Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]2[N:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[CH2:9][C:10]([OH:12])=[O:11])=[CH:4][N:3]=1.[H][H]>C(O)C.[Pd]>[CH3:1][C:2]1[N:3]=[CH:4][C:5]([CH:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]2[NH:26][CH2:25][CH2:24][CH2:23][N:22]=2)[CH2:9][C:10]([OH:12])=[O:11])=[CH:6][N:7]=1
Reactant: Cc1ncc(C(CCCCCCCNc2ncccn2)CC(=O)O)cn1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1ncc(C(CCCCCCCNC2=NCCCN2)CC(=O)O)cn1
Yield: 78.1 %

Procedure:
A solution of 24-9 (47 mg, 0.131 mmol) in ethanol (1 mL) was treated with 10% palladium on carbon (7 mg) and hydrogen gas at one atmosphere (6 days). The reaction mixture was filtered through celite and the filtrate evaporated in vacuo. PCTLC (SiO2, 1 mm, 2% AcOH; 18% MeOH; 80% CHCl3) afforded 24-10 (37 mg).
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH3:22])[S:7](=[O:21])(=[O:20])[C:8]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:9]=2[C:10]=1[OH:11])=[O:4].[NH2:23][C:24]1[S:25][C:26]([CH3:30])=[C:27]([CH3:29])[N:28]=1>C(Cl)CCl>[CH3:29][C:27]1[N:28]=[C:24]([NH:23][C:3]([C:5]2[N:6]([CH3:22])[S:7](=[O:21])(=[O:20])[C:8]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]=[CH:12][C:9]=3[C:10]=2[OH:11])=[O:4])[S:25][C:26]=1[CH3:30]
Reactant: Cc1nc(N)sc1C
Reactant: COC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1C
Solvent: ClCCCl
Product: Cc1nc(NC(=O)C2=C(O)c3ccc4ccccc4c3S(=O)(=O)N2C)sc1C
Yield: 31 %

Procedure:
N-(4,5-Dimethyl-2-thiazolyl)-4-hydroxy-2-methyl-2 H-naphtho[2,1-e]-1,2-thiazine-3-carboxamide-1,1-dioxide was prepared analogous to Example 22 from 4-hydroxy-2-methyl-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxylic acid methylester-1,1-dioxide and 2-amino-4,5-dimethyl-thiazole. Yield: 31% of theory; m.p. 264°-265° C (decomp.; from ethylene chloride).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[CH2:5]([O:7][C:8](=[O:17])[CH:9](Cl)[C:10](=O)[C:11]([F:14])([F:13])[F:12])[CH3:6]>CCO>[CH2:5]([O:7][C:8]([C:9]1[S:3][C:2]([NH2:4])=[N:1][C:10]=1[C:11]([F:12])([F:13])[F:14])=[O:17])[CH3:6]
Reactant: NC(N)=S
Reactant: CCOC(=O)C(Cl)C(=O)C(F)(F)F
Solvent: CCO
Product: CCOC(=O)c1sc(N)nc1C(F)(F)F
Reaction time: 3 h

Procedure:
A mixture of thiourea (8.7 g) and 2-chloro-4,4,4-trifluoro-3-oxo-butyric acid ethyl ester (25 g) in 200 mL of EtOH is heated with stirring for 3 h. The solvent is evaporated and water is added to the residue, and basified with NaHCO3. The solid is collected with filtration, washed with water and hexane, and dried to afford the title compound.
Reaction SMILES: [Cl:1][CH:2]([Cl:14])[C:3]([F:13])([F:12])[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1.Cl.[Cl:16][C:17]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:18]=1[C:19]([N:21]=[C:22]=[O:23])=[O:20]>C1(C)C(C)=CC=CC=1>[Cl:16][C:17]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:18]=1[C:19]([NH:21][C:22]([NH:11][C:8]1[CH:7]=[CH:6][C:5]([O:4][C:3]([F:12])([F:13])[CH:2]([Cl:1])[Cl:14])=[CH:10][CH:9]=1)=[O:23])=[O:20]
Reactant: Nc1ccc(OC(F)(F)C(Cl)Cl)cc1
Reactant: O=C=NC(=O)c1c(Cl)cccc1Cl
Agent: Cl
Solvent: Cc1ccccc1C
Product: O=C(NC(=O)c1c(Cl)cccc1Cl)Nc1ccc(OC(F)(F)C(Cl)Cl)cc1
Reaction time: 2 h
Yield: 463.9 %

