Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[C:14]([Cl:15])=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[C:8]([CH2:16][N:17]([CH3:19])[CH3:18])[CH:9]=[N:10]2.[NH3:21]>CO>[Cl:15][C:14]1[C:5]([CH2:4][C:3]([NH2:21])=[O:2])=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][C:8]([CH2:16][N:17]([CH3:19])[CH3:18])=[CH:7]2
Reactant: COC(=O)Cc1c(Cl)ccc2ncc(CN(C)C)cc12
Reactant: N
Solvent: CO
Product: CN(C)Cc1cnc2ccc(Cl)c(CC(N)=O)c2c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 94 %

Procedure:
A solution of (6-chloro-3-dimethylaminomethyl-quinolin-5-yl)-acetic acid methyl ester (462 mg, 1.58 mmol) in a mixture of methanol (4 mL) and liquid ammonia (20 mL) was stirred for 4 days in an autoclave at room temperature. After careful evaporation of the ammonia, the remaining solvent was evaporated in vacuo to afford the title compound as a pale brown solid (413 mg, 1.48 mmol, 94%). 1H NMR (400 MHz, DMSO-d6, 298 K): δ=8.85 (d, J=2.0 Hz, 1H), 8.31 (bs, 1H), 7.93 (d, J=9.1 Hz, 1H), 7.75 (d, J=9.1 Hz, 1H), 7.62 (bs, 1H), 7.08 (bs, 1H), 4.10 (s, 2H), 3.67 (bs, 2H), 2.23 (bs, 6H). MS (ES+): 278 (M(C14H1635ClN3O)+H)+.
Reaction SMILES: Cl[C:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)=[O:3].C(N(CC)C(C)C)(C)C.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]([CH3:44])[C:31]([C:37]2[CH:42]=[CH:41][N:40]=[C:39]([Cl:43])[CH:38]=2)([OH:36])[C:32]([F:35])([F:34])[F:33])=[C:26]([Cl:45])[CH:25]=1.ClC(C1C=CC(C([O-])=O)=CC=1)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:11][O:10][C:8](=[O:9])[C:7]1[CH:12]=[CH:13][C:4]([C:2]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH:30]([CH3:44])[C:31]([C:37]3[CH:42]=[CH:41][N:40]=[C:39]([Cl:43])[CH:38]=3)([OH:36])[C:32]([F:33])([F:34])[F:35])=[C:26]([Cl:45])[CH:25]=2)=[O:3])=[CH:5][CH:6]=1
Reactant: CC(c1ccc(N)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Agent: O=C([O-])O
Agent: O=C([O-])c1ccc(C(=O)Cl)cc1
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)Nc2ccc(C(C)C(O)(c3ccnc(Cl)c3)C(F)(F)F)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of methyl 4-chlorocarbonylbenzoate (CAS Reg. No. 7377-26-6, 30 mg) and N,N-diisopropylethylamine (0.05 ml) in DCM (5 ml) was added to a solution of 3-(4-amino-2-chloro-phenyl)-2-(2-chloro-pyridin-4-yl)-1,1,1-trifluoro-butan-2-ol (50 mg) in DCM (1 ml). The mixture was stirred for 2 h at room temperature. Additional 4-chlorocarbonylbenzoate (CAS Reg. No. 7377-26-6, 54 mg) and N,N-diisopropylethylamine (0.1 ml) were added. The mixture was stirred for 4 h at room temperature. The mixture was poured on a saturated aqueous NaHCO3 solution (20 ml) and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and then concentrated to an oil. The residue was purified by flash chromatography (SiO2, 0 to 30% EtOAc/heptane) to give the title compound (57 mg) as a white foam. MS (m/e)=527.0 [M+H+].
Reaction SMILES: [CH2:1]([NH:3][S:4]([C:7]1[CH:18]=[C:11]2[C:12]([O:14]C(=O)[NH:16][C:10]2=[CH:9][CH:8]=1)=O)(=[O:6])=[O:5])[CH3:2].[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>CC(C)=O.C(O)C>[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([C:12](=[O:14])[C:11]2[C:10](=[CH:9][CH:8]=[C:7]([S:4](=[O:5])(=[O:6])[NH:3][CH2:1][CH3:2])[CH:18]=2)[NH2:16])[CH2:22][CH2:21]1
Reactant: CN1CCNCC1
Reactant: CCNS(=O)(=O)c1ccc2[nH]c(=O)oc(=O)c2c1
Solvent: CCO
Solvent: CC(C)=O
Product: CCNS(=O)(=O)c1ccc(N)c(C(=O)N2CCN(C)CC2)c1

