Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][NH2:13])=[N:4][N:3]=1.[CH3:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=O)=[CH:18][CH:17]=1>C1(C)C=CC=CC=1.C(N(CC)CC)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2=[N:12][N:13]=[C:20]([C:19]3[CH:23]=[CH:24][C:16]([O:15][CH3:14])=[CH:17][CH:18]=3)[N:4]2[N:3]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: NNc1nnc(Cl)c2ccccc12
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1ccc(-c2nnc3c4ccccc4c(Cl)nn23)cc1
Temperature: 110 °C
Reaction time: 6 h
Yield: 54.3 %

Procedure:
6.0 g (4-chloro-phthalazin-1-yl)-hydrazine (compound C1) are suspended in a mixture of 160 ml toluene and 18 ml triethylamine at 60° C. and treated with a solution of 6.0 g 4-methoxy-benzoyl chloride in 48 ml toluene. The mixture is stirred at 110° C. for 6 h, cooled to ambient temperature, filtered with suction and rinsed with toluene. The solid is recrystallized from N,N-dimethylformamide, the precipitate is washed with water and dried to yield 5.2 g of the title compound (m.p.: 192-193° C.).
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:33][CH2:32][C@@:31]2([CH3:34])[C:11](=[CH:12][CH:13]=[C:14]3[C@@H:30]2[CH2:29][CH2:28][C@@:27]2([CH3:35])[C@H:15]3[CH2:16][CH2:17][C@@H:18]2[C@H:19]([CH3:26])[CH2:20][CH2:21][CH2:22][C:23]([CH3:25])=[CH2:24])[C:10]1([CH3:37])[CH3:36])(C(C)(C)C)(C)C.C1C=CC=CC=1.[ClH:44]>C(O)C>[Cl:44][C:23]([CH2:22][CH2:21][CH2:20][C@H:19]([C@@H:18]1[C@:27]2([CH3:35])[C:15]([C:14]3[CH2:13][CH2:12][C@@H:11]4[C@:31]([C:30]=3[CH2:29][CH2:28]2)([CH3:34])[CH2:32][CH2:33][C@H:9]([OH:8])[C:10]4([CH3:37])[CH3:36])=[CH:16][CH2:17]1)[CH3:26])([CH3:25])[CH3:24]
Reactant: Cl
Reactant: C=C(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C(C)(C)[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: c1ccccc1
Solvent: CCO
Product: C[C@H](CCCC(C)(C)Cl)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3

Procedure:
A mixture of 3β-(tert-butyldimethylsilyloxy)-4,4-dimethylcholesta-5,7,25-triene (50 mg), benzene (5 mL), ethanol (5 mL) and concentrated HCl (2 mL) was heated under reflux for 4 hours. The reaction was concentrated to half volume under reduced pressure and water (5 mL) was added. Extraction of the aqueous phase with dichloromethane and concentration under reduced pressure gave a residue, which was purified by flash chromatography. Recrystallisation from ethyl acetate:hexane gave the title compound as a white solid (35 mg).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.[OH-].[K+].Cl.O>CO>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: COC(=O)c1ccc(Br)cc1OC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc(Br)ccc1C(=O)O
Temperature: 65 °C

Procedure:
A solution of methyl 4-bromo-2-methoxybenzoate (1 g, 4.08 mmol) in 20 ml of MeOH was treated with 4.08 ml of a 2 N solution of potassium hydroxide and refluxed at 65° C. for 2.5 hours. MeOH was removed in vacuo and the remaining water was taken-up in 100 ml of EtOAc and quenched with 30 ml of 1 N HCl (3.5 eq.) and 100 ml of water. Layers were separated and the aqueous layer was extracted twice with EtOAc. Organics were combined, dried over sodium sulfate, and concentrated under reduced pressure to a yellow-white solid (950.7 mg crude).
Reaction SMILES: COC[O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:23]COC)[C:13]=1[CH2:14]/[CH:15]=[CH:16]/[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:8]([OH:10])=[O:9].OS(O)(=O)=O.[CH3:32]O>>[CH3:32][O:10][C:8](=[O:9])[C:7]1[CH:6]=[C:5]([OH:4])[C:13]([CH2:14]/[CH:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:12]([OH:23])[CH:11]=1
Reactant: COCOc1cc(C(=O)O)cc(OCOC)c1C/C=C/c1ccccc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(O)c(C/C=C/c2ccccc2)c(O)c1
Yield: 73 %

