Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1([C:13]#[N:14])[CH2:12][CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].O>C1COCC1>[C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1([CH2:13][NH2:14])[CH2:12][CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(C#N)CCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1(CN)CCCC1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a cooled 0° C. solution of (1-cyano-cyclopentyl)-carbamic acid tert-butyl ester (430 mg, 2.04 mmol) in dry THF (4.3 ml) under an atmosphere of argon is added dropwise 1.0 M LiAlH4 (6.13 ml, 6.13 mmol). The reaction mixture is allowed to warm to room temperature and stirred for 3.5 hours. The mixture is then re-cooled to 0° C. and cautiously quenched with water (0.4 ml): 15% NaOH (0.8 ml): water (1.2 ml) (1:2:3 eq). The resultant mixture is filtered through Celite® (filter material) to remove the inorganic solids and rinsed with MeOH. The filtrate is concentrated in vacuo, to yield a white solid, which is purified by chromatography on silica eluting with 30% MeOH in DCM to afford (1-Aminomethyl-cyclopentyl)-carbamic acid tert-butyl ester; [M+H]+ 215.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][CH2:3][CH:2]1[CH:11]=O.[NH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH2:20][NH:19][C:18]1=[S:23].[C:24]([OH:29])(=[O:28])[C:25]([OH:27])=[O:26]>CO.[Pd]>[C:24]([OH:29])(=[O:28])[C:25]([OH:27])=[O:26].[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][CH2:3][CH:2]1[CH2:11][NH:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH2:20][NH:19][C:18]1=[S:23]
Reactant: NCCCN1CCCNC1=S
Reactant: O=CC1CCc2ccccc2O1
Agent: [Pd]
Agent: O=C(O)C(=O)O
Solvent: CO
Product: S=C1NCCCN1CCCNCC1CCc2ccccc2O1
Reaction time: 48 h
Yield: 7 %

Procedure:
A mixture of 3.4-dihydro-2H-1-benzopyran-2-carboxaldehyde (0.015 mol) and 1-(3-aminopropyl)tetrahydro-2(1H)-pyrimidinethione (0.01 mol) in methanol (150 ml) was hydrogenated for 2 days at room temperature (atmospheric pressure) with palladium on activated carbon (2 g) as a catalyst. After uptake of H2 (1 eq.), the catalyst was filtered off and the filtrate was evaporated. The residue was purified by column chromatography over silica gel (eluent: C2Cl2/(CH3OH/NH3) 95/5). The pure fractions were collected and the solvent was evaporated. The residue (0.3 g) was dissolved in ethanol (30 ml) and converted into the ethanedioic acid salt (1:1 ) with ethanedioic acid (0.3 g; 0.0124 mol). The precipitate was filtered off and dried (vacuum), yielding 0.3 g (7%) of (±)-1-[3-[[(3,4-dihydro-2H-1-benzopyran-2-yl)-methyl]amino]propyl]tetrahydro-2(1H)-pyrimidinethione ethanedioate(1:1); mp. 217.6° C. (comp. 14).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:19]=[C:18]2[C:14]([CH:15]=[CH:16][NH:17]2)=[CH:13][CH:12]=1>>[NH:17]1[C:18]2[C:14](=[CH:13][CH:12]=[C:11]([NH:10][C:2]3[N:7]=[C:6]([NH:10][C:11]4[CH:19]=[C:18]5[C:14]([CH:15]=[CH:16][NH:17]5)=[CH:13][CH:12]=4)[C:5]([F:9])=[CH:4][N:3]=3)[CH:19]=2)[CH:15]=[CH:16]1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Nc1ccc2cc[nH]c2c1
Product: Fc1cnc(Nc2ccc3cc[nH]c3c2)nc1Nc1ccc2cc[nH]c2c1

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 6-aminoindole were reacted to yield N2,N4-bis(indol-6-yl)-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time: 22.39 min.; purity: 85%; MS (m/e): 359 (MH+).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:15])=[C:4]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:5]([O:7][CH3:8])=[O:6].[CH3:16][O:17][CH2:18][CH2:19]Cl.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:16][O:17][CH2:18][CH2:19][O:1][C:2]1[C:3]([CH3:15])=[C:4]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(O)c1C
Reactant: COCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCOc1c([N+](=O)[O-])ccc(C(=O)OC)c1C
Temperature: 90 °C
Reaction time: 20 h
Yield: 106.3 %

