Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.Br[CH2:12][C:13]([O:15][CH3:16])=[O:14].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH3:16][O:15][C:13](=[O:14])[CH2:12][O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccc(O)cc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(C(N)=O)cc1
Yield: 63 %

Procedure:
A mixture of p-hydroxybenzamide (3.43 g), methyl bromoacetate (2.37 ml) and K2CO3 (3.45 g) was stirred for 12 hr in 25 ml of DMF. The reaction mixture was diluted with water (150 ml); the solid was filtered, washed with water, and air dried. Crystallization from ethanol gave 3.3 g (63%) of the title compound as white crystals.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11]([OH:13])=[O:12])=[CH:9][C:4]=2[CH2:3][CH2:2]1.[C:14]1(C)C=CC=C[CH:15]=1.C(O)C.S(=O)(=O)(O)O>O.C(OCC)(=O)C.O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: O=C(O)Cc1ccc2c(c1)CCO2
Reactant: Cc1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1ccc2c(c1)CCO2
Reaction time: 6 h

Procedure:
2,3-dihydrobenzofuran-5-ylacetic acid (5.4 g) was heated at reflux in a solution of toluene (200 ml), ethanol (20 ml) and concentrated sulfuric acid (0.5 ml) with the azeotropic removal of water. When the reaction was complete, approximately 6 hours, the mixture was added to water/ethyl acetate and extracted with ethyl acetate. The organic extracts were combined and washed with 10% sodium carbonate, dried over sodium sulfate and the solvent evaporated to give the title compound as an oil.
Reaction SMILES: C(C1C=CC=CC=1)(=O)CC.[C:11]1([C:17](=[O:23])[C:18](=[N:21][OH:22])[CH2:19]C)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:11]1([C:17](=[O:23])[C:18](=[N:21][OH:22])[CH3:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCC(=NO)C(=O)c1ccccc1
Solvent: CCC(=O)c1ccccc1
Product: CC(=NO)C(=O)c1ccccc1
Yield: 84 %

Procedure:
Propiophenone (0.100 g, 0.746 mmol) was reacted as described for the synthesis of 1-phenyl-butane-1,2-dione 2-oxime and gave the title material (0.103 g, 84%). HPLC 98.7% (220 nm), LCMS (+ESI, M+H+) m/z 279; 1H NMR (400 MHz, methanol-d4) δ (ppm): 2.09 (3H, s), 7.42 (2H, m), 7.55 (1H, m), 7.89 (2H, d, J=7.1 Hz).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[CH:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=1.[OH:15][CH2:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1.C(O)C>C1(C)C=CC=CC=1.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>[NH2:14][C:11]1[N:12]=[CH:13][C:8]([C:21]2[CH:22]=[C:17]([CH2:16][OH:15])[CH:18]=[CH:19][CH:20]=2)=[CH:9][CH:10]=1
Reactant: OCc1cccc(B(O)O)c1
Reactant: Nc1ccc(Br)cn1
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: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Nc1ccc(-c2cccc(CO)c2)cn1
Temperature: 80 °C
Yield: 86.2 %

Procedure:
2.0 g of tetrakis(triphenylphosphine)palladium and 75 ml of a 2M solution of sodium carbonate are added to a round-bottomed flask containing a solution of 5.0 g of 5-bromopyridin-2-ylamine and 5.7 g of 3-(hydroxymethyl)phenylboronic acid in 140 ml of toluene, and 70 ml of ethanol degassed beforehand. The mixture is heated at 80° C. for 16 h. After cooling, the reaction mixture is concentrated under reduced pressure. The residue is taken up between water and ethyl acetate. The organic phase is separated, dried and concentrated under reduced pressure. The residue is purified by silica gel chromatography, elution being carried out with a dichloromethane/methanol mixture. 4.99 g of compound are obtained.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:29]2[S:30][C:31]3[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=3[N:33]=2)=[C:5]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:6]=1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[Na].[OH-:39].[K+]>O1CCOCC1>[CH2:8]([O:7][C:6]1[C:5]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[C:4]([C:29]2[S:30][C:31]3[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=3[N:33]=2)[S:3][C:2]=1[C:2]1[S:3][C:4]([C:29]2[S:30][C:31]3[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=3[N:33]=2)=[C:5]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:6]=1[O:39][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCCCOc1c(Br)sc(-c2nc3ccccc3s2)c1OCCCCCCCCCC
Reactant: [OH-]
Agent: [K+]
Agent: [Na]
Solvent: C1COCCO1
Product: CCCCCCCCCCOc1c(-c2nc3ccccc3s2)sc(-c2sc(-c3nc4ccccc4s3)c(OCCCCCCCCCC)c2OCCCCCCCCCC)c1OCCCCCCCCCC
Temperature: 100 °C
Reaction time: 1 h
Yield: 66.5 %

