Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([C:14](=[O:20])/[CH:15]=[CH:16]/N(C)C)=[C:8]([N+:21]([O-])=O)[CH:7]=1>C(O)(=O)C.[Fe]>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:9]([C:14](=[O:20])[CH:15]=[CH:16][NH:21]2)=[CH:10][C:11]=1[O:12][CH3:13]
Reactant: COc1cc(C(=O)/C=C/N(C)C)c([N+](=O)[O-])cc1OCCCCl
Agent: [Fe]
Solvent: CC(=O)O
Product: COc1cc2c(=O)cc[nH]c2cc1OCCCCl
Temperature: 40 °C
Reaction time: 2 h
Yield: 67.4 %

Procedure:
0.44 moL of (E)-1-(4-(3-Chloropropoxy)-5-methoxy-2-nitrophenyl)-3-(dimethylamino)prop-2-en-1-one (intermediate IV) (150 g) was dissolved in 1200 mL of glacial acetic acid (8 v/w), and the mixture was heated to 40° C. After intermediate IV was completely dissolve, 2.20 mol (123.1 g) Iron powder was added slowly, then the reaction mixture was heated to 80° C. with mechanical stirring for 2 h. After completion of the reaction, the reaction mixture was filtered immediately to remove iron powder. The filtrate was collected and cooled to precipitate solid, and then filtered to give yellow solid, which was dissolved in glacial acetic acid and the solution was stirred at 80° C. for 30 min then filtered immediately again. The filtrate was cooled to precipitate solid, filtered, and the filter cake was washed with water until the aqueous layer became neutral, dried to give solid 79 g. Yield: 65%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:21]3[C:20](=O)[CH2:19][CH2:18][CH2:17][C:16]=3[NH:15][C:14]3[CH2:13][CH2:12][CH2:11][C:10](=[O:23])[C:9]2=3)=[CH:4][CH:3]=1.C(O)C.[BH4-].[Na+]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:9]3[C:10](=[O:23])[CH2:11][CH2:12][CH2:13][C:14]=3[NH:15][C:16]3[CH2:17][CH2:18][CH2:19][CH2:20][C:21]2=3)=[CH:4][CH:3]=1
Reactant: O=C1CCCC2=C1C(c1ccc(Cl)cc1)C1=C(CCCC1=O)N2
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCO
Product: O=C1CCCC2=C1C(c1ccc(Cl)cc1)C1=C(CCCC1)N2
Yield: 17.4 %

Procedure:
To a stirred 70° C. mixture of 9-(4-chlorophenyl)-3,4,6,7,9,10-hexahydro-1,8(2H,5H)-acridinedione (6.0 g), ethanol (160 mL) and pyridine (50 mL) was added sodium borohydride (7.5 g, 198.4 mmole) in two portions over six hours. The solvent was removed; the resulting yellow solid washed well with water and dried in vacuo. Chromatography (methylene chloride/ethyl acetate; 85/15) and recrystallization from ethanol provided the title compound (1.0 g) as a white solid, mp 253°-254° C.; NMR: 1.41-1.51 (m,3, CH2), 1.60-1.88 (m,5, CH2), 2.07-2.14 (m,4, CH2), 2.38-2.41 (m,2, CH2), 4.16 (s,1, CH), 7.16 (d,2, J=8.4, Ar), 7.25 (d,2, J=8.4, Ar), 8.39 (s,1, NH); (CI, CH4) MS: m/z=314(M+1). Analysis for C19H20ClNO: Calculated C, 72.72; H, 6.37; N, 4.46; Found: C, 72.35; H, 6.60; N, 4.29.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].F[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15].C[O:18][C:19]([CH2:21][CH:22]1[NH:27][CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23]1)=[O:20].CS(C)=O>O.Cl>[C:31]([O:30][C:28]([N:24]1[CH2:25][CH2:26][N:27]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])[CH:22]([CH2:21][C:19]([OH:20])=[O:18])[CH2:23]1)=[O:29])([CH3:34])([CH3:32])[CH3:33]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: COC(=O)CC1CN(C(=O)OC(C)(C)C)CCN1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccccc2[N+](=O)[O-])C(CC(=O)O)C1
Temperature: 100 °C
Reaction time: 22 h

