Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]([CH:24]([CH3:33])[CH2:25][S:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[CH:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C.[C:38](Cl)(=[O:40])[CH3:39]>C1C=CC=CC=1>[C:38]([C:10](=[C:9]([NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:24]([CH3:33])[CH2:25][S:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=1)=[O:12])(=[O:40])[CH3:39]
Reactant: CC(CSc1ccccc1)C(=CC(=O)OCc1ccc([N+](=O)[O-])cc1)NCc1ccccc1
Reactant: CC(=O)Cl
Agent: CN(C)C
Solvent: c1ccccc1
Product: CC(=O)C(C(=O)OCc1ccc([N+](=O)[O-])cc1)=C(NCc1ccccc1)C(C)CSc1ccccc1

Procedure:
p-Nitrobenzyl 3-benzylamino-4-methyl-5-phenylthio-2-pentenoate (1.58 g; 3.51 mmole) was dissolved in tolune (5 ml), and trimethylamine (1.06 g; 10.5 mmole) was added thereto at 50° to 60° C. Acetyl chloride (630 mg; 8.0 mmole) was further added thereto all at once, and the resultant mixture was stirred for 10 minutes. Benzene (50 ml) was added to the reaction mixture, which was washed successively with a saturated sodium bicarbonate solution, water, dilute hydrochloric acid and an aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to give p-nitrobenzyl 2-acetyl-3-benzylamino-4-methyl-5-phenylthio-2-pentenoate.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:23]=[CH:22][C:8]([CH:9]=[C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12]/[C:11]/2=[N:20]\[OH:21])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH2:24](I)[CH3:25].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>ClCCl.O>[CH2:24]([O:21]/[N:20]=[C:11]1/[C:10](=[CH:9][C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:23][CH:22]=2)[C:19]2[C:14]([CH2:13][CH2:12]/1)=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH3:25]
Reactant: CS(=O)(=O)c1ccc(C=C2/C(=N/O)CCc3ccccc32)cc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: CCO/N=C1\CCc2ccccc2C1=Cc1ccc(S(C)(=O)=O)cc1
Temperature: 62.5 °C
Reaction time: 8 h
Yield: 82.5 %

