Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:11]=[N:12][C:13]([N:16]3[CH2:21][CH2:20][O:19][C@H:18]([CH2:22][N:23]4[C:27]5=[N:28][C:29]([C:32]6[CH:33]=[N:34][N:35]([CH3:37])[CH:36]=6)=[CH:30][N:31]=[C:26]5[N:25]=[N:24]4)[CH2:17]3)=[N:14][CH:15]=2)[CH:7]=[CH:6][C:3]=1[CH:4]=O.CC(O)=O.[CH3:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1.C([O-])([O-])=O.[K+].[K+]>ClCCl>[F:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:11]=[N:12][C:13]([N:16]3[CH2:21][CH2:20][O:19][C@H:18]([CH2:22][N:23]4[C:27]5=[N:28][C:29]([C:32]6[CH:33]=[N:34][N:35]([CH3:37])[CH:36]=6)=[CH:30][N:31]=[C:26]5[N:25]=[N:24]4)[CH2:17]3)=[N:14][CH:15]=2)[CH:7]=[CH:6][C:3]=1[CH2:4][N:46]1[CH2:47][CH2:48][N:43]([CH3:42])[CH2:44][CH2:45]1
Reactant: CN1CCNCC1
Reactant: Cn1cc(-c2cnc3nnn(C[C@@H]4CN(c5ncc(-c6ccc(C=O)c(F)c6)cn5)CCO4)c3n2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN1CCN(Cc2ccc(-c3cnc(N4CCO[C@H](Cn5nnc6ncc(-c7cnn(C)c7)nc65)C4)nc3)cc2F)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.8 %

Procedure:
(S)-2-fluoro-4-(2-(2-((6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)-methyl)morpholino)pyrimidin-5-yl)benzaldehyde (41 mg, 0.09 mmol) was dissolved in dichloromethane (3 mL), and then AcOH (0.006 mL, 0.10 mmol) and 1-methylpiperazine (0.02 mL, 0.17 mmol) were added. The mixture was stirred at room temperature for 30 minutes, and then NaBH(OAC)3 (28 mg, 0.13 mmol) was added, followed by stirring at room temperature for 13 hours. When the reaction was completed, the reaction mixture was adjusted to pH 8 with 5% K2CO3, followed by extraction with dichloromethane and water two times or more. The organic layer was extracted with ethyl acetate and water, and the extra water was removed by sodium sulfate, followed by concentration under reduced pressure. PLC using 10% dichloromethane/methanol gave (S)-4-(5-(3-fluoro-4-((4-methylpiperazin-1-yl)methyl)phenyl)pyrimidin-2-yl)-2-((6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholine (20 mg, 0.034 mmol) with a yield of 46%.
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.I[C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([OH:22])=[O:21].C(O)CO.Cl>[Cu]I.C(OCC)C.O.CC(O)C>[CH2:9]([NH:16][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([OH:22])=[O:21])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(O)c1ccccc1I
Reactant: NCc1ccccc1
Agent: [Cu]I
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Solvent: CCOCC
Solvent: O
Solvent: CC(C)O
Product: O=C(O)c1ccccc1NCc1ccccc1
Yield: 70.8 %

