Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:3]=1[NH:4][C:5](=[O:10])[C:6]([F:9])([F:8])[F:7].CI.[C:20]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:3]=1[N:4]([CH3:20])[C:5](=[O:10])[C:6]([F:7])([F:8])[F:9]
Reactant: O=C([O-])[O-]
Reactant: O=C(Nc1cc([N+](=O)[O-])ccc1F)C(F)(F)F
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN(C(=O)C(F)(F)F)c1cc([N+](=O)[O-])ccc1F
Temperature: 90 °C
Reaction time: 24 h
Yield: 83 %

Procedure:
To a solution of compound 32-NO2—H (13.9 g, 55.2 mmol) and MeI (14.8 g, 0.104 mol) in DMF (80 mL), K2CO3 (12.5 g, 90.6 mmol) was added. After vigorous stirring for 24 h at 90° C., volatile materials were evaporated in vacuum. The residue was diluted with water (200 mL), the organic layer was separated, and the aqueous layer was extracted with ether (3×100 mL). Combined organic solutions were dried, and the solvent was evaporated at an ambient pressure (bath temperature 50° C.). The title compound was isolated by chromatography on SiO2 (600 g) with hexane/EtOAc mixture (1:0→1:1) as an eluent; yellowish oil (13.6 g, purity ca. 90%, yield 83%). 1H NMR (CDCl3, 300 MHz, ppm): δ=3.36 (s, 3 H, CH3), 7.39 (t, 3JHH=JHF=8.8, 1H, H-3), 8.25 (dd, 4JHH=2.6, 4JHF=6.5, 1H, H-6), 8.32-8.38 (m, 1H, H-4); EI-MS: m/z (rel. int., %)=266 (100) [M], 197 (57) [M-CF3], 184 (32), 170 (23), 123 (37), 110 (18).
Reaction SMILES: [C:1]1([N:7]2[C:12](=O)C3SC=C(C4C=CC=CC=4)C=3N=C2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:23][C:24]1[C:28]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH3:38])[CH:30]=2)=[CH:27][S:26][C:25]=1[C:39]([O:41]C)=O.C(OCC)(OCC)OCC.[Cl:53]C1C=CC(N)=CC=1>C(O)(=O)C>[Cl:53][C:4]1[CH:5]=[CH:6][C:1]([N:7]2[C:39](=[O:41])[C:25]3[S:26][CH:27]=[C:28]([C:29]4[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH3:38])[CH:30]=4)[C:24]=3[N:23]=[CH:12]2)=[CH:2][CH:3]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: COC(=O)c1scc(-c2ccc(OC)c(OC)c2)c1N
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Solvent: CC(=O)O
Solvent: CCOC(OCC)OCC
Product: COc1ccc(-c2csc3c(=O)n(-c4ccc(Cl)cc4)cnc23)cc1OC
Yield: 28 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-(3,4-dimethoxyphenyl)thiophene-2-carboxylate (30 mg, 0.13 mmol), triethyl orthoformate (0.31 ml), 4-chloroaniline (29.7 mg, 0.23 mmol), and acetic acid (0.04 ml) were used to give 14.5 mg (0.04 mmol, 28% yield) of the title compound.
Reaction SMILES: Cl.[C:2]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([OH:19])=[C:10]([CH:18]=1)[C:11]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[O:12])(=[O:4])[CH3:3].[CH3:20]O>>[C:2]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([OH:19])=[C:10]([CH:18]=1)[C:11]([CH2:13][CH2:14][C:15]([O:17][CH3:20])=[O:16])=[O:12])(=[O:4])[CH3:3]
Reactant: CO
Reactant: CC(=O)Nc1ccc(O)c(C(=O)CCC(=O)O)c1
Agent: Cl
Product: COC(=O)CCC(=O)c1cc(NC(C)=O)ccc1O
Temperature: 0 °C
Yield: 59 %

