Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[CH:22]=[C:21]([C:23]2[CH:24]=[CH:25][C:26]([N:29]3[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]3)=[N:27][CH:28]=2)[CH:20]=[C:19]2[C:15]=1[C:16]([CH3:45])=[N:17][N:18]2[CH:42]([CH3:44])[CH3:43])=[O:13].[ClH:46]>C(Cl)Cl.O1CCOCC1>[ClH:46].[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[C:16]([CH3:45])=[N:17][N:18]([CH:42]([CH3:43])[CH3:44])[C:19]=2[CH:20]=[C:21]([C:23]2[CH:28]=[N:27][C:26]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[CH:25][CH:24]=2)[CH:22]=1)=[O:13]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)nc3)cc3c2c(C)nn3C(C)C)c(=O)[nH]1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(N4CCNCC4)nc3)cc3c2c(C)nn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
To a stirred solution of tert-butyl 4-(5-(4-((1,2-dihydro-4,6-dimethyl-2-oxopyridin-3-yl)methylcarbamoyl)-1-isopropyl-3-methyl-1H-indazol-6-yl)pyridin-2-yl)piperazine-1-carboxylate (250 mg, 0.407 mmol) in DCM (50 mL) was added 4M HCl in 1,4-dioxane (6 mL) at 0° C. and stirred at room temperature for 2 h. The reaction mixture was concentrated and then co-distilled with toluene (50 mL). The residue was dried under reduced pressure to get the crude HCl salt (195 mg). The residue was triturated with diethyl ether (100 mL), DCM (100 mL) and n-hexane (100 mL) to afford the title compound as a pale brown solid (135 mg, 60%). 1H NMR (DMSO-d6, 400 MHz): δ 1.454 (d, J=6.4 Hz, 6H), 2.119 (s, 3H), 2.244 (s, 3H), 2.412 (s, 3H), 3.222 (s, 4H), 3.839 (s, 4H), 4.369 (d, J=4.4 Hz, 2H), 5.005-5.071 (m, 1H), 5.888 (s, 1H), 7.125 (d, J=8.8 Hz, 1H), 7.348 (s, 1H), 7.942 (s, 1H), 8.158 (d, J=8 Hz, 1H), 8.429 (t, J=4.6 Hz, 1H), 8.613 (d, J=2.0 Hz, 1H), 9.145 (s, 2H), 11.519 (brs, 1H). LCMS (ES+): 514.24 [M+H].
Reaction SMILES: [N+:1]([C:4]1[S:8][C:7]([CH:9]=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].BrBr.C(O)(=[O:15])C.C([O-])(=O)C.[Na+]>>[N+:1]([C:4]1[S:8][C:7]([C:9]([OH:15])=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=Cc1ccc([N+](=O)[O-])s1
Reactant: CC(=O)O
Agent: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Product: O=C(O)c1ccc([N+](=O)[O-])s1
Yield: 98.5 %

Procedure:
As an example, a trial performed with 5-nitro-2-formyl-thiophene and bromine in a medium maintained at pH=4.6 by means of a acetic acid/sodium acetate mixture provided crude 5-nitro-2-thenoic acid in a yield of 98.5% or the pure acid in a yield of 81%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:22][C:21]2[C:16]3[N:17]=[C:18]([CH3:20])[O:19][C:15]=3[C:14]([C:23]([OH:25])=O)=[CH:13][C:12]=2[N:11]=1.S(Cl)(Cl)=O.[F:30][C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=1.[H-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:22][C:21]2[C:16]3[N:17]=[C:18]([CH3:20])[O:19][C:15]=3[C:14]([C:23]([NH:35][C:34]3[CH:36]=[CH:37][C:31]([F:30])=[CH:32][CH:33]=3)=[O:25])=[CH:13][C:12]=2[N:11]=1
Reactant: Nc1ccc(F)cc1
Reactant: Cc1nc2c(o1)c(C(=O)O)cc1nc(Nc3c(F)cccc3Cl)[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: Cc1nc2c(o1)c(C(=O)Nc1ccc(F)cc1)cc1nc(Nc3c(F)cccc3Cl)[nH]c12
Yield: 31.9 %