Procedure:
Solid K2CO3 (1070 mg, 7.74 mmol) was added to a mixture of 1-fluoro-2-nitrobenzene (655 mg, 4.65 mmol) and the product of Example 22B (1000 mg, 3.87 mmol). Dimethyl sulfoxide (40 mL) was added, and the mixture was heated at 100° C. with stirring under nitrogen. After 22 hours, additional 1-fluoro-2-nitrobenzene (350 mg) was added and heating was continued for 14 hours longer. The mixture was cooled to 40° C., diluted with water (400 mL), and aqueous 10% HCl (25 mL) was added to bring the pH˜3-4. The mixture was extracted with CHCl3 (4×200 mL). The combined extract was concentrated under vacuum to a residue that was purified by chromatography (SiO2, eluted with hexanes-ethyl acetate, 100:0-50:50-0:100) to provide the title compound: 1H NMR (300 MHz, CDCl3) δ ppm 1.48 (s, 9H), 2.34-2.55 (m, 1H), 2.73-2.90 (m, 1H), 3.20-3.42 (m, 2H), 3.55-3.82 (m, 4H), 3.93-4.12 (m, 1H), 7.13-7.23 (m, 2H), 7.45-7.55 (m, 1H), 7.74 (dd, J=7.9, 1.6 Hz, 1H).
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([CH:32]=[O:33])[CH:19]=[N:20][C:21]=3[NH:22][C:23]3[CH:24]=[N:25][C:26]([O:30][CH3:31])=[C:27]([F:29])[CH:28]=3)[N:10]=2)=CC=1.[CH3:45][S:46]([N:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1)(=[O:48])=[O:47]>>[F:29][C:27]1[CH:28]=[C:23]([NH:22][C:21]2[C:16]([C:11]3[N:12]=[C:13]([CH3:15])[N:14]=[C:9]([NH2:8])[N:10]=3)=[CH:17][C:18]([C:32]([N:52]3[CH2:53][CH2:54][N:49]([S:46]([CH3:45])(=[O:48])=[O:47])[CH2:50][CH2:51]3)=[O:33])=[CH:19][N:20]=2)[CH:24]=[N:25][C:26]=1[O:30][CH3:31]
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C=O)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Product: COc1ncc(Nc2ncc(C(=O)N3CCN(S(C)(=O)=O)CC3)cc2-c2nc(C)nc(N)n2)cc1F

Procedure:
The title compound was prepared in an analogous manner to that described in Example 151 using 5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-((5-fluoro-6-methoxy-3-pyridinyl)amino)-3-pyridinecarbaldehyde and 1-methanesulfonylpiperazine (Oakwood Products, West Columbia, S.C.), and the desired product 4-(2-((5-fluoro-6-methoxy-3-pyridinyl)amino)-5-((4-(methylsulfonyl)-1-piperazinyl)carbonyl)-3-pyridinyl)-6-methyl-1,3,5-triazin-2-amine was isolated as a yellow solid (52% for two steps). 1H NMR (400 MHz, d6-DMSO) δ 12.11 (s, 1H) 8.85-8.93 (m, 1H) 8.45 (dd, J=2.15, 0.39 Hz, 1H) 8.42 (d, J=2.35 Hz, 1H) 8.30-8.39 (m, 1H) 7.95 (br. s., 1H) 7.83 (br. s., 1H) 3.95 (s, 3H) 3.61-3.73 (m, 4H) 3.19 (t, 4H) 2.91 (s, 3H) 2.45 (s, 3H). m/z (ESI, +ve ion) 518.0 (M+H)+.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([OH:8])[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.Cl[CH2:17][CH2:18]Cl>CCCC[N+](CCCC)(CCCC)CCCC.[Br-].[OH-].[Na+]>[O:8]1[CH:7]2[CH:2]([CH2:3][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:6]2)[O:1][CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)C(O)C1
Reactant: ClCCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCC2OCCOC2C1
Temperature: 55 °C
Yield: 75 %