Procedure:
In a manner analogous to that described in Example 1, the reaction of 5-(N-ethylsulfamoyl)-isatoic anhydride with 1-methylpiperazine yields 5-(N-ethylsulfamoyl)-anthranilic acid (4-methyl)-piperazide with a melting point of 175°-177° (from acetone/ethanol).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH2:7][CH2:8][C:9]2=O.[C:15]([BH3-])#[N:16].[Na+].C(O)(=O)C.O>C(O)C.CN>[CH3:15][NH:16][CH:9]1[C:10]2[C:6](=[C:5]([O:4][CH2:3][O:2][CH3:1])[CH:13]=[CH:12][CH:11]=2)[CH2:7][CH2:8]1
Reactant: [BH3-]C#N
Reactant: COCOc1cccc2c1CCC2=O
Agent: CN
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: CNC1CCc2c(OCOC)cccc21
Temperature: 25 °C
Yield: 56.6 %

Procedure:
To a solution of 1.00 g of 4-(methoxymethoxy)-1-indanone in 10 ml of ethanol, 2.8 ml of 40% methylamine (methanol solution) and 367 mg of sodium cyanoborohydride were added. While stirring at room temperature, 0.55 ml of acetic acid was added dropwise and the mixture was heated at reflux for 4 hours. The reaction solution was air-cooled, combined with water and then extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, the solvent was evaporated. The residue was purified by silica gel column chromatography to obtain 0.61 g of the desired compound as a deep green oily substance.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([OH:13])=O)=[CH:9][N:10]=2)[CH:7]=1.C(Cl)(=O)C(Cl)=O.C(N(C(C)C)CC)(C)C.[CH2:29]([N:36]1[C:44]2[CH:43]=[CH:42][CH:41]=[C:40]([NH2:45])[C:39]=2[CH:38]=[N:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)Cl.CCOCC.CN(C=O)C>[CH2:29]([N:36]1[C:44]2[C:39](=[C:40]([NH:45][C:11]([C:8]3[N:6]4[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]4=[N:10][CH:9]=3)=[O:13])[CH:41]=[CH:42][CH:43]=2)[CH:38]=[N:37]1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C(O)c1cnc2ccc(Br)cn12
Reactant: Nc1cccc2c1cnn2Cc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1cccc2c1cnn2Cc1ccccc1)c1cnc2ccc(Br)cn12
Yield: 47.2 %

Procedure:
6-Bromoimidazo[1,2-a]pyridine-3-carboxylic acid (200 mg; 0.83 mmol) was suspended in methylene chloride (2 mL) with a catalytic (0.005 mL) amount of DMF. A solution of oxalyl chloride (0.913 mmol; 2M solution on dichloromethane) was added. The mixture was stirred in a sealed vial (with occasional venting to release gas) until effervescence ceased (about 30 minutes). A white suspension resulted. Diisopropylethylamine (188 μL; 1.08 mmol) was added. A clear solution resulted. 1-Benzyl-1H-indazol-4-amine (185 mg; 0.83 mmol) was added as a solution in methylene chloride followed by addition of further diisopropylethylamine (188 μL). The mixture was stirred at ambient temperature for 24 hours. A suspension resulted. The mixture was diluted with ether (10 mL) and the solids were collected by filtration. The filter pad was washed with ether and water and the solids were dried under vacuum to provide the desired product as a white solid (175 mg). MS (APCI) positive scan, m/z=446, 449 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.[N:16]#[C:17][NH2:18].[N+:19]([O-:22])([OH:21])=[O:20]>C(O)C.O.Cl>[N+:19]([O-:22])([OH:21])=[O:20].[N+:19]([O-:22])([OH:21])=[O:20].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:17]([NH2:18])=[NH:16])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Reactant: N#CN
Agent: Cl
Solvent: O
Solvent: O=[N+]([O-])O
Solvent: CCO
Product: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 58.4 %

