Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[CH3:3][N:4]1[CH2:8][CH2:7][C:6]2([CH2:12][CH2:11][NH:10][CH2:9]2)[CH2:5]1.N12CCCN=C1CCCCC2.[F:24][C:25]1[C:26](F)=[C:27]2[O:32][CH2:31][CH:30]([CH3:33])[N:29]3[CH:34]=[C:35]([C:40]([OH:42])=[O:41])[C:36](=[O:39])[C:37]([CH:38]=1)=[C:28]23>C(#N)C>[F:24][C:25]1[C:26]([N:10]2[CH2:11][CH2:12][C:6]3([CH2:7][CH2:8][N:4]([CH3:3])[CH2:5]3)[CH2:9]2)=[C:27]2[O:32][CH2:31][CH:30]([CH3:33])[N:29]3[CH:34]=[C:35]([C:40]([OH:42])=[O:41])[C:36](=[O:39])[C:37]([CH:38]=1)=[C:28]23
Reactant: CC1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reactant: CN1CCC2(CCNC2)C1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC1COc2c(N3CCC4(CCN(C)C4)C3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.6 %

Procedure:
A suspension of 0.42 g (1.97 mmol) 2-methyl-2,7-diazaspiro[4.4]nonane dihydrochloride in 25 ml acetonitrile was treated with 0.85 g (5.80 mmol) 1,8-diazabicyclo[5.4.0]undec-7-ene and 0.52 g (1.85 mmol) 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de]1,4-benzoxazine-6-carboxylic acid was added. The mixture was stirred two hours at room temperature and then refluxed overnight. The product which crystallized on cooling was filtered, washed with acetonitrile and recrystallized from acetonitrile to afford 0.45 g of the title compound, mp 227°-230° C. (dec).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[NH2:14][C:15]1[CH:21]=[CH:20][C:18]([OH:19])=[CH:17][C:16]=1O.C(=O)([O-])[O-].[Na+].[Na+]>>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]2[O:8][C:16]3[CH:17]=[C:18]([OH:19])[CH:20]=[CH:21][C:15]=3[N:14]=2)=[CH:5][CH:4]=1
Reactant: Nc1ccc(O)cc1O
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Oc1ccc2nc(-c3ccc(C(F)(F)F)cc3)oc2c1

Procedure:
1.5 ml (10 mmol) of 4-trifluoromethylbenzoyl chloride were heated to 190° C. in an oil bath and 1.6 g (10 mmol) of 4-aminoresorcinol were added in portions. After 1 hour the reaction mixture was introduced into 100 ml of 10% strength sodium carbonate solution and heated. The unreacted acid chloride was hydrolyzed during this procedure. The product was then extracted with ethyl acetate and purified by column chromatography (silica gel 60, ethyl acetate or chloroform/glacial acetic acid 9:1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[SH:12])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:13]1([CH2:19][C:20](O)=O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+]>>[CH2:19]([C:20]1[S:12][C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1cnc2ccccc2c1S
Reactant: O=C(O)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: c1ccc(Cc2nc3cnc4ccccc4c3s2)cc1
Temperature: 140 °C
Reaction time: 2 h
Yield: 59.7 %

Procedure:
A mixture of 17.62 g (0.1 mole) of 3-amino-4-mercapto-quinoline, 15 g (0.11 mole) of phenyl acetic acid and 200 g of polyphosphoric acid is slowly heated to 140° C. under stirring. The reaction mixture is allowed to stand at this temperature for 2 hours, cooled and added to 1000 g of crushed ice under vigorous stirring. The mixture is made alkaline with an aqueous sodium hydroxide solution, extracted three times with 250 ml of chloroform each and the chloroform extract is evaporated. Thus 16.5 g of 2-benzyl-thiazolo[4,5-c]quinoline are obtained, m.p.: 111°-113° C., yield 60%.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1.[CH:13](=O)[C:14]1[CH:21]=[CH:20][CH:19]=[C:16]([CH:17]=[O:18])[CH:15]=1.C(OC(=O)C)(=O)C.CCCCCC>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](/[CH:12]=[CH:13]/[C:14]3[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=3)[CH:17]=[O:18])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(C=O)c1
Reactant: Cc1ccc2ccc(Cl)cc2n1
Solvent: Cc1ccccc1C
Solvent: CC(=O)OC(C)=O
Solvent: CCCCCC
Product: O=Cc1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1

