Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:36])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25](=[O:34])(=[O:33])[NH:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:35])[CH:14]=2)[CH:9]=1.C1COCC1.O>CCCCCC>[CH:27]1([NH:26][S:25]([C:22]2[CH:21]=[CH:20][C:19]([C:16]3[C:15]4[C:10](=[CH:11][CH:12]=[C:13]([F:35])[CH:14]=4)[CH:9]=[C:8]([CH2:7][C:6]([OH:36])=[O:5])[C:17]=3[CH3:18])=[CH:24][CH:23]=2)(=[O:34])=[O:33])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(S(=O)(=O)NC3CCCCC3)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1c(CC(=O)O)cc2ccc(F)cc2c1-c1ccc(S(=O)(=O)NC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.2 %

Procedure:
Lithium hydroxide monohydrate (0.018 g, 0.42 mmol) was added to a solution of [4-(4-cyclohexylsulfamoyl-phenyl)-6-fluoro-3-methyl-naphthalen-2-yl]-acetic acid methyl ester (0.05 g, 0.10 mmol) in a 3:1 mixture of THF—H2O mixture (6 mL). The reaction mixture was stirred for 16 hours at room temperature. The reaction mixture was concentrated to remove the THF, and the crude material was diluted with water, acidified [pH˜2] with a 6 N aqueous solution of hydrochloric acid. The mixture was extracted twice with ethyl acetate. The collected organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. Trituration with hexane gave [4-(4-cyclohexylsulfamoyl-phenyl)-6-fluoro-3-methyl-naphthalen-2-yl]-acetic acid (0.042 g, 87%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.46 (br. s, 1 H), 7.95-8.06 (m, 3 H), 7.90 (s, 1 H), 7.72 (d, J=7.80 Hz, 1 H), 7.46 (d, J=8.31 Hz, 2 H), 7.38 (td, J=8.40, 2.40 Hz, 1 H), 6.63 (dd, J=11.20, 2.40 Hz, 1 H), 3.85 (s, 2 H), 3.00-3.09 (m, 1 H), 2.08 (s, 3 H), 1.52-1.67 (m, 4 H), 1.41-1.51 (m, 1H), 1.03-1.25 (m, 5H). MS calcd. for C25H25FNO4S [(M−H)−] 454, obsd. 454.4.
Reaction SMILES: N1C2C(=CC=CC=2)C=C1.C([N:17]1[C:29]2[C:28]([OH:30])=[C:27]3[N:31](C(OC(C)(C)C)=O)[C:32]4[CH:33]=[CH:34][C:35]([Br:38])=[CH:36][C:37]=4[C:26]3=[CH:25][C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[C:21]([Br:46])[CH:22]=2)(OC(C)(C)C)=O.[CH3:47][O:48][CH2:49][CH2:50]O>>[Br:46][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:29]1[C:28]([O:30][CH2:50][CH2:49][O:48][CH3:47])=[C:27]3[NH:31][C:32]4[CH:33]=[CH:34][C:35]([Br:38])=[CH:36][C:37]=4[C:26]3=[CH:25][C:24]2=1
Reactant: CC(C)(C)OC(=O)n1c2ccc(Br)cc2c2cc3c4cc(Br)ccc4n(C(=O)OC(C)(C)C)c3c(O)c21
Reactant: COCCO
Agent: c1ccc2[nH]ccc2c1
Product: COCCOc1c2[nH]c3ccc(Br)cc3c2cc2c1[nH]c1ccc(Br)cc12

Procedure:
The title compound was prepared in a manner analogous to Example 28 except the starting indole is 5,7-diBOC-2,10-dibromo-6-hydroxyindolo[2,3-b]carbazole and the reagent is 2-methoxyethanol. 1H-NMR (400 MHz, CDCl3) δ ppm 8.75 (s, 1H), 8.21 (s, 2H), 7.45 (d, J=6.8 Hz, 2H), 7.32-7.24 (m, 2H), 4.43 (t, J=4.4 Hz, 2H), 3.85 (t, J=4.4 Hz, 2H), 3.65 (s, 3H); MS (ESI) m/z 487.0 (M−H)−