Procedure:
The title compound was prepared following the procedure as described for Example-177 using 7-[(2-chloro-6-fluorophenyl)amino]-2-methyl-8H-imidazo[4,5-e][1,3]benzoxazole-4-carboxylic acid (Intermediate-56, 0.050 g, 0.138 mmol), thionyl chloride (2.0 mL), 4-fluoro aniline (0.052 g, 0.138 mmol), THF (5.0 mL) and 60% NaH (0.017 g, 0.692 mmol). The obtained product was further purified by column chromatography on neutral alumina eluting with 1.5-2.0% MeOH: DCM to afford 0.020 g of the desired product. 1HNMR (DMSO-d6): δ 2.65 (s, 3H), 7.20 (t, J=7.8 Hz, 2H), 7.40-7.46 (m, 3H), 7.63 (s, 1H), 7.80-7.82 (m, 2H), 9.34 (s, 1H), 10.08 (s, 1H), 11.63 (s, 1H); MS [M−H]−: 452.23.
Reaction SMILES: Cl.[N:2]1([C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>N1C=CC=CC=1>[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([N:5]2[CH2:4][CH2:3][N:2]([C:8]3[CH:9]=[CH:10][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:17][CH:18]=3)[CH2:7][CH2:6]2)=[O:25])=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1ccc(N2CCN(C(=O)c3ccc(Cl)cc3)CC2)cc1
Temperature: 40 °C
Reaction time: 6 h
Yield: 82 %

Procedure:
To a mixture of 13.5 g. (50 mmole) ethyl 4-(piperazin-1-yl)-benzoate hydrochloride and 130 ml. anhydrous pyridine are added, at 5°-10° C., 50 mmole 4-chlorobenzoyl chloride. The temperature is allowed to come to 20° C. and the reaction mixture is subsequently stirred for 6 hours at 40° C. After cooling, it is stirred into 400 ml. ice water, extracted twice with 250 ml. amounts of methylene chloride and the organic phase is dried with anhydrous sodium sulphate and evaporated in a vacuum. The residue is triturated with ligroin and recrystallised from 150 ml. ethanol to give 15.6 g. of the desired product as colourless crystals; m.p. 147°-150° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:12]#N)=[CH:7][CH:8]=2)[NH:3]1.C(O)=[O:15]>[Ni]>[O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([CH:12]=[O:15])=[CH:7][CH:8]=2)[NH:3]1
Reactant: N#Cc1ccc2c(c1)NC(=O)CC2
Reactant: O=CO
Agent: [Ni]
Product: O=Cc1ccc2c(c1)NC(=O)CC2
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a formic acid (250 mL) solution of the compound (32.6 g) obtained in Step 1-3, Raney nickel catalyst (50.0 g) was added and the mixture was stirred at 50° C. for 2 hours. After the reaction mixture was filtrated by Celite, the filtrate was concentrated under reduced pressure. To the residue, a saturated aqueous NaHCO3 solution was added and the mixture was adjusted to pH 6 and filtrated to obtain solid A. The filtrate was extracted three times with CHCl3 and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue and solid A were combined and suspended in a solution mixture of EtOAc/CHCl3/acetone (10/10/1; v/v/v) and the mixture was stirred at room temperature for one hour and filtrated to obtain 2-oxo-1,2,3,4-tetrahydroquinoline-7-carbaldehyde (19.8 g, a light yellow solid).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:14])[C:5](=[C:11]([CH3:13])[CH3:12])[O:6]2.C(=O)([O-])[O-].[K+].[K+].[Cl:21][CH2:22][C:23]#[C:24][CH2:25]Cl>CN(C)C=O>[Cl:21][CH2:22][C:23]#[C:24][CH2:25][O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:14])[C:5](=[C:11]([CH3:12])[CH3:13])[O:6]2
Reactant: CC(C)=C1Oc2cccc(O)c2C1=O
Reactant: ClCC#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)=C1Oc2cccc(OCC#CCCl)c2C1=O
Temperature: 50 °C