Procedure:
Hydrogen chloride gas was passed through a gently boiling solution of 3-(5-acetamido-2-hydroxybenzoyl)propionic acid (1.2 g, 0.0048 mole) in dry methanol (20 ml) until esterification was complete. The reaction mixture was poured into ice-water and extracted with chloroform. The extract was washed with sodium bicarbonate solution and water, dried and evaporated to give methyl 3-(5-acetamido-2-hydroxybenzoyl)propionate (0.75 g, 59%, m.p. 145°-147°). (Found: M+, 265. C13H15NO5 requires: M, 265).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([S:34][CH3:35])=[CH:30][CH:29]=3)=[C:20]([C:36]([F:39])([F:38])[F:37])[CH:19]=2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.[Cl:41]C1C=CC=C(C(OO)=[O:49])C=1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[ClH:41].[NH2:7][C:8]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([S:34]([CH3:35])=[O:49])=[CH:30][CH:29]=2)=[C:20]([C:36]([F:39])([F:38])[F:37])[CH:19]=1)([CH2:13][OH:12])[CH2:9][OH:10]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc(CCCOc2ccc(CCC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)cc2C(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)c1ccc(CCCOc2ccc(CCC(N)(CO)CO)cc2C(F)(F)F)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 12.3 %

Procedure:
Compound 96-3 (720 mg) was dissolved in methylene chloride (20 ml), m-chloroperbenzoic acid (containing 25% water, 293 mg) was added under ice-cooling, and the mixture was stirred at room temperature for 20 hr. m-Chloroperbenzoic acid (containing 25% water, 234 mg) was further added to the reaction mixture under ice-cooling, and the mixture was stirred at room temperature for 2 hr. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform, washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 1 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give a white powder. The white powder was separated by HPLC using capcellpac (registered trade mark) UG80 (0.05% trifluoroacetic acid-water/0.05% trifluoroacetic acid-acetonitrile), and the residue obtained by collecting a peak with a shorter retention time (primary peak) was converted to hydrochloride by the addition of hydrogen chloride containing ether (1 mol/l, 10 ml), and the precipitate was collected by filtration and dried to give the object product (75 mg) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([N:10]2[C:14](=[O:15])[CH:13]=[C:12]([OH:16])[CH:11]2[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(O)(=O)C.[BH4-].[Na+].O>C(#N)C.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:9]=[C:8]([N:10]2[C:14](=[O:15])[CH2:13][C@H:12]([OH:16])[C@@H:11]2[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(N2C(=O)C=C(O)C2Cc2ccc(F)cc2)cc1Cl
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CC#N
Product: N#Cc1ccc(N2C(=O)C[C@H](O)[C@@H]2Cc2ccc(F)cc2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.3 %

Procedure:
To a mixture of 2-chloro-4-[2-(4-fluorobenzyl)-3-hydroxy-5-oxo-2,5-dihydro-1H-pyrrol-1-yl]benzonitrile (1.00 g) and acetic acid (1.84 mL) in acetonitrile (10 mL) was added sodium borohydride (276 mg) at 0° C. in small portions. The mixture was warmed to room temperature and stirred for 1 hr. Water and saturated brine were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (eluent: hexane:ethyl acetate=4:1→ethyl acetate), and recrystallized from tetrahydrofuran-hexane to give the title compound as colorless crystals (yield: 717 mg, 71%).
Reaction SMILES: [C:1]([NH2:11])(=[O:10])[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].[OH-].[Na+].[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.Cl[CH2:26]Cl>>[CH3:26][NH:11][C:1]([C@@H:2]([O:3][S:20]([C:17]1[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=1)(=[O:22])=[O:21])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:10]
Reactant: ClCCl
Reactant: NC(=O)C(O)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Product: CNC(=O)[C@@H](OS(=O)(=O)c1ccc(C)cc1)c1ccccc1
Temperature: 25 °C

Procedure:
Alternatively, to the solution of mandelic acid amide in dichloromethane is added 50% aqueous caustic soda at RT. Subsequently p-toluene sulfonic acid chloride (1.0 equivalent) is added as a solution in dichloromethane keeping the temperature below 25° C. The biphasic reaction mixture is stirred at RT until a satisfactory conversion is reached, phases are separated, the aqueous phase is extracted once with dichloromethane and then the combined organic phases are washed with water. After a solvent switch to toluene the solution is concentrated, cooled to 5° C. and the precipitate filtered. The crystals are washed with cooled toluene and dried in vacuo at 40° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:18][C:19]3[N:24]=[C:23]([C:25]([NH2:27])=O)[CH:22]=[CH:21][CH:20]=3)=[C:8]([C:12]3[CH:13]=[N:14][CH:15]=[N:16][CH:17]=3)[NH:9]2)=[CH:5][CH:4]=1.P(Cl)(Cl)(Cl)=O.C(=O)([O-])O.[Na+].O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:18][C:19]3[N:24]=[C:23]([C:25]#[N:27])[CH:22]=[CH:21][CH:20]=3)=[C:8]([C:12]3[CH:17]=[N:16][CH:15]=[N:14][CH:13]=3)[NH:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(Cc3cccc(C(N)=O)n3)c(-c3cncnc3)[nH]c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(Cc3cccc(C#N)n3)c(-c3cncnc3)[nH]c2c1
Yield: 97.8 %

