Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[CH2:2]([N:9]1[CH2:12][CH2:11][CH:10]1[C:13]([O:15]CC)=[O:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CC(CC(C)C)=O>C(O)C>[CH2:2]([N:9]1[CH2:12][CH2:11][C@H:10]1[C:13]([OH:15])=[O:14])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)C1CCN1Cc1ccccc1
Solvent: O
Solvent: CC(=O)CC(C)C
Solvent: CCO
Product: O=C(O)[C@@H]1CCN1Cc1ccccc1
Temperature: 10 °C
Reaction time: 10 h
Yield: 105.8 %

Procedure:
To 77 g of water were added 0.5 g of the immobilized enzyme produced in Example 1 above and 65 g of ethyl N-benzylazetidine-2-carboxylate, followed by stirring at 10° C. for 10 hours. To the reaction mixture, were added 65 g of methylisobutyl ketone and 36 g of ethanol, and further stirring was conducted for 30 minutes. The reaction mixture was thereafter filtrated, and the filtrate was subjected to separation. To the aqueous layer were added 65 g of methylisobutyl ketone and 6.5 g of ethanol followed by stirring for 30 minutes and the separation. This operation was repeated twice. Thus resulting aqueous layer was concentrated under a reduced pressure (10 kPa or lower) to give 60 g of crude (S)-N-benzylazetidine-2-carboxylic acid (43 weight %).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7]CC)=[O:6].Cl[CH2:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[C:15]1([CH2:14][O:1][C:2]2[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=2)[C:5]([OH:7])=[O:6])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1cccc(O)c1
Reactant: ClCc1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: O=C(O)c1cccc(OCc2cccc3ccccc23)c1
Temperature: 25 °C

Procedure:
A mixture comprising ethyl 3-hydroxybenzoate (5.00 g), 1-(chloromethyl)naphthalene (5.40 ml), potassium carbonate (6.24 g), methyl iodide (a catalytic amount) and acetone (50 ml) was heated at reflux for 24 hours. After the reaction mixture was concentrated under reduced pressure to remove the solvent, the residue was mixed with water (200 ml) and was extracted with ethyl acetate. After the organic layer was concentrated, a 1 N aqueous solution of sodium hydroxide (50 ml) was added to the residue dissolved in methanol (50 ml), and the resulting mixture was heated at reflux for 2 hours. After being cooled to room temperature, the reaction mixture was acidified by the addition of concentrated hydrochloric acid and was then extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride, was dried with anhydrous sodium sulfate and was then evaporated under reduced pressure to remove the solvent. The resulting residue was recrystallized from ethyl acetate/hexane to obtain 3-(1-naphthylmethoxy)benzoic acid (7.14 g) as colorless crystals.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:12])[CH3:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[Br:13]Br>[Fe].C(Cl)(Cl)(Cl)Cl>[Br:13][C:9]1[CH:8]=[C:7]([CH:10]([CH3:12])[CH3:11])[CH:6]=[CH:5][C:4]=1[CH:1]([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(C(C)C)cc1
Reactant: BrBr
Agent: [Fe]
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)c1ccc(C(C)C)c(Br)c1

Procedure:
To a one-liter flask containing 243 parts of p-diisopropylbenzene, 300 parts of carbon tetrachloride and 2.5 parts of iron powder is added dropwise 240 parts of bromine and sufficient carbon tetrachloride to make 180 parts of solution during seven hours at a temperature of -5°C. The solution is decanted from the residual ferric bromide and washed twice with 3N HCl. The carbon tetrachloride is removed under reduced pressure. A solution of 40 parts potassium hydroxide in two hundred parts of ethyl alcohol is added and refluxed 0.5 hr. The solution is poured into water, separated, washed with dilute hydrochloric acid, dilute sodium bisulfite solution and water, and dried. The solvent is removed and the 2-bromo-1,4-diisopropylbenzene distilled, bp 142°C at 25 mm, nD25 1.5292.
Reaction SMILES: [C:1]1([CH:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:8]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=[CH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[CH:27]1(O)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[C:1]1([CH:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:8]2[C:12]([C:13]([O:15][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:14])=[CH:11][N:10]=[CH:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1cncn1C(c1ccccc1)c1ccccn1
Reactant: OC1CCCCC1
Agent: O=S(=O)(O)O
Product: O=C(OC1CCCCC1)c1cncn1C(c1ccccc1)c1ccccn1
Temperature: 100 °C
Reaction time: 48 h
Yield: 28.8 %