Procedure:
A solution of 2-bromo-3,4-bis(decyloxy)-5-(benzothiazol-2-yl)-thiophene (12.2 g 20 mmol), and hexabutyl ditin (5.8 g, 10 mmol) in dioxane (100 ml), (freshly distilled from sodium after treatment with potassium hydroxide), was degassed by bubbling nitrogen through the solution for 20 min. Under nitrogen, tetrakistriphenylphosphinopalladium (0.468 g) was added and the mixture was heated at 100° C. for 20 hr. After cooling, pyridine (5 ml) was added and the resulting mixture allowed to stand for 1 hr. The separated solids were filtered and the filtrate diluted with an equal volume of water. The mixture was extracted with an equal volume of toluene, dried over magnesium sulfate and concentrated. The residue was combined with the initial solids and chromatographed over 250 g of silica gel. Elution with 3:1 and 2:1 heptane:toluene gave the desired product which was recrystallized from heptane to give 7.02 g (66.5% yield) mp 93.9°-95° C. Mass Spec. m/z 916 (M+ --C10H20). Elemental Analysis: Calculated for C62H92N2O4S4 : C, 70.36, H, 8.77, N, 2.65, and S, 12.10%. Found: C, 69.98, H, 8.90, N, 2.59, and S, 11.98 %.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([NH:18][CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].C1C=C(Cl)C=C(C(OO)=O)C=1.[NH4+:35].[OH-].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)Cl.C(Cl)(Cl)Cl.O.CO>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([NH:18][CH2:19][CH2:20][CH:21]([CH3:22])[CH3:23])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:35])[C:8]=2[N:17]=1)[CH3:2]
Reactant: CCOCc1nc2cnc3ccccc3c2n1NCCC(C)C
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CCOCc1nc2c(N)nc3ccccc3c2n1NCCC(C)C
Reaction time: 1.5 h