Procedure:
To a solution of 3,5-bis-methoxymethoxy-4-((E)-3-phenyl-allyl)-benzoic acid (220g) (18 g, 0.05 mol) in MeOH (300 mL) was added catalytic amount of conc. H2SO4 (3 mL) in one portion. The mixture was refluxed overnight. The solution was concentrated. The residue was dissolved in CH2Cl2 (75 mL) and washed with sat. NaHCO3 (25 mL). The organic layers were dried and concentrated to give a brown solid (12 g, 73% yield). 1H NMR (400 MHz, CDCl3): δ 9.63 (s, 2H), 7.11˜7.34 (m, 5H), 6.93 (s, 2H), 6.32 (s, 2H), 3.77 (s, 3H), 3.42 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1([NH:22][C:23]2[N:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][N:24]=2)[CH2:6][CH2:5][CH2:4][CH:3]1[NH:7][C:8]([C:10]1[C:15](C2N=CC=CN=2)=[CH:14][CH:13]=[CH:12][N:11]=1)=[O:9].CC1(NC2N=CC(C(F)(F)F)=CN=2)CCCC1N.[N:51]1[N:52](C2C(C(O)=O)=NC=CC=2)[N:53]=[CH:54][CH:55]=1>>[CH3:1][C:2]1([NH:22][C:23]2[N:28]=[CH:27][C:26]([C:29]([F:31])([F:32])[F:30])=[CH:25][N:24]=2)[CH2:6][CH2:5][CH2:4][CH:3]1[NH:7][C:8]([C:10]1[C:15]([N:52]2[N:53]=[CH:54][CH:55]=[N:51]2)=[CH:14][CH:13]=[CH:12][N:11]=1)=[O:9]
Reactant: O=C(O)c1ncccc1-n1nccn1
Reactant: CC1(Nc2ncc(C(F)(F)F)cn2)CCCC1NC(=O)c1ncccc1-c1ncccn1
Agent: CC1(Nc2ncc(C(F)(F)F)cn2)CCCC1N
Product: CC1(Nc2ncc(C(F)(F)F)cn2)CCCC1NC(=O)c1ncccc1-n1nccn1

Procedure:
Prepared according to the procedure for N-(2-methyl-2-{[5-(trifluoromethyl)pyrimidin-2-yl]amino}cyclopentyl)-3-(pyrimidin-2-yl)pyridine-2-carboxamide (Example 153) from 1-methyl-1-N-[5-(trifluoromethyl)pyrimidin-2-yl]cyclopentane-1,2-diamine (Intermediate 50; 150 mg, 0.58 mmol) and 3-(2H-1,2,3-triazol-2-yl)pyridine-2-carboxylic acid (CAS number 1252907-86-0; 110 mg, 0.58 mmol) and then triturated with heptane to afford the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:17])[NH:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][OH:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](O)=[CH:21][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH2:1]([O:8][C:9](=[O:17])[NH:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][C:22]1[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: O=C(NCCOCCO)OCc1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(NCCOCCOc1ccc(Cl)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 11 h
Yield: 99.8 %

