Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([S:9][CH3:10])=[C:4]([Cl:11])[N:3]=1.C(N(CC)CC)C.[CH:19]([O:22][CH2:23][CH2:24][CH2:25][NH2:26])([CH3:21])[CH3:20]>C1(C)C=CC=CC=1>[Cl:11][C:4]1[C:5]([S:9][CH3:10])=[C:6]([Cl:8])[N:7]=[C:2]([NH:26][CH2:25][CH2:24][CH2:23][O:22][CH:19]([CH3:21])[CH3:20])[N:3]=1
Reactant: CC(C)OCCCN
Reactant: CSc1c(Cl)nc(Cl)nc1Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CSc1c(Cl)nc(NCCCOC(C)C)nc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.2 %

Procedure:
68.5 g (0.3 mole) of 2,4,6-trichloro-5-methylthiopyrimidine are dissolved in 300 ml of toluene. 30.3 g (0.3 mole) of triethylamine and 35.1 g (0.3 mole) of isopropoxypropylamine are added dropwise at 0° C. After the mixture had been subsequently stirred at room temperature for 1 hour, it is diluted with 500 ml of toluene and the organic phase is washed with water. After drying over sodium sulphate and removal of the solvent in vacuo, the resulting residue is stirred with 100 ml of petroleum ether, filtered off with suction, rinsed with petroleum ether and dried. 25.3 g (27.2% of theory) of the above-mentioned pyrimidine, melting point: 88° C., are thus obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][C:7]=1N.S(=O)(=O)(O)O.N([O-])=O.[Na+].[C-:30]#[N:31].[Na+]>O.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][C:7]=1[C:30]#[N:31]
Reactant: CS(=O)(=O)c1ccc(Oc2ccc(Cl)c(Cl)c2)c(N)c1
Reactant: [C-]#N
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CS(=O)(=O)c1ccc(Oc2ccc(Cl)c(Cl)c2)c(C#N)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 95.8 %

Procedure:
A mixture of 5.0 g (0.0151 mole) of 2-(3,4-dichlorophenoxy)-5-(methylsulfonyl)benzenamine (Example 16), 75 ml of glacial acetic acid, 37.5 ml of water and 3.0 g (0.0306 mole) of concentrated sulfuric acid was cooled to 0° C. and 1.5 g (0.0217 mole) of sodium nitrite dissolved in 15 ml of water was added slowly. The mixture was stirred at 0° C. for 20 minutes and then added slowly to a mixture of 7.5 g (0.0838 mole) of cuprous cyanide and 30 g (0.612 mole) of sodium cyanide dissolved in 150 ml of water at 0° C. The mixture was stirred at 0° C. for 45 minutes and allowed to warm to room temperature. The mixture was then heated at 50° C. for 1 hr. The mixture was poured into water and the crystalline product collected by filtration, washed with water and dried, to obtain 4.95 g (96.1% yield) of product. Purification was accomplished by column chromatography using silica gel as the support and chloroform as the eluent followed by recrystallization from ethyl acetate, which gave purified 2-(3,4-dichlorophenoxy)-5-(methylsulfonyl)benzonitrile, mp 162°-163° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:22])=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=1[Cl:20])=[O:8].[N:23]1([C:29](Cl)=[O:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][C:29]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:30])=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:19])[F:18])=[CH:12][C:11]=1[Cl:20])=[O:8]
Reactant: O=C(Cl)N1CCOCC1
Reactant: O=C(Nc1ccc(C(F)(F)F)cc1Cl)c1cc(Br)ccc1O
Product: O=C(Nc1ccc(C(F)(F)F)cc1Cl)c1cc(Br)ccc1OC(=O)N1CCOCC1
Yield: 93.5 %