Procedure:
In 200 milliliters of xylene, 11.5 grams (0.04 mole) of β,β-dichloro-α,α-difluoro-p-phenetidine.HCl and 3.6 grams (0.04 mole) of 2,6-dichlorobenzoyl isocyanate were refluxed with stirring for two hours. The xylene was thereafter removed by vacuum distillation. The residue which remained was mixed with 200 milliliters of hexane and a crystalline solid precipitated. This precipitated material was collected by suction filtration, washed with hexane and dried. The dried crude product was a light tan gummy solid melting at 160°-185° C. This crude product was purified by recrystallization from 60 milliliters of 83 percent aqueous acetic acid, leaving 85 grams of a white solid melting at 211°-213° C. (56 percent of theoretical). Nuclear magnetic resonance spectroscopy confirmed the structure as being ##STR13##
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]2[C:12]([N+:16]([O-])=O)=[C:13]([CH3:15])[N:14]=[C:10]2[CH:9]=[CH:8][CH:7]=1)=[O:5])[CH3:2]>CO.[Pd]>[NH2:16][C:12]1[N:11]2[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=[CH:9][C:10]2=[N:14][C:13]=1[CH3:15]
Reactant: CCOC(=O)c1cccc2nc(C)c([N+](=O)[O-])n12
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)c1cccc2nc(C)c(N)n12
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.7 %

Procedure:
To a solution of 300 mg of 5-ethoxycarbonyl-2-methyl-3-nitroimidazo[1,2-a]pyridine in 20 ml of methanol was added 10% Pd—C (wet, 90 mg). The mixture was stirred for two hours at room temperature under hydrogen atmosphere. The catalyst was filtered off and washed with methanol. The filtrate and the washing were combined, and the solvent was filtered off. The residue was purified by column chromatography (eluent: ethyl acetate) to afford 184 mg of the object product (69.7%, an orange solid)
Reaction SMILES: [CH2:1]([CH:3]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]2[C:5](=[C:6]([Cl:20])[C:7]([Cl:19])=[C:8]([OH:18])[CH:9]=2)[C:4]1=[O:21])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][C:30]([O:32]CC)=[O:31]>CN(C)C=O>[O:21]=[C:4]1[C:5]2[C:10](=[CH:9][C:8]([O:18][CH2:29][C:30]([OH:32])=[O:31])=[C:7]([Cl:19])[C:6]=2[Cl:20])[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]1[CH2:1][CH3:2]
Reactant: CCOC(=O)CBr
Reactant: CCC1C(=O)c2c(cc(O)c(Cl)c2Cl)C1c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC1C(=O)c2c(cc(OCC(=O)O)c(Cl)c2Cl)C1c1ccccc1

Procedure:
(1-Oxo-2-ethyl-3-phenyl-6,7-dichloro-5-indanyloxy)acetic acid is prepared following substantially the same procedure described in Example 4, Step F, using the following substances: 2-ethyl-3-phenyl-5-hydroxy-6,7-dichloro-1-indanone (16.6 g., 0.0518 mole); potassium carbonate (14.4 g., 0.104 mole); ethyl bromoacetate (17.3 g., 0.104 mole); and dimethylformamide (80 ml.); and hydrolyzing the resultant ester in accordance with Example 4, Step F, there is obtained 14.4. g. (74%) of (1-oxo-2-ethyl-3-phenyl-6,7-dichloro-5-indanyloxy)acetic acid which after recrystallization from acetic acid melts at 203°-206° C.
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][CH2:4][OH:5].[C:7]1([CH3:17])[CH:12]=CC(S(O)(=O)=O)=[CH:9][CH:8]=1>>[CH2:4]([O:5][CH2:9][CH:8]=[C:7]([CH3:17])[CH3:12])[CH:3]=[C:2]([CH3:6])[CH3:1]
Reactant: CC(C)=CCO
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)=CCOCC=C(C)C
Yield: 50 %