Procedure:
Methyl 3-hydroxy-2-methyl-4-nitrobenzoate (1.55 g) and 2-chloroethyl methyl ether (1.8 g) were dissolved in anhydrous DMF (20 mL), and potassium carbonate (1.25 g) and potassium iodide (300 mg) were added, followed by stirring at 90° C. for 20 hours. To the reaction mixture, ethyl acetate (200 mL) was added, followed by washing twice with saturated brine. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain methyl 3-(2-methoxyethoxy)-2-methyl-4-nitrobenzoate (2.1 g) as pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)[NH2:5].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[S:22])=[CH:16][C:15]=1[C:23]([F:26])([F:25])[F:24]>>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:21]([NH:20][C:17]2[CH:18]=[CH:19][C:14]([Cl:13])=[C:15]([C:23]([F:26])([F:24])[F:25])[CH:16]=2)=[S:22])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: Nc1cc(F)cc(C(F)(F)F)c1
Reactant: FC(F)(F)c1cc(N=C=S)ccc1Cl
Product: Fc1cc(NC(=S)Nc2ccc(Cl)c(C(F)(F)F)c2)cc(C(F)(F)F)c1

Procedure:
The title compound was synthesized according to the procedure used in example 2 starting with 3-Fluoro-5-(trifluoromethyl)-aniline and 4-Chloro-3-(trifluoromethyl)-phenylisothiocyanate. Yield: 98 mg (47%).
Reaction SMILES: Cl[C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[S:14]([CH3:17])(=[O:16])=[O:15].[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C(OCC)(=O)C.Cl>O>[CH3:17][S:14]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:2]=1[N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[C:6]([OH:8])=[O:7])(=[O:16])=[O:15]
Reactant: C1CCNCC1
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Product: CS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1N1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The mixture of 4-chloro-3-methylsulfonyl-5-nitrobenzoic acid (5.0 g) and piperidine (25.0 ml) was stirred for 1 hour at ambient temperature. To the mixture was added a mixture of ethyl acetate and water and the mixture was adjusted to pH 1 with conc. hydrochloric acid. The separated organic layer was washed with water and dried over magnesium sulfate. The solvent was removed by concentration and the residue was triturated with a mixture of diisopropyl ether and n-hexane to give 3-methylsulfonyl-5-nitro-4-piperidinobenzoic acid (5.66 g).
Reaction SMILES: [CH:1]([C:3]1[CH:16]=[CH:15][C:6]([O:7][CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1)=O.[Cl:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1>C1C=CC=CC=1>[Cl:17][C:18]1[CH:24]=[CH:23][C:21]([N:22]=[CH:1][C:3]2[CH:16]=[CH:15][C:6]([O:7][CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=2)=[CH:20][CH:19]=1
Reactant: CCOC(=O)C(C)Oc1ccc(C=O)cc1
Reactant: Nc1ccc(Cl)cc1
Solvent: c1ccccc1
Product: CCOC(=O)C(C)Oc1ccc(C=Nc2ccc(Cl)cc2)cc1
Reaction time: 6 h
Yield: 94.8 %

Procedure:
(a) In 100 ml of dried benzene are dissolved 17.0 g of ethyl 2-(4-formylphenoxy)propionate and 9.73 g of 4-chloroaniline, and the mixture is refluxed under heating and with stirring for 6 hours. Concentration of the reaction mixture gives 24.0 g of ethyl 2-[4-{N-(4-chlorophenyl)formimidoyl}phenoxy]propionate as an oily product.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([S:16](=[O:32])(=[O:31])[NH:17][CH:18]2[CH2:23][CH2:22][N:21]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:20][CH2:19]2)=[CH:8][CH:7]=1)=[O:5].[CH3:34][Mg]Br>C1COCC1>[CH2:24]([N:21]1[CH2:20][CH2:19][CH:18]([NH:17][S:16]([C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:6]([C:4](=[O:5])[CH3:34])=[CH:7][CH:8]=2)(=[O:32])=[O:31])[CH2:23][CH2:22]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1ccc(S(=O)(=O)NC2CCN(Cc3ccccc3)CC2)c2ccccc12
Solvent: C1CCOC1
Product: CC(=O)c1ccc(S(=O)(=O)NC2CCN(Cc3ccccc3)CC2)c2ccccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.9 %