Procedure:
Using 5-bromo-N-[2-chloro-4-(trifluoromethyl)phenyl]-2-hydroxybenzamide and morpholine-4-carbonyl chloride as the raw materials, the same operation as the Example 71 gave the title compound.
Reaction SMILES: [C:1]([C:4]1[N:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=O)(=[O:3])[CH3:2].[F:13][C:14]1[CH:15]=[C:16]([NH:21][C:22](=[O:25])[NH:23][NH2:24])[CH:17]=[C:18]([F:20])[CH:19]=1>CO>[F:13][C:14]1[CH:15]=[C:16]([NH:21][C:22](=[O:25])[NH:23][N:24]=[C:6]([OH:8])[C:5]2[CH:9]=[CH:10][CH:11]=[N:12][C:4]=2[C:1](=[O:3])[CH3:2])[CH:17]=[C:18]([F:20])[CH:19]=1
Reactant: NNC(=O)Nc1cc(F)cc(F)c1
Reactant: CC(=O)c1ncccc1C(=O)O
Solvent: CO
Product: CC(=O)c1ncccc1C(O)=NNC(=O)Nc1cc(F)cc(F)c1

Procedure:
To 50 mg of 2-acetylnicotinic acid are added 56 mg of 4-(3,5-difluorophenyl)semicarbazide and 1 mL of methanol. After a minute of stirring the product begins precipitating from the solution. After stirring overnight (15 h) the stir vane is removed and rinsed with 0.2 mL of methanol. The reaction mixture is centrifuged and the supernatant solution removed. In the same way the solid is rinsed with methanol (3×0.5 mL) and ether (1×0.5 mL). The solid is dried in vacuo with heating to give 2-acetylnicotinic acid 4-(3,5-difluorophenyl)semicarbazone (also known as 2-[methyl-{[(3,5-difluorophenylamino)carbonyl]hydrazono}methyl]-3-pyridine-carboxylic acid), m.p. 186° (compound 31, Table A).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)=[O:21])=[CH:16][CH:15]=1.I[CH3:35]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([N:22]([CH3:35])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:33])[F:31])[CH:25]=2)=[O:21])=[CH:16][CH:15]=1
Reactant: CI
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NCc4cccc(C(F)(F)F)c4)cc3)c2)o1
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)N(C)Cc4cccc(C(F)(F)F)c4)cc3)c2)o1

Procedure:
2′-Methyl-N-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(3-trifluoromethylbenzyl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5methyl-1,3,4-oxadiazol-2-yl)-N-(3-trifluoromethylbenzyl)-1,1′-biphenyl-4-carboxamide and iodomethane using method L. NMR; δH [2H6]—DMSO 7.89,(1H, d), 7.76-7.49,(10H, m), 4.79-4.65,(2H, m), 2.94,(3H, s), 2.55,(3H, s), 2.32,(3H, s). LCMS; retention time 3.62 min, MH+ 466.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:25]([OH:27])=O)[CH:5]=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[CH2:17][O:16][C:15]2=[O:24])[CH2:10][CH2:9]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:40][CH:41]([NH2:44])[CH2:42][OH:43]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:25]([NH:44][CH:41]([CH3:40])[CH2:42][OH:43])=[O:27])[CH:5]=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[CH2:17][O:16][C:15]2=[O:24])[CH2:10][CH2:9]1
Reactant: O=C(O)c1cnc(N2CCC(N3C(=O)OCc4ccccc43)CC2)c(Cl)c1
Reactant: CC(N)CO
Agent: O=C(n1ccnc1)n1ccnc1
Product: CC(CO)NC(=O)c1cnc(N2CCC(N3C(=O)OCc4ccccc43)CC2)c(Cl)c1