Procedure:
To 30 g of 3-methyl-2-buten-1-ol [prenol] was added 0.74 g of p-toluenesulfonic acid, and the mixture was stirred under reflux (at 130°-140° C.) for 3 hours. The reaction solution separated into two layers. The lower layer comprised water and the upper layer was subjected to gas chromatographic analysis revealing that about 4% of the starting prenol remained and that diprenyl ether was formed in a yield of about 50% based on the starting prenol together with unknown products. After distillation under reduced pressure was isolated diprenyl ether having the following properties.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([N:15]([S:17]([C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]([CH3:32])=[CH2:31])[CH:21]=3)(=[O:19])=[O:18])[CH3:16])[C:9]=2[CH:8]=[N:7]1)[CH3:2].[N+](=[CH2:36])=[N-]>O1CCCC1.C(OCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:3][C:4](=[O:33])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([N:15]([CH3:16])[S:17]([C:20]3[CH:25]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:23]=[C:22]([C:30]4([CH3:36])[CH2:32][CH2:31]4)[CH:21]=3)(=[O:18])=[O:19])[C:9]=2[CH:8]=[N:7]1)[CH3:2]
Reactant: C=[N+]=[N-]
Reactant: C=C(C)c1cc(C(F)(F)F)cc(S(=O)(=O)N(C)[C@@H]2CCCc3c2cnn3CC(=O)OCC)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)Cn1ncc2c1CCC[C@H]2N(C)S(=O)(=O)c1cc(C(F)(F)F)cc(C2(C)CC2)c1
Reaction time: 0.17 h
Yield: 99 %

Procedure:
To a solution of {(R)-4-[(3-isopropenyl-5-trifluoromethyl-benzenesulfonyl)-methyl-amino]-4,5,6,7-tetrahydro-indazol-1-yl}-acetic acid ethyl ester (70.7 mg, 0.15 mmol) in tetrahydrofuran (2 mL) was added a solution of diazomethane in diethyl ether (1M, 8 mL) slowly at 0° C. under an argon atmosphere, and then a portion of palladium acetate (5 mg) was added. After the mixture was stirred for 10 minutes, a second portion of palladium acetate (5 mg) was added and the mixture was stirred for another 20 minutes, followed by addition of a second portion of a solution of diazomethane in diethyl ether (1M, 5 mL). After being stirred at 0° C. for 2 hours under an argon atmosphere, the reaction mixture was then quenched by the addition of a few drops of acetic acid, and then filtered through a glass funnel and concentrated in vacuo. The residue was purified by flash column (gradient elution, 0-10% methanol in dichloromethane) to afford ((R)-4-{methyl-[3-(1-methyl-cyclopropyl)-5-trifluoromethyl-benzenesulfonyl]-amino}-4,5,6,7-tetrahydro-indazol-1-yl)-acetic acid ethyl ester (74.5 mg, 99%) as a colorless semisolid. MS cald. for C23H28F3N3O4S 499, obsd. (ESI+) [(M+H)+] 500.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH2:13][CH:12]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[C:18]([O:23]C)[CH:17]=3)[CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br>C(O)(=O)C>[C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH2:13][CH:12]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[C:18]([OH:23])[CH:17]=3)[CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1cc(C2CCCN(CCCc3ccccc3)C2)ccc1F
Agent: Br
Solvent: CC(=O)O
Product: Oc1cc(C2CCCN(CCCc3ccccc3)C2)ccc1F
Yield: 32 %