Procedure:
A mixture of 7 parts of 1-[phenyl(2-pyridinyl)methyl]-1H-imidazole-5-carboxylic acid, 5.5 parts of concentrated sulfuric acid and 140 parts of cyclohexanol was stirred for 2 days at 100° C. The reaction mixture was evaporated (at an oil pump) and the residue was taken up in dichloromethane. The organic layer was washed with a sodium hydroxide solution, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried in vacuo at 60° C., yielding 2.6 parts (28.8%) of cyclohexyl 1-[phenyl(2-pyridinyl)methyl]-1H-imidazole-5-carboxylate; mp. 161.0° C. (compound 1.255).
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11]1)=[O:7])(C)(C)C.[CH3:19][N:20]=[C:21]=[S:22].[NH2:23][C:24]1[C:32]([Cl:33])=[CH:31][C:27](C(O)=O)=[C:26]([O:34][CH3:35])[CH:25]=1>>[NH2:23][C:24]1[C:32]([Cl:33])=[CH:31][C:27]([C:6]([NH:8][CH2:9][CH:10]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:21]([NH:20][CH3:19])=[S:22])[CH2:11]2)=[O:7])=[C:26]([O:34][CH3:35])[CH:25]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: CN=C=S
Reactant: CC(C)(C)OC(=O)NCC1CCN(CCCN)C1
Product: CNC(=S)NCCCN1CCC(CNC(=O)c2cc(Cl)c(N)cc2OC)C1

Procedure:
3-(3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)propylamine (1.06 g) as starting compound was reacted and treated in the same manner as in Example 34 using methyl isothiocyanate (0.32 ml) and 4-amino-5-chloro-2-methoxybenzoic acid (0.91 g) to give 4-amino-5-chloro-2-methoxy-N-(1-(3-(3-methylthioureido)propyl)pyrrolidin-3-ylmethyl)benzamide.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([SH:9])[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+].Cl.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][Cl:22]>C(O)C>[ClH:22].[F:11][C:2]([F:1])([F:10])[C:3]1[CH:4]=[C:5]([S:9][CH2:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][N:15]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1cccc(S)c1
Reactant: ClCc1ccccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: FC(F)(F)c1cccc(SCc2ccccn2)c1
Reaction time: 5 h
Yield: 56 %

Procedure:
m-Trifluoromethylbenzenethiol (5 g) was added to a solution of NaOH (2.25 g) in ethanol (50 ml) and the resulting solution was treated with a solution of 2-picolyl chloride, hydrochloride (4.6 g) in ethanol (25 ml) and the mixture was stirred for 5 hours. The resulting suspension was filtered through kieselghur and the solvent was removed by evaporation. The residue was converted into the hydrochloride in ether with ethereal HCl and recrystallised from acetone-ether to give 2-(((3-trifluoromethylphenyl)thio)methyl)pyridine hydrochloride (4.8 g) mp 145°-6° C. (Found: C,51.1; H,4.0; N,4.7 C13H10F3NS.HCl requires C,51.0; H,3.6; N,4,6%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]([NH:19][CH3:20])=[O:18])=[C:15]3[C:10]([CH:11]=[C:12]([N:24]([CH2:29][CH2:30]CO)[S:25]([CH3:28])(=[O:27])=[O:26])[C:13]([CH:21]4[CH2:23][CH2:22]4)=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.[N:33]1C=CC=C[CH:34]=1.[CH:39]1([C:43](Cl)=[O:44])[CH2:42][CH2:41][CH2:40]1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]([C:17]([NH:19][CH3:20])=[O:18])=[C:15]3[C:10]([CH:11]=[C:12]([N:24]([CH2:29][CH2:30][CH2:34][NH:33][C:43]([CH:39]4[CH2:42][CH2:41][CH2:40]4)=[O:44])[S:25]([CH3:28])(=[O:26])=[O:27])[C:13]([CH:21]4[CH2:22][CH2:23]4)=[CH:14]3)=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(Cl)C1CCC1
Reactant: c1ccncc1
Reactant: CNC(=O)c1c2cc(C3CC3)c(N(CCCO)S(C)(=O)=O)cc2nn1-c1ccc(Br)cc1
Solvent: ClCCl
Product: CNC(=O)c1c2cc(C3CC3)c(N(CCCNC(=O)C3CCC3)S(C)(=O)=O)cc2nn1-c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 43 %

