Cl)[CH3:22]>O>[CH2:10]=[C:6]([CH2:7][CH2:8][CH3:9])[CH:2]([O:1][Si:23]([CH2:27][CH3:28])([CH2:25][CH3:26])[CH2:21][CH3:22])[CH2:3][C:4]#[CH:5]
Reactant: C#CCC(O)C(=C)CCC
Reactant: CC[Si](Cl)(CC)CC
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: C#CCC(O[Si](CC)(CC)CC)C(=C)CCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 30.0 g. of 4-hydroxy-5-methylene-1-octyne and 31.02 g. of imidazole in 80 ml. of dimethylformamide at 0° C., is added 40.9 g. of triethylchlorosilane. The mixture is stirred at room temperature for 30 minutes, poured into cold water and extracted with petroleum ether. The petroleum ether is removed and the residue is distilled. The product is recovered in the fraction boiling at 103°-106° C. (1.5 mm.).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH:16]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][OH:39])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)=[O:17].[C:40](O)(=[O:43])[CH:41]=[CH2:42]>CN(C)C1C=CN=CC=1.ClCCl>[CH:16]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][O:39][C:40](=[O:43])[CH:41]=[CH2:42])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)=[O:17]
Reactant: O=Cc1ccc(-c2ccc(OCCCCCCCCO)cc2)cc1
Reactant: C=CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=CC(=O)OCCCCCCCCOc1ccc(-c2ccc(C=O)cc2)cc1
Reaction time: 8 h
Yield: 56.4 %

Procedure:
2.9 g of N,N'-dicyclohexylcarbodiimide were added within 5 minutes while stirring to a solution of 3.8 g of 4-formyl-4'-(8-hydroxyoctyloxy)biphenyl, 0.9 g of acrylic acid and 0.05 g of 4-(dimethylamino)pyridine in 25 ml of dichloromethane. The reaction mixture was stirred overnight, filtered and then concentrated. Chromatography of the residue on silica gel with hexane/ethyl acetate (vol. 8:2) and recrystallization from ethyl alcohol of the fractions which were pure according to thin-layer chromatography gave 2.5 g of 4-formyl-4'-(8-acryloyloxyoctyloxy)biphenyl.
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3](=[O:30])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24](OCC)=[O:25])[C:6]1=[O:29].[NH2:32][CH2:33][CH2:34][N:35]([CH3:40])[S:36]([CH3:39])(=[O:38])=[O:37]>>[CH3:1][N:2]([CH3:31])[C:3](=[O:30])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24]([NH:32][CH2:33][CH2:34][N:35]([CH3:40])[S:36]([CH3:39])(=[O:38])=[O:37])=[O:25])[C:6]1=[O:29]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N(C)C)c1=O
Reactant: CN(CCN)S(C)(=O)=O
Product: CN(C)C(=O)Cn1c(=O)c(C(=O)NCCN(C)S(C)(=O)=O)c(O)c2ncc(Cc3ccc(F)cc3)cc21