Procedure:
The general procedure under argon was followed using copper(I) iodide (10 mg, 0.05 mmol), K3PO4 (636 mg, 3.00 mmol), benzylamine (131 μL, 1.20 mmol), 2-iodobenzoic acid (248 mg, 1.00 mmol), ethylene glycol (111 μL, 2.00 mmol) and 2-propanol (1.0 mL). After heated for a specified duration, the reaction was allowed to reach room temperature. Water and diluted HCl (10%) was added until ˜pH 3. Diethyl ether (2 mL) was added and the organic layer was analyzed by tlc. The reaction mixture was further extracted by diethyl ether (4×10 mL) and the combined organic phase was washed with brine and dried over Na2SO4. The solvent was rotary evaporated and the yellowish-brown residue was purified by column chromatography using a solvent mixture (diethyl ether/ethyl acetate=1/1, Rƒ=0.3) to afford 2-(N-benzyl)aminobenzoic acid (161 mg, 71% isolated yield) as light yellow solid. For aryl bromide substrate: copper(I) iodide (19 mg, 0.10 mmol), K3PO4 (636 mg, 3.00 mmol), benzylamine (131 μl, 1.20 mmol), 2-bromobenzoic acid (201 mg, 1.00 mmol), ethylene glycol (111 μl, 2.00 mmol) and 1-butanol (1.0 mL) was used and heated to 100° C. The above workup procedures was followed and obtained 2-(N-benzyl)aminobenzoic acid (120 mg, 53% isolated yield) as light yellow solid. For aryl chloride substrate: copper(I) iodide (19 mg, 0.10 mmol), K3PO4 (636 mg, 3.00 mmol), benzylamine (131 μl, 1.20 mmol), 2-chlorobenzoic acid (157 mg, 1.00 mmol), ethylene glycol (111 μl, 2.00 mmol) and 1-butanol (1.0 mL) was used and heated to 100° C. The above workup procedures was followed and obtained 2-(N-benzyl)aminobenzoic acid (109 mg, 48% isolated yield) as light yellow solid. The spectral data (1H NMR) matched with the literature references and indicated >95% purity. See Chang, M. R.; Takeuchi, Y.; Hashigaki, K.; Yamato, M. Heterocycles 1992, 33, 147-152. Moore, J. A.; Sutherland, G. J.; Sowerby, R.; Kelly, E. G.; Palermo, S.; Webster, W. J. Org. Chem. 1969, 34, 887-892.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]([F:13])([F:12])[F:11])=[CH:5][CH:4]=1.[OH-].[K+].[C:16]1([C:22](=[N:29][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[C:16]1([C:22](=[N:29][C@@H:30]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([O:9][C:10]([F:13])([F:12])[F:11])=[CH:5][CH:4]=2)[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(OC(F)(F)F)cc1)N=C(c1ccccc1)c1ccccc1
Yield: 87.8 %

Procedure:
1-(Bromomethyl)-4-(trifluoromethoxy)benzene (28.1 g, 0.110 mol) and 50% potassium hydroxide (225 mL, 2.00 mol) were added to a toluene (1 L) suspension of tert-butyl [(diphenylmethylene)amino]acetate (29.5 g, 0.10 mol) and N-(9-anthracenylmethyl)cinchonidinium chloride (5.79 g, 0.01 mol) under ice-cooling with stirring. The mixture was vigorously stirred at the same temperature for 3.25 hours and then separated into an organic layer and an aqueous layer. The aqueous layer was extracted with ethyl acetate (200 mL), and the organic layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate, 20:1, 15:1, and 10:1, V/V) to give 41.2 g of the title compound (mixture of a yellow oil and a yellow solid, yield: 88%, optical purity: 88%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:25])=[CH:4][C:5]([N+:22]([O-])=O)=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:7]=1.O.NN>C(O)C.[Ni]>[NH2:22][C:5]1[CH:4]=[C:3]([F:25])[C:2]([Cl:1])=[CH:7][C:6]=1[NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(Cl)c(F)cc2[N+](=O)[O-])CC1
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(Cl)c(F)cc2N)CC1
Temperature: 40 °C

Procedure:
1,1-Dimethylethyl 4-[(5-chloro-4-fluoro-2-nitrophenyl)amino]-piperidinecarboxylate (D2) (0.91 mmol, 340 mg) was dissolved in ethanol (20 ml) and an aqueous suspension of Raney-Nickel (1 ml) was added at room temperature; the mixture was heated to 40° C. and hydrazine monohydrate (15 eq., 13.7 mmol, 0.424 ml) was added over 20 min at 40° C. The reaction mixture was then cooled to room temperature, filtered through celite and the solvent was evaporated to yield the title compound, which was purified by chromatography, complete conversion, 312 mg, M+−H=342.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[C:27]1([S:33](Cl)(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][S:33]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)(=[O:35])=[O:34])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=S(=O)(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1)c1ccccc1