Procedure:
A solution of N-(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)(3-methylbutyl)amine (1.24 g, 3.97 mmol) in 45 mL of CH2Cl2 was treated with MCPBA (1.87 g, 7.04 mmol, 77% max). After 1.5 h, the reaction mixture was treated with 15 mL of concentrated NH4OH solution and p-toluenesulfonyl chloride (0.795 g, 4.17 mmol). After 30 min, the reaction mixture was diluted with CHCl3 and water and the phases were separated. The organic portion was washed with 5% Na2CO3 solution, water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure to yield a sticky orange foam. Chromatography (SiO2, 97:3 CHCl3:MeOH) gave an off white foam. The foam was triturated with diethyl ether and hexanes and filtered to give 2-ethoxymethyl-N1-(3-methylbutyl)-1H-imidazo[4,5-c]quinoline-1,4-diamine (0.435 g) as a cream colored solid. mp 129–132° C.; 1H NMR (300 MHz, CDCl3) δ 8.48 (dd, J=8.1, 1.1 Hz, 1H), 7.78 (d, J=8.3 Hz, 1H), 7.56–7.50 (m, 1H), 7.36–7.30 (m, 1H), 5.59 (t, J=6.7 Hz, 1H), 5.42 (s, 2H), 4.87 (s, 2H), 3.64 (q, J=7.0 Hz, 2H), 3.29 (q, J=7.0 Hz, 2H), 1.76 (s, J=6.7 Hz, 1H), 1.60 (q, J=6.9 Hz, 2H), 1.27 (t, J=7.0 Hz, 3H), 0.97 (d, J=6.6 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 151.2, 147.8, 144.9, 133.1, 127.8, 126.6, 124.0, 122.3, 120.7, 115.2, 66.8, 65.3, 51.1, 36.7, 26.0, 22.6, 15.1; MS (APCI) m/z 328 (M+H)+; Anal. Calcd for C18H25N5O.0.06H2O: C, 65.81; H, 7.71; N, 21.32; Found: C, 65.42; H, 7.75; N, 21.11. Karl Fischer analysis 0.32% water.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:9]1[C@@:13]2([CH3:31])[CH2:14][CH2:15][CH:16]3[C@@:21]4([CH3:30])[CH2:22][CH2:23][CH:24]([O:26][C:27](Cl)=[O:28])[CH2:25][C:20]4=[CH:19][CH2:18][CH:17]3[CH:12]2[CH2:11][CH2:10]1)[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].[NH2:32][CH:33]([CH2:36][OH:37])[CH2:34][OH:35].Cl.C(N(CC)CC)C>C(Cl)Cl.CO>[OH:35][CH2:34][CH:33]([NH:32][C:27](=[O:28])[O:26][C@H:24]1[CH2:23][CH2:22][C@@:21]2([CH3:30])[C:20](=[CH:19][CH2:18][C@@H:17]3[C@@H:16]2[CH2:15][CH2:14][C@@:13]2([CH3:31])[C@H:12]3[CH2:11][CH2:10][C@@H:9]2[C@H:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7])[CH2:25]1)[CH2:36][OH:37]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CCC2C3CC=C4CC(OC(=O)Cl)CC[C@]4(C)C3CC[C@@]21C
Reactant: NC(CO)CO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(=O)NC(CO)CO)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 45 h
Yield: 76.7 %

Procedure:
A solution of 5.00 g of cholesteryl chloroformate in 20 ml of methylene chloride is added dropwise to a mixture of 1.4 g of DL-serinol.HCl and 3.1 ml of triethylamine in 30 ml of methylene choride. After stirring for 45 hours the mixture is taken up in aqueous methanol and extracted with chloroform. The organic phase is dried and concentrated. After chromatography over SiO2 with chloroform and then with ether there are obtained 4.3 g of cholest-5-en-3β-yl [2-hydroxy-1-(hydroxymethyl)ethyl]carbamate, m.p. 158° C. (decomposition). b) A solution of 3.7 g of the product of a) in 30 ml of methylene chloride, 10 ml of THF and 0.6 ml of pyridine is treated under argon with 1 ml of phenyl chloroformate in 15 ml of methylene chloride. After stirring for 1 hour the solution is taken up in 200 ml of water and 50 ml of 0.1N HCl and extracted with 150 ml of methylene chloride. The organic phase is dried and concentrated. After chromatography over SiO2 with n-hexane/ether (1:1) and ether there are obtained 2.1 g of cholest-5-en-3β-yl [(RS)-2-hydroxy-1-[(phenoxycarbonyl)oxymethyl]ethyl]carbamate.
Reaction SMILES: C([O:3][C:4](=[O:46])[C@H:5]([OH:45])[CH2:6][NH:7][C:8](=[O:44])[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([NH:28][C:29]([NH:31][C:32]2[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[C:34]([O:42][CH3:43])[CH:33]=2)=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)=[CH:11][CH:10]=1)C.[OH-].[Na+]>C(O)C>[CH:22]1([C:19]2[CH:18]=[CH:17][C:16]([CH:15]([NH:28][C:29]([NH:31][C:32]3[CH:37]=[C:36]([C:38]([F:40])([F:41])[F:39])[CH:35]=[C:34]([O:42][CH3:43])[CH:33]=3)=[O:30])[C:12]3[CH:13]=[CH:14][C:9]([C:8]([NH:7][CH2:6][C@@H:5]([OH:45])[C:4]([OH:46])=[O:3])=[O:44])=[CH:10][CH:11]=3)=[CH:21][CH:20]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CCOC(=O)[C@H](O)CNC(=O)c1ccc(C(NC(=O)Nc2cc(OC)cc(C(F)(F)F)c2)c2ccc(C3CCCCC3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(NC(=O)NC(c2ccc(C(=O)NC[C@@H](O)C(=O)O)cc2)c2ccc(C3CCCCC3)cc2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(R)-3-{4-[1-(4-Cyclohexylphenyl)-3-(3-methoxy-5-trifluoromethylphenyl)ureidomethyl]benzoyl-amino}-2-hydroxypropionic acid ethyl ester was dissolved in ethanol (15 mL) and sodium hydroxide (2 N, 2 mL) was added. The reaction mixture was stirred at room temperature for 60 min. Then ethanol was removed in vacuo, water (50 mL) was added and pH was adjusted with 4 N hydrochloric acid to acidic reaction. Filtration and washing with water (5×5 mL) and drying in vacuo afforded 460 mg of the title compound as a crystalline solid.
Reaction SMILES: O.[C:2]1([CH3:12])[CH:7]=[CH:6][C:5](S(O)(=O)=O)=[CH:4][CH:3]=1.[C:13]([OH:40])(=[O:39])[CH2:14][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][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37].C(O)C1C=CC=CC=1>C1C=CC=CC=1>[C:13]([O:40][CH2:12][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:39])[CH2:14][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][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37]
Reactant: O=C(O)CCCCCCCCCCCCCCCCCCCCCCC(=O)O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: OCc1ccccc1
Solvent: O
Solvent: c1ccccc1
Product: O=C(O)CCCCCCCCCCCCCCCCCCCCCCC(=O)OCc1ccccc1