Procedure:
This compound was prepared from ethyl 1-[2-(dimethylamino)-2-oxoethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and N-(2-aminoethyl)-N-methylmethanesulfonamide employing methods similar to those described in Example 245 and was purified by reverse phase preparative HPLC (C-18 stationary phase; 10-100% CH3CN/water/0.1% formic acid mobile phase). The product was obtained as a cream-colored solid: 1H NMR (d6-DMSO) δ 10.20 (1H, br t, J=6 Hz), 8.51 (1H, s), 7.76 (1H, s), 7.31 (2H, dd, J=8.3, 6 Hz), 7.12 (2H, t, J=˜9 Hz), 5.12 (2H, s), 4.11 (2H, s), 3.55 (2H, q, J=6 Hz), 3.25 (2H, m), 3.12 (3H, s), 2.85 (3H, s), 2.81 (3H, s), 2.79 (3H, s); HRMS calcd for C24H28FN5O6+H+: 534.1823. Found: 534.1812.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C@H:10]([C:12]([O:14][CH3:15])=[O:13])[CH3:11])[CH:5]=[CH:6][C:7]=1[F:8].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[I-].C([NH3+])(C)(C)C.[H-].[Na+]>CN(C=O)C.CCOC(C)=O>[CH2:16]([N:9]([C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=1)[C@H:10]([C:12]([O:14][CH3:15])=[O:13])[CH3:11])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)[C@H](C)Nc1ccc(F)c(Cl)c1
Reactant: BrCc1ccccc1
Agent: CC(C)(C)[NH3+]
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](C)N(Cc1ccccc1)c1ccc(F)c(Cl)c1
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
Methyl N-(3-chloro-4-fluorophenyl)alaninate (1-3, 0.740 g, 3.194 mmol) was treated with benzyl bromide (0.955 mL, 7.986 mmol) and tertbutylammonium iodide (0.118 g, 0.319 mmol) at 25° C. in DMF (100 mL) then allowed to stir 15 min. NaH was added (0.100 g, 4.153 mmol) and the resulting suspension was warmed at 50° C. while stirring over 48 h. Upon completion, the reaction was diluted with EtOAc (100 mL) and washed with NaHCO3 (sat. aq) (3×75 mL). The organic fractions were dried over sodium Na2SO4, filtered, and concentrated under vacuum. The residue was purified by flash column chromotography (SiO2, 0-40% EtOAc/hexanes gradient) to give methyl N-benzyl-N-(3-chloro-4-fluorophenyl)alaninate (2-1). 1H NMR (300 MHz, CDCl3) δ 7.31 (m, 5H), 6.91 (t, J=8.8 Hz, 1H), 6.73 (m, 1H), 6.49 (m, 1H), 4.47 (m, 3H), 3.73 (s, 3H), 1.22 (d, J=6.0 Hz, 3H). MS 322.3 found, 322.8 (M+H+) required.
Reaction SMILES: O/[N:2]=[C:3](\[NH:13][C:14](=[O:22])[O:15]C1C=CC=CC=1)/[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([I:11])=[C:7]([CH3:12])[CH:6]=1>C1(C)C=CC=CC=1>[I:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][C:3]2[NH:13][C:14](=[O:15])[O:22][N:2]=2)=[CH:6][C:7]=1[CH3:12]
Reactant: Cc1cc(C/C(=N/O)NC(=O)Oc2ccccc2)ccc1I
Solvent: Cc1ccccc1
Product: Cc1cc(Cc2noc(=O)[nH]2)ccc1I

Procedure:
(Z)-Phenyl 1-(hydroxyimino)-2-(4-iodo-3-methylphenyl)ethylcarbamate (Intermediate 29-2; 1.67 g, 4.07 mmol) was dissolved in anhydrous toluene (30 mL). The resulting solution was stirred at reflux for 16 hours. The cooled reaction mixture was evaporated to dryness and redissolved in DCM (50 mL) and extracted with saturated NaHCO3 (50 mL). The aqueous layer was acidified with 2M HCl and extracted with EtOAc (3×50 mL). The organic layers were combined and dried over MgSO4, filtered and evaporated to afford desired product. 3-(4-iodo-3-methylbenzyl)-1,2,4-oxadiazol-5(4H)-one (0.787 g, 61.2%) as a yellow solid.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:24]=[CH:23][CH:22]=[C:21]4[C:16]=3[CH2:17][CH2:18][CH2:19][NH:20]4)[N:11]=2)=[CH:6][CH:5]=1)[CH2:2][CH3:3].[CH:25]([C:27]1([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:32][O:31][C:30]([CH3:34])([CH3:33])[O:29][CH2:28]1)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.CCOC(C)=O>[CH3:33][C:30]1([CH3:34])[O:29][CH2:28][C:27]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])([CH2:25][N:20]2[C:21]3[C:16](=[C:15]([C:12]4[N:11]=[C:10]([C:7]5[CH:6]=[CH:5][C:4]([CH2:1][CH2:2][CH3:3])=[CH:9][CH:8]=5)[O:14][N:13]=4)[CH:24]=[CH:23][CH:22]=3)[CH2:17][CH2:18][CH2:19]2)[CH2:32][O:31]1
Reactant: CCCc1ccc(-c2nc(-c3cccc4c3CCCN4)no2)cc1
Reactant: CC(C)(C)OC(=O)NC1(C=O)COC(C)(C)OC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CCCc1ccc(-c2nc(-c3cccc4c3CCCN4CC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)no2)cc1
Temperature: 25 °C
Yield: 53.3 %