Procedure:
To a solution of 6-[3-aminopropyl(methylsulfonyl)amino]-2-(4-bromophenyl)-5-cyclopropyl-N-methyl-indazole-3-carboxamide (i) (5 mg, 0.01 mmol) in DCM (0.5 mL) at 0° C. was added pyridine (50 μL) followed by cyclobutanecarbonyl chloride (3 μL, 0.026 mmol). The mixture was then stirred at RT for 16 h. More pyridine (20 μL) and cyclobutylcarbonyl chloride (10 μL) were added and the mixture was left to stir for another 5 h. The solvent was then evaporated under reduced pressure. The residue was taken up in EtOAc (2 mL), washed with saturated aqueous sodium bicarbonate solution (1 mL), dried (MgSO4) and concentrated in vacuo. The crude material was purified by preparative LCMS (5-40-70-100% ACN in 0.1% aqueous formic acid) to afford Compound (62) as a white solid (2.5 mg, 43%). ESI-MS m/z calculated for [M+H]+: 602.1/604.1; found: 601.9/603.9; 1H NMR (400 MHz, CDCl3) δ 7.74 (s, 1H), 7.71-7.60 (m, 2H), 7.50-7.41 (m, 2H), 7.36 (s, 1H), 5.82 (t, J=6.0 Hz, 2H), 3.92-3.65 (m, 2H), 3.55-3.26 (m, 2H), 3.04 (d, J=11.1 Hz, 3H), 3.02-2.90 (m, 4H), 2.44-2.30 (m, 1H), 2.30-2.07 (m, 4H), 2.03-1.81 (m, 2H), 1.77 (p, J=6.6 Hz, 2H), 1.17-0.94 (m, 3H), 0.72-0.52 (m, 1H).
Reaction SMILES: C[O:2][C:3]1(OC)[CH2:6][C:5]([C:13]([O:15][CH:16]([CH3:18])[CH3:17])=[O:14])([C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8])[CH2:4]1>FC(F)(F)C(O)=O.O.CCOC(C)=O>[O:2]=[C:3]1[CH2:6][C:5]([C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8])([C:13]([O:15][CH:16]([CH3:17])[CH3:18])=[O:14])[CH2:4]1
Reactant: COC1(OC)CC(C(=O)OC(C)C)(C(=O)OC(C)C)C1
Solvent: O
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)OC(=O)C1(C(=O)OC(C)C)CC(=O)C1
Temperature: 0 °C
Reaction time: 4 h
Yield: 99.1 %

Procedure:
A mixture of diisopropyl 3,3-dimethoxycyclobutane-1,1-dicarboxylate (3 g, 0.01 mol) in 20 mL of trifluoroacetic acid-water (95:5) was stirred at 0° C. for 4 h. The reaction was diluted with EtOAc, washed with water, saturated NaHCO3 solution, and brine, dried over MgSO4 and evaporated to give crude product (2.4 g) as yellow oil, which was used directly in the next step. H NMR (CDCl3, 400 MHz) δ 5.07 (2H, h, J=6.8 Hz), 3.54 (4H, s), 1.23 (12H, d, J=6.8 Hz) ppm.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]=[C:9]([C:11]3[C:12]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)=[N:13][N:14]4[C:19]=3[CH2:18][CH2:17][CH2:16][NH:15]4)[CH:8]=[CH:7][N:6]=2)[CH2:3][CH2:2]1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1.O>[CH:1]1([NH:4][C:5]2[N:10]=[C:9]([C:11]3[C:12]([C:20]4[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=4)=[N:13][N:14]4[C:19]=3[CH2:18][CH2:17][CH2:16][N:15]4[C:27](=[O:29])[CH3:28])[CH:8]=[CH:7][N:6]=2)[CH2:3][CH2:2]1
Reactant: Fc1ccc(-c2nn3c(c2-c2ccnc(NC4CC4)n2)CCCN3)cc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)N1CCCc2c(-c3ccnc(NC4CC4)n3)c(-c3ccc(F)cc3)nn21