Procedure:
A stirred solution of 7-chloroquinaldine [J. Org. Chem. 42, 911 (1977)] (4.46 g, 25 mmol) and isophthalaldehyde (5.02 g, 37.5 mmol) in acetic anhydride (7.1 ml, 75 mmol) and xylene (25 ml) was heated under reflux for 7 hours. Crystals formed on cooling. Hexane (25 ml) was added slowly to give crude product, m.p. 146°-150°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]([F:18])=[CH:16][C:15]([Br:19])=[CH:14][C:10]=1[C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][NH:21][CH3:22].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1.Cl>[CH2:1]([O:8][C:9]1[C:17]([F:18])=[CH:16][C:15]([Br:19])=[CH:14][C:10]=1[C:11]([N:21]([CH3:22])[CH3:20])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC
Reactant: O=C(O)c1cc(Br)cc(F)c1OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cc(Br)cc(F)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Benzyloxy-5-bromo-3-fluoro-benzoic acid (product from step 2) (0.2 g, 0.615 mmol) is dissolved in THF (10 ml) and treated with 2M dimethylamine in THF (0.308 ml), N-methylmorpholine (0.270 ml, 2.46 mmol) and HATU (0.234 g, 0.615 mmol) and stirred at room temperature overnight. The reaction mixture is diluted with 2M HCl and extracted with EtOAc (2×), the organic portions are combined washed with brine, dried over MgSO4 and concentrated in vacuo. The resulting crude residue is dry loaded onto silica and purification by flash chromatography eluting with EtOAc affords the title compound as a white solid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[OH:16][C:17]1[C:30]2[C:29](=[O:31])[C:28]3[C:23](=[C:24]([O:32][CH3:33])[CH:25]=[CH:26][CH:27]=3)[O:22][C:21]=2[CH:20]=[C:19](O)[CH:18]=1.N1C=CC=CC=1>C(Cl)Cl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:19]1[CH:18]=[C:17]([OH:16])[C:30]2[C:29](=[O:31])[C:28]3[C:23]([O:22][C:21]=2[CH:20]=1)=[C:24]([O:32][CH3:33])[CH:25]=[CH:26][CH:27]=3)(=[O:5])=[O:4]
Reactant: COc1cccc2c(=O)c3c(O)cc(O)cc3oc12
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cccc2c(=O)c3c(O)cc(OS(=O)(=O)C(F)(F)F)cc3oc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.8 %

Procedure:
Trifluoromethanesulfonic anhydride (3.1 mL, 18.43 mmol) was slowly added to a solution of 1,3-dihydroxy-5-methoxy-xanthen-9-one (3.32 g, 12.85 mmol) and pyridine (32.0 mL) in CH2Cl2 (130 mL) at 0° C. See, D. K. Ho et al., J. Org. Chem., 52, pp. 342-347 (1987). The reaction mixture then was allowed to slowly warm to RT and stirred for 16 h. The resulting orange mixture was concentrated to a brown oil, then dissolved in EtOAc (750 mL) and washed with 5% citric acid (3×100 mL), water (1×100 mL), and brine (1×100 mL). The organics were dried (MgSO4) and concentrated to yield 3.0 g (60%) of trifluoromethanesulfonic acid, 1-hydroxy-5-methoxy-9-oxo-9H-xanthen-3-yl ester as a light brown solid. Rf=0.65 (50% EtOAc/hexanes). 1H NMR (DMSO-d6, 400 MHz) δ: 12.89 (s, 1H), 7.74 (d, 1H), 7.60 (m, 1H), 7.50 (m, 1H), 7.42 (s, 1H), 7.04 (s, 1H), 3.97 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]2.[CH:15](Cl)(Cl)Cl.CO>CO.OS(O)(=O)=O>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:5]2
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Reactant: ClC(Cl)Cl
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1ccc2cc(O)ccc2c1