Procedure:
The title compound was prepared from the product of example 148 step (i) (0.14 g), carbonyldiimidazole (0.064 g) and DL-2-amino-1-propanol (0.05 g) using the method of example 115 step (i). Purification was by chromatography eluting with 20% ethyl acetate/isohexane. Yield 0.04 g as a solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:20][CH:19]2[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]3[C:16]([C:22]([NH:24][S:25]([CH:28]4[CH2:30][CH2:29]4)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]2=[O:21])[CH2:15]3)[CH2:3]1.[C:40]([C:42]1[CH:43]=[C:44]([CH:48]=[CH:49][CH:50]=1)[C:45](Cl)=[O:46])#[N:41]>>[C:40]([C:42]1[CH:43]=[C:44]([CH:48]=[CH:49][CH:50]=1)[C:45]([O:1][CH:2]1[CH2:20][CH:19]2[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]3[C:16]([C:22]([NH:24][S:25]([CH:28]4[CH2:30][CH2:29]4)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]2=[O:21])[CH2:15]3)[CH2:3]1)=[O:46])#[N:41]
Reactant: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(O)CN2C1=O
Reactant: N#Cc1cccc(C(=O)Cl)c1
Product: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(OC(=O)c3cccc(C#N)c3)CN2C1=O
Yield: 38.5 %

Procedure:
Prepared by way of method I using 18-hydroxy-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]-nonadec-7-ene (100 mg, 0.175 mmol) and 3-cyanobenzoyl chloride (87 mg, 0.53 mmol). The final trituration (diethyl ether/hexane) and filtration gave 47 mg (37%) of 18-(3-cyanobenzoyloxy)-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo-[14.3.0.04,6]-nonadec-7-ene as a white powder: 98.1% pure (HPLC), MS m/z 696 (M−H)−, HRMS: calcd. 698.2860 and found 698.2849 (M+H)+, mp 151-153° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:18]([F:21])([F:20])[F:19])=[C:13](I)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:22]([SH:24])[CH3:23]>>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:18]([F:21])([F:20])[F:19])=[C:13]([S:24][CH2:22][CH3:23])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCS
Reactant: CC(C)(C)OC(=O)N1Cc2cc(I)c(C(F)(F)F)cc2C1
Product: CCSc1cc2c(cc1C(F)(F)F)CN(C(=O)OC(C)(C)C)C2

Procedure:
Prepared in analogy to Example A5(a) from 5-iodo-6-trifluoromethyl-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and ethyl mercaptan. White solid. MS (m/e): 292.1 ([M+H-Me2C═CH2]+, 100%).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:16]=[CH:15][C:10]([O:11][CH2:12][CH2:13][NH2:14])=[CH:9][CH:8]=2)[N:6]=1.[C:17]([NH:20][C:21]1[N:26]=[CH:25][C:24]([CH:27]([O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[CH2:28]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:23][CH:22]=1)(=[O:19])[CH3:18].C(N(C(C)C)CC)(C)C>CS(C)=O>[C:44]([Si:41]([CH3:43])([CH3:42])[O:40][C@H:27]([C:24]1[CH:23]=[CH:22][C:21]([NH:20][C:17](=[O:19])[CH3:18])=[N:26][CH:25]=1)[CH2:28][NH:14][CH2:13][CH2:12][O:11][C:10]1[CH:15]=[CH:16][C:7]([C:5]2[N:6]=[C:2]([CH3:1])[S:3][CH:4]=2)=[CH:8][CH:9]=1)([CH3:47])([CH3:46])[CH3:45]
Reactant: Cc1nc(-c2ccc(OCCN)cc2)cs1
Reactant: CC(=O)Nc1ccc(C(COS(=O)(=O)c2ccc(C)cc2)O[Si](C)(C)C(C)(C)C)cn1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1ccc([C@H](CNCCOc2ccc(-c3csc(C)n3)cc2)O[Si](C)(C)C(C)(C)C)cn1
Temperature: 80 °C
Yield: 44.6 %