Procedure:
Toluene-4-sulfonic acid monohydrate (0.05 g, 0.28 mmol) is added to a suspension of tetracosanedioic acid (5.0 g, 80%, 10.03 mmol) in benzene (180 ml). The mixture is heated to 80° C., whereafter benzyl alcohol (1.08 g, 10.03 mmol) in benzene (10 ml) is added dropwise to the resulting solution. The reaction mixture is refluxed for 20 hours and water is removed azeotropically with a Dean Stark trap. The solvent is removed under reduced pressure and the residue washed with petroleum ether. The product is dissolved in refluxing diethyl ether and purified by flash chromatography on a silica column with methylene chloride/methanol (20:1) as eluant to yield the title compound as a white crystalline solid. 13C NMR (75 MHz, CDCl3): δ 24.0, 28.5, 29.7, 30.9, 34.4, 66.2, 128.2, 128.5, 136.0, 174.1, 176.9.
Reaction SMILES: Br[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[S:9][C:4]=2[C:3]=1[CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.[CH:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O)=[CH2:21].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:14]1([C:3]2[C:4]3[S:9][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][C:5]=3[NH:6][C:2]=2[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[CH:20]=[CH2:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: C=Cc1ccccc1B(O)O
Reactant: COC(=O)c1cc2[nH]c(Br)c(C3CCCCC3)c2s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: C=Cc1ccccc1-c1[nH]c2cc(C(=O)OC)sc2c1C1CCCCC1
Reaction time: 1 h
Yield: 71 %

Procedure:
Methyl 5-bromo-6-cyclohexyl-4H-thieno[3,2-b]pyrrole-2-carboxylate (prepared as described in Example 7, Step 1) and (2-vinylphenyl)boronic acid (1.5 eq.) were dissolved in dioxane (0.06 M) and 2M aq. Na2CO3 (6 eq.) was added. The solution was degassed by bubbling argon, Pd(PPh3)2Cl2 (0.2 eq.) was added, and the reaction mixture was placed in an oil bath preheated to 110° C. and stirred for 1 h; after removing all volatiles the title compound was isolated by chromatography (PE/EtOAc 10:1). Yield: 71%. 1H-NMR (400 MHz, CDCl3, 300 K, δ) 8.16 (bs, 1H), 7.69 (d, 1H, J 7.9), 7.68 (s, 1H), 7.45-7.35 (m, 3H), 6.67 (dd, 1H, J 17.5, 11.0), 5.74 (d, 1H, J 17.5), 5.25 (d, 1H, J 11.0), 3.91 (s, 3H), 2.54-2.47 (m, 1H), 1.81-1.23 (m, 10H); MS (ES+) m/z 366 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14](Br)[CH:15]=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]3=[N:18][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccccn1
Reactant: CC(C)(C)OC(=O)N1CCC(C(Br)C=O)CC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2cnc3ccccn23)CC1
Yield: 35.4 %