Procedure:
(E)-1-(4-methanesulfonyl-benzylidene)-3,4-dihydro-1H-naphthalene-2-one oxime (50 mg, 0.15 mmol), ethyl iodide (0.0147 ml, 0.18 mmol) and potassium carbonate (0.063 g, 0.46 mmol) were added into dimethylformamide (2.0 ml). Then, the solution was stirred at 60-65° C. overnight, and cooled to room temperature. Again, water and dichloromethane were added, and an organic layer was separated, washed with water and brine, and dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to remove organic solvent. The residue was purified through silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/2, v/v). As a result, 44 mg of the present compound (productive yield 81%) was obtained as a white solid crystal.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[O:13][C:14]2[C:20]([OH:21])=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1)[CH2:9][C:10]#[CH:11]>>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:11]#[C:10][CH2:9][CH2:8][C:12]1[O:13][C:14]2[C:20]([OH:21])=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1
Reactant: C#CCCc1nc2cccc(O)c2o1
Reactant: Brc1ccccn1
Product: Oc1cccc2nc(CCC#Cc3ccccn3)oc12
Yield: 5.5 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (110 mg, 0.69 mol) and 2-(but-3-ynyl)benzo[d]oxazol-7-ol (130 mg, 0.69 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 98:2) to yield 10 mg (38 μmol, 5%) of 2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazol-7-ol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>O1CCCC1.C(OCC)C>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][C:8]([C:9]#[N:10])([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH3:27]
Reactant: CCOC(=O)CBr
Reactant: N#CCc1ccc(Cl)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)CC(C#N)(CC(=O)OCC)c1ccc(Cl)cc1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
Combine 4-chlorophenylacetonitrile (50.0 mmol) and tetrahydrofuran (140 mL). Cool to about 5° C. Add dropwise a solution of sodium bis(trimethylsilyl)amide (800 mL, 1 M in tetrahydrofuran, 800 mmol). When the addition is complete, warm the reaction mixture to ambient temperature and allow to stir for 1 hour. Transfer the above solution via cannula into a cooled (−8° C.) solution of ethyl bromoacetate.(84.5 mL, 762 mmol) in tetrahydrofuran (500 mL) at such a rate that the temperature of the reaction mixture does not rise above about 20° C. Allow to stir at ambient temperature. After 18 hours, dilute with diethyl ether (1.5 L) and extract with saturated aqueous solution of ammonium chloride, then water, and then saturated aqueous solution of sodium chloride. Dry the organic layer over MgSO4, filter, and concentrate in vacuo to give the title compound. Elemental Analysis calculated for C16H18ClNO4: C 59.35; H 5.60; N 4.33; Found: C 59.27; H 5.54; N 4.33.
Reaction SMILES: [C:1]1([S:7]([C:10]2[S:14][C:13]([NH:15]C(=O)OC(C)(C)C)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>FC(F)(F)C(O)=O>[NH2:15][C:13]1[S:14][C:10]([S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])=[CH:11][CH:12]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(S(=O)(=O)c2ccccc2)s1
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(S(=O)(=O)c2ccccc2)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl [5-(phenylsulfonyl)thien-2-yl]carbamate (0.37 g, 1.1 mmol) is dissolved in 5 ml of trifluoroacetic acid and the solution is stirred at room temperature for 2 hours. The trifluoroacetic acid is distilled off and the residue is partitioned between semisaturated sodium hydrogen carbonate solution and dichloromethane. The phases are separated and the aqueous phase is subjected to extraction with dichloromethane. The combined organic phases are dried over potassium carbonate and filtered and the solvent is distilled off.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]=[CH:9][C:10]2[C:18]3[C:13](=[CH:14][C:15]([NH:19][C:20]4[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=4[C:22](O)=[O:23])=[CH:16][CH:17]=3)[N:12]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][O:30]3)[N:11]=2)[CH:3]=1.C([Si](C)(C)[O:40][CH2:41][C:42]#[C:43][CH2:44][NH2:45])(C)(C)C>>[OH:40][CH2:41][C:42]#[C:43][CH2:44][NH:45][C:22](=[O:23])[C:21]1[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=1[NH:19][C:15]1[CH:14]=[C:13]2[C:18]([C:10]([CH:9]=[CH:8][C:4]3[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][N:5]=3)=[N:11][N:12]2[CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][O:30]2)=[CH:17][CH:16]=1
Reactant: CC(C)(C)[Si](C)(C)OCC#CCN
Reactant: Cc1ccnc(C=Cc2nn(C3CCCCO3)c3cc(Nc4ccccc4C(=O)O)ccc23)c1
Product: Cc1ccnc(C=Cc2nn(C3CCCCO3)c3cc(Nc4ccccc4C(=O)NCC#CCO)ccc23)c1

Procedure:
Prepared in a similar manner to that described for Example 6 except using 2-[3-[2-(4-methyl-pyridin-2-yl)-vinyl]-1-(tetrahydro-pyran-2-yl)-1H-indazol-6-ylamino]-benzoic acid and 4-(tert-Butyl-dimethyl -silanyloxy)-but-2-ynylamine. 1H NMR (CDCl3): δ 9.48 (H, s), 8.46 (1H, d, J=5.3 Hz), 7.92 (1H, d, J=9.0 Hz), 7.83 (1H, d, J=16.2 Hz), 7.52 (1H, d, J=16.6 Hz), 7.46–7.41 (2H, m), 7.34–7.31 (3H, m), 7.12 (1H, dd, J=8.7, 1.9 Hz), 6.99 (1H, d, J=4.9 Hz), 6.81 (1H, t, J=6.8 Hz), 6.40 (1H, t, J=4.9 Hz), 5.62 (1H, dd, J=9.4, 3.0 Hz), 4.28–4.23 (4H, m), 4.08–4.01 (1H, m), 3.76–3.67 (1H, m), 2.63–2.49 (1H, m), 2.38 (3H, s), 2.22–2.06 (2H, m), 1.80–1.60 (3H, m).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[C:6]([O:13][CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:5]=1>CO.[Cl-].[NH4+].C(OCC)(=O)C.[Zn]>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([O:13][CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:5]=1
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(OCc2cccnc2)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(N)c(OCc2cccnc2)c1
Reaction time: 12 h
Yield: 97 %