Procedure:
To a solution of 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine (5.08 g, 25.0 mmol) in ethanol (25 mL) was added at 20° C. cyanamide (3.15 g, 75 mmol) dissolved in water (3.2 mL) and then 37% aqueous hydrochloric acid solution (4.9 g, 50 mmol). The solution was heated for 3 h to reflux. Additional cyanamide (2.1 g) in water (2.1 mL) and 37% aq hydrochloric acid solution (2.8 mL) were added and the mixture was heated to reflux for another 2 h. At 20° C. 65% aqueous nitric acid (3.5 mL, 50 mmol) was added. The reaction was stirred for 30 minute at 20° C. and the formed precipitate was filtered off, washed with ethanol and diethyl ether. (Caution: the filtrate may contain the ethyl ester of nitric acid). The solid was dried under reduced pressure at 20° C. to yield the title compound (5.42 g, 58%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]([CH2:30][CH3:31])=[C:17]3[CH:25]=[CH:24][CH:23]=[C:22]4[N:18]3[C:19]=2[CH:20]=[C:21]4[C:26](OC)=[O:27])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C(OCC)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:19]3=[CH:20][C:21]([CH2:26][OH:27])=[C:22]4[N:18]3[C:17](=[CH:25][CH:24]=[CH:23]4)[C:16]=2[CH2:30][CH3:31])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCc1c(-c2ccc(OCc3ccccc3)cc2)c2cc(C(=O)OC)c3cccc1n32
Agent: O=C([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CCc1c(-c2ccc(OCc3ccccc3)cc2)c2cc(CO)c3cccc1n32
Yield: 97 %

Procedure:
Methyl 3-(4-benzyloxyphenyl)-4-ethylpyrrolo[2,1,5-cd]indolizine-1-carboxylate (8.5 g, 20.8 mmol) was dissolved in 170 ml of dry tetrahydrofurane under a nitrogen atmosphere. Lithium aluminium hydride (1.24 g, 32.6 mmol) was added in portions and stirring was continued for 21/2 hours. Water (10 ml) was added dropwise, and 95 ml of saturated aqueous potassium carbonate and 200 ml of diethyl ether was added. The organic layer was separated, and the aqueous layer was extracted with diethyl ether (2×300 ml). The combined organic layers were washed with 200 ml of water and dried over sodium hydrogen carbonate. The solvent was evaporated and the remaining product was dried to afford 7.7 g (97%) of the title compound as yellow crystals. M.p. 148-150° C. MS(SP): m/z 381 (M+). 1H-NMR (CDCl3, 300 MHz) δ: 1.48 (t, 3H); 3.23 (q, 2H); 5,17 (s, 2H); 5.18 (s, 2H); 7.14 (d, 2H); 7.32-7.52 (m, 5H); 7.57 (s, 1H); 7.65 (t, 1H); 7.72 (d, 2H); 7.92 (d, 1H); 8.02 (d, 1H).
Reaction SMILES: CC([O-])(C)C.[Na+].CC1C=CC2C=CC3C=CC(C)=NC=3C=2N=1.[F:23][C:24]1[CH:25]=[C:26]([SH:30])[CH:27]=[CH:28][CH:29]=1.[Cl:31][C:32]1[C:33](I)=[C:34]([O:38][CH3:39])[CH:35]=[CH:36][CH:37]=1>[Cu]I>[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[C:33]=1[S:30][C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([F:23])[CH:25]=1
Reactant: Fc1cccc(S)c1
Reactant: COc1cccc(Cl)c1I
Agent: [Cu]I
Agent: CC(C)(C)[O-]
Agent: Cc1ccc2ccc3ccc(C)nc3c2n1
Product: COc1cccc(Cl)c1Sc1cccc(F)c1
Temperature: 105 °C
Reaction time: 8 h