Procedure:
A mixture of 5.0 g 4-hydroxy-2-isopropylidenecoumaran-3-one, 4.6 g potassium carbonate, 3.3 ml 1,4-dichloro-but-2-yne and 100 ml dimethylformamide is warmed to 50° C. for 3 hours, then evaporated, mixed with water and extracted with dichloromethane. After evaporation of the extract, the residue (9.2 g) is purified by silica gel chromatography (eluent isohexane/ethyl acetate 9:1) to give 2.2 g of the desired intermediate.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[Br:10][C:11]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:12]=1[NH2:13]>>[Br:10][C:11]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:12]=1[N:13]([C:7]([C:5]1[S:6][C:2]([CH3:1])=[CH:3][CH:4]=1)=[O:9])[C:7]([C:5]1[S:6][C:2]([CH3:1])=[CH:3][CH:4]=1)=[O:9]
Reactant: COc1ccc(N)c(Br)c1
Reactant: Cc1ccc(C(=O)O)s1
Product: COc1ccc(N(C(=O)c2ccc(C)s2)C(=O)c2ccc(C)s2)c(Br)c1
Yield: 37 %

Procedure:
Following Step 1 from General Procedure A, 5-methylthiophene-2-carboxylic acid (8.5 g, 60 mmol) was reacted with 2-bromo-4-methoxyaniline (6.7 g, 30 mmol) to afford the desired product (5.0 g, 57%) as a solid: ESI MS m/z 327 [C13H12BrNO2S+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30][NH:29][CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:7]=[C:8]([C:10]([OH:12])=[O:11])[CH:9]=1)([OH:3])=[O:2].Cl[CH2:36][C:37]([O-:39])=[O:38].[Na+].Cl>>[C:37]([CH2:36][N:26]1[CH2:25][CH2:24][N:23]([CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:6]2[CH:7]=[C:8]([C:10]([OH:12])=[O:11])[CH:9]=[C:4]([C:1]([OH:3])=[O:2])[CH:5]=2)[CH2:34][CH2:33][N:32]([CH2:4][C:1]([OH:3])=[O:2])[CH2:31][CH2:30][N:29]([CH2:8][C:10]([OH:12])=[O:11])[CH2:28][CH2:27]1)([OH:39])=[O:38]
Reactant: O=C(O)c1cc(CCCCCCCCCCN2CCNCCNCCNCC2)cc(C(=O)O)c1
Reactant: O=C([O-])CCl
Agent: Cl
Agent: [Na+]
Product: O=C(O)CN1CCN(CCCCCCCCCCc2cc(C(=O)O)cc(C(=O)O)c2)CCN(CC(=O)O)CCN(CC(=O)O)CC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To an aqueous solution of 1-[10-(3,5-dicarboxyphenyl)decyl]-1,4,7,10-tetraazacyclododecane (0.16 mols in 500 mL water) is added an aqueous solution of sodium chloroacetate (0.71 mols sodium chloroacetate in 68 mL of water). This solution is stirred at 80° C. overnight while maintaining the pH at 9-10. After cooling to ambient temperature the pH of the solution is adjusted to 2.5 with aqueous HCl. The resulting precipitate is collected by filtration, washed with acetone, and dried in vacuo to afford 18.
Reaction SMILES: [F:1][CH:2]([CH3:35])[CH2:3][N:4]([S:26]([C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1)(=[O:28])=[O:27])[C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][CH2:11]2)=[CH:7][C:6]=1[O:14][CH2:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][N:17]=1.[OH-].[Na+]>C1COCC1.CO>[F:1][CH:2]([CH3:35])[CH2:3][N:4]([S:26]([C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1)(=[O:28])=[O:27])[C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][CH2:11]2)=[CH:7][C:6]=1[O:14][CH2:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([OH:22])=[O:21])=[CH:18][N:17]=1
Reactant: COC(=O)c1ccc(COc2cc3c(cc2N(CC(C)F)S(=O)(=O)c2cccnc2)CCC3)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(F)CN(c1cc2c(cc1OCc1ccc(C(=O)O)cn1)CCC2)S(=O)(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.9 %