Procedure:
In a round-bottomed flask, 2-[4-(2-methyl-thiazol-4-yl)-phenoxy]-ethylamine (175 mg, 0.747 mmol) and toluene-4-sulfonic acid 2-(6-acetylamino-pyridin-3-yl)-2-(tert-butyl-dimethyl-silanyloxy)-ethyl ester (231 mg, 0.498 mmol) were dissolved in dimethylsulfoxide (0.50 mL), and diisopropyl ethyl amine (0.105 mL, 0.600 mmol) was added in one portion. The resulting mixture was heated to about 80° C. for about sixteen hours, and was then partitioned between diethyl ether and water. The aqueous phase was extracted with diethyl ether four times, and the combined organic extracts were then washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting white solid was purified by column chromatography (methylene chloride to 10% methanol/methylene chloride) to afford 117 mg (45%) of the desired product. LRMS ([M+1]+): 527.1.
Reaction SMILES: [NH2:1][C:2](=[N:27][N+:28]([O-:30])=[O:29])[NH:3][CH2:4][CH2:5][CH2:6][C@H:7]([C:24](O)=[O:25])[NH:8][C:9](=[O:23])[CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:31][NH:32][C:33]([C:35]1[CH:40]=[CH:39][C:38]([CH2:41][NH2:42])=[CH:37][CH:36]=1)=[O:34].C(C1C=CC(C(NC)=O)=CC=1)#N.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(#N)C.[Pd].CN(C)C=O>[NH2:1][C:2](=[N:27][N+:28]([O-:30])=[O:29])[NH:3][CH2:4][CH2:5][CH2:6][C@H:7]([C:24]([NH:42][CH2:41][C:38]1[CH:37]=[CH:36][C:35]([C:33]([NH:32][CH3:31])=[O:34])=[CH:40][CH:39]=1)=[O:25])[NH:8][C:9](=[O:23])[CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NC(=N[N+](=O)[O-])NCCC[C@@H](NC(=O)C(c1ccccc1)c1ccccc1)C(=O)O
Reactant: CNC(=O)c1ccc(CN)cc1
Agent: [Pd]
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNC(=O)c1ccc(C#N)cc1
Solvent: CC#N
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(CNC(=O)[C@@H](CCCNC(N)=N[N+](=O)[O-])NC(=O)C(c2ccccc2)c2ccccc2)cc1
Yield: 22 %

Procedure:
Prepared, analogously to Example 67a) but using acetonitrile as solvent instead of dimethylformamide, from (R)-N5 -[amino(nitroimino)methyl]-N2 -(diphenylacetyl)-ornithine, 4-[(methylamino)carbonyl]benzenemethylamine (prepared from 4-cyano-N-methylbenzamide by catalytic hydrogenation in the presence of palladium/animal charcoal) and TBTU in a yield of 22% of theory.
Reaction SMILES: [C:1]([O:7][CH2:8][CH2:9][O:10][CH2:11]/[C:12](/[CH3:27])=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:16][CH:15]=1)(=[O:6])[CH2:2][C:3]([CH3:5])=O.[NH3:28].CCCCCC>CC(O)C>[NH2:28]/[C:3](/[CH3:5])=[CH:2]\[C:1]([O:7][CH2:8][CH2:9][O:10][CH2:11]/[C:12](/[CH3:27])=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:16][CH:15]=1)=[O:6]
Reactant: CC(=O)CC(=O)OCCOC/C(C)=C/c1ccc(Cc2cccnc2)cc1
Reactant: N
Solvent: CCCCCC
Solvent: CC(C)O
Product: C/C(N)=C/C(=O)OCCOC/C(C)=C/c1ccc(Cc2cccnc2)cc1
Yield: 80.2 %