Procedure:
A dry round bottomed flask was charged with NaOtBu (398 mg, 4.14 mmol), CuI (62 mg, 0.33 mmol), neocuproin (66 mg, 0.30 mmol), 3-fluoro-thiophenol (394 mg, 3.07 mmol) and 3-chloro-2-iodoanisole (698 mg, 2.60 mmol). The flask was evacuated and backfilled with Ar three times. Dry toluene (10 mL) was added and the mixture stirred at 105° C. overnight. The mixture was diluted with toluene (40 mL) and filtered through a pad of silica gel and evaporated to dryness to give a quantitative yield of crude 1-Chloro-2-(3-fluoro-phenylsulfanyl)-3-methoxy-benzene. The material was dissolved in toluene (20 mL) and cooled to 0° C. Neat BBr3 (0.38 mL, 4.02 mmol) was added dropwise and the mixture was allowed to reach room temperature overnight. The mixture was quenched by the addition of H2O/ice (80 mL) and diethyl ether (100 mL). The organic layer was washed with brine. After drying over Na2SO4 the crude product was adsorbed onto silica gel. After flash chromatography using silica gel, eluting with heptanes/EtOAc, 96:4 the title compound was obtained as a yellow oil Yield: 642 mg, 97% over two steps.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]([CH3:18])[CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:13]=2)=[CH:5][CH:4]=1>C(O)(=O)C.Br.O>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]([CH3:18])[CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:13]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2nc(C(F)(F)F)cn2C)cc1
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: Cn1cc(C(F)(F)F)nc1-c1ccc(O)cc1