Procedure:
A catalytic amount of 4-dimethylaminopyridine (ca. 5 mg) was added to a solution of N-cyclopropyl-4-[2-(4-fluorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-b]pyridazin-3-yl]-2-pyrimidinamine (i.e. the product of Step E) (42.1 mg, 0.12 mmol) and acetic anhydride (0.023 mL, 0.24 mmol) in 2 mL of pyridine at room temperature. After 3 h the reaction mixture was diluted with water and extracted with ethyl acetate (3×10 mL). The combined organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by medium pressure liquid chromatography using 20-100% ethyl acetate in hexanes as eluent to give 25 mg of the title product, a compound of the present invention, as a white solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[N:9]=[CH:8][C:7]([C:10]2[CH:19]=[CH:18][C:17]3[N:16]=[CH:15][C:14]4[CH2:20][N:21]([CH3:31])[C:22](=[O:30])[N:23]([CH:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)[C:13]=4[C:12]=3[N:11]=2)=[CH:6][CH:5]=1.[C:32](O)(=[O:36])[C@@H:33]([CH3:35])[OH:34].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CO.ClCCl.C(N(CC)CC)C>[OH:34][C@H:33]([CH3:35])[C:32]([N:27]1[CH2:28][CH2:29][CH:24]([N:23]2[C:13]3[C:12]4[N:11]=[C:10]([C:7]5[CH:8]=[N:9][C:4]([O:3][CH3:2])=[CH:5][CH:6]=5)[CH:19]=[CH:18][C:17]=4[N:16]=[CH:15][C:14]=3[CH2:20][N:21]([CH3:31])[C:22]2=[O:30])[CH2:25][CH2:26]1)=[O:36]
Reactant: C[C@@H](O)C(=O)O
Reactant: COc1ccc(-c2ccc3ncc4c(c3n2)N(C2CCNCC2)C(=O)N(C)C4)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1ccc(-c2ccc3ncc4c(c3n2)N(C2CCN(C(=O)[C@@H](C)O)CC2)C(=O)N(C)C4)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.4 %

Procedure:
9-(6-methoxypyridin-3-yl)-3-methyl-1-(piperidin-4-yl)-3,4-dihydropyrimido[5,4-c][1,5]naphthyridin-2(1H)-one hydrochloride (hydrochloride of Compound 114 (100 mg, 0.227 mmol)) and triethylamine (0.177 mL) were added to dichloromethane (20 mL), stirred at room temperature for 0.5 h, then to the system sequentially added (R)-lactic acid (26.7 mg, 0.296 mmol), 1-hydroxybenzotriazole (37.8 mg, 0.280 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (70.8 mg, 0.37 mmol). The reaction mixture was stirred at room temperature for 2 h. After confirming the reaction was completed by a thin layer chromatography plate (dichloromethane:methanol=10:1), the reaction liquid was washed sequentially with a saturated aqueous solution of sodium carbonate, water and saturated brine, and the organic layer was dried over anhydrous sodium sulfate, concentrated and subjected to silica gel column chromatography (dichloromethane:methanol=10:1) to give 88 mg of a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[C:8]([C:15]3[CH:20]=[CH:19][C:18]([O:21]C)=[CH:17][CH:16]=3)=[N:9][N:10]([CH3:14])[C:11]=2[CH:12]=[O:13])=[C:5]([CH3:23])[O:4][N:3]=1.[Li+].[BH4-].S(C)C>C(OCC)C>[CH3:1][C:2]1[C:6]([C:7]2[C:8]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)=[N:9][N:10]([CH3:14])[C:11]=2[CH2:12][OH:13])=[C:5]([CH3:23])[O:4][N:3]=1
Reactant: COc1ccc(-c2nn(C)c(C=O)c2-c2c(C)noc2C)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: CSC
Solvent: CCOCC
Product: Cc1noc(C)c1-c1c(-c2ccc(O)cc2)nn(C)c1CO
Temperature: 25 °C
Yield: 69.2 %