Procedure:
A mixture of tert-butyl 3,4-dihydroxypiperidine-1-carboxylate (300 mg, 1.38 mmol, 1 eq), 1,2-dichloroethane (6 mL) and TBAB (90 mg, 0.28 mmol, 0.2 eq) in 35% NaOH (10 mL) aqueous solution was heated at 55° C. for 72 h, then cooled to room temperature and extracted with CH2Cl2 (100 mL). The organic phase was washed with water (30 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (20:1 (v/v) CH2Cl2/MeOH) to afford the title compound as pale yellow oil (250 mg, 75.00%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 244.2 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:33]=[C:32]([N:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[CH:31]=[CH:30][C:16]=2[C:17]([NH:19][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][C:25]=2[C:26]([O:28]C)=[O:27])=[O:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO.C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:33]=[C:32]([N:34]3[CH2:35][CH2:36][CH2:37][CH2:38]3)[CH:31]=[CH:30][C:16]=2[C:17]([NH:19][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][C:25]=2[C:26]([OH:28])=[O:27])=[O:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccncc1NC(=O)c1ccc(N2CCCC2)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(N3CCCC3)ccc2C(=O)Nc2cnccc2C(=O)O)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of methyl 3-[2-(1-tert-butoxycarbonyl-piperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]pyridine-4-carboxylate (2.78 g, 5.3 mmol) in MeOH (100 mL) and THF (50 mL) was treated with 1 N NaOH (11 mL) and stirred at ambient temperature for 4 h. The reaction was quenched with glacial acetic acid (1 g) and concentrated to dryness. The residue was mixed with brine (50 mL) and extracted with 10% MeOH in CHCl3 (3×). The extracts were dried over MgSO4 and concentrated to 2.2 g (4.3 mmol, 81%) of a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:21])[C:9]=1[O:10][C:11]1[CH:12]=[N:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=1)[CH:5]=[O:6].[BH4-].[Na+].[NH4+].[Cl-]>CO>[F:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:7]=[C:8]([F:21])[C:9]=1[O:10][C:11]1[CH:12]=[N:13][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:15][CH:16]=1
Reactant: O=Cc1cc(F)c(Oc2ccc(C(F)(F)F)nc2)c(F)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: OCc1cc(F)c(Oc2ccc(C(F)(F)F)nc2)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a solution of 3,5-difluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzaldehyde (1.78 g, 5.87 mmol) in methanol (15 mL) was added NaBH4 (0.222 g, 5.87 mmol). The mixture was stirred at room temp for 0.5 h. NH4Cl solution was added to the reaction mixture, and the reaction mixture was extracted by DCM. The organic phase was then dried over Na2SO4 and evaporated to give the product (1.702 g, 95%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[N:10]([CH3:15])[C:11]([SH:14])=[N:12][N:13]=2)[CH:6]=[CH:5][N:4]=1.I[CH3:17]>[OH-].[Na+].C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[N:10]([CH3:15])[C:11]([S:14][CH3:17])=[N:12][N:13]=2)[CH:6]=[CH:5][N:4]=1
Reactant: CI
Reactant: COc1cc(-c2nnc(S)n2C)ccn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(-c2nnc(SC)n2C)ccn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 97.2 %

Procedure:
The title compound of example 24.1 (21.30 g, 95.83 mmol) was set stirring in 1 M sodium hydroxide in a cold water bath. Iodomethane (21.76 g, 153.3 mmol) in ethanol (63 mL) was added to the reaction. As the reaction progressed, solid began to precipitate out. The reaction was allowed to stir at RT for 12 hours. The reaction mixture was extracted with dichloromethane and the organic extracts were washed with brine, dried and concentrated to afford the title compound as a white solid (22 g, 97%).
Reaction SMILES: [CH3:1][NH2:2].C[O:4][C:5](=O)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.C(OCC)(=O)C>CO>[CH3:1][NH:2][C:5](=[O:4])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: CN
Solvent: CO
Solvent: CCOC(C)=O
Product: CNC(=O)Cc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
Monomethylamine, (22.43 kg, 722.15 mol, 6 eq.) was added over a 7-hour period to a solution of methyl-4-hydroxyphenylacetate (20.0 kg, 120.35 mol, 1.0 eq.) in methanol (31.7 gal, 120 L) and stirred overnight at room temperature. Methanol was then displaced under vacuum with ethyl acetate. The resulting slurry (about 20 gal, 75.7 L) was stirred at +10° C. for 1 hour, then filtered and dred under vacuum at 45° C. to yield the title compound(18.68 kg, 94% of theory).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5]C1C=CC=CC=1)C.[C:12]1([C:18]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([OH:27])[CH2:19][CH2:20]N2CCCCC2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:1][N:2]1[CH2:4][CH2:5][CH2:20][C@H:19]1[C:18]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[OH:27]
Reactant: OC(CCN1CCCCC1)(c1ccccc1)c1ccccc1
Reactant: CN(C)CCc1ccccc1
Product: CN1CCC[C@H]1C(O)(c1ccccc1)c1ccccc1