Procedure:
9.3 g of 2-(4-methoxyphenyl)-1-methyl-4-(trifluoromethyl)-imidazole are dissolved in a mixture of 46.1 ml of acetic acid and 46.5 ml of 48% strength hydrobromic acid and the solution is heated under reflux for 48 hours. The solution is concentrated in a rotary evaporator to form a thick paste which is diluted with water; the pH is adjusted to 11 with concentrated ammonia and finally extraction is carried out several times with ethyl acetate. After drying the organic phase and filtration, concentration is carried out in a rotary evaporator until a thick suspension is produced. After cooling, the suspension is filtered and the crystallisate is dried in vacuo, yielding the 2-(4-hydroxyphenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole having a melting point of 220°-221°.
Reaction SMILES: [F:1][C:2]1[C:3]([F:14])=[C:4]2[C:11](=[CH:12][CH:13]=1)[C:7]([CH2:8][CH2:9][NH2:10])=[CH:6][NH:5]2.[N:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=2)[CH:25]=O)=[CH:17][CH:16]=1.Cl>CO.C(Cl)Cl.O>[F:1][C:2]1[C:3]([F:14])=[C:4]2[C:11]([C:7]([CH2:8][CH2:9][NH:10][CH2:25][C:24]3[CH:27]=[CH:28][CH:29]=[C:22]([O:21][C:18]4[CH:17]=[CH:16][N:15]=[CH:20][CH:19]=4)[CH:23]=3)=[CH:6][NH:5]2)=[CH:12][CH:13]=1
Reactant: O=Cc1cccc(Oc2ccncc2)c1
Reactant: NCCc1c[nH]c2c(F)c(F)ccc12
Agent: Cl
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: Fc1ccc2c(CCNCc3cccc(Oc4ccncc4)c3)c[nH]c2c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Combine 6,7-difluoro tryptamine (0.285 g, 1.450 mmol), 3-pyridin-4-yloxybenzaldehyde (0.303 g, 1.52 mmol, 1.05 eq.) and molecular sieves 4A (0.30 g) and stir in methanol (12 mL). After 4 h. filter the molecular sieves and wash several times with MeOH. To this MeOH solution, add portionwise NaH4 (55.0 mg, 1.45 mmol), and stir at room temperature for 1 h. Remove MeOH in vacuo, dilute the residue with CH2Cl2/water, extract with CH2Cl2, combine organic layers, dry over Na2SO4 and concentrate in vacuo. Purification by flash chromatography on silica gel (CH2Cl2/MeOH) to give the free base which is converted to the hydrochloride salt: 1H NMR (300 MHz, DMSO-d6) 3.13 (s, 4H), 4.20 (s, 2H), 6.85-7.55 (m, 10H), 8.47-8.50 (m, 1H), 9.58 (br, 1H), 11.57 (br, 1H): MS (electrospray) m/e: 380.2 (M+1−HCl), 378.3 (M−1−HCl).
Reaction SMILES: CC1[CH:15]=[C:14]2[C:5]([S:6](=[O:23])(=[O:22])[C:7]3[CH:8]=[C:9]([C:17]4[NH:21][N:20]=[N:19][N:18]=4)[CH:10]=[CH:11][C:12]=3[C:13]2=[O:16])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[C:29]([OH:32])(=[O:31])[CH3:30]>O.[O-2].[O-2].[O-2].[Cr+6]>[C:29]([C:30]1[CH:3]=[CH:4][C:5]2[S:6](=[O:23])(=[O:22])[C:7]3[C:12](=[CH:11][CH:10]=[C:9]([C:17]4[NH:21][N:20]=[N:19][N:18]=4)[CH:8]=3)[C:13](=[O:16])[C:14]=2[CH:15]=1)([OH:32])=[O:31]
Reactant: CC(=O)O
Reactant: Cc1ccc2c(c1)C(=O)c1ccc(-c3nnn[nH]3)cc1S2(=O)=O
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: O
Product: O=C(O)c1ccc2c(c1)C(=O)c1ccc(-c3nnn[nH]3)cc1S2(=O)=O
Reaction time: 16 h