Procedure:
To a solution of 1.15 g of 1-(t-butoxycarbonyl)-4-(1-bromo-2-oxoethyl)piperidine (from Procedure 23, Step C) in 15 mL ethanol was added 388 mg of 2-aminopyridine. After refluxing for 18 h, the solvent was evaporated. The mixture was partitioned between ethyl acetate and saturated sodium bicarbonate solution. Aqueous layer was extracted with ethyl acetate (3×). The combined organic phase was washed with brine, dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography with 50% ethyl acetate in hexanes, followed by 100% ethyl acetate to give 401 mg of the title compound as a solid.
Reaction SMILES: S(=O)(=O)(O)O.[N:6]1[CH:11]=[CH:10][CH:9]=[N:8][C:7]=1[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.II.[I:20](O)(=O)(=O)=O>C(O)(=O)C.C(Cl)(Cl)Cl.O>[N:12]1([C:7]2[N:8]=[CH:9][C:10]([I:20])=[CH:11][N:6]=2)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: [O-][I+3]([O-])([O-])O
Agent: II
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CC(=O)O
Product: Ic1cnc(N2CCNCC2)nc1

Procedure:
In a mixture of acetic acid (5 ml), water (1 ml) and sulfuric acid (0.15 ml) was dissolved 2 g of 1-(2-pyrimidyl)piperazine which was then reacted with 0.86 g of iodine in the presence of 0.38 g of periodic acid at 100° C. for 6 hours with stirring. Chloroform was added to the reaction mixture, followed by washing with sodium hydrogen carbonate and brine. The organic layer thus obtained was dehydrated, filtered and concentrated under vacuum. Purification with column chromatography provided the title compound. 600 mg.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[N:9]=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([Cl:19])[N:14]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:26].[O:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[S:32](Cl)(=[O:34])=[O:33]>>[Cl:1][C:2]1[C:7]([C:8]2[N:9]=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([Cl:19])[N:14]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:26][S:32]([C:28]1[O:27][CH:31]=[CH:30][CH:29]=1)(=[O:34])=[O:33]
Reactant: O=S(=O)(Cl)c1ccco1
Reactant: Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1Cl
Product: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1Cl)c1ccco1

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using {2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]phenyl}amine (1.03 g, 2.52 mmol) and 2-furansulfonyl chloride (0.588 g, 3.53 mmol) the title compound of Step E was obtained as an off-white solid (430 mg, 0.735 mmol, 29.1% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.53 (s, 1H), 8.38 (d, J=5.5 Hz, 1H), 7.91 (d, J=0.9 Hz, 1H), 7.43-7.58 (m, 2H), 7.31-7.43 (m, 1H), 7.08 (d, J=3.5 Hz, 1H), 6.55 (dd, J=3.5, 1.8 Hz, 1H), 6.18 (d, J=5.5 Hz, 1H), 3.71 (t, J=4.8 Hz, 4H), 3.55 (t, J=4.7 Hz, 4H). MS (ESI): 537.96 [M+H]+.
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]1[O:21][C:8]2([CH2:13][CH2:12][C:11](O)([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[CH2:10][CH2:9]2)[O:7][CH2:6]1.[OH-].[Na+]>N1C=CC=CC=1>[CH2:6]1[O:7][C:8]2([CH2:13][CH2:12][C:11]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[CH:10][CH2:9]2)[O:21][CH2:5]1
Reactant: OC1(c2cccnc2)CCC2(CC1)OCCO2
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: C1=C(c2cccnc2)CCC2(C1)OCCO2
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
Thionyl chloride (45 mL, 622.5 mmol) was slowly added to a solution of 4-hydroxy-4-(3-pyridyl)cyclohexanone ethylene ketal (prepared as in step a, 29.3 g, 124.5 mmol) in pyridine (250 mL) at −10° C. After stirring at 0° C. for 2.5 h, the reaction mixture was poured onto ice and adjusted to pH 8 with 2 N NaOH. The aqueous layer was extracted with CH2Cl2 (100 mL×3) and the combined organic layers were washed with brine (200 mL), dried with MgSO4, and concentrated in vacuo to afford crude 4-(3-pyridyl)cyclohex-3-en-1-one ethylene ketal, which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[SH:9].Cl[CH2:11][C:12]([CH3:17])([CH3:16])[C:13]([OH:15])=[O:14].CC(C)=O.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[S:9][CH2:11][C:12]([CH3:17])([CH3:16])[C:13]([OH:15])=[O:14]
Reactant: Cc1ccc(C)c(S)c1
Reactant: CC(C)(CCl)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1ccc(C)c(SCC(C)(C)C(=O)O)c1
Temperature: 25 °C
Yield: 79.7 %