Procedure:
6-Hydroxy-2-naphthoic acid (5.0 g, 26.6 mmol) was dissolved in 125 mL of methanol and refluxed with 6 drops of conc. H2SO4 for 36 hours. TLC analysis (SiO2, 10:1 CHCl3 /MeOH) revealed only a trace of the acid left. The solution was cooled partially and concentrated to dryness on a rotary evaporator. The solid residue was dissolved in 200 mL of ether and washed successively with 100 mL of saturated aq. NaHCO3 and brine Drying over MgSO4 and evaporating the solvent left 4.6 g of (85.5%) slightly yellow solid which showed only one spot on TLC. The material is sufficiently pure for use in subsequent reactions but may be purified solid mp 169°-169.5° C.; 1H NMR delta 3.976 (s, 3H), 5.3 (br s, 1H), 7.16-8.54 (m, 6H); IR (KBr) 3370, 1680, 1630, 1435, 1310, 1210 cm-1. ##STR23##
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([C:15]2[N:16]=[C:17]([CH2:20][N:21]3[CH:25]=[C:24]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:23]=[N:22]3)[S:18][CH:19]=2)[CH:12]=[CH:13][CH:14]=1)=[O:7].I[CH3:32].O>CN(C)C=O.O1CCCC1>[CH3:3][O:4][CH2:5][C:6]([N:8]([CH3:32])[C:9]1[CH:10]=[C:11]([C:15]2[N:16]=[C:17]([CH2:20][N:21]3[CH:25]=[C:24]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:23]=[N:22]3)[S:18][CH:19]=2)[CH:12]=[CH:13][CH:14]=1)=[O:7]
Reactant: CCOC(=O)c1cnn(Cc2nc(-c3cccc(NC(=O)COC)c3)cs2)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn(Cc2nc(-c3cccc(N(C)C(=O)COC)c3)cs2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
Under a nitrogen atmosphere at 0° C., to a solution (2 mL) of sodium hydride (60% in mineral oil, 93 mg, 2.3 mmol) in N,N-dimethylformamide was added dropwise a solution (2 mL) of the compound (720 mg, 1.8 mmol) obtained in Example 26b in tetrahydrofuran, and the mixture was stirred at room temperature for 30 min. Then, iodomethane (0.22 mL, 3.6 mmol) was added to the reaction mixture and the mixture was stirred at room temperature for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was purified by column chromatography (hexane-ethyl acetate) to give the title compound (500 mg, 67%) as a colorless oil.
Reaction SMILES: C[O:2][C:3](=[O:25])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:17]#[C:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>CO.O.O1CCCC1>[CH:6]1([CH2:5][CH:4]([C:11]2[CH:12]=[CH:13][C:14]([C:17]#[C:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)=[CH:15][CH:16]=2)[C:3]([OH:25])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(C#Cc2ccccn2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)C(CC1CCCC1)c1ccc(C#Cc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 98 %

Procedure:
A solution of 3-cyclopentyl-2-(4-pyridin-2-ylethynyl-phenyl)-propionic acid methyl ester (930 mg, 2.79 mmol) in methanol (5 mL), water (2 mL) and tetrahydrofuran (1 mL) was treated with lithium hydroxide (80 mg, 1.90 mmol). The reaction mixture was stirred at 25° C. for 60 h. At this time, additional lithium hydroxide (100 mg, 2.38 mmol) was added. The reaction was stirred at 25° C. for 3 h. At this time, the reaction was diluted with water (10 mL) and then concentrated in vacuo. The resulting aqueous layer was washed with ethyl acetate (2×10 mL), acidified with a 1N aqueous hydrochloric acid solution, and then extracted with ethyl acetate (2×25 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo to afford 3-cyclopentyl-2-(4-pyridin-2-ylethynyl-phenyl)-propionic acid (873 mg, 98%) as an amber solid: mp 143-147° C.; EI-HRMS m/e calcd for C21H21NO2 (M+) 319.1572, found 319.1580.
Reaction SMILES: F[C:2]1[C:3]([N+:18]([O-:20])=[O:19])=[C:4]([CH:14]=[C:15]([F:17])[CH:16]=1)[NH:5][C:6]1[CH:11]=[CH:10][C:9]([I:12])=[CH:8][C:7]=1[F:13].[NH2:21][C:22]1[CH:23]=[C:24]([OH:29])[CH:25]=[CH:26][C:27]=1[F:28].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[NH2:21][C:22]1[CH:23]=[C:24]([CH:25]=[CH:26][C:27]=1[F:28])[O:29][C:2]1[C:3]([N+:18]([O-:20])=[O:19])=[C:4]([CH:14]=[C:15]([F:17])[CH:16]=1)[NH:5][C:6]1[CH:11]=[CH:10][C:9]([I:12])=[CH:8][C:7]=1[F:13]
Reactant: O=[N+]([O-])c1c(F)cc(F)cc1Nc1ccc(I)cc1F
Reactant: Nc1cc(O)ccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Nc1cc(Oc2cc(F)cc(Nc3ccc(I)cc3F)c2[N+](=O)[O-])ccc1F
Temperature: 25 °C
Reaction time: 72 h
Yield: 59 %

Procedure:
1 g of 3,5-difluoro-N-(2-fluoro-4-iodophenyl)-2-nitroaniline (Intermediate 1A; 2.537 mmol, 1 eq.), 194 mg 3-amino-4-fluorophenol (1.522 mmol, 0.6 eq.) and 1.240 g caesium carbonate (3.806 mmol, 1.5 eq.) were suspended in 12 mL DMF and stirred at rt for 72 h. The reaction mixture was partitioned between butan-2-one and half saturated brine. The layers were separated and the aqueous layer was reextracted twice with ethyl butan-2-one. The combined organic layers were washed with brine, dried, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (n-hexane/ethyl acetate gradient) providing 450 mg of a mixture of the desired product with its para regioisomer that eluted with the same retention time (63% UV purity). This material was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([NH:12][CH2:13][C@H:14]2[O:19][CH2:18][CH2:17][N:16]([C:20]([O:22]C(C)(C)C)=O)[CH2:15]2)[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[CH:3]=1.[F:27][CH:28]([F:32])C(O)=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>Cl.C(OCC)(=O)C>[Cl:1][C:2]1[N:11]=[C:10]([NH:12][CH2:13][C@@H:14]2[CH2:15][N:16]([C:20](=[O:22])[CH:28]([F:32])[F:27])[CH2:17][CH2:18][O:19]2)[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[CH:3]=1
Reactant: O=C(O)C(F)F
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](CNc2nc(Cl)cc3nccnc23)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C(C(F)F)N1CCO[C@H](CNc2nc(Cl)cc3nccnc23)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.4 %