Procedure:
To a suspension of 6-(6-methoxy-2-pyrimidin-5-yl-1H-indol-3-ylmethyl)pyridine-2-carboxamide (351 mg) in N,N-dimethylformamide (9.8 mL) was added phosphoryl chloride (0.133 mL) under ice-cooling, and the mixture was stirred under ice-cooling for 3 hours. To the reaction mixture were added a saturated aqueous sodium hydrogen carbonate and water, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine successively, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by aminopropylated silica gel column chromatography (eluting solvent: methanol-ethyl acetate) to obtain the title compound (326 mg). 1H-NMR (CDCl3) δ ppm: 3.87 (3H, s), 4.40 (2H, s), 6.81 (1H, dd, J=2.3, 8.5 Hz), 6.90-6.95 (1H, m), 7.30-7.39 (2H, m), 7.50-7.57 (1H, m), 7.64-7.72 (1H, m), 8.20 (1H, br s), 9.00 (2H, s), 9.20 (1H, s).
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]([C:5]([O:7][C@@H:8]1[C@@H:13]2[C@@H:14]([CH2:19][CH2:20][C@@H:21]([OH:29])[CH2:22][C@@H:23]([OH:28])[CH2:24][C:25]([O-:27])=[O:26])[C@@H:15]([CH3:18])[CH:16]=[CH:17][C:12]2=[CH:11][C@@H:10]([OH:30])[CH2:9]1)=[O:6])[CH3:4].[Na+].[Br:32][CH2:33][CH2:34][CH2:35][CH2:36]Br.O.C(OCC)C>CN(C)C=O>[Br:32][CH2:33][CH2:34][CH2:35][CH2:36][O:26][C:25](=[O:27])[CH2:24][CH:23]([OH:28])[CH2:22][CH:21]([OH:29])[CH2:20][CH2:19][CH:14]1[CH:13]2[C:12](=[CH:11][CH:10]([OH:30])[CH2:9][CH:8]2[O:7][C:5](=[O:6])[CH:3]([CH3:4])[CH2:2][CH3:1])[CH:17]=[CH:16][CH:15]1[CH3:18]
Reactant: BrCCCCBr
Reactant: CC[C@H](C)C(=O)O[C@H]1C[C@H](O)C=C2C=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(=O)[O-])[C@H]21
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: CCC(C)C(=O)OC1CC(O)C=C2C=CC(C)C(CCC(O)CC(O)CC(=O)OCCCCBr)C21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of pravastatin sodium (9.25 g, 21 mmol) in N,N-dimethylformamide (70 ml) a mixture of 1,4-dibromobutane (3.68 ml, 31 mmol) in N,N-dimethylformamide (30 ml) was added dropwise. The reaction mixture was stirred at room temperature for 24 h. The solution was then treated with water and diethyl ether, the organic layers were dried with sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography, with n-hexane/ethyl acetate 3/7 as eluent. The title compound was obtained as a white powder (7.8 g).
Reaction SMILES: [N:1]([C@@H:4]([C@@H:8]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1)[C:5](O)=[O:6])=[N+:2]=[N-:3].[NH2:24][C:25]1[CH:55]=[CH:54][CH:53]=[C:52]([F:56])[C:26]=1[CH2:27][CH2:28][C@H:29]1[O:34][CH2:33][C@@H:32]([CH2:35][O:36][C:37](=[O:44])[NH:38][CH2:39][C:40]([F:43])([F:42])[F:41])[N:31]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:30]1.O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[N:1]([C@@H:4]([C@@H:8]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1)[C:5]([NH:24][C:25]1[CH:55]=[CH:54][CH:53]=[C:52]([F:56])[C:26]=1[CH2:27][CH2:28][C@H:29]1[O:34][CH2:33][C@@H:32]([CH2:35][O:36][C:37](=[O:44])[NH:38][CH2:39][C:40]([F:43])([F:41])[F:42])[N:31]([C:45]([O:47][C:48]([CH3:49])([CH3:50])[CH3:51])=[O:46])[CH2:30]1)=[O:6])=[N+:2]=[N-:3]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(N)cccc2F)OC[C@H]1COC(=O)NCC(F)(F)F
Reactant: [N-]=[N+]=N[C@H](C(=O)O)[C@H](c1cccc(F)c1)c1ccc(F)c(F)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(F)cccc2NC(=O)[C@@H](N=[N+]=[N-])[C@H](c2cccc(F)c2)c2ccc(F)c(F)c2)OC[C@H]1COC(=O)NCC(F)(F)F
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
The product from step 1 (134 mg, 0.42 mmol) and the product from step 4 (200 mg, 0.42 mmol) were dissolved in pyridine (4 mL) and the stirred solution was cooled to −10° C. in an ice/acetone bath. To the cold solution was added POCl3 dropwise (0.04 mL, 0.46 mmol). The mixture was stirred at −10° C. for 30 min. The reaction was quenched by the addition of saturated aqueous NaHCO3 solution (5 mL) and the mixture was allowed to warm to ambient temperature. The mixture was diluted with water (20 mL) and extracted with dichloromethane (3×15 mL). The combined dichloromethane phases were dried (Na2SO4), filtered, and the filtrate solvents were removed in vacuo. The residue was purified on a 12 g silica gel column using a gradient elution of 0-100% EtOAc:hexanes. Fractions containing product were combined and the solvents were removed in vacuo to give the title compound as a gum. (M+H-Boc)+=683.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:36])=[C:24]([NH:27][S:28]([C:31]3[S:32][CH:33]=[CH:34][CH:35]=3)(=[O:30])=[O:29])[CH:25]=2)[NH:20][C:19](=[O:37])[C:18]=1[C:38]1[CH:43]=[C:42]([CH3:44])[CH:41]=[C:40]([CH3:45])[CH:39]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl.C1(OC)C=CC=CC=1>[Cl:36][C:23]1[CH:22]=[C:21]2[C:26]([C:17]([O:16][CH2:15][CH2:14][CH:9]3[CH2:10][CH2:11][CH2:12][CH2:13][NH:8]3)=[C:18]([C:38]3[CH:43]=[C:42]([CH3:44])[CH:41]=[C:40]([CH3:45])[CH:39]=3)[C:19](=[O:37])[NH:20]2)=[CH:25][C:24]=1[NH:27][S:28]([C:31]1[S:32][CH:33]=[CH:34][CH:35]=1)(=[O:30])=[O:29]
Reactant: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c3cc(NS(=O)(=O)c4cccs4)c(Cl)cc3[nH]c2=O)c1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C)cc(-c2c(OCCC3CCCCN3)c3cc(NS(=O)(=O)c4cccs4)c(Cl)cc3[nH]c2=O)c1
Temperature: 25 °C