Procedure:
[2-(2-Hydroxy-ethoxy)-ethyl]-carbamic acid benzyl ester (2.39 g, 10 mmol), 4-chlorophenol (1.29 g, 10 mmol), and triphenylphosphine (2.89 g, 11 mmol) were dissolved in tetrahydrofuran (50 ml), followed by the dropwise addition of diethylazodicarboxylate (1.73 ml, 11 mmol). After the addition, the reaction solution was stirred at room temperature for 10-12 hours. The solvent was then removed in vacuo. The remaining residue was stirred in 30% EtOAc in hexane (200 mL) for 10 minutes and a white solid was formed. This solid was then filtered and washed with 30% EtOAc in hexane (3×20 mL). The filtrates were combined and the solvents were removed in vacuo. The remaining residue was purified by flash column chromatography (SiO2, 2:1 hexane:EtOAc) to give {2-[2-(4-chloro-phenoxy)-ethoxy]-ethyl}-carbamic acid benzyl ester as clear solid (3.49 g, 99.8% yield). 1H-NMR (CDCl3, ppm) 7.35 (m, 5H), 7.20 (d, 2H), 6.82 (d, 2H), 5.22 (b, 1H), 5.10 (s, 2H), 4.07 (t, 2H), 3.80 (t, 2H), 3.62 (t, 2H), 3.41 (q, 2H). ESMS 350.1 (M+l), 372.1 (M+23).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH:5]([NH2:8])[C:6]#[N:7])[CH3:2].[CH:10](OCC)(OCC)OCC.[CH:20]1([NH2:23])[CH2:22][CH2:21]1>C(#N)C>[CH2:1]([O:3][C:4]([C:5]1[N:8]=[CH:10][N:23]([CH:20]2[CH2:22][CH2:21]2)[C:6]=1[NH2:7])=[O:9])[CH3:2]
Reactant: CCOC(OCC)OCC
Reactant: NC1CC1
Reactant: CCOC(=O)C(N)C#N
Solvent: CC#N
Product: CCOC(=O)c1ncn(C2CC2)c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
A solution of amino-cyano-acetic acid ethyl ester (333 mg, 2.6 mmol) and triethyl orthoformate (454 μL, 2.73 mmol) in acetonitrile is heated at reflux for 45 min. After cooled down to room temperature, cyclopropylamine (180 μL, 2.6 mmol) is added. After stirred at room temperature overnight, the solution is concentrated and purified with chromatography. The desired product is obtained a white solid as product (290 mg, 57% yield). 1H NMR (CDCl3) δ 7.08 (s, 1H), 5.01 (b, 2H), 4.27 (q, 2H), 2.95 (m, 1H), 1.31 (t, 3H), 1.04 (m, 2H), 0.91 (m, 2H); m/z 196.1 (M+H4).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[CH:9]=[CH:10]/[CH:11]=O.[N:13]([CH2:16][C:17]([O:19][CH2:20]C)=[O:18])=[N+:14]=[N-:15].O>CO>[N:13](/[C:16](=[CH:11]\[CH:10]=[CH:9]\[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])/[C:17]([O:19][CH3:20])=[O:18])=[N+:14]=[N-:15]
Reactant: CCOC(=O)CN=[N+]=[N-]
Reactant: COc1ccccc1/C=C/C=O
Solvent: CO
Solvent: O
Product: COC(=O)/C(=C/C=C/c1ccccc1OC)N=[N+]=[N-]
Temperature: -20 °C
Reaction time: 2 h
Yield: 93.8 %

Procedure:
28%-Sodium metholate-methanol solution (4.4 ml) was diluted with methanol (5 ml), and cooled to −20° C. A solution of (2E)-3-(2-methoxyphenyl)prop-2-enal (2.4 g) and ethyl azidoacetate (7.5 g) in methanol (8 ml) was added over 30 min, and the mixture was stirred at −10° C. for 1 hr and at room temperature for 2 hr. The reaction mixture was poured into water and extracted with ether. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:4) was concentrated under reduced pressure to give methyl (2Z,4E)-2-azido-5-(2-methoxyphenyl)penta-2,4-dienoate (3.6 g). A part (3.5 g) thereof was dissolved in chloroform (10 ml), zinc iodide (214 mg) was added and the mixture was stirred at room temperature for 12 hr. The reaction mixture was poured into water, and extracted with 1,2-dichloroethane. The extract was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:4) was concentrated under reduced pressure to give the object product (3.26 g).
Reaction SMILES: [CH2:1]([O:8][C@H:9]([CH3:31])[CH2:10][NH:11][C:12]([CH3:30])([CH3:29])[CH2:13][C:14]([NH:16][C@@H:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[NH:19][C:18]1=[O:28])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].BrC[C:36]1[CH:37]=[C:38]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[C:39]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[CH:40][CH:41]=1.[CH3:55]N(C)C=O>>[CH2:1]([O:8][C@H:9]([CH3:31])[CH2:10][NH:11][C:12]([CH3:30])([CH3:29])[CH2:13][C:14]([NH:16][C@@H:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]([CH2:55][C:45]2[CH:44]=[CH:43][C:42]([C:39]3[C:38]([C:48]([O:50][C:51]([CH3:53])([CH3:54])[CH3:52])=[O:49])=[CH:37][CH:36]=[CH:41][CH:40]=3)=[CH:47][CH:46]=2)[C:18]1=[O:28])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)c1cc(CBr)ccc1-c1ccccc1
Reactant: C[C@H](CNC(C)(C)CC(=O)N[C@@H]1CCc2ccccc2NC1=O)OCc1ccccc1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: C[C@H](CNC(C)(C)CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)C1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 92 %