Procedure:
To a stirred, cooled (about 0° C.) solution of 4-nitro-3-(pyridin-3-ylmethoxy)-benzoic acid methyl ester (288 mg, 1.0 mmol) in methanol (2 mL) and saturated aqueous ammonium chloride (1 mL) was added zinc dust (13.1 mg, 2.0 Mmol). After stirring for 12 hours, the reaction was diluted with 30 mL of ethyl acetate and washed with 30 mL of 10% aqueous sodium carbonate (2×30 mL), brine (1×30 mL), then dried (MgSO4), and filtered. The filtered solution was concentrated under reduced pressure to yield the desired product as a yellow solid (97% yield). 1H-NMR (400 MHz, CDCl3) δ 8.78 (s, 1H), 8.61 (d, 1H), 779 (d, 1H), 7.59 (m, 2H), 7.39 (m, 1H), 6.71 (d, 1H), 5.18 (s, 2H), 4.28 (br s, 2H), 3.85 (s, 3H).
Reaction SMILES: C(NC(C)C)(C)C.CCCCCC.[CH3:14][O:15][C:16]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:17].Br[CH2:25][CH:26]([CH2:29][CH3:30])[CH2:27][CH3:28].Cl>C1COCC1.C(OCC)(=O)C>[CH3:14][O:15][C:16]([C:18]1([CH2:25][CH:26]([CH2:29][CH3:30])[CH2:27][CH3:28])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:17]
Reactant: COC(=O)C1CCCCC1
Reactant: CCC(CC)CBr
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: CCC(CC)CC1(C(=O)OC)CCCCC1
Temperature: -65 °C
Reaction time: 0.33 h
Yield: 65.8 %

Procedure:
To a solution of diisopropylamine (2.37 g, 23.4 mmol) in THF (12 mL) 1.6 M n-BuLi in hexane (13.2 mL, 21.09 mmol) was added with stirring over 20 min at −65° C. The suspension was warmed up to −40° C. and then added via a teflon tube over 15 min to a stirred solution of cyclohexanecarboxylic acid methyl ester (2.0 g, 14.1 mmol) in THF (20 mL) at −65° C. The resulting yellow solution was stirred 10 min at −65° C., then it was added over 30 min to a solution of 1-bromo-2-ethylbutane (3.714 g, 22.5 mmol) in THF (10 mL) at 0° C. The solution was stirred 1 h at 0° C. and then overnight without a cooling bath while warming up to room temperature. At 5° C. ice-water (15 mL) was added, followed by 2N HCl (30 mL). The organic phase was diluted with ethyl acetate and washed with sat. aq. NaHCO3 and with aq. NaCl. The aqueous phases were extracted with ethyl acetate. The organic phases were combined, dried over sodium sulfate and concentrated. The crude product (3.3 g) was distilled at 45° C. (0.01 mbar) to give 2.1 g (66%) 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid methyl ester as a colorless oil, purity 92.5% (GC area). The structure of the title compound was confirmed by GC-MS (M=226).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH2:7][C:8]#[N:9])[C:3]=1[C:10]#[N:11].C([O-])([O-])=O.[K+].[K+].Cl[CH2:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[CH2:24][CH2:23]1)=[O:21].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:10]#[N:11])=[C:4]([CH2:7][C:8]#[N:9])[N:5]([CH2:19][C:20]([N:22]2[CH2:23][CH2:24][N:25]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH2:26][CH2:27]2)=[O:21])[N:6]=1
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Reactant: N#CCc1n[nH]c(N)c1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#CCc1c(C#N)c(N)nn1CC(=O)N1CCN(c2ccc(F)cc2)CC1