Procedure:
7-Methyl-3-(5-tetrazolyl)thioxanthone-10,10-dioxide (0,78g) was suspended in acetic acid (50 ml) and chromium trioxide (0.98g) in water (2.0 ml) added dropwise, followed by concentrated sulphuric acid (0.5 ml) added dropwise. The mixture was heated on the steam bath for 1 hr., then boiled under reflux for 4 hr. Further chromium trioxide (0.98g) was added and the mixture boiled for a further 16 hr. The green solution was diluted with water, and the precipitated solid filtered off and washed with water. The solid was boiled with acetic acid (200 ml), filtering at the boil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:42]([C:43]([O:45]C)=[O:44])=[C:11]3[CH:12]=[C:13]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30](=[O:41])[NH:31][C:32]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)([CH3:34])[CH3:33])[CH:25]=4)[C:14]([N:16]([CH2:21][CH2:22][OH:23])[S:17]([CH3:20])(=[O:19])=[O:18])=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.C1COCC1.[OH-].[Li+].Cl>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:42]([C:43]([OH:45])=[O:44])=[C:11]3[CH:12]=[C:13]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30](=[O:41])[NH:31][C:32]([C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=5)([CH3:34])[CH3:33])[CH:25]=4)[C:14]([N:16]([CH2:21][CH2:22][OH:23])[S:17]([CH3:20])(=[O:18])=[O:19])=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(-c2ccc(F)cc2)nn2cc(N(CCO)S(C)(=O)=O)c(-c3cccc(C(=O)NC(C)(C)c4ccccc4)c3)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(NC(=O)c1cccc(-c2cc3c(C(=O)O)c(-c4ccc(F)cc4)nn3cc2N(CCO)S(C)(=O)=O)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution containing methyl 2-(4-fluorophenyl)-6-(N-(2-hydroxyethyl)methylsulfonamido)-5-(3-(2-phenylpropan-2-ylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxylate (0.021 g, 0.33 mmol), THF (0.20 mL) and methanol (0.13 mL) was added aqueous lithium hydroxide (0.081 mL, 2.0 M). The solution was maintained at room temperature for 20 h, then at 45° C. for 8 h. The solution was adjusted to below pH 4 with aqueous HCl (0.21 mL, 1.0 N) and extracted with ethyl acetate (2×0.50 mL). The combined organic portions were washed with brine (0.50 mL) and concentrated to afford 2-(4-fluorophenyl)-6-(N-(2-hydroxyethyl)methylsulfonamido)-5-(3-(2-phenylpropan-2-ylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid as a light yellow residue which was used without further purification. LCMS: retention time: 1.778 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10u, C18, 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% methanol/90% H2O/10 mM TFA and solvent B was 10% H2O/90% methanol/10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 631 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1O)=[N:13][C:12]([F:17])=[CH:11][CH:10]=2)=[O:5])[CH3:2].C(Cl)(=O)C([Cl:21])=O.CN(C)C=O.CC(C)=O>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Cl:21])=[N:13][C:12]([F:17])=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOC(=O)c1cnc2ccc(F)nc2c1O
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Product: CCOC(=O)c1cnc2ccc(F)nc2c1Cl

Procedure:
To a suspension of 3a in chloroform were added 4 equivalents of oxalyl chloride followed by 0.1 equiv. of dimethylformamide. The solution was refluxed for 3 hours and was quenched with 5 M sodium hydroxide solution at 4° C. The chloroform layer was collected, washed with 100 mL water and brine solution, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Product was obtained by recrystallization using acetone. 1H-NMR (CDCl3) δ (ppm): 1.47 (3H, t, J=7.14 Hz), 4.53 (2H, q, J=7.14 Hz), 7.45 (1H, dd, J=8.79, 3.02 Hz), 8.54 (1H, dd, J=9.06, 7.41), 9.21 (1H, s). m/z 255.7 (MH+).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][C:3]=1[C:13]([OH:15])=[O:14].C[O-].[Na+].[CH2:19](Br)[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][CH3:34].Cl>CN(C)C=O>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH3:19])=[CH:4][C:3]=1[C:13]([OH:15])=[O:14]
Reactant: CCCCCCCCCCCCCCCCBr
Reactant: O=C(O)c1cc(O)c2ccccc2c1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCOc1cc(C(=O)O)c(O)c2ccccc12
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 43.8 %

Procedure:
12.3 g of 1,4-dihydroxy-2-naphthoic acid was dissolved in 100 ml of dimethylformamide, and to the solution was added 23.2 g of a 28% methanolic solution of sodium methylate in a nitrogenous atmosphere at 40° C. with stirring. The mixture was heated to 60° C., and 15.3 g of hexadecyl bromide was added thereto dropwise over a period of 30 minutes. The resulting mixture was heated for 3 hours while stirring, cooled, and then poured into 1 liter of ice-water to which 50 ml of concentrated hydrochloric acid had already been added with stirring. The precipitated crude crystals were filtered and washed with water. After addition of 1 g of activated carbon, the mixture was dissolved in 100 ml of methanol while heating. The activated carbon was filtered, and the filtrate was cooled. The precipitated crystals were filtered, washed with methanol and dried to obtain 9.4 g of 1-hydroxy-4-hexadecyloxy-2-naphthoic acid. Melting Point: 121°-124° C.
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH2:19][CH2:18][CH2:17][CH:16]([C:21]([NH2:23])=[O:22])[C:15]=2[C:14]2[C:9]1=[CH:10][C:11]([O:26][CH3:27])=[CH:12][C:13]=2[O:24][CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd].CCOCCOCCO>[CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([C:21](=[O:22])[NH2:23])[C:15]=2[C:14]2[C:9]1=[CH:10][C:11]([O:26][CH3:27])=[CH:12][C:13]=2[O:24][CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(OC)c2c3c(n(Cc4ccccc4)c2c1)CCCC3C(N)=O
Agent: [Pd]
Solvent: CCOCCOCCO
Product: COc1cc(OC)c2c3c(C(N)=O)cccc3n(Cc3ccccc3)c2c1