Procedure:
To a solution of 600 mg(1.42 mmol) of 3-[2(R)-benzyloxypropyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]butanamide (Step C) in 10 mL of N,N-dimethylformamide at 0° C. under nitrogen was added 59.5 mg(1.49 mmol) of 60% sodium hydride/oil dispersion. After stirring for 5 minutes, a solution of 450 mg (1.49 mmol) of t-butyl 4-bromomethyl-1,1'-biphenyl-2-carboxylate (prepared according to the procedure of D. J. Carini, et. al. EPO publication 324,377) in 4 mL of dimethylformamide was added dropwise via cannula. The flask originally containing the t-butyl 4-bromomethyl-1,1'-biphenyl-2-carboxylate was rinsed with 2 mL dimethylformamide which was added to the reaction mixture. The mixture was warmed to room temperature and stirred for 1.5 hours. The reaction mixture was diluted with 300 mL of ethyl acetate and washed with 50 mL of water, 50 mL of saturated aqueous sodium bicarbonate and 50 mL of brine, dried over magnesium sulfate, filtered and the solvents removed under vacuum. The residue was purified by column flash chromatography on silica gel eluting with chloroform/10% ammonium hydroxide in methanol (93/7) to give 900 mg (92%) of the product. 1H NMR (200MHz, CD3OD): δ1.10 (s, 3H), 1.12 (s, 9H), 1.15 (s, 3H), 1.25 (d, 7 Hz, 3H), 2.15-2.70 (m, 7H), 3.84 (q, 6 Hz, 1H), 4.48-4.68 (m, 3H), 4.82 (d, 15 Hz, 1H), 5.31 (d, 15 Hz, 1H), 7.08-7.48 (m, 16H), 7.7 (dd; 2, 7 Hz; 1H). FAB-MS: calculated for C43H51N3O5 689; found 690 (M+H,70%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][N:17]3[CH:21]=[N:20][CH:19]=[N:18]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([F:30])[CH:24]=1.[OH-].[K+]>>[ClH:1].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][N:17]4[CH:21]=[N:20][CH:19]=[N:18]4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][CH:3]=2)=[C:25]([F:30])[CH:24]=1
Reactant: COc1cc2c(Cl)ccnc2cc1OCCn1cncn1
Reactant: Oc1ccc(Cl)cc1F
Agent: [K+]
Agent: [OH-]
Product: COc1cc2c(Oc3ccc(Cl)cc3F)ccnc2cc1OCCn1cncn1
Product: Cl
Yield: 56.7 %

Procedure:
A mixture of 4-chloro-6-methoxy-7-(2-([1,2,4]-triazol-1-yl)ethoxy)quinoline (132 mg, 0.43 mmol), 4-chloro-2-fluorophenol (400 mg, 2.7 mmol) and potassium hydroxide (28 mg, 0.49 mmol) was head at 165° C. for 3 hours under argon. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with water, brine, dried (MgSO4) and the volatiles were removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol (95/5). The purified product was dissolved in methylene chloride and 2M ethereal hydrogen chloride (0.5 ml) was added. The volatiles were removed by evaporation and the residue was triturated with ether, collected by filtration and dried under vacuum to give 4-(4-chloro-2-fluorophenoxy)-6-methoxy-7-(2-([1,2,4]-triazol-1-yl)ethoxy)quinoline hydrochloride (110 mg, 61%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]#[N:12])=[N:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:14][C:15]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][N:16]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]#[N:12])=[N:7][N:8]2[CH2:14][C:15]2[C:20]([F:21])=[CH:19][CH:18]=[CH:17][N:16]=2)=[CH:4][CH:3]=1
Reactant: Fc1cccnc1CCl
Reactant: N#Cc1n[nH]c2cc(Cl)ccc12
Product: N#Cc1nn(Cc2ncccc2F)c2cc(Cl)ccc12
Yield: 92.7 %

