Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][NH:21][CH:20]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:20]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: COC(=O)CC1CN(C(=O)OC(C)(C)C)CCN1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)CC1CN(C(=O)OC(C)(C)C)CCN1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
4-Chlorophenyl boronic acid (1.08 g, 6.97 mmol) and 3-methoxycarbonylmethyl-piperazine-1-carboxylic acid tert-butyl ester (0.9 g, 3.48 mmol) were dissolved in dichloromethane. To this mixture was added copper acetate (0.63 g, 3.48 mmol), 4 Å molecular sieves and pyridine (0.56 mL, 6.97 mmol) and the reaction mixture was stirred at room temperature for 72 h. The reaction mixture was concentrated in vacuo and dissolved in ethyl acetate, filtered through celite and concentrated. The crude product was purified using gradient elution from hexane/ethyl acetate (5%) to hexane/ethyl acetate (20%). ESI-MS m/z: 369 (M+1), UV retention time: 2.97 min.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[CH3:11][NH:12][CH3:13]>O>[CH3:11][N:12]([CH3:13])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1
Reactant: CNC
Reactant: O=C(O)c1ccc(Cl)nc1
Solvent: O
Product: CN(C)c1ccc(C(=O)O)cn1

Procedure:
6-Chloronicotinic acid (0.5 g, 3.17 mmol) and dimethyl amine 10 ml, 40% in water) were heated in a sealed pressure vessel at 130° C. for 6 h. The solvent was then removed and the residue was taken up in water and the pH was adjusted to 4–5. Extraction with dichloromethane yielded the pure intermediate depicted above (0.1 g, 20%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]([C:15]([O:17]C)=[O:16])[CH:12]=[CH:11][C:10]=1[F:19].O.[OH-].[Li+].C1COCC1.Cl>O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]([C:15]([OH:17])=[O:16])[CH:12]=[CH:11][C:10]=1[F:19]
Reactant: COC(=O)c1ccc(F)c(-c2c(F)cccc2F)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(F)c(-c2c(F)cccc2F)n1
Temperature: 50 °C
Yield: 81.4 %

Procedure:
To a mixture of methyl 6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxylate (210.2 mg, 0.7867 mmol) and lithium hydroxide, monohydrate (162 mg, 3.86 mmol), THF (3.0 mL) was added followed by water (1.0 mL). The mixture was heated at 50° C. for 3 h. The reaction mixture was then cooled to 0° C., and 1 M HCl was added slowly until the pH reached 2. The reaction mixture was then diluted with water (20 mL), extracted with EtOAc (3×20 mL) and the combined organic layers were washed with brine (30 mL), dried over Na2SO4, and concentrated under reduced pressure to yield the sub-title compound as a white solid (162.1 mg, 81%). LCMS calc. for C12H7F3NO2 (M+H)+: m/z=254.0. found 254.0.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([C:12]([O:14]C)=[O:13])=[CH:5][N:6]=[CH:7]2.[OH-].[K+].Cl>CO.O>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([C:12]([OH:14])=[O:13])=[CH:5][N:6]=[CH:7]2
Reactant: COC(=O)c1cncc2cccc(Cl)c12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cncc2cccc(Cl)c12

Procedure:
To a stirred solution of methyl 5-chloroisoquinolin-4-carboxylate (Intermediate-42) (3.8 g, 17.1 mmol) in MeOH (30 mL) was added, KOH (9.62 g, 171 mmol) solution in H2O (20 mL) and the reaction mixture was heated to 70° C. for 3 h. After completion (TLC), it was concentrated under vacuum to give crude product (3.5 g) that was diluted with water, acidified with 1N HCl (pH=3) and the aqueous phase was extracted with EtOAc, dried and concentrated under vacuum to afford the desired acid derivative (3 g, 84%) as an off white solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]([OH:11])=[CH:9][C:8]2[C:12](=[O:17])[CH2:13][CH2:14][CH2:15][CH2:16][N:6]3[C:7]=2[C:3]=1[CH:4]=[C:5]3[C:18]([O:20][CH2:21][CH3:22])=[O:19].[CH3:23][O:24][CH2:25]Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[C:10]([O:11][CH2:23][O:24][CH3:25])=[CH:9][C:8]2[C:12](=[O:17])[CH2:13][CH2:14][CH2:15][CH2:16][N:6]3[C:7]=2[C:3]=1[CH:4]=[C:5]3[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: COCCl
Reactant: CCOC(=O)c1cc2c(Cl)c(O)cc3c2n1CCCCC3=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(Cl)c(OCOC)cc3c2n1CCCCC3=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.6 %