Procedure:
To a 0° C. solution of 4-(1-benzyl-piperidin-4-ylsulfamoyl)-naphthalene-1-carboxylic acid methoxy-methyl-amide 35 (200 mg, 0.43 mmol) in THF (5 mL) was slowly added methylmagnesium bromide (5.71 mL, 17.1 mmol, IM THF solution). After stirring at 25° C. for 4 h, the resultant mixture was quenched with saturated ammonium chloride solution. The aqueous layer was extracted with CH2Cl2. The organic extracts were combined, washed with brine and dried over MgSO4. The solution was filtered and concentrated in vacuo to give the crude product. The crude material was purified by Flash column chromatography (hexane/EtOAc) to provide 118 mg of 4-acetyl-naphthalene-1-sulfonic acid (1-benzyl-piperidin-4-yl)-amide 36 in 56% overall yield (for two steps). LCMS showed m/z: 423 (M+H)+.
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl:10][C:11]1[CH:20]=[C:19]2[C:14]([CH:15]=[CH:16][C:17]([CH2:21][O:22][C:23]3[CH:38]=[CH:37][C:26]4[O:27][CH2:28][C:29]5[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=5[C:31](=[O:32])[C:25]=4[CH:24]=3)=[N:18]2)=[CH:13][C:12]=1F>CN(C)C=O>[Cl:10][C:11]1[CH:20]=[C:19]2[C:14]([CH:15]=[CH:16][C:17]([CH2:21][O:22][C:23]3[CH:38]=[CH:37][C:26]4[O:27][CH2:28][C:29]5[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=5[C:31](=[O:32])[C:25]=4[CH:24]=3)=[N:18]2)=[CH:13][C:12]=1[S:3][CH2:1][CH3:2]
Reactant: O=C1c2ccccc2COc2ccc(OCc3ccc4cc(F)c(Cl)cc4n3)cc21
Reactant: CCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCSc1cc2ccc(COc3ccc4c(c3)C(=O)c3ccccc3CO4)nc2cc1Cl
Temperature: 90 °C
Reaction time: 4 h

Procedure:
0.37 ml of ethyl mercaptan and 1.12 g of potassium carbonate were added to 2.0 g of 2-(7-chloro-6-fluoroquinolin-2-yl)methoxy-11-oxo-6,11-dihydrodibenz[b,e]oxepine dissolved in 80 ml of dimethylformamide and the mixture was stirred at 90° C. for 4 hours.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2].[NH2:15][CH2:16][C:17]([OH:19])=[O:18]>>[N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:15]([CH2:16][C:17]([OH:19])=[O:18])[C:8](=[O:10])[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2]
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Reactant: NCC(=O)O
Product: O=C(O)CN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O
Yield: 86.1 %

Procedure:
4-nitrophthalic anhydride (0.25 g, 0.0013 mol) and glycine (0.097 g, 0.0013 mol) were refluxed as above overnight. The clear solution was purified as per 120 to yield 0.28 g (86%) 140 as very pale yellow crystals: mp=195-96° C.; Rf0.79 (A): Rf0.75 (B): Rf0.28 (D): IR (cm−1): 2811-3150 (OH), 3115 (C═CH), 1787 (C═O), 1730 (bs, C═O), 1622 (C═C), 1551 (N═O), 1412 (C═C), 1391 (C—O), 1351 (N═O), 1117 (C—O), 720 (C═CH); MS m/z (rel intensity) 250 (7), 249 (62), 205 (100), 122 (10).
Reaction SMILES: O.[NH2:2]N.C[N:5]([CH2:7][CH:8]1[C:17](=O)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[O:10][CH2:9]1)C>C(O)C>[N:2]1[NH:5][CH2:7][CH:8]2[CH2:9][O:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:17]=12
Reactant: NN
Reactant: CN(C)CC1COc2ccccc2C1=O
Solvent: O
Solvent: CCO
Product: c1ccc2c(c1)OCC1CNN=C21
Temperature: 0 °C
Yield: 105.5 %

Procedure:
Hydrazine monohydrate (7.2 g) was dissolved in ethanol (10 ml). Thereto was dropwise added a solution of 3-(N,N-dimethylaminomethyl)-4-chromanone (6.7 g) dissolved in ethanol (10 ml) in a nitrogen atmosphere at room temperature. The resulting mixture was refluxed for 4 hours with heating. The reaction mixture was poured into ice water. Extraction with chloroform was conducted, followed by drying and concentration, to obtain 6 g of a title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1/[CH:12]=[CH:13]/[C:14]([O:16][CH3:17])=[O:15])[C:5]([O:7][CH3:8])=[O:6].[S:18](=[O:21])([OH:20])[O-:19].[Na+]>C(O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:9]=[CH:10][C:11]=1[CH:12]([S:18]([OH:21])(=[O:20])=[O:19])[CH2:13][C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)/C=C/c1ccc(C(=O)OC)cc1Br
Reactant: O=S([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COC(=O)CC(c1ccc(C(=O)OC)cc1Br)S(=O)(=O)O
Temperature: 165 °C
Reaction time: 0.5 h
Yield: 68.2 %