Procedure:
148 mg of methyl 6-[({6-[(2-fluoropropyl)(pyridin-3-ylsulfonyl)amino]-2,3-dihydro-1H-inden-5-yl}oxy)methyl]nicotinate was dissolved in 3.00 mL of THF and 1.50 mL of methanol, and 1.50 mL of a 1 M aqueous sodium hydroxide solution was added thereto, followed by stirring overnight at room temperature. The reaction liquid was concentrated under reduced pressure, and to the obtained residue was added a 5% w/v aqueous citric acid solution, followed by extraction with chloroform. The organic layer was concentrated under reduced pressure, and the obtained crude product was crystallized by the addition of isopropanol/diisopropyl ether, collected by filtration, and dried under reduced pressure to obtain 79 mg of 6-[({6-[(2-fluoropropyl)(pyridin-3-ylsulfonyl)amino]-2,3-dihydro-1H-inden-5-yl}oxy)methyl]nicotinic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[N+:16]([O-])=O)[O:5][CH2:6][CH2:7][N:8]([CH2:11][CH3:12])[CH2:9][CH3:10]>[Ni].CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([O:5][CH2:6][CH2:7][N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])[CH:13]=[CH:14][C:15]=1[NH2:16]
Reactant: CCN(CC)CCOc1ccc([N+](=O)[O-])c(Cl)c1
Agent: [Ni]
Solvent: CCOC(C)=O
Product: CCN(CC)CCOc1ccc(N)c(Cl)c1

Procedure:
A suspension of 1.24 g (4.547 mmol) [2-(3-chloro-4-nitro-phenoxy)-ethyl]diethyl-amine (Z27a) and 300 mg Raney nickel in EtOAc was hydrogenated at RT and 3 bar. The catalyst was filtered off and the filtrate evaporated down i. vac.
Reaction SMILES: [CH:1]1([N:6]2[C:10]([NH2:11])=[C:9]([C:12]([NH2:14])=[O:13])[C:8]([CH2:15][CH3:16])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:17]([O:19][C:20]([CH2:22][O:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=O)=[O:21])[CH3:18]>>[CH:1]1([N:6]2[C:10]3=[N:11][C:27]([C:26]4[CH:29]=[CH:30][CH:31]=[C:24]([O:23][CH2:22][C:20]([O:19][CH2:17][CH3:18])=[O:21])[CH:25]=4)=[N:14][C:12](=[O:13])[C:9]3=[C:8]([CH2:15][CH3:16])[NH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Reactant: CCOC(=O)COc1cccc(C=O)c1
Product: CCOC(=O)COc1cccc(-c2nc3n(C4CCCC4)[nH]c(CC)c-3c(=O)n2)c1
Temperature: 160 °C
Yield: 37.9 %

