Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([NH:7][C:8]1[C:9]([S:17][CH3:18])=[N:10][C:11]([CH3:16])=[CH:12][C:13]=1[S:14][CH3:15])=[O:6].[SH:19][C:20]1[O:21][C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[N:24]=1.C1OCCOCCOCCOCCOCCOC1.C(=O)([O-])[O-].[K+].[K+]>O.CN(C=O)C>[O:21]1[C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[N:24]=[C:20]1[S:19][CH2:2][CH2:3][CH2:4][C:5]([NH:7][C:8]1[C:9]([S:17][CH3:18])=[N:10][C:11]([CH3:16])=[CH:12][C:13]=1[S:14][CH3:15])=[O:6]
Reactant: Sc1nc2ccccc2o1
Reactant: CSc1cc(C)nc(SC)c1NC(=O)CCCBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1cc(C)nc(SC)c1NC(=O)CCCSc1nc2ccccc2o1
Temperature: 80 °C
Reaction time: 3 h
Yield: 53.2 %

Procedure:
To a DMF (2 ml) solution of this amide (105 mg, 0.3 mmol) and 2-mercaptobenzoxazole (50 mg, 0.33 mmol) were added 18-crown-6 (8 mg, 0.03 mmol) and potassium carbonate (50 mg, 0.36 mmol), and the mixture was stirred at 80° C. for 3 hours. The reaction mixture was diluted with water, and then extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Subsequently, the solvent was distilled off, and the resulting crude product was purified through preparative thin-layer chromatography (eluent—hexane:ethyl acetate=3:2, eluted twice) to obtain 67 mg (yield 53%) of the desired compound as a colorless needle crystal.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26](B5OC(C)(C)C(C)(C)O5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:40]1[C:45]([CH3:46])=[CH:44][CH:43]=[CH:42][N:41]=1.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:24]=[CH:25][C:26]([C:40]5[C:45]([CH3:46])=[CH:44][CH:43]=[CH:42][N:41]=5)=[CH:27][CH:28]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(B5OC(C)(C)C(C)(C)O5)cc4)CC3)n2CCS1
Reactant: Cc1cccnc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1cccnc1-c1ccc(C2(c3nnc4n3CCSC(C)(CO[Si](C)(C)C(C)(C)C)C4)CC2)cc1
Temperature: 25 °C
Yield: 82.6 %

Procedure:
A solution of the compound (555 mg, 1.0 mmol) obtained in Example 16-5), 2-bromo-3-picoline (344 mg, 2 mmol), tetrakis(triphenylphosphine)palladium(0) (231 mg, 0.2 mmol), and potassium carbonate (276 mg, 2 mmol) in dimethoxyethane (4 mL) and water (1 mL) was stirred at 100° C. for 1 h under microwave irradiation. The reaction mixture was cooled to room temperature and purified by silica gel chromatography (Isco Combiflash, 40 g, methanol:ethyl acetate=0:100 to 20:80, gradient) to obtain the title compound (430 mg, 83%) as a light yellow oily substance.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].[CH:31]([C:33]1[CH:38]=[CH:37][C:36]([CH2:39][C:40]([OH:42])=[O:41])=[CH:35][CH:34]=1)=O>>[C:40]([CH2:39][C:36]1[CH:37]=[CH:38][C:33]([CH2:31][CH2:2][CH2:1][NH:3][C:4]2[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=2[C@H:14]2[CH2:23][CH2:22][C:21]3[CH:20]=[C:19]([O:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])[CH:18]=[CH:17][C:16]=3[CH2:15]2)=[CH:34][CH:35]=1)([OH:42])=[O:41]
Reactant: CCNc1cc(OC)c(OC)cc1[C@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: O=Cc1ccc(CC(=O)O)cc1
Product: COc1cc(NCCCc2ccc(CC(=O)O)cc2)c([C@H]2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)cc1OC
Yield: 98.5 %