Procedure:
A 100-ml round-bottomed flask was charged with 1.38 g (10.00 mmol) of 2,5-dimethylthiophenol, 1.40 g (10.26 mmol) of 3-chloropivalic acid and 15 ml of acetone. Then, 2.07 g (15.0 mmol) of potassium carbonate was added, and the mixture was refluxed under heat for 30 minutes. The reaction mixture was allowed to cool to room temperature, and then about 100 ml of water was added. An aqueous layer was washed with n-hexane once, and neutralized and acidified with a 5 wt % hydrochloric acid aqueous solution. A precipitated solid was extracted with ethyl acetate, and an organic layer was washed with diluted hydrochloric acid and with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 1.90 g (yield 80%) of 3-(2,5-dimethylphenylthio)pivalic acid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Br[CH2:7][CH2:8][CH2:9][CH2:10][Cl:11].[OH-].[Na+].O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CC(C)=O>[Cl:11][CH2:10][CH2:9][CH2:8][CH2:7][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: ClCCCCBr
Reactant: c1c[nH]cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: ClCCCCn1ccnc1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
Imidazole (680 mg), 1-bromo-4-chlorobutane (0.93 ml), tetrabutylammonium iodide (10 mg), and a 3 M aqueous sodium hydroxide solution (1 ml) were dissolved in acetone (10 ml), and the solution was stirred at 50° C. for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by chromatography by development with chloroform to give an intermediate (1-(4-chlorobutyl)-1H-imidazole, 756 mg).
Reaction SMILES: [NH3:1].[C:2]1([CH2:8][O:9][C:10](=[O:29])[NH:11][CH:12](SC(C)C)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22](=O)[CH3:23])=[O:14])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1.[Hg](Cl)Cl>[CH3:23][C:22]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[NH:15][C:13](=[O:14])[CH:12]([NH:11][C:10](=[O:29])[O:9][CH2:8][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:1]=1
Reactant: CC(=O)c1ccccc1NC(=O)C(NC(=O)OCc1ccccc1)SC(C)C
Reactant: N
Agent: Cl[Hg]Cl
Solvent: C1CCOC1
Product: CC1=NC(NC(=O)OCc2ccccc2)C(=O)Nc2ccccc21
Reaction time: 6 h

Procedure:
Ammonia gas was passed through a solution of phenylmethyl[2-[(2-acetylphenyl)amino]-1-[(1-methylethyl)thio]-2-oxoethyl]carbamate (14.74 g) in dry THF (250 ml) at 0° for 0.5 h. Mercury (II) chloride (10.00 g) was added and the mixture was rapidly stirred for 6 h whilst continuing to pass ammonia gas through the mixture. The mixture was filtered through hyflo and the solvent removed from the filtrate by evaporation in vacuo. The residue was treated with acetic acid (290 ml) and sodium acetate (13.35 g) and the resulting mixture stirred at 23° for 18 h. The solvent was evaporated in vacuo and the residue was purified by chromatography. Elution with EA gave the title compound (5.70 g).