Procedure:
The title compound, white solid (96 mg, 82%), MS (ISP) m/z=469.4 [(M+H)+], mp 130° C., was prepared in accordance with the general method of example 47 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydro chloride (intermediate B) (100 mg, 0.25 mmol) and benzenesulfonyl chloride.
Reaction SMILES: CC1(C)[O:6][C:5](=[CH:7][C:8]([N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[O:11][CH3:12])=[O:9])[C:4](=[O:21])O1.[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1.[H-].[Na+]>C1COCC1>[F:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][N:10]([O:11][CH3:12])[C:8](=[O:9])[CH:7]=[C:5]([OH:6])[C:4](=[O:21])[NH:32][S:29]([C:26]2[CH:27]=[CH:28][C:23]([CH3:33])=[CH:24][CH:25]=2)(=[O:30])=[O:31])=[CH:19][CH:18]=1
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Reactant: CON(Cc1ccc(F)cc1)C(=O)C=C1OC(C)(C)OC1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CON(Cc1ccc(F)cc1)C(=O)C=C(O)C(=O)NS(=O)(=O)c1ccc(C)cc1
Reaction time: 8 h
Yield: 18.9 %

Procedure:
2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-benzyl)-N-methoxy-acetamide (309 mg, 1 mmol) and toluene-4-sulfonamide (171 mg, 1 mmol) were dissolved in 2 mL of THF. To this was added 40 mg of NaH (60% dispersion in mineral oil) and the resulting mixture stirred overnight. The reaction was quenched with 1N HCl and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and solvent removed to yield an oily solid. The product was triturated with MeOH to yield 80 mg solid (19% yield). HRMS (M−H) calcd for C19H18FN2O6S: 412.0870. Found: 421.0876. Anal calcd for C19H19FN2O6S: C, 54.02; H, 4.53; N, 6.63. Found: C, 54.07; H, 4.51; N, 6.51. 1H NMR (500 MHz, CDCl3) δ: 2.44 (s, 3), 3.64 (s, 3), 4.76 (s, 2), 6.45 (s, 1), 7.03 (m, 2), 7.25 (m, 2), 7.35 (d, 2, J=8), 8.00 (d, 2, J=8), 9.11 (s, 1). 13C NMR (125 MHz, CDCl3) δ: 21.68, 48.21, 63.07, 92.21, 115.67, 115.84, 128.70, 129.64, 130.18, 131.01, 135.14, 145.55, 158.85, 159.30, 161.60, 163.56, 170.87.
Reaction SMILES: [Br:1][C:2]1[C:18]([F:19])=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:13]=[CH:12][S:11][C:10]=2[C:14]([NH2:16])=[O:15])=O)=[C:4]([F:20])[CH:3]=1.[OH-].[Na+]>CO>[Br:1][C:2]1[C:18]([F:19])=[CH:17][C:5]([C:6]2[NH:8][C:9]3[CH:13]=[CH:12][S:11][C:10]=3[C:14](=[O:15])[N:16]=2)=[C:4]([F:20])[CH:3]=1
Reactant: NC(=O)c1sccc1NC(=O)c1cc(F)c(Br)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=c1nc(-c2cc(F)c(Br)cc2F)[nH]c2ccsc12