Reaction SMILES: O=[C:2]1[C:7]2[C:8]([C:11]([OH:13])=[O:12])=[CH:9][O:10][C:6]=2[CH2:5][CH2:4][CH2:3]1.Cl.[NH2:15][OH:16].C([O-])(=O)C.[Na+].O>C(O)C>[OH:16]/[N:15]=[C:2]1/[CH2:3][CH2:4][CH2:5][C:6]2[O:10][CH:9]=[C:8]([C:11]([OH:13])=[O:12])[C:7]/1=2
Reactant: O=C(O)c1coc2c1C(=O)CCC2
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(O)c1coc2c1/C(=N\O)CCC2
Yield: 95.4 %

Procedure:
To a solution of 30.0 g of 4,5,6,7-tetrahydro-4-oxo-3-benzofurancarboxylic acid in 225 ml of ethanol is added 22.97 g of hydroxylamine hydrochloride, followed by 18.10 g of sodium acetate and 55 ml of water. The reaction mixture is heated at reflux for 2.5 hours and concentrated in vacuo to a residue which is diluted with 600 ml of ethyl acetate, washed with 2×200 ml of water, brine and dried over Na2SO4. The organic layer is concentrated in vacuo to a residue which is dried under vacuum to give 31.0 g of the desired product as a solid.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10]([NH:11][NH2:12])=[CH:9][C:8](=[O:13])[N:7]([CH3:14])[C:6]2=[O:15])[CH2:3][CH2:2]1.[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH:26]=O.[CH:28]([C:30]1[N:34]([CH3:35])[CH:33]=[C:32]([C:36]([O:38][CH3:39])=[O:37])[CH:31]=1)=O>>[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH2:26][N:12]1[C:28]([C:30]2[N:34]([CH3:35])[CH:33]=[C:32]([C:36]([O:38][CH3:39])=[O:37])[CH:31]=2)=[C:9]2[C:10]([N:5]([CH2:4][CH:1]3[CH2:2][CH2:3]3)[C:6](=[O:15])[N:7]([CH3:14])[C:8]2=[O:13])=[N:11]1
Reactant: O=Cc1c[nH]c2ccc(Cl)cc12
Reactant: Cn1c(=O)cc(NN)n(CC2CC2)c1=O
Reactant: COC(=O)c1cc(C=O)n(C)c1
Product: COC(=O)c1cc(-c2c3c(=O)n(C)c(=O)n(CC4CC4)c3nn2Cc2c[nH]c3ccc(Cl)cc23)n(C)c1

Procedure:
This compound was made following the procedure described above, starting with 1-(cyclopropylmethyl)-6-hydrazino-3-methylpyrimidine-2,4(1H,3H)-dione, and condensing first with 5-chloro-1H-indole-3-carbaldehyde, followed by methyl 5-formyl-1-methyl-1H-pyrrole-3-carboxylate. Mass: 520.97 (M+H).
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][CH2:5][NH2:6].C(N(CC)CC)C.[C:14](=[O:19])=[N:15]C(Cl)=O.C1C[O:23][CH2:22]C1>>[Br:2][CH2:3][CH2:4][CH2:5][N:6]([N:15]=[C:14]=[O:19])[CH:22]=[O:23]
Reactant: O=C=NC(=O)Cl
Reactant: C1CCOC1
Reactant: NCCCBr
Agent: Br
Solvent: CCN(CC)CC
Product: O=C=NN(C=O)CCCBr
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To 3-bromo-1-propylamine hydrobromide (1.0 g, 4.56 mmol) in THF (20 mL) was added triethylamine (2.31 g, 22.8 mmol). The mixture was cooled to -78° C., triturated with N-(chlorocarbonyl)isocyanate (723 mg, 6.85 mmol) and stirred for 10 min. It was then concentrated, and the residue was partitioned between EtOAc and water. The organic layer was dried over Na2SO4, filtered and concentrated to give, in quantitative yield, the crude product which was used without purification.