Procedure:
To a solution of 4-(3,5-dimethylisoxazol-4-yl)-3-(4-methoxyphenyl)-1-methyl-1H-pyrazole-5-carbaldehyde (4.1 mg, 0.013 mmol) in diethyl ether (3 mL) was added LiBH4 (12 mg, 0.55 mmol) and stirred at room temperature over night. The reaction was then quenched with water and extracted with EtOAc, filtered through a phase separator and concentrated. To the raw product in DCM (1 mL) was added BF3.Me2S (1 M solution in DCM, 0.2 mL, 0.2 mmol) and stirred over night at room temperature. The formed precipitate was twice washed with 0.5 mL DCM, dissolved in MeOH and purified on preparative HPLC to give E11 4-(4-(3,5-dimethylisoxazol-4-yl)-5-(hydroxymethyl)-1-methyl-1H-pyrazol-3-yl)phenol (2.8 mg, 0.009 mmol, 71%). ES/MS m/z: 299.6 (M+H), 297.7 (M−H); 1H NMR (MeOD, 500 MHz): 7.18 (m, 2H), 6.71 (m, 2H), 3.98 (s, 3H), 3.74 (s, 2H), 2.20 (s, 3H) and 1.87 (s, 3H).
Reaction SMILES: C1C2C(=O)C3C(=CC=CC=3)C(=O)C=2C=CC=1.[N+:17]([C:20]1[C:33]2[C:32](=[O:34])[C:31]3[C:26](=[C:27]([N+]([O-])=O)[CH:28]=[CH:29][CH:30]=3)[C:25](=[O:38])[C:24]=2[CH:23]=[CH:22][CH:21]=1)([O-:19])=[O:18].[N+:39]([O-])([OH:41])=[O:40]>>[N+:39]([C:30]1[C:31]2[C:32](=[O:34])[C:33]3[C:24](=[CH:23][CH:22]=[CH:21][C:20]=3[N+:17]([O-:19])=[O:18])[C:25](=[O:38])[C:26]=2[CH:27]=[CH:28][CH:29]=1)([O-:41])=[O:40]
Reactant: O=[N+]([O-])O
Reactant: O=C1c2cccc([N+](=O)[O-])c2C(=O)c2cccc([N+](=O)[O-])c21
Agent: O=C1c2ccccc2C(=O)c2ccccc21
Product: O=C1c2cccc([N+](=O)[O-])c2C(=O)c2c1cccc2[N+](=O)[O-]

Procedure:
The procedure is as described in Example 5, except that the mixed dinitration of anthraquinone is carried out not only with the extract left after stirring of the 1,5-dinitroanthraquinone, but also with the HNO3 -moist filter cake containing 1,5- and 1,8-dinitroanthraquinone obtained in accordance with variant (a) or (b) of Example 5.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](Cl)=[O:9])=[N:6][CH:7]=1.[Cl:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.N1C=CC=CC=1.Cl>C(#N)C.CN(C)C1C=CN=CC=1.O>[Cl:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)=[O:9])=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1ccc(Br)cn1
Reactant: Nc1ccc(Cl)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC#N
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1ccc(Cl)cc1)c1ccc(Br)cn1
Temperature: 68 °C
Reaction time: 8 h