Procedure:
Synthesized from pivalic acid (S)-6-(2-ethylamino-4,5-dimethoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (59 mg) and (4-formylphenyl)acetic acid (72 mg) according to an analogous synthetic method to Example 212,the title compound (79 mg) was obtained.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH:5]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:6]1[C:7]([CH3:27])=[N:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)=[CH:13][C:12]1[CH2:23][CH2:24][CH2:25][CH2:26][C:11]=1[CH:10]=2)C.[OH-].[Na+]>C(O)C.O1CCCC1>[C:29]([O:28][CH:5]([C:6]1[C:7]([CH3:27])=[N:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)=[CH:13][C:12]1[CH2:23][CH2:24][CH2:25][CH2:26][C:11]=1[CH:10]=2)[C:4]([OH:33])=[O:3])([CH3:32])([CH3:31])[CH3:30]
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)nc2cc3c(cc2c1-c1ccc(C)cc1)CCCC3
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ccc(-c2c(C(OC(C)(C)C)C(=O)O)c(C)nc3cc4c(cc23)CCCC4)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
A 50 mL flask containing a solution of tert-butoxy-(2-methyl-4-p-tolyl-6,7,8,9-tetrahydro-benzo[g]quinolin-3-yl)-acetic acid ethyl ester (11.1 mg 25.0 μmol) in ethanol (1 mL) and tetrahydrofuran (1 mL) under nitrogen was added sodium hydroxide solution (1.0 M, 250 μL, 250 μmol) and stirred at ambient temperature overnight. Complete conversion was then achieved by heating to 60 C for 30 min. Evaporated in vacuo and azeotroped with toluene (2×5 mL). Residue was taken up in water (10 mL) and acidified to pH=2 with hydrochloric acid solution (2 M) then extracted into ethyl acetate (2×10 mL). Organics were dried with magnesium sulfate and evaporated onto silica gel. Chromatographed using ISCO Companion with a Redisep silica gel 4 g cartridge with an isocratic gradient of ethyl acetate:acetic acid (90:10). Evaporation gave tert-butoxy-(2-methyl-4-p-tolyl-6,7,8,9-tetrahydro-benzo[g]quinolin-3-yl)-acetic acid as a colorless solid 7.1 mg (68% Yield). LCMS (12 min acidic) 5.32 min 100% pure by ELSD and UV AP+ and ES+ 418. HNMR (CDCl3) >95% pure 7.77 (br-s, 1H), 7.59 (br-d, 1H), 7.36-7.32 (br-m, 2H), 7.22 (br-d, 1H), 7.10 (br-s, 1H), 5.29 (br-s, 1H), 2.99 (br-t, 2H), 2.85-2.78 (m, 4H), 2.49 (s, 3H), 2.18 (s, 3H), 1.86-1.81 (m, 4H), 0.98 (s, 9H)
Reaction SMILES: C([Li])CCC.[S:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[CH:7]1.[C:15](=[O:17])=[O:16].O>O1CCCC1>[S:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C:15]([OH:17])=[O:16]
Reactant: O=C=O
Reactant: c1ccc2scnc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1nc2ccccc2s1
Yield: 47 %