Procedure:
A mixture of ethyl 5,6,7,8-tetrahydro-11-chloro-10-hydroxy-8-oxo-4H-azocino[3,2,1-hi]indole-2-carboxylate (0.95 g, 2.93 mmol), chloromethyl methyl ether (0.35 g, 4.40 mmol), potassium carbonate (1.22 g, 8.80 mmol) and N,N-dimethylformamide (25 ml) was stirred at room temperature for 1 hour. The insoluble material was filtered off and the filtrate was poured into ice water and extracted twice with ethyl acetate. The extract solution was washed with a 5% aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/98) to obtain 0.51 g of ethyl 5,6,7,8-tetrahydro-11-chloro-10-methoxymethyloxy-8-oxo-4H-azocino[3,2,1-hi]indole-2-carboxylate.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[OH:34][C@H:35]1[CH2:39][CH2:38][NH:37][C:36]1=[O:40].[F:41][C:42]1[CH:55]=[CH:54][C:45]([O:46][C:47]2[N:52]=[CH:51][C:50](O)=[CH:49][CH:48]=2)=[CH:44][CH:43]=1>C(Cl)Cl.C1COCC1>[F:41][C:42]1[CH:43]=[CH:44][C:45]([O:46][C:47]2[N:52]=[CH:51][C:50]([O:34][C@@H:35]3[CH2:39][CH2:38][NH:37][C:36]3=[O:40])=[CH:49][CH:48]=2)=[CH:54][CH:55]=1
Reactant: O=C1NCC[C@@H]1O
Reactant: Oc1ccc(Oc2ccc(F)cc2)nc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C1NCC[C@H]1Oc1ccc(Oc2ccc(F)cc2)nc1

Procedure:
A mixture of THF (200 mL) and DCM (100 mL) under argon was added triphenylphosphine (polymer, 1.8 mmol/g, 20 g). Diisopropylazodicarboxylate (8.87 g) was added. After 5 minutes (S)-3-hydroxy-pyrrolidin-2-one (3.1 g) and 6-(4-fluoro-phenoxy)-pyridin-3-ol (6.0 g) were added. After 30 minutes the mixture was filtered and the filtrate concentrated. The residue was purified by chromatography (SiO2; DCM/MeOH 15:1) to provide the title compound. MS ESI+: m/z=289 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([CH:11]=[O:12])[O:10][C:6]=2[C:5]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]2=[O:25])=[C:4]([F:26])[CH:3]=1.[CH3:27][Mg]Br.O>O1CCCC1>[Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([CH:11]([OH:12])[CH3:27])[O:10][C:6]=2[C:5]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]2=[O:25])=[C:4]([F:26])[CH:3]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c3cc(C=O)oc23)c1=O
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: O
Product: CC(O)c1cc2c(Cl)cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c2o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.3 %

Procedure:
4.0 g (10.2 mmol) of 3-(4-chloro-6-fluoro-2-formylbenzofuran-7-yl)-1-methyl-6-trifluoromethyluracil was dissolved in 20 ml of tetrahydrofuran, and 12.3 ml of methyl magnesium bromide (1.0M tetrahydrofuran solution) was dropwise added thereto at -65° C. After stirring at room temperature for 1 hour, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed sequentially with water and a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. Then, the obtained residue was purified by silica gel column chromatography to obtain 2.3 g (yield: 55.3%) of the desired product as pale yellow crystals. Melting point: 154-157° C.
Reaction SMILES: Cl.[C:2]([NH:6][NH2:7])([CH3:5])([CH3:4])[CH3:3].[OH-].[Na+].[C:10](Cl)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1(C)C=CC=CC=1>[C:2]([NH:6][NH:7][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)NN
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(C)(C)NNC(=O)c1ccccc1
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
To a stirred suspension of t-butylhydrazine hydrochloride (2 g, 0.016M) in toluene (50 ml) at room temperature was added dropwise a 50% aqueous solution of sodium hydroxide (1.28 g, 0.016M). After 15 min., the reaction mixture was cooled to 5° C. and a solution of benzoyl chloride (2.3 g, 0.017M) in toluene (5 ml) and a solution of aqueous 50% sodium hydroxide (1.36 g, 0.017M) were added dropwise simultaneously from separate addition funnels while maintaining the temperature at or below 10° C. Following the addition, the reaction mixture was warmed to room temperature and stirred for 1 hr. The reaction mixture was diluted with hexane and the solid N'-t-butyl-N-benzoylhydrazine was isolated by filtration.
Reaction SMILES: [F-].[K+].[Br:3][C:4]1[C:11]([OH:12])=[C:10]([O:13][CH3:14])[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7].F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1.O>CS(C)=O>[Br:3][C:4]1[C:11]([O:12][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[C:10]([O:13][CH3:14])[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: COc1ccc(C=O)c(Br)c1O
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(C=O)c(Br)c1Oc1ccc([N+](=O)[O-])cc1
Temperature: 140 °C
Reaction time: 4 h
Yield: 65.4 %