Procedure:
In 8 ml of 2-propanol was dissolved 2.0 g of 2-[(E)-3-[4-(pyridin-3-ylmethyl)phenyl]-2-methylallyloxy]ethyl acetoacetate, and ammonia gas was introduced into the resulting solution for 2 hours with ice-cooling. And, the solution was subjected to reaction at room temperature for 15 hours. Subsequently, the solvent was removed by distillation under reduced pressure, and to the residue thus obtained were added 2 ml of 2-propanol and [ml of n-hexane, after which the resulting mixture was stirred. The crystals thus precipitated were collected by filtration to obtain 1.6 g (yield 80.2%) of 2-[(E)-3-[4-(pyridin-3-ylmethyl)phenyl]-2-methylallyloxy]ethyl 3-aminocrotonate.
Reaction SMILES: [Na+].[F:2][C:3]([F:23])([F:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:15]3[N:16]=[CH:17][C:18]([C:19]([O-:21])=[O:20])=[C:14]3[N:13]=[CH:12][CH:11]=2)[CH:5]=1.Cl>C(Cl)Cl>[F:22][C:3]([F:2])([F:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:15]3[N:16]=[CH:17][C:18]([C:19]([OH:21])=[O:20])=[C:14]3[N:13]=[CH:12][CH:11]=2)[CH:5]=1
Reactant: O=C([O-])c1cnn2c(-c3cccc(C(F)(F)F)c3)ccnc12
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: O=C(O)c1cnn2c(-c3cccc(C(F)(F)F)c3)ccnc12

Procedure:
A mixture of 0.70 g. of 7-(α,α,α-trifluoro-m-tolyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid sodium salt, 25 ml. of methylene chloride and 10 ml. of 1 N hydrochloric acid is stirred overnight. The solid which forms is collected by filtration. The filtrate is evaporated to produce more solid. The solids are combined and recrystallized from methylene chloride giving the desired product, m.p. 248°-250° C.
Reaction SMILES: [CH3:1][C@H:2]1[C:7](=[O:8])[CH2:6][C@H:5]([C:9]([CH3:11])=[CH2:10])[CH2:4][CH2:3]1.C1C(C(C)C)=CC=C(C)C=1O.[OH-].[Mg+2].[OH-]>O>[CH3:1][C:2]1[C:7](=[O:8])[CH2:6][C@H:5]([C:9]([CH3:11])=[CH2:10])[CH2:4][CH:3]=1
Reactant: C=C(C)[C@@H]1CC[C@@H](C)C(=O)C1
Agent: Cc1ccc(C(C)C)cc1O
Agent: [Mg+2]
Agent: [OH-]
Solvent: O
Product: C=C(C)[C@@H]1CC=C(C)C(=O)C1
Temperature: 216 °C

Procedure:
A mixture of 100 parts of R-(+)-1,2-limonene oxide, 75 parts of dihydrocarvone, 3 parts of carvacrol and 1 part magnesium hydroxide was refluxed at 212-220° C. for 10 hours in a three-necked flask equipped with agitator, temperature probe, and Dean-Stark trap (about 1 part water was removed). The reaction mixture was cooled down to 40° C., the catalyst was flittered out and the filtrate distilled under vacuum using Vigreux column. Distillate (160 parts) contains 28% unreacted 1,2-limonene oxide and 31% R-(−)-carvone. The yield of R-(−)-carvone is 49.6 parts or 68.8% on reacted 1,2-limonene oxide. This mixture was further purified using conventional separation techniques to obtain flavor grade R-(−)-carvone.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C@H:12]1[C@H:15]([CH2:16]O)[C@@H:14]([CH2:18][OH:19])[O:13]1.OC[C@H]1O[C@@H](N2C=NC3C2=NC=NC=3N)[C@@H]1C>>[CH3:1][NH:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C@H:12]1[C@H:15]([CH3:16])[C@@H:14]([CH2:18][OH:19])[O:13]1
Reactant: CNc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@H]1CO
Agent: C[C@H]1[C@H](n2cnc3c(N)ncnc32)O[C@@H]1CO
Product: CNc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@H]1C