Procedure:
A mixture of 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (3.54 g, 15.95 mmol), 3-(ethoxycarbonylmethoxy) benzaldehyde (4.3 g) and xylenes (20 ml) was heated at 160° C. overnight. The reaction mixture was cooled to room temperature, a solid formed which was collected by filtration and washed with methanol and then ether. The product was recrystallized from acetonitrile to afford 2.48 g of 1-cyclopentyl-3-ethyl-6-[3-(ethoxycarbonylmethoxy)phenyl]pyrazolo[3,4-d]pyrimidin-4-one. An additional 0.3 g of product was also obtained from the recrystallization of the filtrate for a total of 2.78 g.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([C:12]1[CH:33]=[CH:32][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[N:24]=[CH:25][C:18]=23)=[CH:14][CH:13]=1)(=[O:11])=[O:10].[C:34](Cl)(=[O:38])[CH:35]([CH3:37])[CH3:36]>>[CH3:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:27][CH2:28][N:29]([C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH2:30][CH2:31]4)[N:24]=[CH:25][C:18]=23)=[CH:32][CH:33]=1)(=[O:11])=[O:10]
Reactant: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCNCC2)cc1
Reactant: CC(C)C(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C(=O)N1CCC(n2ncc3c(Oc4ccc(S(C)(=O)=O)cc4)ncnc32)CC1

Procedure:
1-{4-[4-(4-Methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidin-1-yl}-2-methyl-propan-1-one was prepared according to General Procedure I by the reaction of 4-(4-methanesulfonyl-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoroacetate salt (Intermediate 27) with isobutyryl chloride (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA). 1H NMR (400 MHz, DMSO-d6) δ 1.05 (d, 6H, J=6.9 Hz), 1.95-2.06 (m, 4H), 2.80-2.86 (m, 1H), 2.92-2.99 (m, 1H), 3.30 (methyl sulfonyl and water peak), 4.10-4.14 (m, 1H), 4.54-4.57 (m, 1H), 5.08-5.12 (m, 1H), 7.63-7.65 (m, 2H), 8.05-8.07 (m, 2H), 8.38 (s, 1H), 8.57 (s, 1H). Mass spectrum MH+=444.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][N:9]=1)C#N.C[Mg]Br.CCCCCC.CC[O:21][CH2:22][CH3:23]>>[F:1][C:2]1[CH:3]=[C:4]([C:22](=[O:21])[CH3:23])[CH:7]=[CH:8][N:9]=1
Reactant: N#Cc1ccnc(F)c1
Reactant: CCOCC
Agent: C[Mg]Br
Solvent: CCCCCC
Product: CC(=O)c1ccnc(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-fluoroisonicotinonitrile (10 g, 82 mmol) in anhydrous Et2O (250 mL) cooled in an ice-water bath was slowly added 3M methyl magnesium bromide in hexane (40 mL, 120 mmol). The mixture was stirred at 25° C. overnight. The reaction was quenched slowly with 1N aq. citric acid solution at 0° C. until all solids dissolved. Brine was added and the two phases were separated. The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo to give 1-(2-fluoropyridin-4-yl)-ethanone (6.2 g) as a brown oil. The aqueous phase was stirred at 25° C. for 3 h, then extracted with CH2Cl2. The dichloromethane layer was dried over Na2SO4, filtered, and concentrated in vacuo to give an additional 1.1 g of the product, for a total of 7.3 g, used in the next step without further purification. MS m/z 139. 1H NMR (CDCl3): δ 8.25 (dd, 1H), 7.47 (d, 1H), 7.21 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[N:12][C:11]([S:22]([CH3:24])=[O:23])=[N:10]2)=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:33])C=1.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[N:12][C:11]([S:22]([CH3:24])(=[O:33])=[O:23])=[N:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2nc(S(C)=O)nn2-c2ccc(OC)cc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(-c2nc(S(C)(=O)=O)nn2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 81.7 %