Procedure:
To a stirred suspension of potassium fluoride (1.89 gm, 0.0326 mol) in dry DMSO (10 ml) was added a solution of 2-bromoisovanillin (5.0 gm, 0.0217 mol) in DMSO (10 ml). A solution of 4-fluoronitrobenzene (5.0 gm, 0.0260 mol) in DMSO (5 ml) was added to the above suspension and the reaction mixture was stirred at 140° C. for 4 h. The reaction mixture was cooled to room temperature and the contents were poured into water (150 ml) and extracted with ethyl acetate (50 ml×3). The organic extracts were combined and washed with 1N sodium hydroxide (25 ml×2), water and brine and dried over anhydrous sodium sulfate. The dried organic layer was concentrated in vacuo and the residue was purified by silica-gel column chromatography using 20% ethyl acetate-petroleum ether as the eluent to give 2-bromo-3-(p-nitrophenoxy)-4-methoxy benzaldehyde as a pale yellow solid (5.0 gm) mp: 132-140° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:23])[CH:11]=2)[CH:6]=1.[Br:25]N1C(=O)CCC1=O>C(#N)C.O>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:23])[CH:11]=2)[C:6]=1[Br:25]
Reactant: COC(=O)Cc1cc(OCc2ccccc2)c2cc(F)ccc2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CC#N
Product: COC(=O)Cc1cc(OCc2ccccc2)c2cc(F)ccc2c1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.8 %

Procedure:
To a stirred solution of (4-benzyloxy-6-fluoro-naphthalen-2-yl)-acetic acid methyl ester (350 mg, 1.08 mmol) in acetonitrile (10 mL) was added N-bromosuccinimide (385 mg, 2.16 mmol). After being stirred at room temperature for 1 hour, the resulting mixture was diluted with water (20 mL), and extracted with ethyl acetate (20 mL×2). The combined organic layers were washed with water (15 mL) and brine (20 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (gradient elution with 0-20% ethyl acetate in hexanes) to afford (4-benzyloxy-1-bromo-6-fluoro-naphthalen-2-yl)-acetic acid methyl ester (400 mg, 92%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9](Cl)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH2:19]([NH2:24])[CH2:20][CH2:21][CH2:22][CH3:23].[OH-].[Na+]>C(O)CCC>[NH2:1][C:2]1[N:10]=[C:9]([NH:24][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCCCCN
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Product: CCCCCNc1nc(N)c2ncn(Cc3ccccc3)c2n1
Temperature: 100 °C
Yield: 69.5 %