Procedure:
LC-MS (ESI) m/z (%): 268 (0) [M0+H]+, 269 (4), 270 (13), 271 (22), 272 (22), 273 (16), 274 (14), 275 (7), 276 (1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]([CH2:34][CH3:35])[C:16]2[C:17]([CH3:33])=[C:18]([C:29]([O:31][CH3:32])=[O:30])[CH:19]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[CH:21]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:37][CH2:38][O:39][CH3:40].C([O-])([O-])=O.[Cs+].[Cs+].O>C(#N)C>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]([CH2:34][CH3:35])[C:16]2[C:17]([CH3:33])=[C:18]([C:29]([O:31][CH3:32])=[O:30])[CH:19]=[C:20]([C:22]3[CH:23]=[CH:24][C:25]([O:28][CH2:37][CH2:38][O:39][CH3:40])=[CH:26][CH:27]=3)[CH:21]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCBr
Reactant: CCN(c1cc(-c2ccc(O)cc2)cc(C(=O)OC)c1C)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: CCN(c1cc(-c2ccc(OCCOC)cc2)cc(C(=O)OC)c1C)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To a stirred solution of methyl 5-(((trans)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(ethyl)amino)-4′-hydroxy-4-methyl-[1,1′-biphenyl]-3-carboxylate (0.6 g, 1.24 mmol) and 1-bromo-2-methoxyethane (0.519 g, 3.73 mmol) in acetonitrile (6 mL), Cs2CO3 (0.485 g, 1.49 mmol) was added and reaction was stirred at 80° C. for 12 h. On completion, water was added to it and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude compound was purified by column chromatography to afford the title compound (0.6 g, 76.5% yield).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[O:12]1[CH2:16][CH2:15][CH2:14][CH:13]1[C:17]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]Cl)=[O:18].[I-].[K+].C(#N)C>O>[OH:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([O:6][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][O:19][C:17]([CH:13]1[CH2:14][CH2:15][CH2:16][O:12]1)=[O:18])=[O:5]
Reactant: O=C(OCCCCCCCCCl)C1CCCO1
Reactant: O=C(O)c1cc(O)ccc1O
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=C(OCCCCCCCCOC(=O)C1CCCO1)c1cc(O)ccc1O

Procedure:
A mixture of 2,5-dihydroxybenzoic acid (3.9 g), 1,8-diazobicyclo[5.5.0]undec-7-ene (3.8 g), 8-chlorooctyl tetrahydro-2-furancarboxylate (6.0 g), potassium iodide (30.2 g) and acetonitrile (110 ml) was heated, under reflux for 72 h. The cooled reaction mixture was added to water (500 ml) and extracted with ethyl acetate (3×100 ml). The combined organic layers were washed with 1N-hydrochloric acid (150 ml) and water (2×15 ml), dried over magnesium sulphate and filtered. The solvent was removed in vacuum. The residue (8.0 g) was purified by column flash chromatography on silica gel using toluene/ethyl acetate (3:1) as eluent, to give 8-[(2,5-dihydroxybenzoyl)oxy]octyltetrahydro-2-furancarboxylate as colourless oil.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24]C)=[CH:20][CH:19]=4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][C:12]([O:26]C)=[CH:11][CH:10]=3)[CH3:2].B(Br)(Br)Br.[OH-].[Na+].[CH3:34][S:35]([OH:38])(=[O:37])=[O:36]>CO.O.C(Cl)CCl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:16][CH2:17][C:18]4[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][C:12]([OH:26])=[CH:11][CH:10]=3)[CH3:2].[CH3:34][S:35]([OH:38])(=[O:37])=[O:36]
Reactant: CCn1ncc2c(NCc3ccc(OC)cc3)c3cc(OC)ccc3nc21
Agent: BrB(Br)Br
Agent: CS(=O)(=O)O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Solvent: CO
Product: CCn1ncc2c(NCc3ccc(O)cc3)c3cc(O)ccc3nc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-ethyl-6-methoxy-N-(4-methoxyphenylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine (1.0 g, 2.76 mmol), boron tribromide (6 mL, 6 mmol) and 1,2-ethylenedichloride (30 mL) was stirred at room temperature overnight. The reaction mixture was poured into water and then was basified with NaOH. The layers were separated and then the aqueous layer was acidified with acetic acid. The precipitate which formed was collected by filtration, washed with water and dried to afford the product as the free base. The free base was taken up in methanol and treated with methanesulfonic acid. The methanol was evaporated and the solid residue was recrystallized from 2-propanol/methanol/ether and dried in vacuo to afford 350 mg of 1-ethyl-6-hydroxy-N-(4-hydroxyphenyl methyl)-1H-pyrazolo[3,4-b]quinolin-4-amine-CH3SO3H.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[C:18]2[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=2[C:16]1=[O:25].[CH3:26][CH2:27][C@@H:28]([NH2:30])[CH3:29].CN1CCOCC1>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)=[CH:4][C:3]=1[NH:15][C:16](=[O:25])[C:17]1[CH2:24][CH2:23][CH2:22][CH2:21][C:18]=1[C:19]([NH:30][CH:28]([CH2:27][CH3:26])[CH3:29])=[O:20]
Reactant: CC[C@H](C)N
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Solvent: CN1CCOCC1
Solvent: c1ccccc1
Product: CCC(C)NC(=O)C1=C(C(=O)Nc2cc(OC3CCCC3)c(Cl)cc2F)CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.8 %