Procedure:
A precooled (-78° C.) solution of 7.7 ml (19.2 mmol) of n-butyllithium in 50 ml of dry tetrahydrofuran was treated dropwise with 2.0 ml (18.3 mmol) of benzothiazole. After the addition was complete, the solution was poured into a mixture of excess dry ice in 100 ml of tetrahydrofuran. After being allowed to warm, the resulting solution was treated with water, washed with ether, acidified with HCl, and filtered to give a yellow solid. Digestion with boiling ether followed by filtration gave 1.55 g (47%) of the desired compound as a nearly white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]3[O:23][CH2:24][O:25][C:19]=3[CH:18]=2)[N:5]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)(=[O:9])=[O:8])[CH:6]=1.C([Li])(C)(C)C.CN([CH:34]=[O:35])C>>[Cl:16][C:12]1[CH:11]=[C:10]([S:7]([N:5]2[CH:6]=[C:2]([CH:34]=[O:35])[CH:3]=[C:4]2[C:17]2[CH:22]=[CH:21][C:20]3[O:23][CH2:24][O:25][C:19]=3[CH:18]=2)(=[O:9])=[O:8])[CH:15]=[CH:14][CH:13]=1
Reactant: CN(C)C=O
Reactant: O=S(=O)(c1cccc(Cl)c1)n1cc(Br)cc1-c1ccc2c(c1)OCO2
Agent: [Li]C(C)(C)C
Product: O=Cc1cc(-c2ccc3c(c2)OCO3)n(S(=O)(=O)c2cccc(Cl)c2)c1

Procedure:
The title compound is prepared from 4-bromo-1-(m-chlorobenzensulfonyl)-2-(3,4-methylenedioxyphenyl)-pyrrole, tert-butyl lithium and DMF following the procedure of Example 3a. 1H-NMR (300 MHz, CDCl3): 9.89 (s, 1H); 8.08 (d, J=2.0 Hz, 1H); 7.6-7.5 (m, 1H); 7.4-7.25 (m, 4H); 6.8-6.7 (m, 1H); 6.65-6.55 (m, 1H); 6.55 (d, J=2.0, 1H); 6.05 (s, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[C:15]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2].[CH:29](O)(C)C>[Ti+4]>[CH:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[C:15]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:14]=[CH:13][CH:12]=3)=[O:5])([CH3:29])[CH3:2]
Reactant: CCOC(=O)c1ncc2[nH]c3cccc(Oc4ccccc4)c3c2c1COC
Reactant: CC(C)O
Agent: [Ti+4]
Product: COCc1c(C(=O)OC(C)C)ncc2[nH]c3cccc(Oc4ccccc4)c3c12
Reaction time: 2 h
Yield: 82 %

Procedure:
540 mg of 5-phenoxy-4-methoxymethyl-beta-carboline-3-carboxylic acid ethyl ester in 30 ml of isopropanol is refluxed with 0.2 ml of titanium(IV) isopropylate for 2 hours. After concentration, it is mixed with 0.5N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate phase is dried, filtered and concentrated and digested with diisopropyl ether. 450 mg (82% of theory) of 5-phenoxy-4-methoxymethyl-beta-carboline-3-carboxylic acid isopropyl ester with a melting point of 207°-209° C. is obtained.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[CH:10][C:11](=[O:14])[NH:12][N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:17][O:18][C:19](=[O:28])[CH:20](Br)[CH2:21][CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.O>O1CCCC1>[CH3:17][O:18][C:19](=[O:28])[CH:20]([N:12]1[C:11](=[O:14])[CH:10]=[CH:9][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:13]1)[CH2:21][CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: O=c1ccc(Oc2ccccc2)n[nH]1
Reactant: COC(=O)C(Br)CC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C(CC1CCCC1)n1nc(Oc2ccccc2)ccc1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 72 %