Procedure:
The procedure of Example 9 can be repeated replacing the starting compound of Example 9 (a) with the product of Example 1 to obtain the desired compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13])[NH:8][C:7](C(O)=O)=[C:6]2[CH3:19].Cl>N1C2C(=CC=CC=2)C=CC=1.CCOC(C)=O.[Cu]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[C:12]([F:15])([F:13])[F:14])[NH:8][CH:7]=[C:6]2[CH3:19]
Reactant: COc1cc2c(C)c(C(=O)O)[nH]c2cc1C(F)(F)F
Agent: [Cu]
Agent: Cl
Solvent: c1ccc2ncccc2c1
Solvent: CCOC(C)=O
Product: COc1cc2c(C)c[nH]c2cc1C(F)(F)F
Yield: 53 %

Procedure:
To a solution of 5-Methoxy-3-methyl-6-trifluoromethyl-1H-indole-2-carboxylic acid (2.0 g, 7 mmol) in 5 ml quinoline was added copper powder (50 mg), and the reaction mixture was heated to reflux for 1.5 hours. Copper powder (50 mg) was added, and the reaction mixture was refluxed for 1 hour. The reaction mixture was cooled, diluted with EtOAc, poured into 50 ml 6 N HCl, and extracted with EtOAc. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed (10% EtOAc/Hexanes) to give 5-Methoxy-3-methyl-6-trifluoromethyl-1H-indole (850 mg, 51%) as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][CH2:15][C:16]([O:18]C)=[O:17])[N:13]=2)=[N:6][CH:7]=1.O.[OH-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])[N:13]=2)=[N:6][CH:7]=1
Reactant: COC(=O)CCc1csc(Nc2ncc(Br)cc2Oc2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCc1csc(Nc2ncc(Br)cc2Oc2ccccc2)n1
Reaction time: 8 h
Yield: 51.7 %

Procedure:
To a mixture of methyl 3-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)propanoate (0.100 g, 0.230 mmol) in 10 mL THF, and 5 mL water was added sodium hydroxide (0.0368 g, 0.921 mmol) and the reaction was stirred overnight. The mixture was concentrated to dryness. Water was added and washed with Et2O and EtOAc. The aqueous was acidified with a saturated NH4Cl solution, extracted with 3:1CH2Cl2-THF. The organics were dried over Na2SO4 and concentrated to a residue. The crude solids were recrystallized from EtOAc/Hexanes to give the title compound (0.050 g, 51.7% yield). 1H NMR (d6 DMSO) δ 2.58 (t, J=7.5 Hz, 2H), 2.81 (t, J=7.5 Hz, 2H), 6.66 (s, 1H), 7.10 (d, J=7.8 Hz, 2H), 7.21 (t, J=7.4 Hz, 1H), 7.39 (d, J=2.0 Hz, 1H), 7.44 (t, J=8.0 Hz, 2H), 8.21 (d, J=2.0 Hz, 1H).
Reaction SMILES: [CH:1]12[C:7](=[O:8])O[C:4](=[O:5])[CH:2]1[CH2:3]2.[CH2:9]([NH:16][NH2:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(#N)C>[CH2:9]([N:16]1[NH:17][C:7](=[O:8])[CH:1]2[CH:2]([CH2:3]2)[C:4]1=[O:5])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C1OC(=O)C2CC12
Reactant: NNCc1ccccc1
Solvent: CC#N
Product: O=C1NN(Cc2ccccc2)C(=O)C2CC12
Yield: 29.8 %