Procedure:
6-Amino-9-benzyl-2-chloropurine (100 mg, 0.385 mmol) and pentylamine (336 mg, 3.85 mmol) suspended in 1-butanol (10 ml) were heated at 100° C. for 10 hours in autoclave. The reaction mixture was condensed in vacuo. To the residue was added 1N aqueous sodium hydroxide and the solution was extracted with chloroform. The organic layer was dried on sodium sulfate, filtered and the solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (2% methanol/chloroform) to give the subject compound (83 mg, yield 70%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([Mg]Br)[CH:6]=[CH:7][CH:8]=1.[CH3:11][N:12]([CH3:35])[C:13]1(C#N)[CH2:18][CH2:17][CH:16]([CH:19]([O:27][CH:28]([O:30][CH2:31][CH3:32])[CH3:29])[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:15][CH2:14]1.O.[Cl-].[NH4+]>O1CCCC1>[CH2:31]([O:30][CH:28]([O:27][CH:19]([CH:16]1[CH2:17][CH2:18][C:13]([N:12]([CH3:35])[CH3:11])([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:14][CH2:15]1)[CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH3:29])[CH3:32]
Reactant: COc1cccc([Mg]Br)c1
Reactant: CCOC(C)OC(Cc1ccccc1)C1CCC(C#N)(N(C)C)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(C)OC(Cc1ccccc1)C1CCC(c2cccc(OC)c2)(N(C)C)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A 1 M solution of 3-methoxyphenylmagnesium bromide in tetrahydrofuran (9.25 ml, 9.25 mmol) was added dropwise to a solution of 1-dimethylamino-4-[1-(1-ethoxy-ethoxy)-2-phenylethyl]cyclohexanecarbonitrile (1.06 g, 3.1 mmol) in tetrahydrofuran (15 ml), while cooling with ice and under an argon atmosphere. The mixture was stirred at room temperature for 48 h and thereafter water and saturated ammonium chloride solution (10 ml of each) were added. The phases were separated and the aqueous phase was extracted with diethyl ether (3×10 ml). The combined organic phases were dried with sodium sulfate and concentrated i. vac.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:14]=[C:13]([CH3:15])[O:12][C:11]=2[CH3:16])[C:5]([F:17])=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=1>>[CH3:16][C:11]1[O:12][C:13]([CH3:15])=[CH:14][C:10]=1[CH2:9][NH:8][C:6]1[C:5]([F:17])=[CH:4][N:3]=[C:2]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([OH:25])[CH:20]=2)[N:7]=1
Reactant: Cc1cc(CNc2nc(Cl)ncc2F)c(C)o1
Reactant: Nc1cccc(O)c1
Product: Cc1cc(CNc2nc(Nc3cccc(O)c3)ncc2F)c(C)o1
Yield: 5 %

Procedure:
In a manner analogous to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of (2,5-dimethyl-3-furyl)methylamine (188 mg, 1.5 mmol) and 2,4-dichloro-5-fluoropyrimidine (50 mg, 0.3 mmol) gave 2-chloro-N4-[(2,5-dimethyl-3-furyl)methyl]-5-fluoro-4-pyrimidineamine. The reaction of 2-chloro-N4-[(2,5-dimethyl-3-furyl)methyl]-5-fluoro-4-pyrimidineamine and 3-aminophenol (200 mg, 1.83 mmol) gave N4-[(2,5-dimethyl-3-furyl)methyl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine (50 mg, 5%). 1H NMR (CDCl3): δ 2.22 (s, 3H), 2.23 (s, 3H), 4.39 (d, J=5.1 Hz, 2H), 5.24 (br, 1H), 5.90 (s, 1H), 6.52 (d, J=6.6 Hz, 1H), 6.99 (d, J=8.1 Hz, 1H), 7.13 (t, J=8.1 Hz, 1H), 7.29 (s, 1H), 7.71 (m, 2H); 19F NMR (282 MHz, CDCl3): δ −167.84; LCMS: ret. time: 19.83 min.; purity: 96.32%; MS (m/e): 329.05 (MH+).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([O:8][CH2:9][C:10]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:11]=2[C:12]([O-:14])=[O:13])[CH2:3]1.[C:20]([O-])(=O)C>>[OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([O:8][CH2:9][C:10]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:11]=2[C:12]([O:14][CH3:20])=[O:13])[CH2:3]1
Reactant: Cc1cccc(CO[C@H]2CCC[C@@H](O)C2)c1C(=O)[O-]
Reactant: CC(=O)[O-]
Product: COC(=O)c1c(C)cccc1CO[C@@H]1CCC[C@H](O)C1

Procedure:
The enantiomer 2-((1S,3R)-3-hydroxycyclohexyloxymethyl)-6-methylbenzoate is generated from the acetate obtained in the chromatography forerun after saponification and re-methylation, and is used to prepare the corresponding enantiomeric example structures.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:15])[N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[CH:6][C:7]=1Cl.[CH3:16][NH:17][NH2:18].O>CO>[Cl:1][C:2]1[C:3](=[O:15])[N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[CH:6][C:7]=1[N:17]([CH3:16])[NH2:18]
Reactant: O=c1c(Cl)c(Cl)cnn1-c1ccccc1
Reactant: CNN
Solvent: CO
Solvent: O
Product: CN(N)c1cnn(-c2ccccc2)c(=O)c1Cl