Procedure:
A solution of 6-phenoxy-2H-pyridazin-3-one (0.78 g, 4.18 mmol) in tetrahydrofuran (21 mL, 0.2M) cooled to 0° C. was treated with a 60% dispersion of sodium hydride in mineral oil (0.2 g, 5.0 mmol). The reaction was stirred at 0° C. for 5 min and then at 25° C. for 35 min. After this time, the reaction was treated with 2-bromo-3-cyclopentyl-propionic acid methyl ester (Intermediate 10, 1.08 g, 4.59 mmol). The reaction was then warmed to 50° C. where it stirred overnight. After this time, the reaction was cooled to 25° C., poured into water (100 mL), and extracted into methylene chloride (3×100 mL). The combined organics were washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over magnesium sulfate, filtered, rinsed with methylene chloride and concentrated in vacuo. Silica gel column chromatography (AnaLogix, 80 g, 20-40% ethyl acetate/hexanes) afforded 3-cyclopentyl-2-(6-oxo-3-phenoxy-6H-pyridazin-1-yl)-propionic acid methyl ester (1.03 g, 72%) as a light yellow oil. 1H-NMR (300 MHz, DMSO-d6) δ ppm 0.98 (d, 2H), 1.32-1.71 (m, 7H), 1.71-1.84 (m, 1H), 1.84-2.05 (m, 1H), 3.59 (s, 3H), 5.19 (dd, J=10.9, 3.9 Hz, 1H), 7.10-7.18 (m, 3H), 7.22 (t, J=7.5 Hz, 1H), 7.42 (t, J=7.5 Hz, 2H), 7.48 (d, J=9.7 Hz, 1H).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[C:10](=[C:12]([C:16]([OH:18])=O)[CH:13]=[CH:14][CH:15]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl.[NH2:21][CH:22]1[CH:27]2[CH2:28][CH2:29][N:24]([CH2:25][CH2:26]2)[CH2:23]1>>[N:24]12[CH2:29][CH2:28][CH:27]([CH2:26][CH2:25]1)[CH:22]([NH:21][C:16]([C:12]1[CH:13]=[CH:14][CH:15]=[C:9]3[O:8][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[N:11][C:10]=13)=[O:18])[CH2:23]2
Reactant: NC1CN2CCC1CC2
Reactant: O=C(O)c1cccc2oc(-c3ccccc3)nc12
Agent: Cl
Product: O=C(NC1CN2CCC1CC2)c1cccc2oc(-c3ccccc3)nc12
Yield: 51 %

Procedure:
N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-phenylbenzoxazole-4-carboxamide was prepared from 2-phenylbenzoxazole-4-carboxylic acid and 3-aminoquinuclidine dihydrochloride using the method outlined in Step C of Example 7. This compound was obtained in 51% yield as an off-white solid: mp 77-80° C.; 1H NMR (500 MHz, CDCl3) δ 9.58 (d, J=7.1 Hz, 1H), 8.24 (d, J=5.2 Hz, 2H), 8.19 (d, 1H, J=6.8 Hz, 1H), 7.72 (d, J=7.1 Hz, 1H), 7.61-7.49 (m, 3H), 7.48 (t, J=7.9 Hz, 1H), 4.31 (m, 1H), 3.51 (dd, J=7.1, 2.3 Hz, 1H), 3.10 (m, 2H), 2.91 (m, 2H), 2.83 (dd, J=10.1, 4.2 Hz, 1H), 2.16 (m, 1H), 2.05 (m, 1H), 1.65-1.43 (m, 3H); MS (APCI) m/z 348 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12]Cl)[C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:5]2[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[C:28]([O:33][CH3:34])[CH:27]=1.[H-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][O:32][C:29]1[CH:30]=[CH:31][C:26]([Cl:25])=[CH:27][C:28]=1[O:33][CH3:34])[C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:5]2[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COc1cc(Cl)ccc1O
Reactant: CCOC(=O)c1c(CCl)nc2ccc(Cl)cc2c1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(COc2ccc(Cl)cc2OC)nc2ccc(Cl)cc2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of ethyl 6-chloro-2-(chloromethyl)-4-phenylquinoline-3-carboxylate (718 mg, 2.0 mmol) in dry N,N-dimethylformamide (3.0 ml) at room temperature was added 4-chloro-2-methoxyphenol (0.301 ml, 2.2 mmol) followed by sodium hydride (88.0 mg of a 60% oil dispersion, 2.2 mol). The mixture was stirred at room temperature for 18 hours, then the reaction mixture was diluted with ethyl acetate and poured into a separatory funnel. The organic phase was washed with saturated sodium bicarbonate and water (2×), then brine. The organic phase was separated, and the solvent removed under reduced pressure to provide a viscous oil. Upon sitting at room temperature overnight a solid formed, to which a mixture of 10% ethyl acetate/hexanes was added, and the resulting solid filtered off. The solid was washed with 20% ethyl acetate/hexanes and dried under reduced pressure to provide ethyl 6-chloro-2-((4-chloro-2-methoxyphenoxy)methyl)-4-phenylquinoline-3-carboxylate then provided PT-011 (558 mg, 58%) as a light yellow powder. TLC Rf=0.38 in 30% ethyl cetate:hexanes on a glass backed silica gel plate. 1H NMR (CDCl3, 400 MHz) δ 8.08 (d, 1H, J=8.9 Hz); 7.69 (dd, 1H, J=8.9, 2.3 Hz); 7.58 (d, 1H, J=2.3 Hz); 7.48-7.52 (m, 3H); 7.36-7.30 (m, 2H); 6.95-6.92 (app d, 1H, J=8.6 Hz); 6.75 (s, 1H); 6.78-6.70 (m, 1H); 5.50 (s, 2H); 3.90 (q, 2H, J=7.0 Hz); 3.80 (s, 3H); 0.82 (t, 3H, J=7.0 Hz). LC MS (CI) shows M+H 482.
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:8]=1)=O.Cl.Cl.[CH2:27]([NH:34]N)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CCN(CC)CC.Cl>CO>[CH2:27]([N:34]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: NNCc1ccccc1
Reactant: CN(C)C=CC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1-c1ccnn1Cc1ccccc1
Temperature: 25 °C
Yield: 47.3 %