Procedure:
A mixture of 3-[(4-bromo-2,5-difluorobenzoyl)amino]thiophene-2-carboxamide; 1M NaOH aq and MeOH was stirred for two hours at 80° C. to give 2-(4-bromo-2,5-difluorophenyl)thieno[3,2-d]pyrimidine-4(1H)-one.
Reaction SMILES: [Cl:1][CH:2]([CH3:10])[C:3]([NH:5][CH2:6][C:7]([OH:9])=O)=[O:4].Cl.[NH2:12][C:13]1[C:18]([OH:19])=[C:17]([Cl:20])[C:16]([CH3:21])=[C:15]([Cl:22])[CH:14]=1.N1C=CC=CC=1.S(Cl)(Cl)=O>O.C(#N)C>[Cl:1][CH:2]([CH3:10])[C:3]([NH:5][CH2:6][C:7]([NH:12][C:13]1[C:18]([OH:19])=[C:17]([Cl:20])[C:16]([CH3:21])=[C:15]([Cl:22])[CH:14]=1)=[O:9])=[O:4]
Reactant: Cc1c(Cl)cc(N)c(O)c1Cl
Reactant: CC(Cl)C(=O)NCC(=O)O
Agent: Cl
Solvent: CC#N
Solvent: O
Solvent: O=S(Cl)Cl
Product: Cc1c(Cl)cc(NC(=O)CNC(=O)C(C)Cl)c(O)c1Cl
Yield: 92.2 %

Procedure:
To a mixture composed of 158 g (0.96 mol) of N-(β-chloropropanoyl)glycine thus obtained and 92 g (0.4 mol) of 6-amino-2,4-dichloro-3-methylphenol hydrochloride were added 228 ml (2.88 mol) of pyridine and 2 liters of acetonitrile and stirred under cooling. To the solution was added dropwise 95.2 g (0.8 mol) of thionyl chloride. After the completion of the reaction, water was added to the reaction solution and the crystals thus deposited were collected by filtration and recrystallized from acetonitrile to obtain 125.2 g of 6-[α-(β-chloropropanamido)acetamido]-2,4-dichloro-3-methylphenol.
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[C:14]([CH2:15]O)=[CH:13][CH:12]=[CH:11][N:10]=1)[CH2:2]2.O=S(Cl)[Cl:19]>ClCCl>[Cl:19][CH2:15][C:14]1[C:9]([N:3]2[CH2:4][CH:5]3[O:8][CH:1]([CH2:7][CH2:6]3)[CH2:2]2)=[N:10][CH:11]=[CH:12][CH:13]=1
Reactant: OCc1cccnc1N1CC2CCC(C1)O2
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: ClCc1cccnc1N1CC2CCC(C1)O2
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
To a cooled (0° C.) solution of (2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)methanol (0.070 g, 0.32 mmol) in dichloromethane was added SOCl2 (0.23 mL, 3.2 mmol) and the reaction mixture was allowed to warm to ambient temperature. After 1 h, the reaction mixture was concentrated and azeotroped with toluene three times to provide 3-(3-(chloromethyl)pyridin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane (0.075 g, 98%) as a clear oil. MS (ES) for C12H15ClN2O: 239 (MH+).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:29][C:30]1[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][C:31]=1[CH:32]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:32][C:31]3[CH:34]=[CH:35][CH:36]=[C:37]([Cl:38])[C:30]=3[Cl:29])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cccc(Cl)c1Cl
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: FC(F)(F)c1cccc2c(-c3cccc(NCc4cccc(Cl)c4Cl)c3)c(Cc3ccccc3)cnc12

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 2,3-dichlorobenzaldehyde according to the procedure of step 1, Example 66. MS (ESI) m/z 537.
Reaction SMILES: [C:1]([C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[CH2:11][CH:10]([C:12]([OH:14])=[O:13])[CH2:9]2)=[CH:5][CH:4]=1)#[N:2].[C:17](O)([CH3:20])([CH3:19])[CH3:18].CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.ClC(Cl)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH2:9][CH:10]([C:12]([O:14][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:13])[CH2:11]2)=[CH:15][CH:16]=1)#[N:2]
Reactant: CC(C)(C)O
Reactant: N#Cc1ccc(CN2CC(C(=O)O)C2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)C1CN(Cc2ccc(C#N)cc2)C1
Yield: 86 %