Procedure:
To a solution consisting of 22.9 grams of 4,5-dichloro-2-phenylpyridazin-3(2H)-one in 120 grams of methanol is added 20 grams of methylhydrazine. The reactants are heated to reflux for two hours, cooled and poured into one kilogram of water. The resulting precipitate is separated by filtration, washed with water and dried. The solid is crystallized from benzene and methanol to yield 4-chloro-2-phenyl-5-(1-methylhydrazino)-pyridazine-3(2H)-one (m.p. 128° to 130° C with decomposition).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]2[C:11]3[CH2:16][CH2:15][NH:14][CH2:13][C:12]=3[C:17](=[O:19])[O:18][C:4]=2[CH:3]=1.C(N(CC)CC)C.Cl.Cl[CH2:29][CH2:30][N:31]1[CH2:37][CH:36]2[CH2:38][CH2:39][CH:33]([CH2:34][CH2:35]2)[CH2:32]1>>[CH:36]12[CH2:38][CH2:39][CH:33]([CH2:34][CH2:35]1)[CH2:32][N:31]([CH2:30][CH2:29][N:14]1[CH2:15][CH2:16][C:11]3[C:5]4[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([CH3:1])=[CH:3][C:4]=4[O:18][C:17](=[O:19])[C:12]=3[CH2:13]1)[CH2:37]2
Reactant: Cc1cc2oc(=O)c3c(c2cc1[N+](=O)[O-])CCNC3
Reactant: ClCCN1CC2CCC(CC2)C1
Agent: Cl
Solvent: CCN(CC)CC
Product: Cc1cc2oc(=O)c3c(c2cc1[N+](=O)[O-])CCN(CCN1CC2CCC(CC2)C1)C3
Yield: 50.7 %

Procedure:
Prepared by the method described for Example 1 from 1,2,3,4-tetrahydro-8-methyl-9-nitro-5H-[1]benzopyrano[3,4-c]pyridin-5-one (8.9 g, 0.034 moles), triethylamine (9.5 ml, 0.069 moles), and 3-(2-chloroethyl)-3-azabicyclo[3.2.2]nonane hydrochloride (7.7 g, 0.034 moles). The product was triturated with 10% aqueous potassium carbonate, filtered off, rinsed with water, and dried to afford the free base. Recrystallization from N,N-dimethylformamide gave the product (7.1 g), mp 187°-188° C.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[C:15]3[S:16][CH:17]=[CH:18][C:14]=3[O:13][N:12]=2)[CH:8]=[CH:9][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[C:25]12([NH2:35])[CH2:34][CH:29]3[CH2:30][CH:31]([CH2:33][CH:27]([CH2:28]3)[CH2:26]1)[CH2:32]2>C(#N)C>[C:25]12([NH:35][CH2:2][CH2:3][O:4][C:5]3[CH:10]=[CH:9][CH:8]=[C:7]([C:11]4[C:15]5[S:16][CH:17]=[CH:18][C:14]=5[O:13][N:12]=4)[CH:6]=3)[CH2:32][CH:31]3[CH2:30][CH:29]([CH2:28][CH:27]([CH2:33]3)[CH2:26]1)[CH2:34]2
Reactant: NC12CC3CC(CC(C3)C1)C2
Reactant: BrCCOc1cccc(-c2noc3ccsc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: c1cc(OCCNC23CC4CC(CC(C4)C2)C3)cc(-c2noc3ccsc23)c1
Reaction time: 8 h

Procedure:
The title compound is prepared from 3-[3-(2-bromo-ethoxy)-phenyl]-thieno[2,3-d]isoxazole, potassium carbonate, 1-adamantanamine and acetonitrile essentially as described above in example 18 except that the reaction is run overnight and the compound is purified by column chromatography using a graded solvent mixture of 5% ethyl acetate in DCM to 10% methanol in ethyl acetate. Purity by LC/MS (APCI)=97%, [M+H]+=395.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH2:7]([O:10][CH:11](O)[CH3:12])[CH:8]=[CH2:9].S(=O)(=O)(O)O>>[C:1]([O:6][CH2:12][CH2:11][O:10][CH2:7][CH:8]=[CH2:9])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=CCOC(C)O
Reactant: C=C(C)C(=O)O
Agent: O=S(=O)(O)O
Product: C=CCOCCOC(=O)C(=C)C