Procedure:
A solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (0.675 g, 2.0 mmol), benzylhydrazine dihydrochloride (1.56 g, 8.0 mmol), and Et3N (2.23 mL, 16 mmol) in MeOH (20 mL) was refluxed for 3 h. After cooling to room temperature, the reaction mixture was poured into 1 M HCl aqueous solution and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was recrystallized from hexane/AcOEt to give the title compound (375 mg, 47% yield) as a white solid: mp 156-157° C.; 1H NMR (300 MHz, CDCl3): δ ppm 5.75 (2H, s), 6.70 (1H, d, J=7.9 Hz), 6.84-6.91 (2H, m), 7.18-7.24 (3H, m), 7.32-7.37 (1H, m), 7.47-7.53 (2H, m), 7.64-7.67 (2H, m), 7.70 (1H, d, J=1.9 Hz), 8.15 (1H, d, J=7.9 Hz). Anal. Calcd for C21H15F3N4O: C, 63.63; H, 3.81; N, 14.14. Found: C, 63.63; H, 3.85; N, 14.16.
Reaction SMILES: [NH:1](C(C1C=CC=CC=1)=O)[C@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.COC1C=C(OC)C=CC=1C[NH-:26].FC(F)(F)S(O)(=O)=O>FC(F)(F)C(O)=O>[NH2:1][C@H:2]([C:10]([NH2:26])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)c1ccccc1
Reactant: COc1ccc(C[NH-])c(OC)c1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)[C@@H](N)Cc1ccccc1