Reaction SMILES: Cl[C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[NH2:16][C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([NH2:25])[CH:24]=1)[CH2:20][OH:21]>>[CH:4]1[C:3]2[C:8](=[N:9][C:10]3[C:15]([C:2]=2[NH:16][C:17]2[CH:24]=[C:23]([CH:22]=[C:19]([CH2:20][OH:21])[CH:18]=2)[NH2:25])=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:7]=[CH:6][CH:5]=1
Reactant: Clc1c2ccccc2nc2ccccc12
Reactant: Nc1cc(N)cc(CO)c1
Product: Nc1cc(CO)cc(Nc2c3ccccc3nc3ccccc23)c1

Procedure:
contacting 9-chloroacridine with 3,5-diaminobenzyl alcohol under suitable conditions to form 3-(9-acridinylamino)-5-hydroxymethylaniline: ##STR3##
Reaction SMILES: C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N.[O:18]=[C:19]1[NH:23][C@H:22]([C:24]([OH:26])=O)[CH2:21][O:20]1.[N+]([O-])(O)=O.[N+:31]([O:34][CH2:35][CH2:36][NH2:37])([O-:33])=[O:32]>O1CCCC1>[N+:31]([O:34][CH2:35][CH2:36][NH:37][C:24]([C@@H:22]1[CH2:21][O:20][C:19](=[O:18])[NH:23]1)=[O:26])([O-:33])=[O:32]
Reactant: O=C1N[C@H](C(=O)O)CO1
Reactant: NCCO[N+](=O)[O-]
Agent: CCOP(=O)(C#N)OCC
Solvent: C1CCOC1
Solvent: O=[N+]([O-])O
Solvent: CCN(CC)CC
Product: O=C1N[C@H](C(=O)NCCO[N+](=O)[O-])CO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.2 ml of triethylamine and 1.5 ml of diethyl cyanophosphonate were added, whilst ice-cooling, to a suspension of 1.0 g of (4S)-2-oxooxazolidine-4carboxylic acid and 1.55 g of N-(2-nitrooxyethyl)amine nitrate in 20 ml of dry tetrahydrofuran, and the resulting mixture was stirred at room temperature for 2 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, and the residue was diluted with ethyl acetate; the mixture was then washed with a saturated aqueous solution of sodium chloride, after which it was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the residual brown oil thus obtained was purified by column chromatography through silica gel, using ethyl acetate as the eluent, to give the title compound as yellowish brown crystals. These crude crystals were recrystallized from ethyl acetate, to give 0.25 g of the title compound as colorless needles, melting at 102°-103° C.
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:18]([O:25][C:26](=[O:29])[CH2:27][NH2:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C.Cl>C(Cl)Cl.O>[CH2:18]([O:25][C:26](=[O:29])[CH2:27][NH:28][C:3](=[O:4])[CH:2]([Br:1])[CH3:6])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCC(=O)OCc1ccccc1
Reactant: CC(Br)C(=O)Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(Br)C(=O)NCC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
55.9 g (326.1 mmol) of 2-bromopropionic acid chloride is added in drops at 0° C. to 100 g (296.4 mmol) of glycine benzyl ester-p-toluenesulfonic acid salt and 33.0 g (326.1 mmol) of triethylamine in 400 ml of methylene chloride. The temperature is not allowed to exceed 5° C. After the addition is completed, it is stirred for one hour at 0° C., then for 2 hours at room temperature. 500 ml of ice water is added, and the water phase is set at pH 2 with 10% aqueous hydrochloric acid. The organic phase is separated, washed once each with 300 ml of 5% aqueous soda solution and 400 ml of water. The organic phase is dried on magnesium sulfate and evaporated to dryness in a vacuum. The residue is recrystallized from diisopropyl ether.