Procedure:
N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (0.900 g, 2.47 mmol), S-(+)-sec-butylamine (0.235 g, 3.21 mmol), N-methylmorpholine (0.270 g, 2.67 mmol) and benzene (25 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. The crystals were washed with hexane and dried to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-(sec-butyl)-3,4,5,6-tetrahydrophthalamide as white crystals (0.300 9, 27.8% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([C:6]([N:8]([CH2:27][C:28](OCC)=[O:29])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][P:18]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][C:11]=2[NH2:26])=[O:7])=[CH:4][CH:3]=1.[N:35]1([C:40]([C:42]2[CH:49]=[CH:48][C:45]([CH:46]=O)=[CH:44][CH:43]=2)=[O:41])[CH2:39][CH:38]=[CH:37][CH2:36]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(N(CC)CC)C>ClCCl.[OH-].[Na+].C(O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:9][C:10]3[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][P:18](=[O:19])([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])=[CH:12][C:11]=3[N:26]([CH2:46][C:45]3[CH:44]=[CH:43][C:42]([C:40]([N:35]4[CH2:39][CH:38]=[CH:37][CH2:36]4)=[O:41])=[CH:49][CH:48]=3)[C:28](=[O:29])[CH2:27]2)=[O:7])=[CH:33][CH:34]=1
Reactant: CCOC(=O)CN(Cc1ccc(CCP(=O)(OCC)OCC)cc1N)C(=O)c1ccc(Cl)cc1
Reactant: O=Cc1ccc(C(=O)N2CC=CC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: CCOP(=O)(CCc1ccc2c(c1)N(Cc1ccc(C(=O)N3CC=CC3)cc1)C(=O)CN(C(=O)c1ccc(Cl)cc1)C2)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
180 mg (0.35 mmol) of ethyl ((4-chlorobenzoyl)-(4-(2-(diethoxyphosphoryl)ethyl)-2-aminobenzyl)amino)acetate and 92 mg (0.46 mmol) of 4-(2,5-dihydro-1H-pyrrol-1-ylcarbonyl)benzaldehyde were dissolved in 10 ml of dichloromethane. 0.040 ml (0.7 mmol) of acetic acid was added to the obtained solution. They were stirred at room temperature for 30 minutes. 185 mg (0.88 mmol) of sodium triacetoxyborohydride was added to the obtained mixture and they were stirred at room temperature overnight. After the treatment with dichloromethane as the extracting solvent by an ordinary method, the obtained crude product was dissolved in a mixture of 2 ml of 1 N sodium hydroxide and 4 ml of ethanol, and the obtained solution was stirred at room temperature for 5 hours. After the treatment with ethyl acetate as the extracting solvent by an ordinary method, the obtained crude product was dissolved in 10 ml of dichloromethane. 78 mg (0.46 mmol) of 2-chloro-1,3-dimethylimidazonium chloride and 0.15 ml (1.05 mmol) of triethylamine were added to the obtained solution, and they were stirred overnight. The solvent was evaporated and the obtained crude product was treated in the same manner as in step 3 in Example 1 to obtain the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9](=O)[CH2:10][CH:11]([C:19]2[CH:33]=[CH:32][C:22]([C:23]([NH:25][CH2:26][CH2:27][S:28]([CH3:31])(=[O:30])=[O:29])=[O:24])=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:3]1.Cl.[NH2:36][OH:37].C(=O)([O-])O.[Na+]>>[OH:37]/[N:36]=[C:9](/[C:4]1[CH:5]=[CH:6][C:7](=[O:8])[N:2]([CH3:1])[CH:3]=1)\[CH2:10][CH:11]([C:19]1[CH:33]=[CH:32][C:22]([C:23]([NH:25][CH2:26][CH2:27][S:28]([CH3:31])(=[O:29])=[O:30])=[O:24])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18]
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)NCCS(C)(=O)=O)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(C(=O)NCCS(C)(=O)=O)cc1