Procedure:
To a mixture of 1-(4-cyanobenzyl)azetidine-3-carboxylic acid (3.25 g, 15.0 mmol), DMAP (1.84 g, 15.0 mmol), and tert-butanol (14.1 mL, 150 mmol) in dichloroethane (150 mL) was added EDCI (4.32 g, 22.5 mmol), and the reaction mixture was allowed to stir over the weekend. The volatiles were removed under reduced pressure, and the residue was partitioned between ethyl acetate (250 mL) and a saturated aqueous solution of sodium bicarbonate (250 mL). The organic layer was washed with water (250 mL), washed with brine (100 mL), and dried over anhydrous magnesium sulfate. Concentration under reduced pressure afforded a light yellow oil which was chromatographed on a 5×15 cm silica gel column, eluting with a 0-40% ethyl acetate/hexane gradient to give tert-butyl 1-(4-cyanobenzyl)azetidine-3-carboxylate (3.5 g, 12.9 mmol, 86% yield) as a colorless liquid. HPLC retention time=1.38 minutes−Column: YMC-Combi 4.6×50 mm S-5 ODS column) eluting with 10-90% aqueous methanol+0.2% phosphoric acid over a 4 minute gradient. MS:(M+H)=273.18. 1H NMR (400 MHz, CDCl3) δ ppm 1.46 (s, 9H), 3.26 (m, 3H), 3.52 (m, 2H), 3.66 (s, 2H), 7.39 (d, J=8.3 Hz, 2H), and 7.60 (d, J=8.3 Hz, 2H).
Reaction SMILES: [OH:1][CH2:2][CH:3]=[C:4]([CH3:32])[CH2:5][CH:6]([OH:31])[CH:7]=[C:8]([CH3:30])[CH2:9][CH:10]([C:21]1[C:26]([CH3:28])([CH3:27])[CH2:25][CH2:24][CH2:23][C:22]=1[CH3:29])[S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12].C(=O)([O-])[O-].[Na+].[Na+].[C:39](OC(=O)C)(=[O:41])[CH3:40].O>CCCCCC.[Cl-].C([N+](C)(C)C)CCCCCCCCCCC>[C:39]([O:1][CH2:2][CH:3]=[C:4]([CH3:32])[CH2:5][CH:6]([OH:31])[CH:7]=[C:8]([CH3:30])[CH2:9][CH:10]([C:21]1[C:26]([CH3:27])([CH3:28])[CH2:25][CH2:24][CH2:23][C:22]=1[CH3:29])[S:11]([C:14]1[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=1)(=[O:12])=[O:13])(=[O:41])[CH3:40]
Reactant: CC(=CCO)CC(O)C=C(C)CC(C1=C(C)CCCC1(C)C)S(=O)(=O)c1ccc(C)cc1
Reactant: CC(=O)OC(C)=O
Agent: CCCCCCCCCCCC[N+](C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCCCCC
Solvent: O
Product: CC(=O)OCC=C(C)CC(O)C=C(C)CC(C1=C(C)CCCC1(C)C)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Yield: 92 %