Reaction SMILES: C([NH:8][CH2:9][CH2:10][CH2:11][C@@H:12]([C:14]([OH:16])=[O:15])[NH2:13])(OC(C)(C)C)=O.CCN=C=NCCCN(C)C.[ClH:28].[C:29]([NH:39][CH2:40][C:41]1[CH:49]=[CH:48][C:44]([C:45]([OH:47])=O)=[CH:43][CH:42]=1)([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30]>CN(C=O)C.CN(C1C=CN=CC=1)C>[ClH:28].[C:29]([NH:39][CH2:40][C:41]1[CH:42]=[CH:43][C:44]([C:45]([NH:13][C@H:12]([C:14]([OH:16])=[O:15])[CH2:11][CH2:10][CH2:9][NH2:8])=[O:47])=[CH:48][CH:49]=1)([O:31][CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)=[O:30]
Reactant: CC(C)(C)OC(=O)NCCC[C@H](N)C(=O)O
Reactant: O=C(NCc1ccc(C(=O)O)cc1)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: NCCC[C@H](NC(=O)c1ccc(CNC(=O)OCc2ccccc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 38 %

Procedure:
The compound obtained in Example 23-2 (350 mg) was dissolved in DMF (7 ml). After the addition of WSCI hydrochloride (265.0 g), DMAP (169 mg), and the compound obtained in Example 41-1 (276.0 mg), the mixture was stirred for 24 hours at room temperature. After the reaction, the solvent was removed by distillation. The residue was dissolved in chloroform, washed with 1 mol/l aqueous solution of hydrochloric acid and saturated aqueous solution of sodium hydrogencarbonate, and dried over sodium hydrogensulfate. The solvent was removed by distillation and the residue was purified by silica gel column chromatography (20 g, chloroform/methanol=10/1). 130 mg of the obtained product was dissolved in methanol (2.6 ml) and 4 mol/l hydrochloric acid/dioxane solution (2.6 ml) was added. The mixture was stirred for 70 minutes at room temperature. After the reaction, the solvent was removed by distillation and the residue was dried under vacuum to obtain hydrochloride of the title compound (147 mg) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:21]O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:23]1(=[O:33])[NH:27][C:26](=[O:28])[C:25]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:24]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:21][N:27]2[C:23](=[O:33])[C:24]3=[CH:32][CH:31]=[CH:30][CH:29]=[C:25]3[C:26]2=[O:28])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2CO)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2CN2C(=O)c3ccccc3C2=O)CC1
Temperature: 25 °C
Reaction time: 21 h
Yield: 41.3 %

Procedure:
1-(tert-Butoxycarbonyl)-4-[(2-hydroxymethylphenyl)amino]piperidine (716 mg) was dissolved in tetrahydrofuran (7 ml), added with phthalimide (349 mg), triphenylphosphine (736 mg) and diethyl azodicarboxylate (0.43 ml) and stirred at room temperature for 21 hours. The reaction mixture was added with water (10 ml) and extracted twice with dichloromethane (10 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane:ethyl acetate=4:1) to obtain crude 1-(tert-butoxycarbonyl)-4-[(2-phthalimidylmethylphenyl)amino]piperidine (420 mg).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:8](Cl)=[O:9])([CH3:4])[CH3:3].[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:35][NH:36][C:37](=[O:39])[CH3:38].[H-].[Na+]>O1CCCC1>[C:37]([N:36]([CH2:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=1)[C:8](=[O:9])[C:7]1[CH:11]=[CH:12][C:13]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[C:5]([C:2]([CH3:4])([CH3:3])[CH3:1])[CH:6]=1)(=[O:39])[CH3:38]
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)Cl)cc1C(C)(C)C
Reactant: CC(=O)NCc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)N(Cc2ccccn2)C(C)=O)cc1C(C)(C)C
Yield: 51.9 %

Procedure:
The title compound is prepared by the procedure of Example 27 using 9.7 g of product from Example 33, 3.74 g of product from Example 12, 1.2 g of washed 50% sodium hydride and 100 ml of tetrahydrofuran. The residue is purified by column chromatography (silica gel:30% ethyl acetate/hexane) to give 6.43 g of the desired product as colorless crystals.