Procedure:
To 5-Bromo-pyridine-2-carbonyl chloride (69, 0.76 g, 3.4 mmol) in acetonitrile (29.0 mL) were added p-chloroaniline (53, 0.702 g, 5.50 mmol), 4-dimethylamino-pyridine (0.12 g, 0.96 mmol) and pyridine (2.9 mL, 0.036 mol). The reaction was stirred at 68° C. overnight, then poured into water, acidified with 1 N HCl to pH around 1 and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with dichloromethane to give a white solid (70, 0.75 g, 70.0%).
Reaction SMILES: [SH:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:11](O)[CH3:12].S(=O)(=O)(O)O>C1C=CC=CC=1>[SH:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:11][CH3:12])=[O:5]
Reactant: CCO
Reactant: O=C(O)c1ccccc1S
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: CCOC(=O)c1ccccc1S
Yield: 40 %

Procedure:
Using a procedure similar to that of Example I, a mixture of 50 g (0.32mole) of 2-mercaptobenzoic acid, 60 g (1.3 moles) of absolute ethanol, 200 ml. of benzene and 1.0 g of sulfuric acid (98%) was heated at refux for 28 hours and yielded ethyl 2-mercaptobenzoate: 23.3 g (40% yield); bp 99°-100°C/0.8 mm; mol. wt. 182:
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])[C:5]([NH2:18])=[CH:4][CH:3]=1.[CH:19]1([S:24](Cl)(=[O:26])=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20]1>>[F:8][C:7]1[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])=[C:5]([NH:18][S:24]([CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)(=[O:26])=[O:25])[CH:4]=[CH:3][C:2]=1[F:1]
Reactant: Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F
Reactant: O=S(=O)(Cl)C1CCCC1
Product: O=S(=O)(Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F)C1CCCC1

Procedure:
According to the general procedure B, 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine was reacted with cyclopentanesulfonyl chloride to obtain the desired product 1H NMR (300 MHz, CDCl5): δ 7.42 (dd, J=2.1 & 10.5 Hz, 1H), 7.36 (ddd, J=2.4, 4.8, & 9.3 Hz, 1H), 7.25 (m, 2H), 7.10 (dd, J=9.6 & 17.7 Hz, 1H), 6.67 (br s, D2O exchangeable, 1H), 6.20 (dt, J=1.5, 8.4 & 17.4 Hz, 1H), 3.53 (p, 1H), 1.80 (m, 8H); m/z=495 [M−1]−.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:15]([OH:17])=O)=[CH:13][N:14]=[C:8]2[CH:7]=1.C(Cl)(=O)C(Cl)=O.[CH2:24]([N:31]1[C:39]2[CH:38]=[CH:37][CH:36]=[C:35]([NH2:40])[C:34]=2[CH:33]=[N:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.CN(C=O)C>[CH2:24]([N:31]1[C:39]2[C:34](=[C:35]([NH:40][C:15]([C:12]3[N:9]4[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:7][C:8]4=[N:14][CH:13]=3)=[O:17])[CH:36]=[CH:37][CH:38]=2)[CH:33]=[N:32]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COCCOc1ccn2c(C(=O)O)cnc2c1
Reactant: Nc1cccc2c1cnn2Cc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COCCOc1ccn2c(C(=O)Nc3cccc4c3cnn4Cc3ccccc3)cnc2c1
Yield: 72.3 %