Procedure:
In 150 ml of acetonitrile was dissolved 42 g (374 mmol) of 1,2-cyclopropanedicarboxylic acid anhydride, and to the solution was added dropwise a solution of 45.8 g (374 mmol) of benzylhydrazine in 50 ml of acetonitrile, and the mixture was heated under reflux for 15 hours. The solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography. Crystallization from ethyl acetate gave 24.1 g (29.7%) of the titled compound.
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].[C:32]([NH:36][CH3:37])([CH3:35])([CH3:34])[CH3:33]>C(Cl)Cl>[C:32]([N:36]([CH:18]=[C:17]1[C:16]2[C:15]([CH3:30])([C:14]3[CH:5]([O:4][C:2](=[O:3])[CH3:1])[CH2:6][C:7]4([CH3:31])[CH:8]([C:13]=3[C:21](=[O:22])[C:20]=2[OH:19])[CH2:9][CH2:10][CH:11]4[OH:12])[CH:26]([CH2:27][O:28][CH3:29])[O:25][C:23]1=[O:24])[CH3:37])([CH3:35])([CH3:34])[CH3:33]
Reactant: CNC(C)(C)C
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Solvent: ClCCl
Product: COCC1OC(=O)C(=CN(C)C(C)(C)C)C2=C(O)C(=O)C3=C(C(OC(C)=O)CC4(C)C(O)CCC34)C21C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 100 mg (0.23 mmol) 17-hydroxywortmannin in 2 mL CH2Cl2 is added N-tert-butylmethylamine (55 μL, 0.46 mmol). The reaction mixture is stirred at room temperature for 12 hours and then concentrated in vacuo. The residue is dissolved in EtOAc and precipitated with hexane. The precipitate is washed two times with hexane to give the product as a yellow solid. MS (ESI) m/z 519 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[S:13][CH:14]=2)=[CH:4][CH:3]=1.CS[C:21]1[S:22][CH2:23][CH2:24][N:25]=1.Cl>>[S:22]1[CH2:23][CH2:24][N:25]=[C:21]1[NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[S:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)Nc1nc(CCc2ccc(N)cc2)cs1
Reactant: CSC1=NCCS1
Agent: Cl
Product: CC(=O)Nc1nc(CCc2ccc(NC3=NCCS3)cc2)cs1
Temperature: 120 °C
Reaction time: 10 h
Yield: 20.3 %

Procedure:
N-(4-(2-(4-Aminophenyl)ethyl)-1,3-thiazol-2-yl)acetamide (1.8 g) prepared in a similar manner according to Step 6 of Production Example 1, 2-(methylsulfanyl)-4,5-dihydro-1,3-thiazole (918 mg), hydrochloric acid concentrate (0.57 ml) and 2-methoxyethanol (28 ml) were combined under nitrogen atmosphere, and stirred at 120° C. for 10 hours. After cooled to room temperature, the reaction mixture was concentrated in vacuo. The residue was dissolved in tetrahydrofuran/water, and made basic with aqueous potassium carbonate. The mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by flash column chromatography over silica gel with chloroform/methanol (30:1→20:1) as an eluent, and triturated with ethyl acetate to give N-(4-(2-(4-(4,5-dihydro-1,3-thiazol-2-ylamino)phenyl)ethyl)-1,3-thiazol-2-yl)acetamide (484.7 mg) as an off-white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH:5]([C:9]1[CH:10]=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[CH:12]=[C:13]([O:15]CC2C=CC=CC=2)[CH:14]=1)[CH2:6][CH2:7][CH3:8])[CH3:2]>CCO.[Pd]>[CH2:1]([O:3][C:4](=[O:33])[CH:5]([C:9]1[CH:10]=[C:11]([C:23]2[CH:24]=[CH:25][C:26]([C:29]([F:31])([F:30])[F:32])=[CH:27][CH:28]=2)[CH:12]=[C:13]([OH:15])[CH:14]=1)[CH2:6][CH2:7][CH3:8])[CH3:2]
Reactant: CCCC(C(=O)OCC)c1cc(OCc2ccccc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Agent: [Pd]
Solvent: CCO
Product: CCCC(C(=O)OCC)c1cc(O)cc(-c2ccc(C(F)(F)F)cc2)c1
Reaction time: 19 h
Yield: 96.7 %

Procedure:
2-(5-Benzyloxy-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (1.1 g, 2.4 mmol) was dissolved in EtOH (10 mL) and stirred with 10% Pd/C (116 mg) under an atmosphere of hydrogen. After 19 h, the mixture was filtered through Celite and concentrated in vacuo to afford 2-(5-hydroxy-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (0.85 g) as a colourless oil.