Procedure:
A mixture of 1,5-bis(4-methoxyphenyl)-3-(methylsulfinyl)-1H-1,2,4-triazole (152 mg, 0.443 mmol) and m-chloroperbenzoic acid (115 mg, 0.664 mmol) in dichloromethane (1.5 mL) was stirred at room temperature for 6 hours. Dichloromethane and sat. sodium bicarbonate solution were poured into the mixture and the organic layer was separated. The aqueous layer was extracted with dichloromethane. A combined organic layer was washed with sat. sodium bicarbonate solution and brine and dried over magnesium sulfate. The solvent was removed under reduced pressure. The residue was triturated with diisopropyl ether and the precipitate was isolated by filtration, washed with diisopropyl ether, and dried in vacuo to give 1,5-bis(4-methoxyphenyl)-3-(methylsulfonyl)-1H-1,2,4-triazole (130 mg, 81.7% yield).
Reaction SMILES: [CH3:1][S:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15]CC3C=CC=CC=3)=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][N:4]=1.O.[OH-].[Na+]>FC(F)(F)C(O)=O>[CH3:1][S:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([OH:15])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][N:4]=1
Reactant: COc1cc2c(SC)ncnc2cc1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(SC)ncnc2cc1O
Yield: 90.8 %

Procedure:
A solution of 4-(methylthio)-6-methoxy-7-benzyloxyquinazoline (29.5 g, 0.095 mol) in trifluoroacetic acid (250 ml) was heated at reflux for 3 hours. The mixture was cooled, water was added, and the pH adjusted to pH 5 with sodium hydroxide (2.0 N). The solid was filtered, washed with water and diethyl ether and dried in vacuo. The solid was redissolved in methanol (2000 ml) and water (500 ml), the pH was adjusted to 7 with sodium hydroxyde (2.0 N) and the precipitated solid was collected by suction filtration. Drying in vacuo yielded 4-(methylthio)-6-methoxy-7-hydroxy-quinazoline (19.18 g, 91% yield):
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]#[N:8])=[CH:4][C:3]=1[CH2:9][OH:10].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[Cl:1][C:2]1[S:6][C:5]([C:7]#[N:8])=[CH:4][C:3]=1[CH:9]=[O:10]
Reactant: N#Cc1cc(CO)c(Cl)s1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: N#Cc1cc(C=O)c(Cl)s1
Yield: 151.8 %

Procedure:
To a solution of 3.0 g of 5-chloro-4-hydroxymethylthiophene-2-carbonitrile in 34 mL of dichloromethane was added 8.06 g of Dess-Martin reagent at room temperature, and stirred at this temperature for a day. After diluting with dichloromethane, washing successively with aqueous sodium hydrogen carbonate and saturated brine, and drying over anhydrous magnesium sulfate, the solvent was evaporated, to afford 4.5 g of a crude product of the title compound as colorless crystals.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:19]=[CH:18][S:17][C:16]=2[C:20]([O:22][CH3:23])=[O:21])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:24](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O.Cl>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([C:15]2[CH:19]=[CH:18][S:17][C:16]=2[C:20]([O:22][CH3:23])=[O:21])[CH3:24])(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1sccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1sccc1N(C)S(=O)(=O)c1ccc(C(C)(C)C)cc1
Temperature: 65 °C
Yield: 83.6 %

Procedure:
To a solution of 55 (0.15 g; 0.42 mmol) in N,N-dimethylformamide (2 mL) at room temperature was added potassium carbonate (0.282 g; 2.12 mmol) followed by iodomethane (0.053 mL; 0.85 mmol). The reaction mixture was heated at 65° C. for 12 hours, cooled to room temperature, diluted with aqueous hydrochloric acid (50 mL; 2M) and extracted with dichloromethane (3×25 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield a crude residue that was purified by chromatography on silica gel eluting with a 0 to 10% ethyl acetate/hexanes gradient to give the title product (0.129 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:11]3([N:15]=[C:14]([NH2:16])[C:13]([CH3:17])=[N:12]3)[CH2:10][CH:9]([CH:18]3[CH2:23][CH2:22][CH2:21][O:20][CH2:19]3)[O:8][C:5]2=[CH:6][CH:7]=1.[Cl:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1>>[Cl:24][C:25]1[CH:30]=[C:29]([C:2]2[CH:3]=[C:4]3[C:11]4([N:15]=[C:14]([NH2:16])[C:13]([CH3:17])=[N:12]4)[CH2:10][CH:9]([CH:18]4[CH2:23][CH2:22][CH2:21][O:20][CH2:19]4)[O:8][C:5]3=[CH:6][CH:7]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: CC1=NC2(CC(C3CCCOC3)Oc3ccc(Br)cc32)N=C1N
Reactant: OB(O)c1cccc(Cl)c1
Product: CC1=NC2(CC(C3CCCOC3)Oc3ccc(-c4cccc(Cl)c4)cc32)N=C1N