Procedure:
The 1-(3-phenylpropyl)-3-(4-fluoro-3-methoxyphenyl)-piperidine from Preparation 5 was reacted with 48% aqueous hydrobromic acid in glacial acetic acid using the procedure of Example 3. The product was chromatographed on silica gel, eluting with ethyl acetate/hexane/triethylamine (5:5:3). This afforded a 32% yield of the title compound, [alpha]D25 =-21.2° (c=1; C2H5OH).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1(S)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(OC(=O)C(Cl)(Cl)CC[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][Br:31])C.O>CN(C)C=O>[Br:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH:22]=[CH:21][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Sc1ccccc1
Reactant: CCOC(=O)C(Cl)(Cl)CCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: BrCCCCCCCCC=Cc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 89.7 %

Procedure:
3.46 g (25.0 mmol) potassium carbonate and 2.75 g (25.0 mmol) thiophenol were added to a solution of 10.1 g (25.0 mmol) 3 in 200 ml dimethylformamide. It was stirred for 12 h at room temperature, 300 ml water was added, it was extracted with ether, washed with water, dried over sodium sulfate and the solvent was removed on a rotary evaporator. 6.62 g (61%) 66 was obtained as a nearly colourless oil after flash chromatography of the residue (silica gel, heptane/toluene 5:1).
Reaction SMILES: [OH:1][CH:2]([C:8]1[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=1)[O:11][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[C:26](OC(=O)C)(=[O:28])[CH3:27]>N1C=CC=CC=1>[C:26]([O:1][CH:2]([C:8]1[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=1)[O:11][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])(=[O:28])[CH3:27]
Reactant: CCCCCC(O)c1cccc(OCc2ccc3ccccc3n2)c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCCCCC(OC(C)=O)c1cccc(OCc2ccc3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-[[3-(1-hydroxyhexyl)phenoxymethyl]quinoline (1.7 g) in pyridine at 0° C. was added acetic anhydride (2.7 ml). The reaction mixture was stirred overnight at room temperature. The solvent was removed in vacuo to obtain the crude product.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[CH:22]=[CH:23][C:24](I)=[C:25]([CH:34]=1)[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:27].[CH2:36]([N:39]1[C:43](=[O:44])[C:42]2=[CH:45][CH:46]=[CH:47][CH:48]=[C:41]2[C:40]1=[O:49])[C:37]#[CH:38]>[Pd](Cl)Cl.C(Cl)Cl>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([C:38]#[C:37][CH2:36][N:39]2[C:43](=[O:44])[C:42]3=[CH:45][CH:46]=[CH:47][CH:48]=[C:41]3[C:40]2=[O:49])=[C:25]([C:26](=[O:27])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:34]=1
Reactant: C#CCN1C(=O)c2ccccc2C1=O
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1I
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(c1ccccc1)c1cc(Cl)ccc1C#CCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C

Procedure:
A mixture of 0.71 g (4.0 mmole) of palladium chloride, 2.1 g (8.0 mmole) of triphenylphosphine, 0.80 g (4.2 mmole) of cuprous iodide, 68.8 g (0.20 mole) of 5-chloro-2-iodobenzophenone, 200 ml ofdiethylamine, and 400 ml of methylene chloride was stirred at room temperature under argon until complete solution was obtained. In one portion, 40.0 g (0.22 mole) of N-propargylphthalimide was added to the solution and the resulting mixture stirred for 20 hr. The volatiles were removed at reduced pressure and the residue was triturated with 200 ml of isopropanol. The resulting percipitate was collected by filtration to give crude end product. Recrystallization from acetone gave cream colored prisms, mp 148°-150° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7](Cl)=[CH:8][N:9]=1)(=[O:3])[CH3:2].[CH3:11][N:12]1[CH:16]=[CH:15][N:14]=[C:13]1[SH:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([NH:4][C:5]1[S:6][C:7]([S:17][C:13]2[N:12]([CH3:11])[CH:16]=[CH:15][N:14]=2)=[CH:8][N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ncc(Cl)s1
Reactant: Cn1ccnc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ncc(Sc2nccn2C)s1
Temperature: 130 °C
Yield: 91.1 %