Procedure:
To a solution of 2-{2-[7-chloro-3-(3,5-dimethylphenyl)-2-oxo-6-(thiophene-2-sulfonylamino)-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester in 5 mL methylene chloride was added a few drops of anisole followed by 1.0 mL of trifluoroacetic acid and the mixture stirred at room temperature. After 30 minutes the solvents were removed in vacuo and the resulting residue purified by flash chromatography on silica gel (methylene chloride:10% ammonium hydroxide in methanol, 95:5; then 90:10) to give the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:20])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([NH2:19])[C:17]#[N:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30](Cl)(=[O:32])=[O:31])([O-])=O>>[CH2:1]([O:8][C:9](=[O:20])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([NH:19][S:30]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:24]=1)(=[O:32])=[O:31])[C:17]#[N:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CC(N)CCCCCNC(=O)OCc1ccccc1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Product: N#CC(CCCCCNC(=O)OCc1ccccc1)NS(=O)(=O)c1ccccc1
Yield: 40.9 %

Procedure:
Using the general procedure described in step A of scheme 1, (6-amino-6-cyano-hexyl -carbamic acid benzyl ester (2.8 g, 10 mmol) was sulfonylated with 2-nitrobenzenesulfonyl chloride (2.5 g, 11 mmol) at 0° C. to yield the titled compound (1.7 g, 36%); yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.CO>C1COCC1>[OH:7][CH2:6][C:5]1[CH:9]=[CH:10][C:2]([OH:1])=[CH:3][C:4]=1[C:11]([F:12])([F:13])[F:14]
Reactant: O=C(O)c1ccc(O)cc1C(F)(F)F
Solvent: CO
Solvent: C1CCOC1
Product: OCc1ccc(O)cc1C(F)(F)F
Temperature: 80 °C
Yield: 102 %