Procedure:
Protocol T was followed using 5-amino-3-cyanomethyl-1H-pyrazole-4-carbonitrile, K2CO3, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=3/2) afforded the title compound as white solid. 1H NMR (400 MHz, CDCl3): 6.96–7.2 (m, 2H), 6.86–6.92 (m, 2H), 5.2 (s, 2H), 4.86 (s, 2H), 3.78–3.86 (m, 4H), 3.7 (s, 2H), 3.08–3.16 (m, 4H). MS (ES) M+H expected 367.39, found 368.1.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=2[Cl:21])=[CH:6][C:5]=1[NH:22][CH2:23][P:24](=[O:33])([O:29]C(C)C)[O:25]C(C)C)([O-:3])=[O:2]>Cl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:13][C:12]=2[Cl:21])=[CH:6][C:5]=1[NH:22][CH2:23][P:24](=[O:25])([OH:29])[OH:33])([O-:3])=[O:2]
Reactant: CC(C)OP(=O)(CNc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])OC(C)C
Agent: Cl
Product: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1NCP(=O)(O)O

Procedure:
3.0 (5.9 mmoles) of diisopropyl N-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenyl]-aminomethylphosphonate are refluxed for 16 hours in 100 ml of 20% hydrochloric acid. The solution is concentrated in vacuo, affording 2.3 g (92% of theory) of the title compound in the form of yellow crystals with a melting point of 148°-150° C.
Reaction SMILES: C([O:3][C:4](=O)[C:5]([CH3:25])([CH3:24])[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[CH:11][CH:10]=1)=[O:7])C.[OH-].[NH4+:28]>>[F:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[CH2:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]([CH3:25])([CH3:24])[C:4]([NH2:28])=[O:3])=[CH:10][CH:11]=1
Reactant: CCOC(=O)C(C)(C)C(=O)Nc1ccc(OCc2cccc(F)c2)cc1
Reactant: [NH4+]
Agent: [OH-]
Product: CC(C)(C(N)=O)C(=O)Nc1ccc(OCc2cccc(F)c2)cc1

Procedure:
The title compound is prepared in analogy to example 3 from N-[4-(3-fluoro-benzyloxy)-phenyl]-2,2-dimethyl-malonamic acid ethyl ester and ammonium hydroxide. Colorless solid. MS: m/e=331.4 (M++H).
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([C:13]([CH3:40])([CH3:39])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:32]3[CH2:36][CH2:35][CH2:34][C@H:33]3[CH2:37]O)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:43]1(=[O:53])[NH:47][C:46](=[O:48])[C:45]2=[CH:49][CH:50]=[CH:51][CH:52]=[C:44]12.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.[OH-].[Na+]>[F:41][C:2]([F:1])([F:42])[C:3]1[CH:4]=[C:5]([C:13]([CH3:39])([CH3:40])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:32]3[CH2:36][CH2:35][CH2:34][C@H:33]3[CH2:37][N:47]3[C:43](=[O:53])[C:44]4[C:45](=[CH:49][CH:50]=[CH:51][CH:52]=4)[C:46]3=[O:48])=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1cc(F)ccc1-c1cc(N2CCC[C@H]2CO)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1-c1cc(N2CCC[C@H]2CN2C(=O)c3ccccc3C2=O)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 29.2 %

Procedure:
To a solution of 0.20 g (0.33 mmol) (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide and 54 mg (0.37 mmol) phthalimide in 3 ml tetrahydrofuran were added 71 mg (0.37 mmol) diethyl azodicarboxylate (90%) and 97 mg (0.37 mmol) triphenylphosphine at 0° C. After stirring for 90 min. the reaction mixture was allowed to warm to room temperature over night. The mixture was diluted with a 0.1 M aqueous sodium hydroxide solution and extracted with three portions of tert-butyl methyl ether. The combined organic extracts were dried over sodium sulphate and concentrated. Flash column chromatography gave 70 mg (29%) of the title compound as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:14]2[CH2:19][CH2:18][CH:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][CH:15]=2)=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2>CCO>[Cl:1][C:2]1[C:3]([CH:14]2[CH2:15][CH2:16][CH:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:18][CH2:19]2)=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2
Reactant: CCOC(=O)C1CC=C(c2nc3ccc(OC)cc3cc2Cl)CC1
Solvent: CCO
Product: CCOC(=O)C1CCC(c2nc3ccc(OC)cc3cc2Cl)CC1
Temperature: 30 °C
Reaction time: 96 h
Yield: 25.9 %