Procedure:
Bz-Phe-2,4-dimethoxybenzylamide (4.2 mg) was dissolved in trifluoroacetic acid (1.0 ml) containing 10% (v/v) trifluoromethane sulfonic acid (TFMSA) and the reaction mixture was kept in the dark for 1 h at 20° C. TFA/TFMSA was removed by blowing with N2 and the residue was suspended in 95% (v/v) CH3CN (1.0 ml). The reaction mixture was analyzed by HPLC system-7 and the generated Bz-Phe-NH2 (>95%) was determined quantitatively using a Bz-Phe-NH2 standard solution (Bz-Phe-NH2 was purchased from Bachem, Switzerland).
Reaction SMILES: [CH:1]1([N:6]2[C:10]3=[N:11][C:12]([CH2:16]OS(C)(=O)=O)=[N:13][C:14](=[O:15])[C:9]3=[C:8]([CH2:22][CH3:23])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CC([N:27]1[CH:31]=[CH:30][N:29]=[CH:28]1)=O.C([O-])(O)=O.[Na+]>CC#N>[CH:1]1([N:6]2[C:10]3=[N:11][C:12]([CH2:16][C:28]4[NH:27][CH:31]=[CH:30][N:29]=4)=[N:13][C:14](=[O:15])[C:9]3=[C:8]([CH2:22][CH3:23])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1[nH]n(C2CCCC2)c2nc(COS(C)(=O)=O)nc(=O)c1-2
Reactant: CC(=O)n1ccnc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCc1[nH]n(C2CCCC2)c2nc(Cc3ncc[nH]3)nc(=O)c1-2
Temperature: 0 °C
Yield: 29.8 %

Procedure:
A mixture of 1-cyclopentyl-3-ethyl-6-(methylsulfonyloxy methyl)pyrazolo[3,4-d]pyrimidin-4-one (1.8 g, 15.3 mmol), 1-(methylcarbonyl)imidazole (640 mg, 5.8 mmol) and CH3CN (36 mL) was heated at reflux for 6 hours. The solvent was stripped, ice water and saturated NaHCO3 were added and the mixture was extracted with ethyl acetate, dried over MgSO4, filtered and stripped. The product was combined with that from a similar experimental run and the mixture was recrystallized from ethyl acetate. The product was then treated with 2N HCl, extracted with ethyl acetate and the aqueous layer was neutralized with NaHCO3, extracted with ethyl acetate, dried over MgSO4, filtered and stripped. The residue was recrystallized from ethyl acetate to afford 0.54 g of 1-cyclopentyl-3-ethyl-6-(1-imidazolylmethyl)pyrazolo[3,4-d]pyrimidin-4-one, m.p. 252-253° C.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([NH:11][CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:8]=[CH:9][CH:10]=1.[F:23][C:24]([F:31])([F:30])[CH2:25][S:26](Cl)(=[O:28])=[O:27]>>[F:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([N:11]([CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[S:26]([CH2:25][C:24]([F:31])([F:30])[F:23])(=[O:28])=[O:27])[CH:8]=[CH:9][CH:10]=1
Reactant: Fc1ccccc1Oc1cccc(NCc2cccnc2)c1
Reactant: O=S(=O)(Cl)CC(F)(F)F
Product: O=S(=O)(CC(F)(F)F)N(Cc1cccnc1)c1cccc(Oc2ccccc2F)c1

Procedure:
Using the method of Example 342 using N-(3-(2-fluorophenoxy)phenyl)pyridin-3-ylmethylamine and 2,2,2-trifluoroethanesulfonyl chloride and purifying via radial chromatography eluting with 40:60 to 50:50 THF/hexanes gave the title compound. Anal Calcd for C20H16F4N2O3S: C, 54.54; H, 3.66; N, 6.36. Found: C, 54.23; H, 3.40; N, 6.31. MS found 441.2 [M+H]+
Reaction SMILES: [CH2:1]([N:3]1[C:7]([NH:8][C:9]2[C:10](=[CH:14][CH:15]=[CH:16][C:17]=2[O:18][CH3:19])[C:11](O)=O)=[CH:6][CH:5]=[N:4]1)[CH3:2].[NH4+].[OH-].O=P(Cl)(Cl)[Cl:24]>>[Cl:24][C:11]1[C:10]2[C:9](=[C:17]([O:18][CH3:19])[CH:16]=[CH:15][CH:14]=2)[N:8]=[C:7]2[N:3]([CH2:1][CH3:2])[N:4]=[CH:5][C:6]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCn1nccc1Nc1c(OC)cccc1C(=O)O
Agent: [NH4+]
Agent: [OH-]
Product: CCn1ncc2c(Cl)c3cccc(OC)c3nc21
Temperature: 0 °C