Procedure:
Methyl 3-bromo-4-[(1E)-3-methoxy-3-oxoprop-1-en-1-yl]benzoate (300 mg, 1.00 mmol) dissolved in ethanol (2.0 mL) was added to sodium bisulfite (209 mg, 2.00 mmol) in water (2.0 mL). The reaction mixture was heated in the microwave at 165° C. with stirring for 30 minutes. The colorless solution was purified by preparative LCMS to afford product as a white solid (0.26 g, 68%). 1H NMR (400 MHz, CDCl3): δ 8.19 (d, J=1.5 Hz, 1H), 7.93 (dd, J=8.2, 1.8 Hz, 1H), 7.74 (d, J=8.2 Hz, 1H), 5.18 (dd, J=10.0, 5.1 Hz, 1H), 3.88 (s, 3H), 3.55 (s, 3H), 3.38 (dd, J=16.5, 5.1 Hz, 1H), 3.08 (dd, J=16.5, 10.0 Hz, 1H). LCMS found for C12H12BrO7S (M−H)−: m/z=378, 380.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:23][C:17]3[N:18]=[CH:19][N:20]=[C:21](Cl)[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:24][C:25]1[CH:29]=[CH:28][N:27]([CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:26]=1>C(O)CCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:23][C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH:24][C:25]4[CH:29]=[CH:28][N:27]([CH2:30][CH2:31][C:32]5[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=5)[N:26]=4)[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccn(CCc2ccccc2)n1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Cl)ncnc3[nH]2)CC1
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Nc4ccn(CCc5ccccc5)n4)ncnc3[nH]2)CC1
Temperature: 120 °C

Procedure:
A mixture of 4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (110 mg, 0.33 mmol) and 3-amino-1-phenethyl-1H-pyrazole (74 mg, 0.39 mmol) in 1-butanol (3 mL) was heated at 120° C. overnight, LC-MS showed the reaction was complete. The mixture was concentrated, then dissolved in MeOH-DMSO, and purified by MSDP (using water/acetonitrile/HCOOH mixtures) to give the title compound as a brown solid. LC-MS (ES, Pos.): 486 [MH+]. 1H NMR (CD3OD, 400 MHz): δ=1.49 (s, 9H), 2.54 (m, 2H), 3.16 (t, J=7.1 Hz, 2H), 3.65 (m, 2H), 4.12 (m, 2H), 4.32 (t, J=7.1 Hz, 2H), 6.27 (s, 1H), 6.48 (d, J=2.3 Hz, 1H), 6.53 (s, 1H), 7.14-7.28 (m, 5H), 7.36 (d, J=2.3 Hz, 1H), 8.21 (s, 1H).
Reaction SMILES: CN(C)C=O.[CH2:6]([O:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18](=O)[NH:19][CH:20]=[N:21]2)=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.S(Cl)([Cl:27])=O>>[CH2:6]([O:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18]([Cl:27])=[N:19][CH:20]=[N:21]2)=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=c1[nH]cnc2cc(OCc3ccccc3)ccc12
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Clc1ncnc2cc(OCc3ccccc3)ccc12
Yield: 86.5 %

Procedure:
Dimethylformamide (0.5 ml) was added to a suspension of 7-(benzyloxy)quinazolin-4-(3H)-one (5.04 g, 20 mmol) in thionyl chloride (50 ml) and the mixture heated at reflux for 2 hours. The thionyl chloride was removed in vacuo and the residual oil dissolved in dichloromethane (100 ml). This solution was slowly added to an aqueous saturated solution of sodium bicarbonate (100 ml) and the organic phase recovered. The aqueous phase was extracted with dichloromethane (2×50 ml) and the combined organics dried and concentrated to yield 7-(benzyloxy)-4-chloroquinazoline (4.68 g, 86.5% yield):
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].C(N(CC)CC)C.[NH2:12][C:13]1[CH:14]=[N:15][C:16]2[C:21]([C:22]=1[Cl:23])=[CH:20][CH:19]=[CH:18][CH:17]=2>ClCCl>[Cl:23][C:22]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=[CH:14][C:13]=1[NH:12][C:1](=[O:3])[CH3:2]
Reactant: Nc1cnc2ccccc2c1Cl
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1cnc2ccccc2c1Cl
Reaction time: 8 h