Procedure:
A mixture of 2-acetylamino-5-chlorothiazole (5.3 g), 1-methyl-2-mercaptoimidazole (3.6 g) and potassium carbonate (6.2 g) in N,N-dimethylformamide (50 ml) was heated at 130° C. for 5.5 hours with stirring. The reaction mixture was concentrated under reduced pressure and the residue was triturated with water. The precipitates were collected by filtration washed with water and dried in vacuo to give 2-acetylamino-5-(1-methylimidazol-2-ylthio)thiazole (6.95 g, yield: 91.2%). mp: 155°-160° C. (dec.) IR (Nujol): 3400, 1690, 1565, 1300 cm-1
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C@@H:7]([CH2:11][C:12]1[N:13]=[CH:14][NH:15][CH:16]=1)[C:8]([OH:10])=[O:9])=[O:5])#[N:2]>N.CO.[Rh]>[CH:16]1[N:15]=[CH:14][NH:13][C:12]=1[CH2:11][C@H:7]([NH:6][C:4]([CH2:3][CH2:1][NH2:2])=[O:5])[C:8]([OH:10])=[O:9]
Reactant: N#CCC(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O
Agent: [Rh]
Agent: N
Solvent: CO
Product: NCCC(=O)N[C@@H](Cc1cnc[nH]1)C(=O)O
Temperature: 90 °C
Reaction time: 3 h

Procedure:
In a 1-litre pressure autoclave, a solution of 10.00 g (45.0 mmol) of (5)-2-(cyanoacetylamino)-3-(1H-imidazol-4-yl)propionic acid (prepared according to Example 3) in a mixture of 157 g of conc. NH3/methanol (m/m=3:2) was added to 0.88 g of Rh/C (0.4 mol % pure Rh, based on reactant used). The autoclave was closed and flushed twice with 40 bar of nitrogen and once with hydrogen. The mixture was heated to 90° C. and the autoclave was pressurized with 40 bar of hydrogen. After 3 h at 90° C., the reaction mixture was cooled to room temperature, the autoclave was depressurized and the catalyst was filtered off by filtration. An in-process analysis (HPLC) showed that the reaction solution (147.2 g) contained 6.38% (m/m) carnosine, corresponding to a selectivity of 92% for complete conversion. The reaction mixture was then concentrated in a rotary evaporator to 41.2 g. 124 g of ethanol were added dropwise at room temperature and the flask was stored in a refrigerator overnight. On the next day, the precipitate was filtered off, washed with ethanol and dried in a drying oven at 40° C./20 mbar. 7.96 g (78%) of a slightly greenish solid with a content (HPLC) of 98% (m/m) were obtained.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][CH2:7][C@H:8]([OH:12])[C:9]([OH:11])=[O:10].[CH3:13][C:14](=[CH2:16])[CH3:15]>C(COC)OC>[NH2:6][CH2:7][C@H:8]([O:12][C:14]([CH3:16])([CH3:15])[CH3:13])[C:9]([O:11][C:14]([CH3:15])([CH3:13])[CH3:16])=[O:10]
Reactant: NC[C@H](O)C(=O)O
Reactant: C=C(C)C
Agent: O=S(=O)(O)O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)[C@H](CN)OC(C)(C)C
Temperature: -78 °C
Reaction time: 48 h