Procedure:
To a mixture of the product of Step D (0.0334 g; 0.1 mmol), tert-butyl 5-formyl-2,2-dimethyl-1,3-dioxan-5-ylcarbamate (3×0.03 g; 0.33 mmol) and NaBH(OAc)3 (3×0.07 g; 0.93 mmol) in 1,2-dichloroethane (1.5 ml) AcOH (3×0.01 ml) was added portion wise over a period of 3 days with stirring at room temperature. The mixture was then diluted to 15 ml with EtOAc, washed with 10% NaOH, H2O, brine, dried over anhydrous MgSO4, filtered and filtrate evaporated to dryness under reduced pressure. The residue was purified by FCC (SiO2, hexane:EtOAc, 9:1), to give the title compound (0.03 g; 51%) as colourless foam. 1H-NMR (CDCl3) 0.95 (tr, 3H, J=7.4 Hz); 1.44 (m, 15H); 1.61-1.72 (m, 2H); 1.89-1.97 (m, 2H); 2.66 (tr, 2H, J=7.8 Hz); 3.06 (tr, 2H; J=6.5 Hz); 3.34 (tr, 2H, J=5.4 Hz); 3.77 (s, 2H); 3.95 (s, 4H); 4.7 (broad s, 1H); 7.02 (d, 1H, J=7.6 Hz); 7.14 (tr, 1H, J=7.6 Hz); 7.22-7.25 (m, 1H+CDCl3); 7.33 (d, 2H, J=8.3 Hz); 8.09 (d, 2H, J=8.3 Hz).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[O:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[C:14]([C@@H:15]3[CH2:17][C@H:16]3[CH2:18][NH2:19])[C:9]=2[CH2:8][CH2:7]1.[Na+].[Cl-]>>[O:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[C:14]([C@@H:15]3[CH2:17][C@H:16]3[CH2:18][NH:19][C:1](=[O:4])[CH2:2][CH3:3])[C:9]=2[CH2:8][CH2:7]1
Reactant: NC[C@@H]1C[C@H]1c1cccc2c1CCO2
Reactant: CCC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Product: CCC(=O)NC[C@@H]1C[C@H]1c1cccc2c1CCO2

Procedure:
This compound was prepared similar to the above procedure using propionyl chloride and (-)-(trans)-2-(2,3-dihydrobenzofuran-4-yl)-cyclopropanemethanamine to give an oil that solidified upon standing to an off-white solid (61%, mp: 71°-72° C.). IR (NaCl Film): 3298, 1645, 1548, 1459, 1235 cm-1. [α]D25 : -17.3°; Anal. Calc'd for C15H19NO2 : C, 73.44; H, 7.87; N, 5.71; Found: C, 73.28; H, 7.68; N, 5.58.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]([F:10])=[C:4]([F:9])[C:5]([F:8])([F:7])[F:6].[CH:13]1[CH2:17][CH:16]=[CH:15][CH:14]=1>>[F:9][C:4]1([C:5]([F:8])([F:7])[F:6])[C:3]([F:10])([C:2]([F:11])([F:12])[F:1])[CH:16]2[CH2:17][CH:13]1[CH2:14][CH2:15]2
Reactant: C1=CCC=C1
Reactant: FC(=C(F)C(F)(F)F)C(F)(F)F
Product: FC(F)(F)C1(F)C2CCC(C2)C1(F)C(F)(F)F

Procedure:
Also, in a like manner, octafluoro-but-2-ene and cyclopentadiene react to give 2,3-difluoro-2,3-bis(trifluoromethyl) bicyclo[2.2.1] heptane which, after hydrogenation over ruthenium gives 2,3-bis(trifluoromethyl)bicyclo [2.2.1] heptane.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][NH2:14])=[C:11]([CH3:15])[O:10][N:9]=2)=[CH:4][CH:3]=1.[Cl:16][C:17]1[N:18]=[N:19][C:20](Cl)=[CH:21][CH:22]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[Cl:16][C:17]1[N:18]=[N:19][C:20]([NH:14][CH2:13][C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[N:9][O:10][C:11]=2[CH3:15])=[CH:21][CH:22]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: Cc1onc(-c2ccc(F)cc2)c1CN
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1onc(-c2ccc(F)cc2)c1CNc1ccc(Cl)nn1
Temperature: 160 °C
Yield: 31.1 %

Procedure:
A solution of C-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-methylamine (206 mg, 1.0 mmol) and 3,6-dichloropyridazine (149 mg, 1.0 mmol) in DMSO (2 mL) containing N,N-diisopropyl ethyl amine (259 mg, 342 μL, 2.0 mmol) was heated with microwave irradiation to 160° C. for 1 h. After cooling to room temperature the reaction mixture was extracted (ethyl acetate/water). The organic phase was dried over sodium sulfate and concentrated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (99 mg, 31%) as an off white solid after recrystallization from heptane:ethyl acetate. MS: m/e=319.1 [M+H]−.