Procedure:
A mixture of N-(1-ethylpyrazol-5-yl)-3-methoxyanthranilic acid of example 9(d) and POCl3 (50 ml) was refluxed overnight. The reaction mixture was poured into ice-water, neutralized with NH4OH and the mixture was extracted with CH2Cl2 (3×150 ml). The CH2Cl2 extracts were combined, dried over MgSO4, filtered and evaporated. The residue was purified by column chromatography on silica gel eluting with 35% EtOAc/hexane to afford 0.4 g of 4-chloro-1-ethyl-8-methoxy-1H-pyrazolo[3,4-b]quinoline, m.p. 168°-170° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[H][H].Cl>[Pd].O.CO>[CH:17]1[C:16]([NH2:19])=[CH:15][CH:14]=[C:13]([S:10]([C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=2)(=[O:12])=[O:11])[CH:18]=1
Reactant: Nc1ccc(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CO
Product: Nc1ccc(S(=O)(=O)c2ccc(N)cc2)cc1
Yield: 91.9 %

Procedure:
In a hydrogenation vessel 4-(4′-Nitro-benzenesulfonyl)-phenylamine (100 g), p-toluensulfonic acid (68.4 g), methanol (350 ml), water (150 ml) and 10% palladium on charcoal (7.6 g) are charge. The mixture is allowed to react with hydrogen at approximately 50° C. and 5 bar pressure. At reaction completion, hydrochloric acid is added, the catalyst is filtered and dried. 82 g of crude Dapsone are obtained (82% yield; >99.5% purity).
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li].[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16]#[CH:17].[CH:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCCC1>[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16]#[C:17][CH:18]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[OH:25]
Reactant: O=Cc1ccccc1
Reactant: C#Cc1cccs1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Product: OC(C#Cc1cccs1)c1ccccc1
Temperature: 25 °C

Procedure:
Place lithium hexamethyldisilazane (3 mL of a 1M solution in tetrahydrofuran, 3 mmol) under argon atmosphere and cool to 0° C. Add (thiophen-2-yl)acetylene (324 mg, 3 mmol) in tetrahydrofuran (20 mL) and stir at 0° C. until anion formation is complete. Add a solution of benzaldehyde (297 mg, 2.8 mmol) in tetrahydrofuran, remove the ice bath and stir at room temperature until the reaction is complete. Pour onto ethyl ether and water, separate the organic layer and dry (MgSO4). Filter and evaporate the solvent in vacuo. Purify by silica gel chromatography to yield the title compound.
Reaction SMILES: [Na].Cl.[CH3:3][C:4]([CH3:11])([CH3:10])[CH2:5][CH2:6][C:7]([NH2:9])=[NH:8].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]=[C:20]=[S:21])=[CH:15][CH:14]=1>CC(C)=O>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([NH:8][C:7](=[NH:9])[CH2:6][CH2:5][C:4]([CH3:11])([CH3:10])[CH3:3])=[S:21])=[CH:15][CH:14]=1
Reactant: S=C=Nc1ccc(Cl)cc1
Reactant: CC(C)(C)CCC(=N)N
Agent: Cl
Agent: [Na]
Solvent: CC(C)=O
Product: CC(C)(C)CCC(=N)NC(=S)Nc1ccc(Cl)cc1

Procedure:
Following a procedure similar to that described in Example 42 but using 7.22 g. sodium in 705 ml. dry acetone, 51.7 g. 4,4-dimethylvaleramidine hydrochloride, and 53.2 g. 4-chlorophenyl isothiocyanate in 350 ml. dry acetone there was obtained 1-(4-chlorophenyl)-3-(4,4-dimethylpentanimidoyl)-2-thiourea; m.p. 135°-137°C. (from acetonitrile); hydrochloride (80.7 g.), m.p. 182°-186°C.