Procedure:
2.3 g (12.95 mmol) of 6-chloro-1H-indazole-3-carbonitrile (WO 2011/149921, Expl. 58C) were reacted in analogy to Example 53A with 2.07 g (14.25 mmol) of 2-(chloromethyl)-3-fluoropyridine. 3.44 g of the title compound were obtained (93% of theory).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[N:3]1.C([Li])CCC.[CH2:12]([O:19][C@@H:20]1[CH2:26][CH2:25][C@H:24]2[C@H:22]([O:23]2)[CH2:21]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1>[CH2:12]([O:19][C@@H:20]1[CH2:26][CH2:25][C@H:24]([OH:23])[C@@H:22]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)[CH2:21]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: c1ccc(CO[C@@H]2CC[C@@H]3O[C@@H]3C2)cc1
Reactant: Cn1cccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1nccc1[C@H]1C[C@H](OCc2ccccc2)CC[C@@H]1O
Yield: 36.6 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 4a by using 1-methylpyrazole (650 mg, 7.92 mmol), n-butyl lithium (2.69 M solution in hexane; 3.08 mL, 8.28 mmol), (1R*,3R*,6S*)-3-(benzyloxy)-7-oxabicyclo[4.1.0]heptane (Bioorg. Med. Chem. 2004, 12, 1459; 1.54 g, 7.54 mmol) and THF (45 mL), to yield the title compound (790 mg, 37%) as a colorless solid.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH:2]=[CH:3][CH:4]=[CH2:5].O=O.[C:11]([OH:14])(=[O:13])[CH3:12]>>[C:1]([O:7][CH3:8])(=[O:6])[CH:2]=[CH:3][CH:4]=[CH2:5].[C:11]([O:14][CH:3]([CH:4]=[CH:5][CH2:8][O:7][C:1](=[O:6])[CH3:2])[CH2:2][C:1]([O:7][CH3:8])=[O:6])(=[O:13])[CH3:12].[C:11]([O:14][CH:5]=[CH:4][CH:3]=[CH:2][C:1]([O:7][CH3:8])=[O:6])(=[O:13])[CH3:12]
Reactant: CC(=O)O
Agent: C=CC=CC(=O)OC
Agent: O=O
Product: COC(=O)C=CC=COC(C)=O
Product: COC(=O)CC(C=CCOC(C)=O)OC(C)=O

Procedure:
56 g of methyl 2,4-pentadienoate are suspended in 543 g of glacial acetic acid in the presence of 50 g of a Pd/Cu catalyst (5% of Pd and 9.2% of Cu) prepared as described in German Laid-Open Application DOS No. 2,820,519, and reacted with 12 liters of oxygen at 95° C. in the course of 4 hours, all as described in Example 1. The mixture is worked up as described in Example 1 and then fractionally distilled, giving, in addition to unreacted methyl 2,4-pentadienoate, 13 g of methyl 2,5-diacetoxypent-3-enecarboxylate of boiling point 113°-115° C./0.4 mbar (nD20 =1.4600) and 19.5 g of methyl 5-acetoxy-2,4-pentadienoate of boiling point 125°-131° C./13 mbar and melting point 54°-56° C. (from methanol).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3](=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)=O.[CH2:20]([O:22][C:23]([C:25]1[N:26]=[CH:27][NH:28][C:29]=1[NH2:30])=[O:24])[CH3:21]>C(O)(=O)C>[CH2:20]([O:22][C:23]([C:25]1[N:26]=[CH:27][N:28]2[C:3]([C:2]([F:19])([F:18])[F:1])=[CH:4][C:5]([C:7]3[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=3)=[N:30][C:29]=12)=[O:24])[CH3:21]
Reactant: CCOC(=O)c1nc[nH]c1N
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(C(F)(F)F)cc1
Solvent: CC(=O)O
Product: CCOC(=O)c1ncn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Yield: 43.5 %