Procedure:
The following reaction was carried out in a Fischer-Porter tube. Dimethoxyethane (76 ml) and 3.2 ml of concentrated sulfuric acid were added in that order to 4.0 g of 3-amino-(2S)-hydroxypropionic acid (L-isoserine), and the mixture was then cooled to −78° C. Isobutylene (38 ml) was added thereto, and the tube was sealed, followed by shaking at room temperature for 48 hr. The tube was then slowly opened, and isobutylene was removed by distillation at room temperature. The reaction mixture was then added dropwise to 128 ml of ice water, and the mixture was washed twice with 250 ml of ether, was cooled to 0° C., and was then neutralized with a 6 N aqueous sodium hydroxide solution. Further, solid sodium chloride was added to prepare a saturated solution, and the mixture was extracted four times with 100 ml of chloroform. The chloroform layers were combined, and the combined chloroform layers were dried over anhydrous sodium sulfate and were then concentrated under the reduced pressure to give 640 mg of a yellow oil. The yellow oil was purified by column chromatography on silica gel (64 g, chloroform-methanol-concentrated aqueous ammonia=20:1:0.05→10:1:0.1) to give 191 mg of intermediate 1 and 430 mg of intermediate 2.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:18][CH2:19][CH3:20])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[CH:8][C:7]([OH:17])=[CH:6][CH:5]=2.[CH2:21]([O:23][C:24](=[O:29])[C:25](Br)([CH3:27])[CH3:26])[CH3:22]>>[CH2:21]([O:23][C:24](=[O:29])[C:25]([CH3:27])([O:17][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]([CH2:18][CH2:19][CH3:20])[C:2]([CH3:1])=[C:10]2[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)[CH3:26])[CH3:22]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CCCn1c(C)c(-c2ccncc2)c2cc(O)ccc21
Product: CCCn1c(C)c(-c2ccncc2)c2cc(OC(C)(C)C(=O)OCC)ccc21

Procedure:
The above compound was prepared from 2-methyl-1-propyl-3-(4-pyridyl)-1H-indole-5-ol and 2-bromo-2-methylpropanoic acid ethylester using a procedure analogous to that of Example 10.
Reaction SMILES: [CH2:1]1[C:4]2([CH2:9][CH2:8][NH:7][CH2:6][CH2:5]2)[CH2:3][N:2]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C(N(CC)CC)C.[C:24](=O)([O:33]N1C(=O)CCC1=O)[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>ClCCl>[CH2:1]1[C:4]2([CH2:5][CH2:6][N:7]([C:24]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:33])[CH2:8][CH2:9]2)[CH2:3][N:2]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]
Reactant: CC(C)(C)OC(=O)N1CC2(CCNCC2)C1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC2(CCN(C(=O)OCc3ccccc3)CC2)C1
Temperature: 0 °C
Reaction time: 6 h
Yield: 100.2 %

Procedure:
Tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (21.0 g, 92.8 mmol) and triethylamine (20 mL, 186 mmol) were dissolved in dichloromethane (200 mL). The reaction was cooled to 0° C. and a solution of benzyl 2,5-dioxopyrrolidin-1-yl carbonate (23.1 g, 92.8 mmol) in dichloromethane (25 mL) was added dropwise. The ice-bath was removed and the reaction was stirred at room temperature for 6 hours. The reaction was diluted with dichloromethane (100 mL), washed with 10% aqueous citric acid solution (100 mL), water (100 mL) and brine (100 mL). The organic solution was dried over MgSO4, filtered and concentrated to afford 7-benzyl 2-tert-butyl 2,7-diazaspiro[3.5]nonane-2,7-dicarboxylate (33.5 g, 100%) as colorless oil, which was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[NH:7][C:6]=2[CH:5]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[C:27]=1[CH3:36].CCOC(C)=O>CN(C)C=O>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:33])([F:34])[F:35])[C:27]=3[CH3:36])[C:6]=2[CH:5]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:3]=1
Reactant: Cc1c(CBr)cccc1C(F)(F)F
Reactant: Cc1nc2c(Br)cc(N3CCOCC3)cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c(Cn2c(C)nc3c(Br)cc(N4CCOCC4)cc32)cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 70 %