Procedure:
To ethyl 4-(3-chloro-6-methoxyquinolin-2-yl)cyclohex-3-enecarboxylate (900 mg, 2.60 mmol) in EtOH (40 mL) was added Rh(PPh3)3Cl (90.0 mg 0.0900 mmol). The mixture was stirred at 30° C. for 4 days under H2 (15 psi). The mixture was filtered off and the filtrate was concentrated to give the crude product, which was purified by silica gel column (PE/EtOAc=10/1) to give the desired product (234 mg, yield 26%).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9](O)=[O:10])[CH2:5][CH2:4]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1.C(Cl)Cl>[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][OH:10])[CH2:5][CH2:4]1
Reactant: N[C@H]1CC[C@H](C(=O)O)CC1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: N[C@H]1CC[C@H](CO)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.3 %

Procedure:
To a stirred suspension of trans-4-aminocyclohexanecarboxylic acid hydrochloride (0.5 g, 2.8 mmol) in anhydrous THF (10 mL) at 0° C. under argon was added dropwise lithium aluminum hydride (2 M solution in THF, 5.6 mL, 11 mmol). The mixture was stirred for 1 h at 0° C., then allowed to warm to rt and stir for an additional 1 h. The mixture was then heated in a sealed tube at 85° C. for 12 h. The mixture was cooled to 0° C. and H2O (600 μL) was slowly added, followed by a 1 M aq NaOH (1.2 mL) and H2O (1.8 mL). The mixture was diluted with CH2Cl2 (50 mL) and stirred for 30 min at rt. The mixture was filtered, and the filtrate was concentrated under reduced pressure to afford (trans-4-aminocyclohexyl)methanol (323 mg, 90%) as a white solid that did not require further purification.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([C:24]#[N:25])[C:22](Cl)=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.C(N(CC)CC)C>>[CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([C:24]#[N:25])[C:22]([N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cc2c3c(cccc3c1Cl)C(=O)N(OCc1ccccc1)C2=O
Reactant: C1CCNCC1
Solvent: CCN(CC)CC
Product: N#Cc1cc2c3c(cccc3c1N1CCCCC1)C(=O)N(OCc1ccccc1)C2=O
Yield: 75.1 %

Procedure:
Following the procedure of Example B2, 2-benzyloxy-6-chloro-5-cyano-benzo[de]isoquinoline-1,3-dione (0.20 g, 0.55 mmol, from Example A2), piperidine (0.11 g, 1.1 mmol), and triethyl amine (0.11 g, 1.1 mmol) were reacted at ambient temperature for 5 hours to give 0.17 g of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[O:11][CH3:12].S(Cl)(Cl)=O.CN(C)C=O.[CH:22]([NH:25][CH:26]([CH3:28])[CH3:27])([CH3:24])[CH3:23]>ClCCl.C(OCC)(=O)C>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:25]([CH:26]([CH3:28])[CH3:27])[CH:22]([CH3:24])[CH3:23])=[O:8])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: COc1cc(C(=O)O)ccc1O
Reactant: CC(C)NC(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N(C(C)C)C(C)C)ccc1O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A stirred solution of 4-hydroxy-3-methoxy-benzoic acid (5 g, 29.7 mmol) in 35 mL of dichloromethane is treated with thionyl chloride (20 mL, 377 mmol) and N,N-dimethylformamide (1.0 mL, 12.9 mmol). This solution is refluxed for 45 minutes and concentrated in vacuo. The resulting material is dissolved in 125 mL of dichloromethane and treated with diisopropylamine (20 mL, 143 mmol). After stirring at room temperature for 5 minutes, the reaction is diluted with ethyl acetate and filtered. The filtrate is washed with 1N hydrochloride solution, and brine, dried over magnesium sulfate, and concentrated in vacuo to afford 4-hydroxy-3-methoxy-N,N-bis(1-methylethyl)benzamide as a colorless solid.
Reaction SMILES: CS(N(C(=O)[C@H](CC1C=CC=CC=1)N)N)(=O)=[O:3].[Cl:18][C:19]1[CH:36]=[CH:35][C:22]2[O:23][C:24]3[CH:34]=[CH:33][CH:32]=[CH:31][C:25]=3[CH2:26][N:27]([C:28](Cl)=[O:29])[C:21]=2[CH:20]=1>>[Cl:18][C:19]1[CH:36]=[CH:35][C:22]2[O:23][C:24]3[CH:34]=[CH:33][CH:32]=[CH:31][C:25]=3[CH2:26][N:27]([C:28]([OH:3])=[O:29])[C:21]=2[CH:20]=1
Reactant: CS(=O)(=O)N(N)C(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C(Cl)N1Cc2ccccc2Oc2ccc(Cl)cc21
Product: O=C(O)N1Cc2ccccc2Oc2ccc(Cl)cc21