Reaction SMILES: S[C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.C([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])C1OC1.[CH:25]([OH:28])([CH3:27])[CH3:26]>>[CH2:13]([O:12][N:5]1[N:6]=[CH:2][S:3][CH:4]1[S:7][CH2:26][CH:25]([OH:28])[CH3:27])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CC(C)O
Reactant: Sc1nnc(S)s1
Reactant: CCCCCCCCCCCCOCC1CO1
Product: CCCCCCCCCCCCON1N=CSC1SCC(C)O
Temperature: 80 °C

Procedure:
2,5-Dimercapto-1,3,4-thiadiazole(79.9 grams, 0.53 moles) was charged into a reaction flask followed by isopropanol solvent, 200 ml. The epoxide, dodecyl glycidyl ether (272.4 grams, 1.06 moles) was added slowly to the reactor with stirring. The reaction mixture was heated at about 80° C. for 0.5 hours. At this time the solvent was stripped by using a rotary evaporator at approximately 20 mm Hg and 100° C. The product was a low melting solid characterized by the infrared absorption bands at 3400, 2900, 1460, 1380, 1120, and 1050 cm-1.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([O:11][CH3:12])=[O:10])[CH2:5][CH2:4]1.[Cl:13][CH2:14][CH2:15][CH2:16][C:17](Cl)=[O:18].C(N(CC)CC)C>ClCCl>[Cl:13][CH2:14][CH2:15][CH2:16][C:17]([NH:2][C@H:3]1[CH2:4][CH2:5][C@H:6]([C:9]([O:11][CH3:12])=[O:10])[CH2:7][CH2:8]1)=[O:18]
Reactant: O=C(Cl)CCCCl
Reactant: COC(=O)[C@H]1CC[C@H](N)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H]1CC[C@H](NC(=O)CCCCl)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methyl trans-4-aminocyclohexanecarboxylate hydrochloride (45.31 g) is suspended in dichloromethane (1000 ml), thereto is added 4-chlorobutyryl chloride (31.5 ml) under ice-cooling and to the mixture is added dropwise a solution of triethylamine (81.5 ml) in dichloromethane (80 ml). The reaction solution is warmed to room temperature, stirred for 3 hours and the reaction solution is concentrated under reduced pressure. To the resulting residue are poured ethyl acetate and 5% hydrochloric acid, and the organic layer is separated, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer is dried over sodium sulfate and treated with activated carbon, and the filtrate is concentrated under reduced pressure. The resulting residue is suspended in diisopropyl ether, filtered to collect the precipitates, dried to give methyl trans-4-(4-chlorobutyrylamino)cyclohexanecarboxylate (38.81 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:16]([C:30]([OH:32])=[O:31])=[N:17][N:18]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)[C:19](=[O:21])[CH:20]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1.CCOCC>C(Cl)Cl>[ClH:28].[Cl:29][C:24]1[CH:23]=[C:22]([N:18]2[C:19](=[O:21])[CH:20]=[C:15]([O:14][CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[C:16]([C:30]([OH:32])=[O:31])=[N:17]2)[CH:27]=[CH:26][C:25]=1[Cl:28]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(=O)n(-c3ccc(Cl)c(Cl)c3)nc2C(=O)O)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(O)c1nn(-c2ccc(Cl)c(Cl)c2)c(=O)cc1OC1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 181.8 %

Procedure:
To a stirring solution of 4-(1-(tert-butoxycarbonyl)piperidin-4-yloxy)-1-(3,4-dichlorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylic acid (from example 15 step A) (105 mg, 0.217 mmol) in DCM (2 mL) at room temperature under argon was added 4 M HCl in dioxane (0.271 mL, 1.1 mmol). The reaction mixture was stirred at room temperature overnight. Et2O (10 mL) was added to the reaction mixture. The solid product was collected by filtration and further washed with ether (5 mL×2). After drying under reduce pressure over night, 83 mg (100%) of 1(3,4-dichlorophenyl)-6-oxo-4-(piperidin-4-yloxy)-1,6-dihydropyridazine-3-carboxylic acid HCl salt was obtained as an off-white solid. MS (ESI) 384 (M+H).