Procedure:
A mixture of 4,4,4-trifluoro-1-(4-trifluoromethyl-phenyl)-butane-1,3-dione (10.0 g, 35.2 mmol) and 5-amino-1H-imidazole-4-carboxylic acid ethyl ester (5.0 g, 32.2 mmol) in acetic acid (120 ml) was refluxed for 24 h and evaporated. The crude product was further purified by column chromatography on silica gel (ethyl acetate/heptane) and crystallization (diethyl acetate/hexane) to yield 4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine-8-carboxylic acid ethyl ester (5.65 g, 43%) as a yellow solid. MS (EI) 403.1 [(M)+]; mp 243° C.
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][N:5]1[C:9](=[O:10])[N:8]([CH:11]2[CH2:13][CH2:12]2)[C:7]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[N:6]1.[C:25]1([CH3:32])[C:30]([OH:31])=[CH:29][CH:28]=[CH:27][CH:26]=1>C(#N)C.[Cu].[Cu]=O>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:7]2[N:8]([CH:11]3[CH2:13][CH2:12]3)[C:9](=[O:10])[N:5]([CH2:4][C:3]3[CH:21]=[CH:22][CH:23]=[CH:24][C:2]=3[O:31][C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH3:32])[N:6]=2)=[CH:15][CH:16]=1
Reactant: Cc1ccccc1O
Reactant: O=c1n(Cc2ccccc2Br)nc(-c2ccc(Cl)cc2)n1C1CC1
Agent: O=[Cu]
Agent: [Cu]
Solvent: CC#N
Product: Cc1ccccc1Oc1ccccc1Cn1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O
Temperature: 85 °C
Reaction time: 16 h

Procedure:
100 mg (0.25 mmol) of the compound from Example 99A, 53 mg (0.49 mmol) of o-cresol and 91 mg (0.74 mmol) of 4-N,N-dimethylaminopyridine were dissolved in 5 ml of acetonitrile, and 39 mg (0.62 mmol) of copper powder and 49 mg (0.62 mmol) of copper(II) oxide were added. The mixture was stirred at 85° C. for 16 h. For work-up, the mixture was cooled to RT and filtered through silica gel, and the residue was rinsed with a little ethyl acetate. The filtrate was concentrated under reduced pressure and the crude product was then purified chromatographically [Method 19]. This gave 25 mg (23% of theory) of the target compound.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][C:10](=O)[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO.C1COCC1>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH:10]([NH:22][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: NCc1ccccc1
Reactant: O=C1CCc2ccc([N+](=O)[O-])cc2C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc2c(c1)CC(NCc1ccccc1)CC2
Temperature: 0 °C
Reaction time: 14 h

Procedure:
7-Nitro-3,4-dihydro-2(1H)-naphthaleneone (1.50 g, 7.85 mmol), benzylamine (430 ml, 39.3 mmol), acetic acid (8.0 ml), 4 Å molecular sieves (20 ml), THF (15 ml), and MeOH (15 ml) were introduced into a flask and cooled to 0° C. Sodium cyanoborohydride (0.99 g, 15.7 mmol) was then added portionwise over a 5-minute period. The mixture was stirred for 14 hr, filtered through celite, and concentrated to a syrup. The mixture was made basic with 2N NaOH and extracted with ether (3×50 ml). The combined extracts were washed with water, dried over magnesium sulfate, filtered, concentrated and chromatographed over silica gel (3% methanol/methylene chloride) to yield 7-nitro-2-((phenylmethyl)amino)-1,2,3,4-tetrahydronaphthalene: (2.10 g, 95%); M.S. (M+H)+ =283.
Reaction SMILES: [CH3:1][C:2]([C@@H:4]1[CH2:9][CH:8]=[C:7]([CH2:10][OH:11])[CH2:6][CH2:5]1)=[CH2:3].CC(C1CC=C(C[O:22]C(C)=O)CC1)=C.CC1(C)C2CC1CCC12OC1>>[CH:7]1([CH2:10][OH:11])[CH2:6][CH:5]=[C:4]([C:2]([OH:22])([CH3:1])[CH3:3])[CH2:9][CH2:8]1
Reactant: C=C(C)[C@@H]1CC=C(CO)CC1
Reactant: C=C(C)C1CC=C(COC(C)=O)CC1
Agent: CC1(C)C2CCC3(CO3)C1C2
Product: CC(C)(O)C1=CCC(CO)CC1