Procedure:
8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2,[2-[(methylsulfonyl)amino]-1-oxo-3-phenyl]hydrazide (15) was prepared in the manner described above in Example 5 on a 0.51 mmol scale starting with N-(methylsulfonyl)-L-phenylalanine, hydrazide (14), prepared as described above in Example 14, and 8-chlorodibenz[b,f][1,4]-oxazepine-10(11H)-carbonyl chloride (2), prepared as described above in Example 2, to yield 0.11 g (42%) of product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[Cl:11][C:12]1[C:13]([F:20])=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=O.C[O-].[Na+]>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](=[CH:15]/[C:14]2[CH:17]=[CH:18][CH:19]=[C:12]([Cl:11])[C:13]=2[F:20])/[C:9]#[N:10])=[CH:4][CH:3]=1
Reactant: N#CCc1ccc(Br)cc1
Reactant: O=Cc1cccc(Cl)c1F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#C/C(=C\c1cccc(Cl)c1F)c1ccc(Br)cc1
Yield: 100.8 %

Procedure:
In a manner similar to the method described in Example 1b, 4-bromophenylacetonitrile (Aldrich) (4.5 g, 23 mmol) was reacted with 3-chloro-2-fluorobenzaldehyde (5.2 g, 33 mmol), methanolic solution (25 wt %) of sodium methoxide (15 mL, 66 mmol) in methanol (150 mL) at 50° C. for 3 h to give (Z)-2-(4-bromo-phenyl)-3-(3-chloro-2-fluoro-phenyl)-acrylonitrile as a white powder (7.8 g, 100%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].C([O:16][CH2:17][CH2:18][CH2:19][CH2:20]Br)(=O)C.Cl>O>[OH:16][CH2:17][CH2:18][CH2:19][CH2:20][O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1
Reactant: CC(=O)OCCCCBr
Reactant: O=C(O)c1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1ccc(OCCCCO)cc1
Temperature: 10 °C
Reaction time: 1 h

Procedure:
In a 22 liter stirred reactor, 1.16 kilograms of p-hydroxy-benzoic acid (M.W. 138) in 4 liters of water are neutralized by the addition of 0.5 liter of 40% aqueous sodium hydroxide. The temperature is adjusted to 50° C. and over a period of one hour, 1200 milliliters of 4-bromobutyl acetate are slowly added. The temperature is then raised to 90° C.+10° C. and the hot reaction mixture kept at pH 10 by continuous titration with a 40% sodium hydroxide solution. When no change in pH is noted for a period of 45 minutes the reaction is considered complete, an additional liter of water is then added, and sufficient 40% sodium hydroxide solution to raise the pH to 11. While still hot, concentrated hydrochloric acid is added in large enough quantities to lower the pH to 1.2. The mixture is allowed to cool overnight while stirring and the precipitate collected on a filter. The precipitate is then thoroughly washed with water to remove excess acid until the wash has attained a pH of at least 5. The precipitate is then dried and dissolved in hot methanol (15% solution), and the solution filtered to remove any insolubles (usually about 6-7%). While the clear methanol solution is still hot, hot water is added to adjust the solvent ratio to 10:1 methanol/water, and set aside to let the product crystallize out overnight yielding p-(4-hydroxy-n-butoxy)benzoic acid having a melting point of 146°-148° C.