Procedure:
To a solution of 4-hydroxy-2-(trifluoromethyl)benzoic acid (4.62 g, 22.4 mmol, Fluorochem) in THF (60 ml) at ambient temperature under nitrogen was added dropwise 1.0 M borane-tetrahydrofuran complex (48 ml, 48.0 mmol). The solution was heated to 80° C. for 2 h. To the solution at ambient temperature was added methanol dropwise (40 ml). The solution was heated to 80° C. for 30 min. The solvent was removed in vacuo and the residue dissolved in methanol (100 ml). The solvent was removed in vacuo to leave the title compound as a white solid (4.39 g);
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19](Cl)=O)=[CH:14][CH:13]=1.C(OCC)(=O)C.O1CCCC1.[OH-].[Na+]>O>[Br:9][C:5]1[CH:6]=[C:7]2[NH:8][C:19]([CH2:18][C:15]3[CH:16]=[CH:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]=3)=[N:1][C:2]2=[N:3][CH:4]=1
Reactant: Nc1cc(Br)cnc1N
Reactant: COc1ccc(CC(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Cc2nc3ncc(Br)cc3[nH]2)cc1
Temperature: 170 °C
Reaction time: 1.5 h
Yield: 54.9 %

Procedure:
A mixture of 2,3-diamino-5-bromopyridine (Compound of Reference Example 1) (1.32 g) and 4-methoxyphenylacetyl chloride (1.29 g) was stirred in the absence of solvent at 170° C. for 1.5 hour. The mixture was distributed with ethyl acetate-tetrahydrofuran (3:1, v/v) and water (at that time, the water layer was neutralized with 1 N sodium hydroxide). The organic layer was washed with water, dried over MgSO4, and the solvent was distilled off under reduced pressure. The resulting crystals were collected by filtration to obtain 6-bromo-2-(4-methoxybenzyl)-1H-imidazo[4,5-b]pyridine (1.22 g, 55%).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15](Cl)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:2].CS(C)=O.[NH2:21][CH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23]1.CS(O)(=O)=O>CO.O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:21][CH:22]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[CH2:24][CH2:23]4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:2]
Reactant: CCn1ncc2c(Cl)c3ccccc3nc21
Reactant: NC1CCc2ccccc21
Agent: CS(=O)(=O)O
Solvent: O
Solvent: CO
Solvent: CS(C)=O
Product: CCn1ncc2c(NC3CCc4ccccc43)c3ccccc3nc21
Temperature: 110 °C
Yield: 50.8 %

Procedure:
A mixture of 1-ethyl-4-chloro-1H-pyrazolo[3,4-b]quinoline (1.0 g, 0.0043 mol), DMSO (3 mL) and 1-aminoindane (1 g) was heated at 110° C. for 16 hours. The reaction mixture was cooled and then was poured into water (100 mL). The solid which formed was collected by filtration and dried to afford the product as the free base. The free base was dissolved in methanol and then was treated with methanesulfonic acid. The methanol was evaporated and the residue was crystallized from hot methanol/2-propanol and then was recrystallized from hot methanol/2-propanol to afford 717 mg of 1-ethyl-N-(1-indanyl)-1H-pyrazolo[3,4-b]quinolin-4amine.CH3 SO3H, m.p. 233°-235° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([Br:10])=[N:8][CH:9]=1)(=[O:3])[CH3:2].[CH2:11](O)[CH2:12][OH:13].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:10][C:7]1[CH:6]=[CH:5][C:4]([C:1]2([CH3:2])[O:13][CH2:12][CH2:11][O:3]2)=[CH:9][N:8]=1
Reactant: CC(=O)c1ccc(Br)nc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(c2ccc(Br)nc2)OCCO1
Temperature: 140 °C
Reaction time: 5 h
Yield: 78.5 %