Procedure:
The applicant's first preferred method of preparing perillyl alcohol from pure beta pinene oxide is to react pure beta pinene oxide with anhydrous sodium acetate and glacial acetic acid to produce p-menth-1-en-8-acetoxy-7-ol (C), after which the p-menth-1-en-8-acetoxy-7-ol is pyrolyzed to perillyl alcohol in a yield of approximately fifty percent (50%). This represents a facile two step procedure using inexpensive, safe reagents. The applicant's second preferred method of producing perillyl acetate and perillyl alcohol from pure beta pinene oxide is to react pure beta pinene oxide with an acid resin to produce p-menthene-7,8-diol (D) that is then acetylated to afford 7-acetoxy-p-menth-1-en-8-ol (E) which is then dehydrated by any of five different procedures to yield perillyl acetate that can be hydrolyzed to perillyl alcohol.
Reaction SMILES: C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:8])C=CC=CC=1.C([N:20]([CH2:23][CH3:24])[CH2:21]C)C.C([CH2:28][CH2:29][C:30](O)=[S:31])CC>C1C=CC=CC=1>[CH2:30]([S:31][CH2:24][CH2:23][N:20]=[C:21]=[O:8])[CH2:29][CH3:28]
Reactant: CCCCCC(O)=S
Reactant: CCN(CC)CC
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: CCCSCCN=C=O
Temperature: 25 °C

Procedure:
A solution of diphenylphosphoryl azide [N3.PO(OC6H5)2 ] (8.25 g.) in dry benzene (10 ml.) and a solution of triethylamine (3.03 g.) in dry benzene (10 ml.) were added to a solution of 3-propylthiopropionic acid (4.44 g.) in dry benzene (10 ml.) with stirring at ambient temperature. The clear solution was stirred for 30 minutes at 70°-80° C. to give a solution comprising 2-propylthioethyl isocyanate (I.R.: 2260 cm-1).
Reaction SMILES: O=P(Cl)(Cl)Cl.CN([CH:9]=[O:10])C.[CH2:11]1[CH2:19][O:18][C:17]2[C:13](=[CH:14][NH:15][CH:16]=2)[O:12]1.[OH-].[Na+]>C(Cl)Cl>[CH:9]([C:14]1[NH:15][CH:16]=[C:17]2[O:18][CH2:19][CH2:11][O:12][C:13]=12)=[O:10]
Reactant: CN(C)C=O
Reactant: c1[nH]cc2c1OCCO2
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=Cc1[nH]cc2c1OCCO2
Reaction time: 12 h
Yield: 94.2 %

Procedure:
POCl3 (1.67 g, 10.92 mmol) was added to a solution of DMF (0.84 g, 11.44 mmol) in methylene chloride (5.0 mL) at 0° C. and the reaction mixture allowed to come to room temperature. The reaction mixture was then slowly added to a solution of 3,4-ethylenedioxypyrrole (1.3 g, 10.40 mmol) in methylene chloride (5.0 mL) at 0° C. and allowed to come to room temperature. After stirring for 12 h, an excess of 3.0 M NaOH solution was added and stirred for 2 h in a hot water bath. The reaction mixture was extracted with methylene chloride (40 mL×3) and the combined organic layers were dried over MgSO4. Purification of the residue was accomplished by chromatography on silica gel using hexane/ethyl acetate (2:1) as eluent to afford the product as a white solid (1.5 g, 65%): mp 147° C.; 1H NMR (300 MHz, CDCl3) δ9.43 (s, 1H), 9.02 (br, 1H), 6.62 (d, J=3.8 Hz, 1H), 4.24 (m, 4H); Anal. Calcd for C7H7NO3: C, 54.90; H, 4.61; N, 9.15. Found: C, 55.03; H, 4.48; N, 9.14.