Reaction SMILES: [CH3:1][C:2]([CH3:7])=[CH:3][C:4]([OH:6])=[O:5].[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][CH:11]=1.N1CCCCC1>CCOC(C)=O>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:2]([CH3:7])([CH3:1])[CH2:3][C:4]([OH:6])=[O:5])=[CH:12][CH:11]=1
Reactant: CC(C)=CC(=O)O
Reactant: COc1ccc(S)cc1
Solvent: CCOC(C)=O
Solvent: C1CCNCC1
Product: COc1ccc(SC(C)(C)CC(=O)O)cc1
Temperature: 105 °C

Procedure:
A heavy-walled screw cap tube was charged with 3-methyl-2-butenoic acid (13.86 g, 138.4 mmol), 4-methoxy thiophenol (20.0 g, 138.4 mmol), and piperidine (3.45 g, 41.6 mmol). This mixture was heated to 105° C. for 32 hours, cooled to room temperature and dissolved in EtOAc (700 mL). The resulting solution was washed with 1M aqueous HCl, H2O, and saturated aqueous NaCl before being dried over Na2SO4. Concentration of the dry solution under reduced pressure afforded an oil which upon standing in the freezer provided a crystalline solid. 3-(4-methoxy-phenylsulfanyl)-3-methyl-butyric acid was isolated as pale-yellow crystals by washing the crystalline solid with pentane. (27.33 g, 82%). 1H NMR (300 MHz, CDCl3) δ: 7.48 (2H, d, J=9.0 Hz), 6.89 (2H, d, J=8.9 Hz), 3.83 (3H, s), 2.54 (2H, s), 1.40 (6H, s).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:10])[CH:4]=[C:5]([CH3:9])[C:6](=[O:8])[CH:7]=1.[ClH:11].[CH3:12][N:13]([CH3:18])[CH2:14][CH2:15][CH2:16][SH:17]>C(N(CC)CC)C.CC(C)=O>[ClH:11].[ClH:11].[CH3:12][N:13]([CH3:18])[CH2:14][CH2:15][CH2:16][S:17][C:4]1[C:5]([CH3:9])=[C:6]([OH:8])[C:7]([S:17][CH2:16][CH2:15][CH2:14][N:13]([CH3:18])[CH3:12])=[C:2]([CH3:1])[C:3]=1[OH:10]
Reactant: CN(C)CCCS
Reactant: CC1=CC(=O)C(C)=CC1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: Cc1c(O)c(SCCCN(C)C)c(C)c(O)c1SCCCN(C)C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of 27.2 g (0.200 mole) of 2,5-dimethyl-1,4-benzoquinone, 31.1 g (0.200 mole) of 3-(dimethylamino)propanethiol hydrochloride and six drops of triethylamine in 300 ml of acetone was stirred at ambient temperature for 15 hours. The cream-colored, crude, solid product was collected on a filter and recrystallized from methanol to give the pure product, 2,5-bis((3-(dimethylamino)propyl)thio)-3,6-dimethyl-1,4-benzenediol dihydrochloride, as cream-colored platelets, mp 254.5° C.