Procedure:
In a dry flask, 60 mg (0.13 mmol) of 1,5-dihydroxy-3,7-dimethyl-9-(2,6,6-trimehylcyclohexene-1-yl)-9-(4-methylphenysulfonyl)-nona-2,6-diene (hereinafter, referred to as compound [IV-1]) was charged and dissolved in 20 ml of n-hexane, and 3.4 mg (0.013 mmol) of n-dodecyltrimethylammonium chloride, 14 mg (0.13 mmol) of sodium carbonate and 13.3 mg (0.13 mmol) of acetic anhydride were added thereto. After stirring at room temperature for twenty hours, disappearance of the starting material was confirmed, and then water was added to the reaction mass. After extracting with ether, the organic layer was washed with an aqueous solution of ammonium chloride and a saturated aqueous solution of sodium chloride in order. After drying over anhydrous magnesium sulfate, the organic layer was concentrated to give a crude product. The crude product was purified by silica gel chromatography to give l-acetoxy-5-hydroxy-3,7-dimethyl-9-(2,6,6-trimethylcyclohexene-1-yl)-9-(4-methylphenylsulfonyl)-nona-2,6-diene (hereinafter, referred to as compound [III-1]) in a yield of 92%.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([F:10])[C:3]=1[CH2:11][CH:12]([NH:14][C:15]1[CH:20]=[CH:19][NH:18][C:17](=[O:21])[C:16]=1[C:22]1[NH:36][C:25]2=[CH:26][C:27]3[C:28](=[O:35])[N:29]([CH3:34])[C:30](=O)[C:31]=3[CH:32]=[C:24]2[N:23]=1)[CH3:13]>C(O)(=O)C.[Zn]>[CH3:34][N:29]1[CH2:30][C:31]2[CH:32]=[C:24]3[NH:23][C:22]([C:16]4[C:17](=[O:21])[NH:18][CH:19]=[CH:20][C:15]=4[NH:14][CH:12]([CH3:13])[CH2:11][C:3]4[C:4]([F:10])=[C:5]([F:9])[CH:6]=[C:7]([F:8])[C:2]=4[F:1])=[N:36][C:25]3=[CH:26][C:27]=2[C:28]1=[O:35]
Reactant: CC(Cc1c(F)c(F)cc(F)c1F)Nc1cc[nH]c(=O)c1-c1nc2cc3c(cc2[nH]1)C(=O)N(C)C3=O
Agent: [Zn]
Solvent: CC(=O)O
Product: CC(Cc1c(F)c(F)cc(F)c1F)Nc1cc[nH]c(=O)c1-c1nc2cc3c(cc2[nH]1)CN(C)C3=O
Yield: 62.6 %

Procedure:
2-(4-(1-(2,3,5,6-Tetrafluorophenyl)propan-2-ylamino)-2-oxo-1,2-dihydropyridin-3-yl)-6-methylimidazo[4,5-f]isoindole-5,7(1H,6H)-dione (0.51 g, 1.02 mmol) and zinc powder (1.60 g, 24.51 mmol) were suspended in acetic acid (30 mL). The reaction mixture was stirred and heated to reflux overnight under argon. Then, the solvent was removed under reduced pressure. The residue solid was stirred in 100 mL of saturated K2CO3 solution. The white solid was filtered out, dried under vacuum and extracted with CH2Cl2/MeOH (7/3 v/v) three times (300 mL). The extracts were concentrated to dryness. The residue was purified by column chromatography (silica-gel, CH2Cl2/MeOH=9/1 v/v) to give a pale-yellow solid product, 0.31 g, 62.6% yield. MS: 508.0 [M+Na]+. 1H NMR (DMSO-d6, 500 MHz): δ 13.03 (s, 1H), 11.24 (s, 1H), 11.14-11.11 (m, 1H), 7.95 (s, 0.5H), 7.78-7.74 (m, 2H), 7.61 (s, 0.5H), 7.35 (s, 1H), 6.15 (s, 1H), 4.48 (s, 2H), 4.22 (m, 1H), 3.17-3.10 (m, 2H), 3.09 (s, 3H), 1.37 (m, 3H).
Reaction SMILES: C([C:3]1[N:4]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:5]2[C:10]([C:11](=[O:16])[C:12]=1[C:13]([OH:15])=[O:14])=[N:9][CH:8]=[C:7]([Br:17])[CH:6]=2)C.O.[OH-].[Li+]>CO.O>[Br:17][C:7]1[CH:6]=[C:5]2[C:10]([C:11](=[O:16])[C:12]([C:13]([OH:15])=[O:14])=[CH:3][N:4]2[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[N:9][CH:8]=1
Reactant: CCc1c(C(=O)O)c(=O)c2ncc(Br)cc2n1Cc1ccccc1Oc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cn(Cc2ccccc2Oc2ccccc2)c2cc(Br)cnc2c1=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 17.7 %