Procedure:
6-Bromo-5′-methyl-2-(tetrahydro-2H-pyran-3-yl)spiro[chroman-4,2′-imidazol]-4′-amine (Isomeric mixture 2 from Example 47 Step 3, 0.146 g, 0.39 mmol) was reacted with 3-chlorophenylboronic acid (0.091 g, 0.58 mmol) as described above. The isomers were separated using chiral HPLC methods:
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[C:7]([I:12])[C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:16])=O>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[C:7]([I:12])[C:3]=1[C:4]([Cl:16])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1c(I)ccc(Cl)c1Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Cl)c1c(I)ccc(Cl)c1Cl
Reaction time: 2 h

Procedure:
DMF (one drop) was added to a stirred solution of 2,3-dichloro-6-iodobenzoic acid (1.53 g, 4.83 mmol) and oxalyl chloride (2 ml) in ethyl acetate (20 ml). After 2 hours, the solution was evaporated and the product was used immediately.
Reaction SMILES: [Na].[C:2]([O:9][CH2:10][CH3:11])(=[O:8])[C:3]([O:5]CC)=O.[CH3:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20]>C(O)C>[N+:19]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:13]=1[CH2:12][C:3](=[O:5])[C:2]([O:9][CH2:10][CH3:11])=[O:8])([O-:21])=[O:20]
Reactant: CCOC(=O)C(=O)OCC
Reactant: Cc1ccncc1[N+](=O)[O-]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(=O)Cc1ccncc1[N+](=O)[O-]
Temperature: 20 °C
Reaction time: 0.25 h

Procedure:
To a solution of 930 mg of sodium in 50 mL of absolute ethanol are rapidly added 26 mL of diethyl oxalate. The reaction medium is stirred for 15 minutes at 20° C. A solution of 3.8 g of 4-methyl-3-nitropyridine in 50 mL of absolute ethanol is then added dropwise over 1 hour. The reaction medium is stirred for 4 hours at a temperature in the region of 20° C. and then concentrated under reduced pressure. The residue is taken up in 100 mL of ethyl ether and then filtered. The solid is stirred with 40 mL of 5N hydrochloric acid and then filtered, washed with water and dried under vacuum at 40° C. to give 6.2 g of ethyl 3-(3-nitro-4-pyridyl)-2-oxopropionate having the following characteristics:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:38]#[N:39])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:31][CH:32]([O:35][CH3:36])[CH2:33][CH3:34])[C:17]([NH:19][C:20]3[CH:30]=[CH:29][C:23]([C:24]([O:26]CC)=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:37])[CH:9]=2)[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:38]#[N:39])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:31][CH:32]([O:35][CH3:36])[CH2:33][CH3:34])[C:17]([NH:19][C:20]3[CH:30]=[CH:29][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:37])[CH:9]=2)[CH:7]=1
Reactant: CCOC(=O)c1ccc(NC(=O)C(CC(CC)OC)n2cc(OC)c(-c3cc(Cl)ccc3C#N)cc2=O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: O
Product: CCC(CC(C(=O)Nc1ccc(C(=O)O)cc1)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O)OC

Procedure:
631 mg (1.14 mmol) of ethyl 4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxyhexanoyl}amino)benzoate (mixture of racemic diastereomers) in 22.5 ml of methanol/water (4/1) were reacted with 745 mg (2.29 mmol) of caesium carbonate according to General Method 4. Yield: 580 mg (purity 87%, 84% of theory)