Procedure:
A mixture of 2.0 gm. of the product from Example 2, 2 gm. of 5% Pd/C, and 100 mL of carbitol was refluxed for 17 hours,filtered while still hot, and the solid washed well with ethyl acetate. The combined filtrates were washed with water, washed with brine, dried over sodium sulfate, and evaporated in vacuo to give subtitled product, 1.4 gm., 70%, mp 240-243° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:33]=[CH:32][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29](O)=[O:30])[CH:25]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl.[NH2:68][CH2:69][CH2:70][CH2:71][C:72]([O:74][CH3:75])=[O:73].Cl>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:33]=[CH:32][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29]([NH:68][CH2:69][CH2:70][CH2:71][C:72]([O:74][CH3:75])=[O:73])=[O:30])[CH:25]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11]
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)cc2)c1
Reactant: COC(=O)CCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCCNC(=O)c1c[nH]c(-c2cc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)cc3)ccn2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid (Example 115) (200 mg, 0.45 mmol) in 10 ml of anhydrous DMF were added HATU (190 mg, 0.50 mmol) and N,N-diisopropylethylamine (174 mg, 1.35 mmol). The mixture was stirred at room temperature for 10 minutes, followed by addition of methyl 4-aminobutyrate hydrochloride (104 mg, 0.68 mmol). The mixture was stirred for another 10 minutes and poured into 100 ml of water with vigorous stirring. 1M HCl was added slowly until pH=4. The precipitates were filtered, washed with water and dried in vacuo to give methyl 4-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}butanoate as white solid. Yield: 220 mg, 90%.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]1[CH:18]=[CH:17][C:10]([O:11][CH2:12][CH:13]([OH:16])[CH2:14]O)=[CH:9][CH:8]=1.N1C=CC=CC=1.Cl.CS(Cl)(=O)=O.CCOCC>O.CO.N1C=CC=CC=1>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]1[CH:18]=[CH:17][C:10]([O:11][CH2:12][CH:13]2[O:16][CH2:14]2)=[CH:9][CH:8]=1
Reactant: Cn1ccnc1-c1ccc(OCC(O)CO)cc1
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: O
Product: Cn1ccnc1-c1ccc(OCC2CO2)cc1
Reaction time: 0.17 h

Procedure:
Into a flask under N2 was placed 6 (7.0 g, 0.03 mol), pyridine (20 ml), pyridine·HCl (3.9 g, 0.034 mol) and the mixture cooled in an ice bath. To the cooled mixture was added methanesulfonyl chloride (3.26 g, 2.2 ml, 0.028 mol). After 10 minutes, Et2O (130 ml) NaOCH3 (19 g, 0.35 mol), and CH3OH (65 ml) were added and the suspension stirred for 1/2 hour. Water was added and the layers were separated. The aqueous layer was further extracted with CH2Cl2 (3X). The combined extracts were washed with H2O, saturated NaCl, dried, filtered and concentrated to dryness to yield 7; 'H NMR (CDCl7) δ 2.8 (2H, m), 3.3 (1H, m), 3.65 (3H, s), 4.1 (2H, m), 7.4 (6H, m).