Procedure:
In analogy to example 151, step 3, 4-(3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxo-1-o-tolylpropyl)-N-(2-(methylsulfonyl)ethyl)benzamide was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound as an off-white solid containing <10% of the corresponding Z isomer, MS (ESI+): m/z=496.2 [M+H]+.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[I:8].[CH2:9]([S:13]CCCC)[CH2:10][CH2:11][CH3:12]>>[I:8][C:3]1[CH:4]=[CH:5][C:6]([S:13][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:7][CH:2]=1
Reactant: CCCCSCCCC
Reactant: Ic1ccccc1I
Product: CCCCSc1ccc(I)cc1

Procedure:
The general procedure was used to convert diiodobenzene and n-butyl sulfide to the title product. Purification by flash chromatography (hexane as the eluent) gave the analytically pure product as a pale yellow oil (512 mg, 88% yield). 1H NMR (300 MHz, CDCl3) δ 7.58–7.55 (d, J=8.4, 2H; Ha, Ha′), 7.05–7.02 (d, J=8.2, 2H; Hb, Hb′), 2.91–2.86 (t, J=7.3, 2H; Hc), 1.67–1.49 (m, 2H; Hd), 1.42–1.30 (m, 2H; He), 0.94–0.89 (t, J=7.3, 3H; methyl protons). 13C NMR (75 MHz, CDCl3) δ 137.6 (C1, C1′), 137.2 (C4), 130.2 (C2, C2′), 90.0 (C3), 32.9 (C5), 30.9 (C6), 21.9 (C7), 13.6 (C8). High Resolution Mass. Spec. for C10H13S; Expected, 291.9783; Found, 291.9796
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]3[NH:17][N:18]=[C:19]4[C:24]=3[CH2:23][CH2:22][C:21]3[CH:25]=[C:26]([CH:29]=C)[CH:27]=[CH:28][C:20]4=3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[N+]1([O-])CC[O:35]CC1.I([O-])(=O)(=O)=O.[Na+]>C1COCC1.O.[Os](=O)(=O)(=O)=O>[C:1]1([C:7]2[C:11]([C:12]([F:13])([F:14])[F:15])=[C:10]([C:16]3[NH:17][N:18]=[C:19]4[C:24]=3[CH2:23][CH2:22][C:21]3[CH:25]=[C:26]([CH:29]=[O:35])[CH:27]=[CH:28][C:20]4=3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=Cc1ccc2c(c1)CCc1c-2n[nH]c1-c1onc(-c2ccccc2)c1C(F)(F)F
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1ccc2c(c1)CCc1c-2n[nH]c1-c1onc(-c2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 109 %

Procedure:
To 3-phenyl-4-(trifluoromethyl)-5-(7-vinyl-4,5-dihydro-2H-benzo[g]indazol-3-yl)isoxazole (Preparation 22B, 0.15 g, 0.368 mmol) in THF (2 mL) were added sequentially N-methylmorpholine N-oxide (50% aq., 0.17 mL, 0.368 mmol) and osmium tetroxide (4% aq. 0.058 mL, 7.36 μmol) at room temperature under a nitrogen atmosphere. The reaction was stirred at room temperature for 45 min. and sodium periodate (0.118 g, 0.552 mmol) in water (1 mL) was added over a period of 1 min. at room temperature. The milky heterogeneous reaction mixture was stirred at room temperature for 45 min., concentrated, and partitioned between ethyl acetate (20 mL) and water (10 mL). The ethyl acetate layer was dried over sodium sulfate and concentrated to yield 3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydro-2H-benzo[g]indazole-7-carbaldehyde (0.164 g, 0.401 mmol, quantitative yield) as a dark brown oil. LC/MS M+1=410.1.