Procedure:
To a light brown solution of ethyl 7-bromo-4-oxo-1-(2-phenoxybenzyl)-1,4-dihydro-1,5-naphthyridine-3-carboxylate (22) (230 mg, 0.5 mmol) in methanol (20 mL) was added the solid lithium hydroxide monohydrate (438 mg, 10.4 mmol) at room temperature. The resulting light brown solution was stirred for 15 h at room temperature at which time LCMS analysis indicated the absence of starting material. Then, it was diluted with water and the methanol was removed under vacuum. The resulting brown paste was difficult to dissolve in 1.0N NaOH and water. Then, the neutral impurities were extracted into ethyl acetate and the basic aqueous layer was diluted with water (˜100 mL). Then, the basic aqueous solution was neutralized with 1.0N HCl. The resulting solids were collected by filtration and washed with water and hexanes. After air drying, 40 mg of 7-bromo-4-oxo-1-(2-phenoxybenzyl)-1,4-dihydro-1,5-naphthyridine-3-carboxylic acid (23) (17% yield) was isolated as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:20][N:7]2[C:8]3[CH:9]=[C:10]([C:15]([O:17]CC)=[O:16])[CH:11]=[CH:12][C:13]=3[CH:14]=[C:6]2[C:5](=[O:21])[NH:4][CH2:3]1.[OH-].[Na+].C(O)(=O)C.O>C(O)C>[CH3:1][C:2]1([CH3:22])[CH2:20][N:7]2[C:8]3[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[CH:11]=[CH:12][C:13]=3[CH:14]=[C:6]2[C:5](=[O:21])[NH:4][CH2:3]1
Reactant: CCOC(=O)c1ccc2cc3n(c2c1)CC(C)(C)CNC3=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: CC1(C)CNC(=O)c2cc3ccc(C(=O)O)cc3n2C1
Temperature: 80 °C
Yield: 45 %

Procedure:
Ethyl 4,4-dimethyl-1-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indole-8-carboxylate (7.6 g, 25.3 mmol) is dissolved in ethanol (250 mL) and 1M NaOH solution (88.6 mL, 88.6 mmol) is added. The reaction mixture is heated at 80° C. for 2 h. Acetic acid (40 mL) and water (350 mL) are added and the resulting solid is filtered and rinsed with water to afford the title compound (3.1 g, 45%) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:29])[C:7](=[O:28])[C:8]3[CH:18]=[C:17]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][N:24]=[C:23](N)[CH:22]=4)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.N([O-])=[O:31].[Na+]>S(=O)(=O)(O)O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:29])[C:7](=[O:28])[C:8]3[CH:18]=[C:17]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][N:24]=[C:23]([OH:31])[CH:22]=4)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1
Reactant: O=N[O-]
Reactant: CCN1c2ncc(CCc3ccnc(N)c3)cc2C(=O)N(C)c2ccc(Cl)nc21
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CCN1c2ncc(CCc3ccnc(O)c3)cc2C(=O)N(C)c2ccc(Cl)nc21
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 36.6 %

Procedure:
The product of Example 71 (14 mg, 0.03 mmol) was dissolved in conc. sulfuric acid (0.06 mL) and water (0.5 mL), and the resultant solution was cooled to 0° C. Sodium nitrite (2.9 mg, 0.04 mmol) was added, and the reaction mixture was warmed to room temperature. After 40 min, the product was extracted with ethyl acetate and recrystallized (ethyl acetate-hexanes) afforded the title compound (4.5 mg, 32%) as beige crystals, m.p. 243°-244° C.