Procedure:
A suspension of 4-bromo-2-methyl-6-(4-morpholinyl)-1H-benzimidazole, prepared as described in Example 62 (500 mg, 1.688 mmol) and potassium carbonate (700 mg, 5.06 mmol) in N,N-Dimethylformamide (DMF) (6 mL) was stirred at rt for 15 min. 1-(bromomethyl)-2-methyl-3-(trifluoromethyl)benzene (641 mg, 2.53 mmol) was added in and the resulting reaction mixture was stirred for 3 h at 80° C. It was then cooled to room temperature and poured into ice/water. The precipitate was collected by filtration, washed with water, then few mLs of hexanes and air dried. The crude material was purified on a silica gel column (ISCO, 0-80% EtOAc in hexanes) to the desired product (565 mg, 1.182 mmol, 70.0% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.59 (d, J=7.83 Hz, 1H), 7.16 (d, J=2.02 Hz, 1H), 7.10-7.15 (m, 1H), 6.46-6.52 (m, 2H), 5.25 (s, 2H), 3.75-3.89 (m, 4H), 3.05-3.14 (m, 4H), 2.55 (s, 3H), 2.51 (s, 3H). MS(ES+) m/e 468.9 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]1[C:12](=[C:13]([CH3:15])[CH3:14])[CH:7]2[CH:6]=[CH:5]1.[H][H]>[Pd].C1COCC1>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]1[C:12](=[C:13]([CH3:15])[CH3:14])[CH:7]2[CH2:6][CH2:5]1
Reactant: [H][H]
Reactant: CC(C)=C1C2C=CC1c1c(Cl)cccc12
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)=C1C2CCC1c1c(Cl)cccc12
Yield: 97.3 %

Procedure:
170 g of 5-Chloro-9-isopropylidene-1,4-dihydro-1,4-methano-naphthalene (0.785 mol), 0.5 g of Pd 10% (0.2 mmol) and 1 liter THF were charged in an hydrogenation reactor. 19 liter Hydrogen was feed at ambient temperature; the reaction was carried out at 0.05 MPa pressure. After complete conversion, the reaction mixture was filtered off over hyflo and product solution was evaporated to give 167 g product (Purity: 92%; Yield: 90%). The product was crystallized with MeOH, filtered off and dried. Purity: 97.54%
Reaction SMILES: [O-]Cl.[Na+].[OH-].[Na+].[F:6][C:7]([F:22])([F:21])[CH2:8][NH:9][C:10]([C:12]1[S:13][C:14]([CH:18]=[N:19][OH:20])=[CH:15][C:16]=1[CH3:17])=[O:11].[Cl:23][C:24]1[CH:29]=[C:28]([C:30]([C:32]([F:35])([F:34])[F:33])=[CH2:31])[CH:27]=[C:26]([Cl:36])[CH:25]=1>C1COCC1.C(OCC)C>[F:22][C:7]([F:6])([F:21])[CH2:8][NH:9][C:10]([C:12]1[S:13][C:14]([C:18]2[CH2:31][C:30]([C:28]3[CH:27]=[C:26]([Cl:36])[CH:25]=[C:24]([Cl:23])[CH:29]=3)([C:32]([F:33])([F:35])[F:34])[O:20][N:19]=2)=[CH:15][C:16]=1[CH3:17])=[O:11]
Reactant: Cc1cc(C=NO)sc1C(=O)NCC(F)(F)F
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Agent: [Na+]
Agent: [O-]Cl
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)sc1C(=O)NCC(F)(F)F
Reaction time: 21 h
Yield: 15.7 %

Procedure:
Chlorox (4%, 1.02 ml) and NaOH (1N, 0.1 ml) are premixed and then added to a solution of 5-(hydroxyimino-methyl)-3-methyl-thiophene-2-carboxylic acid (2,2,2-trifluoro-ethyl)-amide (200 mg) and 1,3-dichloro-5-(1-trifluoromethyl-vinyl)-benzene (170 mg, example 1, Step A) in THF (3 ml) and diethyl ether (3 ml) at 5° C. The cold bath is then removed. After 21 hours, water is added and the reaction mixture is extracted three times with ethyl acetate. The organic phases are combined, dried over Na2SO4 and concentrated in vacuo. The crude product is purified on a semi-preparative HPLC to yield 5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophene-2-carboxylic acid (2,2,2-trifluoro-ethyl)-amide (56 mg) as light yellow oil. MS (HPLC/MS): 505 (MH+). Retention time: 4.38 min.