Reaction SMILES: CC#N.[OH2:4].[C:5]1(/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(Cl)Cl>CC#N>[C:5]1([C@H:11]2[C@H:12]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[O:4]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C(=C/c1ccccc1)\c1ccccc1
Reactant: O
Solvent: CC#N
Solvent: ClCCl
Product: c1ccc([C@@H]2O[C@H]2c2ccccc2)cc1
Yield: 99 %

Procedure:
Under a flow of F2 (10% in N2) of 20.0 ml min−1 (3.33 mmol h−1) passed through first conduit 12, MeCN:H2O (4:1, 4.95 ml) was added to conduit 16 at a rate of 9.90 ml h−1 (110.0 mmol h−1) and trans-stilbene 24 (0.36 g, 2.0 mmol) (in a 1:1 mixture of DCM:MeCN) was added to conduit 38 at a rate of 9.90 ml h−1. All reaction fluids were collected in a pot 22 containing sodium bicarbonate solution 25 (50 ml). The reaction mixture was then added to another 25 ml of sodium bicarbonate solution, washed with DCM (3×75 ml), dried over MgSO4 and filtered. The solvent was removed under reduced pressure to yield trans-2,3-diphenyloxirane (0.39 g, 1.99 mmol, 99%) as a yellow solid, with no purification required;
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([N:12]=O)[CH2:7][CH:6]([C:14]1[CH:15]=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=1)[CH2:5]2.[Cl-].[NH4+].O.[CH3:24][C:25]([CH3:27])=O>[Zn]>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([N:12]=[C:25]([CH3:27])[CH3:24])[CH2:7][CH:6]([C:14]1[CH:15]=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=1)[CH2:5]2
Reactant: CC(C)=O
Reactant: Cc1ccc2c(c1)CC(c1ccc(C)nc1)CN2N=O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Product: CC(C)=NN1CC(c2ccc(C)nc2)Cc2cc(C)ccc21
Temperature: 15 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To a stirred solution of 6-methyl-3-(6-methylpyridin-3-yl)-1-nitroso-1,2,3,4-tetrahydroquinoline (0.28 g, 0.00104 mol) in acetone (15 mL) was added saturated ammonium chloride solution (0.8 mL) and water (0.8 mL) at RT. The resulting brown colored reaction mixture was cooled to 15° C. Zinc dust (0.954 g, 0.0146 mol) was added portionwise at the same temperature. After the addition, the reaction mixture was stirred for 1 h at RT. After completion of reaction (monitored by TLC), solvent was removed under reduced pressure and the residue extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and the solvent removed under reduced pressure to obtain product as a brown colored oil (0.28 g, 91% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:11](=[O:12])[NH:10][C:9]2[N:8]=[CH:7][C:6](/[CH:13]=[CH:14]/[C:15]([O:17]C(C)(C)C)=[O:16])=[CH:5][C:4]=2[CH2:3]1.C(O)(C(F)(F)F)=O.C(Cl)[Cl:31]>>[ClH:31].[CH3:1][C:2]1([CH3:22])[C:11](=[O:12])[NH:10][C:9]2[N:8]=[CH:7][C:6](/[CH:13]=[CH:14]/[C:15]([OH:17])=[O:16])=[CH:5][C:4]=2[CH2:3]1
Reactant: CC(C)(C)OC(=O)/C=C/c1cnc2c(c1)CC(C)(C)C(=O)N2
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)Cc2cc(/C=C/C(=O)O)cnc2NC1=O
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (E)-tert-butyl 3-(6,6-dimethyl-7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylate (165 mg, 0.55 mmol) in CH2Cl2 (10 mL) was treated with TFA (10 mL). After stirring at room temperature for 2 h, the solution was concentrated in vacuo. The resulting crude product was treated with anhydrous HCl in dioxane (4 mL, 4.0 M) and sonicated for 15 min. The off-white solid product was then isolated by filtration and dried under vacuum. Yield: 152 mg (quant); 1H NMR (300 MHz, DMSO-d6) δ 10.71 (s, 1H), 8.38 (s, 1H), 8.04 (s, 1H), 7.56 (d, J=16.1 Hz, 1H), 6.54 (d, J=16.1 Hz, 1H), 2.81 (s, 2H), 1.09 (s, 6H); ESI MS m/z 247 [C13H14N3O4+H]+