Procedure:
To a suspension of 7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid (50 mg; 0.21 mmol) in methylene chloride (2 mL) was added a catalytic (0.005 mL) amount of DMF followed by oxalyl chloride (0.23 mmol; 2M solution in methylene chloride). The mixture was stirred in a sealed vial until effervescence ceased (approximately 30 minutes), with occasional venting to release gas. 1-Benzyl-1H-indazol-4-amine (Example 155, Steps A-B; 47 mg; 0.21 mmol) was added as a solution in methylene chloride (1 mL) followed by diisopropylethylamine (33 mg; 0.25 mmol). The mixture was stirred for 16 hours at ambient temperature, during which time a suspension formed. The mixture was partitioned between water and methylene chloride and the suspension was extracted multiple times with methylene chloride. The combined organic phases (which contained suspended solids) were concentrated under reduced pressure. The resulting solid material was triturated with ether and collected by filtration. The solids were washed with ether, water and then ether again. The material was dried under vacuum to give an off white solid (67 mg). MS (APCI), m/z=442.2 (M+H).
Reaction SMILES: [CH3:1][I:2].[CH2:3]([O:8][C:9]1[C:10]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[N:11][S:12][N:13]=1)[CH2:4][CH:5]([CH3:7])[CH3:6]>CC(C)=O>[I-:2].[CH2:3]([O:8][C:9]1[C:10]([C:14]2[CH:15]=[N+:16]([CH3:1])[CH:17]=[CH:18][CH:19]=2)=[N:11][S:12][N:13]=1)[CH2:4][CH:5]([CH3:7])[CH3:6]
Reactant: CI
Reactant: CC(C)CCOc1nsnc1-c1cccnc1
Solvent: CC(C)=O
Product: CC(C)CCOc1nsnc1-c1ccc[n+](C)c1
Product: [I-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of methyl iodide (0.5 ml, 10 mmol) and 3-(4-isopentyloxy-1,2,5-thiadiazol-3-yl)pyridine (622 mg, 2.5 mmol) in acetone (5 ml) was stirred at room temperature for 18 h. The title compound precipitated from the solution and was collected by filtration to yield 0.78 g (81%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4](I)[CH:3]=1.[NH2:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=1[NH2:24])[C:17]([O:19][CH3:20])=[O:18].C([O-])([O-])=O.[K+].[K+]>ClC1C=CC=CC=1.C(OCC)(=O)C.[Cu]>[NH2:13][C:14]1[CH:15]=[C:16]([C:17]([O:19][CH3:20])=[O:18])[CH:21]=[CH:22][C:23]=1[NH:24][C:4]1[CH:3]=[C:2]([Cl:1])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(Cl)cc1I
Reactant: COC(=O)c1ccc(N)c(N)c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Clc1ccccc1
Product: COC(=O)c1ccc(Nc2cc(Cl)ccc2C(=O)OC)c(N)c1
Temperature: 25 °C
Yield: 67.7 %

Procedure:
A mixture of methyl 4-chloro-2-iodobenzoate (0.593 g, 2 mmol), methyl 3,4-diaminobenzoate (0.332 g, 2 mmol), copper (0.126 g, 2 mmol), and K2CO3 (0.276 g, 2 mmol) in chlorobenzene (40 mL) was heated to reflux for 20 hours, cooled to room temperature, diluted with ethyl acetate, and filtered through diatomaceous earth (Celite®). The solution was washed with water and brine, dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel with 7:3 hexanes/ethyl acetate to provide 0.453 g (68%) of the desired product. MS (DCI) m/e 334 (M+H)+, 352 (M+NH4)+; 1H NMR (300 MHz, DMSO-d6) δ 8.99 (s, 1H), 7.89 (d, J=8.5 Hz, 1H), 7.47 (d, J=1.0 Hz, 1H), 7.21 (m, 2H), 6.80 (dd, J=8.5, 2.0 Hz, 1H), 6.65 (d, J=2.1 Hz, 1H), 5.30 (s, 2H), 3.86 (s, 3H), 3.82 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH:17]=2)=[CH:12][CH:11]=1)[CH3:2].[H][H]>[Pd].C(O)C>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:12][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)CCCCOc1ccc(C2=CCCCCCC2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCCCOc1ccc(C2CCCCCCC2)cc1

Procedure:
2 g of palladium on charcoal (5% strength) are added to a solution of 20 g of 5-[p-(1-cyclooctenyl)-phenoxy]-pentanoic acid ethyl ester in 100 ml of ethanol and hydrogenation is carried out at room temperature and normal pressure until one equivalent of hydrogen has been absorbed. The catalyst is then filtered off and the filtrate is evaporated to dryness in vacuo. Distillation of the evaporation residue in a high vacuum gives 5-(p-cyclooctyl-phenoxy)-pentanoic acid ethyl ester of boiling point 170° -175° C at 0.05 mm Hg.