Procedure:
Acetyl chloride (3.41 mL, 1.25 eq) and triethylamine (6.79 mL, 1.4 eq) were added sequentially to a solution of 3-amino-4-chloroquinoline (6.22 g, 1.0 eq) in dichloromethane (100 mL). The reaction mixture was stirred overnight and then washed sequentially with aqueous saturated sodium bicarbonate and brine, dried over magnesium sulfate, and then concentrated under reduced pressure to provide 6.68 g of N-(4-chloroquinolin-3-yl)acetamide.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([OH:13])[CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[H-].[Na+].I[CH2:17][CH3:18].Cl>CN(C)C=O.O>[CH2:17]([O:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([OH:13])[CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:18]
Reactant: CCI
Reactant: CCOC(=O)c1cc(O)cc(O)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(O)cc(OCC)c1
Reaction time: 0.5 h
Yield: 39 %

Procedure:
To a solution of ethyl 3,5-dihydroxybenzoate (15.0 g) in N,N-dimethylformamide (180 ml) was gradually added sodium hydride (60% in oil, 3.30 g) at 0° C. and the mixture was stirred for 30 min. Iodoethane (12.9 g) was added and the mixture was further stirred for 2 hrs. The reaction mixture was poured into water, acidified with 2N hydrochloric acid and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography, and ethyl 3-ethoxy-5-hydroxybenzoate (6.75 g, yield 39%) was obtained as crystals from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio). Recrystallization from diethyl ether-hexane gave colorless needle-shaped crystals. melting point: 62–63° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:17]([O-])=O)=[C:6]([NH:8][CH2:9][C:10]2[N:11]=[N:12][C:13]([Cl:16])=[CH:14][CH:15]=2)[CH:7]=1.[N:20]([O-])=O.[Na+]>CC(O)=O.Cl.O.[Fe]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:17]=[N:20][N:8]([CH2:9][C:10]3[N:11]=[N:12][C:13]([Cl:16])=[CH:14][CH:15]=3)[C:6]=2[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1NCc1ccc(Cl)nn1
Reactant: O=N[O-]
Agent: [Fe]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Clc1ccc(Cn2nnc3ccc(Br)cc32)nn1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 90.6 %

Procedure:
To a solution of compound 10E (1.40 g, 4.08 mmol) in HOAc/HCl (50/5 mL) was added iron power (2.2 g, 40 mmol). The reaction mixture was stirred at 50° C. for 30 minutes, then cooled to room temperature and filtered. A solution of NaNO2 (0.35 g, 5 mmol) in water (2 mL) was then added drop wise into above acid solution at 0° C. The reaction solution was stirred for one hour and concentrated to dryness under reduced pressure. The resulting residue was sonicated in ethyl acetate/NaHCO3 solution and the precipitate was filtered off and rinsed thoroughly with ethyl acetate. The organic solution was separated and dried with MgSO4, filtered and concentrated to give 1.2 g of desired product (10F). ESI-MS:m/z 323.9 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[C:5](Cl)=[N:6][OH:7])[CH3:2].[F:10][C:11]([F:21])([F:20])[C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[CH2:17])=[CH:14][CH:13]=1.C(N(CC)CC)C>O1CCCC1>[F:10][C:11]([F:20])([F:21])[C:12]1[CH:13]=[CH:14][C:15]([CH:16]2[O:7][N:6]=[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:9])[CH2:17]2)=[CH:18][CH:19]=1
Reactant: CCOC(=O)C(Cl)=NO
Reactant: C=Cc1ccc(C(F)(F)F)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=NOC(c2ccc(C(F)(F)F)cc2)C1
Reaction time: 16 h
Yield: 88.3 %