Procedure:
A mixture of 5-acetyl-2-bromopyridine (0.6 g, 3.00 mmol), ethylene glycol (0.535 ml, 9.60 mmol), p-toluenesulfonic acid monohydrate (0.171 g, 0.900 mmol), and toluene (12.00 ml) was stirred at 140° C. for 5 hours. The reaction mixture was washed with saturated sodium bicarbonate and brine. The aqueous layer was back extracted with ethyl acetate and the combined organics dried with magnesium sulfate and concentrated to give crude 2-bromo-5-(2-methyl-1,3-dioxolan-2-yl)pyridine (0.575 g, 2.356 mmol, 79% yield) as an orange oil. It was used without further purification.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH2:17][NH:16][CH2:15][CH2:14]2)=[O:10].[C:21](O)(=[O:23])[CH3:22].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.C(N(CC)CC)C>[C:21]([N:16]1[CH2:15][CH2:14][C:13]2[C:18](=[CH:19][CH:20]=[C:11]([C:9]([NH:8][O:7][CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)=[O:10])[CH:12]=2)[CH2:17]1)(=[O:23])[CH3:22]
Reactant: O=C(NOC1CCCCO1)c1ccc2c(c1)CCNC2
Reactant: CC(=O)O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(=O)N1CCc2cc(C(=O)NOC3CCCCO3)ccc2C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 200 mg N-(tetrahydro-2H-pyran-2-yloxy)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide, 0.046 m acetic acid, 111 mg HOBt, 276 mg EDC, 0.603 ml triethylamine and 7 ml DMF is stirred 4 h at ambient temperature. The reaction mixture is then purified by silica gel chromatography.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)=[C:5]([C:10]2[CH:11]=[C:12]([NH:17][C:18]3[CH:19]=[C:20]([CH:30]=[CH:31][CH:32]=3)[O:21][CH2:22][CH2:23][CH2:24]OS(C)(=O)=O)[CH:13]=[CH:14][C:15]=2[CH3:16])[S:6][C:7]=1[S:8][CH3:9])#[N:2].[CH3:39][NH:40][CH3:41].C(N(CC)CC)C.O>C(Cl)Cl>[CH3:39][N:40]([CH3:41])[CH2:24][CH2:23][CH2:22][O:21][C:20]1[CH:19]=[C:18]([NH:17][C:12]2[CH:13]=[CH:14][C:15]([CH3:16])=[C:10]([C:5]3[S:6][C:7]([S:8][CH3:9])=[C:3]([C:1]#[N:2])[C:4]=3[C:33]3[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=3)[CH:11]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: CNC
Reactant: CSc1sc(-c2cc(Nc3cccc(OCCCOS(C)(=O)=O)c3)ccc2C)c(-c2cccnc2)c1C#N
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSc1sc(-c2cc(Nc3cccc(OCCCN(C)C)c3)ccc2C)c(-c2cccnc2)c1C#N
Temperature: 25 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
To a solution of methanesulfonic acid 3-{3-[3-(4-cyano-5-methylsulfanyl-3-pyridin-3-yl-thiophene-2-yl)-4-methyl-phenylamino]-phenoxyl}-propyl ester (20 mg, 0.035 mmol) in DCM (1 mL) was added excess dimethylamine and excess triethylamine. The reaction was stirred at ambient temperature for 3 hours then water (2 ml) was added and the product extracted with DCM (3 mL×3). The combined organic layer were concentrated to afford the crude product as an oil. Purification by chromatography (2% MeOH—CH2Cl2) afforded the desired product (17 mg, 95%). 1H NMR (CDCl3): δ 8.6 (d, 1H), 8.5 (s, 1H), 8.1 (s, 1H), 7.7 (d, 1H), 7.4–7.0 (m, 4H), 7.0 (d, 1H), 6.5 (d, 1H), 4.1 (t, 2H), 2.9 (m, 2H), 2.7 (s, 3H), 2.6 (s, 6H), 2.1 (m, 2H), 1.6 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C([N:27]1[CH:31]=[C:30]([CH:32]=[CH:33][CH2:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])[N:29]=[CH:28]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH:27]1[CH:31]=[C:30]([CH:32]=[CH:33][CH2:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])[N:29]=[CH:28]1
Reactant: O=C(O)CCCC=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCCC=Cc1c[nH]cn1
Yield: 60 %

Procedure:
2 ml of trifluoroacetic acid are added to 0.58 g (1.37 mmol) of 6-(1-trityl-1H-imidazol-4-yl)hex-5-enoic acid in suspension in 8 ml of dichloromethane. After the solvents have been evaporated off, the oil obtained is purified on a silica column (eluent 8/2 DCM/MeOH). 240 mg of 6-(1H-imidazol-4-yl)hex-5-enoic acid trifluoroacetate in the form of a yellow oil are isolated with a yield of 60%.