Procedure:
First, methacrylic acid was reacted with allyloxy ethanol in the presence of the catalyst of sulfuric acid by a usual esterification method to form allyloxyethyl methacrylate (boiling point=64° C.-65° C./2 mmHg, n20D=1.4463, specific gravity d20 4=0.982).
Reaction SMILES: [CH2:1]([C:11]1[CH:12]=[N:13][C:14]([C:17]2[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=2)=[N:15][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].S(Cl)([Cl:28])=O>>[CH2:1]([C:11]1[CH:12]=[N:13][C:14]([C:17]2[CH:25]=[CH:24][C:20]([C:21]([Cl:28])=[O:22])=[CH:19][CH:18]=2)=[N:15][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCCCc1cnc(-c2ccc(C(=O)O)cc2)nc1
Product: CCCCCCCCCCc1cnc(-c2ccc(C(=O)Cl)cc2)nc1
Yield: 99.6 %

Procedure:
4-(5-n-Decyl-2-pyrimidyl)benzoic acid (2.0 g) prepared in the above (3) was added to thionyl chloride (10 g) and a slight amount of N,N-dimethylformaide was added thereto and the mixture was refluxed for 4 hours. Excess thionyl chloride was distilled off to obtain the titled compound (2.1 g).
Reaction SMILES: C[O:2][C:3](=[O:22])[C@H:4]([CH:19]([CH3:21])[CH3:20])[NH:5][C:6]([N:8]([CH3:18])[CH2:9][C:10]1[N:11]=[C:12]([CH:15]([CH3:17])[CH3:16])[O:13][CH:14]=1)=[O:7]>O1CCOCC1.O>[CH3:18][N:8]([C:6]([NH:5][C@H:4]([C:3]([OH:22])=[O:2])[CH:19]([CH3:20])[CH3:21])=[O:7])[CH2:9][C:10]1[N:11]=[C:12]([CH:15]([CH3:17])[CH3:16])[O:13][CH:14]=1
Reactant: COC(=O)[C@@H](NC(=O)N(C)Cc1coc(C(C)C)n1)C(C)C
Solvent: C1COCCO1
Solvent: O
Product: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)O)C(C)C)co1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
To a solution of N-((N-methyl-N-((2-isopropyl-4-oxazolyl)methyl)amino)carbonyl)-L-valine methyl ester 10 (0.511 g, 0.00164 mol) in p-dioxane (10 mL) and H2O (5 mL) was added LiOH monohydrate (0.103 g, 0.00246 mol). After stirring at room temperature for 1 hr, the p-dioxane was removed by rotary evaporation in vacuo, and the remaining aqueous solution was treated with 1N aq HCl (2.46 mL) and extracted with ethyl acetate (4×100 mL). The combined organic extract was washed with saturated brine and dried for 15 mins over Na2SO4. Concentration in vacuo followed by CH2Cl2 chases (2×) afforded the desired compound as a white solid (0.480 g, 0.00161 mol, 98%):
Reaction SMILES: [C:1]1([CH2:11][OH:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[C:1]1([CH:11]=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: OCc1nccc2ccccc12
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: O=Cc1nccc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.1 %

Procedure:
Isoquinolin-1-yl-methanol (123.7 mg) was dissolved in chloroform (6.2 ml) and then added with manganese dioxide (chemically processed product) (1.24 g), followed by stirring at room temperature for 30 minutes. The reaction solution was filtrated through Celite and the solvent was then distilled off. The residue was dried under vacuum, thereby obtaining the subject compound (103.9 mg) as a brown solid.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([Cl:14])[CH:8]=2)[N:3]=1.C([Sn](CCCC)(CCCC)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)CCC>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([Cl:14])[CH:8]=2)[N:3]=[C:2]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[C:11]=1[CH3:12]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: COc1cc2nc(Cl)c(C)c(Cl)c2cc1Cl
Solvent: Cc1ccccc1
Product: COc1cc2nc(-c3ccccn3)c(C)c(Cl)c2cc1Cl

Procedure:
The dichloride was prepared according to Procedure E using 2,4,6-trichloro-7-methoxy-3-methylquinoline (0.69 g, 2.49 mmol), 2-(tributylstannyl)pyridine (1.01 mL, 2.74 mmol), palladium tetrakistriphenylphosphine (0.29 g, 0.25 mmol) in toluene (5.00 mL) to give 4,6-dichloro-7-methoxy-3-methyl-2-(pyridin-2-yl)quinoline as a white solid. Mass Spectrum (ESI) m/e=319.0 (M+1).