Procedure:
To a stirred mixture of 2-chloro-2-hydroxyiminoacetic acid ethyl ester (2.11 g, 13.52 mmol) and 4-trifluoromethystyrene (2.0 g, 11.27 mmol) in anhydrous tetrahydrofuran (15 ml) was added dropwise a solution of triethylamine (3.0 ml, 21.52 mmol) in tetrahydrofuran (5 ml) at room temperature. The resulting reaction mixture was stirred at an atmosphere of nitrogen for 16 hours, filtered, partitioned between water and ethyl acetate (2×50 ml), washed with saturated aqueous sodium bicarbonate, 30% aqueous ammonium chloride, brine, dried over sodium sulfate, and concentrated to afford a pale yellow solid, which was purified by chromatography (2:8 EtOAc:Hexane) to afford ethyl 5-(4-(trifluoromethyl)phenyl)-4,5-dihydroisoxazole-3-carboxylate (2.86 g, M+1=288.2)
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH:6]([CH3:8])[CH2:5][N:4]([CH2:9][C:10]([OH:28])([CH2:15][C:16]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[O:26][CH3:27])([CH3:18])[CH3:17])[C:11]([F:14])([F:13])[F:12])[CH2:3]1.N1C=CC=CC=1.[C:35](OC(=O)C)(=[O:37])[CH3:36]>C(Cl)Cl>[F:25][C:23]1[CH:22]=[CH:21][C:20]([O:26][CH3:27])=[C:19]([C:16]([CH3:18])([CH3:17])[CH2:15][C:10]([OH:28])([C:11]([F:12])([F:13])[F:14])[CH2:9][N:4]2[CH2:3][CH:2]([CH3:1])[N:7]([C:35](=[O:37])[CH3:36])[CH:6]([CH3:8])[CH2:5]2)[CH:24]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(CN1CC(C)NC(C)C1)C(F)(F)F
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CN1CC(C)N(C(C)=O)C(C)C1)C(F)(F)F
Reaction time: 8 h

Procedure:
To a solution of 2-(3,5-dimethylpiperazin-1-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol (18 mg) in methylene chloride (1 mL) was added pyridine (55.8 μL) followed by acetic anhydride (43.4 μL). The resulting mixture was stirred overnight, quenched with saturated aqueous sodium bicarbonate solution and extracted twice with methylene chloride. The combined organic phases were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography with silica gel (eluted with 50% ethyl acetate-hexanes) to give the title compound as a clear oil (20 mg).
Reaction SMILES: C[O:2]C(=O)C1C=CC=C(O)C=1.[C:12]1([P:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[C:25]1([P:18](=[O:2])([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COC(=O)c1cccc(O)c1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: C1CCOC1
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 50 °C

Procedure:
To a well-stirred solution consisting of (7S,9aS)-cis-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-yl)-methanol (3.40 g, 11.83 mmol), methyl-3-hydroxybenzoate (2.70 g, 17.75 mmol), and triphenylphosphine (3.70 g, 14.20 mmol), in anhydrous tetrahydrofuran (68 ml), diethylazodicarboxylate (2.24 ml, 14.20 mmol) was added. The resulting solution was heated at 50° C. for 2 hours. The solvent was removed in vacuo, and the resulting residue was extracted into a biphasic 1N aqueous sodium hydroxide (40 ml)/methylene chloride (50 ml) mixture. The aqueous phase was twice extracted with equal volume portions of fresh methylene chloride. The combined organic extracts were dried (anhydrous magnesium sulfate), and concentrated to an amber oil. An initial flash chromatography (silica gel, 70-230 micron mesh; elution with methanol/methylene chloride=1:99 in volume) afforded partially purified product (3.3 g, contaminants: hydrazine diethylcarboxylate and triphenylphosphine oxide). A second flash chromatography of the entire sample (silica gel, 230-400 micron mesh, elution with methanol/methylene chloride=1:99) afforded the purified title compound (1.37 g, 27% yield) as a colorless amorphous solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:4]=1[C:5]([OH:7])=O.Cl.[CH2:14]([O:16][CH2:17][CH2:18][N:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]=[C:20]1[N:28]1[CH2:34][CH2:33][CH2:32][N:31]([CH2:35][CH2:36][C:37]2([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:41][CH2:40][NH:39][CH2:38]2)[CH2:30][CH2:29]1)[CH3:15]>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:4]=1[C:5]([N:39]1[CH2:40][CH2:41][C:37]([CH2:36][CH2:35][N:31]2[CH2:32][CH2:33][CH2:34][N:28]([C:20]3[N:19]([CH2:18][CH2:17][O:16][CH2:14][CH3:15])[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=3)[CH2:29][CH2:30]2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:38]1)=[O:7]
Reactant: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Reactant: COc1ccc(F)cc1C(=O)O
Agent: Cl
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(F)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 56.1 using 2-methoxy-5-fluorobenzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) to give the title compound.