Procedure:
The (R)-tert-butyl 2-((7-chloropyrido[4,3-b]pyrazin-5-ylamino)methyl)morpholine-4-carboxylate (3.00 g, 8.0 mmol) was dissolved in the solution of HCl in ethyl acetate (20 mL), and the mixture was stirred at room temperature for 2 hours until TLC indicated Boc group was removed. The volatile materials were removed in vacuo and the residues were dissolved in dichloromethane. To the solution, difluoroacetic acid (1.15 g, 12 mmol), HATU (7.60 g, 20.0 mmol) and DIPEA (6.20 g, 48.0 mmol) were added subsequently and stirred at room temperature overnight. The mixture was purified by C18 column chromatography to give the desired amide as yellow solid (2.1 g). MS (m/z): 358 (M+H)+
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[F:12][C:13]1[CH:18]=[C:17]([S:19][CH3:20])[C:16]([F:21])=[CH:15][C:14]=1[F:22].[OH2:23]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[F:12][C:13]1[CH:18]=[C:17]([S:19]([CH3:20])=[O:9])[C:16]([F:21])=[CH:15][C:14]=1[F:22].[F:12][C:13]1[CH:18]=[C:17]([S:19]([CH3:20])(=[O:9])=[O:23])[C:16]([F:21])=[CH:15][C:14]=1[F:22]
Reactant: CSc1cc(F)c(F)cc1F
Reactant: O
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)c1cc(F)c(F)cc1F
Product: CS(=O)c1cc(F)c(F)cc1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 24 %
Yield: 14 %

Procedure:
MCPBA (4.93 g, 22 mmol) in DCM (20 mL) was added to an ice cooled solution of 43a (22 mmol) in DCM (40 mL). After 2 h, the mixture was diluted with water (30 mL) and saturated NaHCO3 (30 mL) and stirred for 20 minutes. The organic layer was removed and the aqueous layer was extracted with DCM (2×20 mL). The combined organic extracts were dried and concentrated. The residue was purified by flash LC(10 to 40% EtOAc+0.1% triethylamine in hexane) to afford 1,2,4-trifluoro-5-methanesulfinyl-benzene 43b (0.41 g, 24% yield, HPLC, LC-MS 195.0 (MH)) and 1,2,4-trifluoro-5-methanesulfonyl-benzene 43c (0.63 g, 14%) as white powders.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([NH:19][C:20]([NH:22][C:23]3[N:27]([C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=4)[N:26]=[C:25]([C:35]([CH3:38])([CH3:37])[CH3:36])[CH:24]=3)=[O:21])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH2:39]([N:41]=[C:42]=[O:43])[CH3:40].CN(C=O)C>C(Cl)Cl>[C:35]([C:25]1[CH:24]=[C:23]([NH:22][C:20]([NH:19][C:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:9]([CH2:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:42]([NH:41][CH2:39][CH3:40])=[O:43])[CH:7]=3)=[CH:10][CH:11]=2)=[O:21])[N:27]([C:28]2[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=2)[N:26]=1)([CH3:38])([CH3:37])[CH3:36]
Reactant: CCN=C=O
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Cc3ccnc(N)c3)c3ccccc23)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCNC(=O)Nc1cc(Cc2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3ccc(C)cc3)c3ccccc23)ccn1
Temperature: 0 °C
Reaction time: 21 h

Procedure:
To a solution of 1-(4-((2-aminopyridin-4-yl)methyl)naphthalen-1-yl)-3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)urea (55 mg, 0.11 mmol) in dry DCM (4.0 mL) under N2 at 0° C. was added ethyl isocyanate (22 μL, 0.27 mmol). The reaction mixture was maintained at 0° C. for 20 min, was then warmed to RT for 2 hr and dry DMF (200 μL) was added. Additional aliquots of ethyl isocyanate were added after 3.5 hr (22 μL, 0.27 mmol), after 21 hr (43 μL, 0.54 mmol) and after 28 hr (65 μL, 0.81 mmol). After 43 hr the reaction was quenched by the addition of a solution of NH3 (1% in MeOH, 3.0 mL) and after 45 min the resulting mixture was evaporated in vacuo. The residue was subjected to SCX capture and release and the crude product so obtained was purified by flash column chromatography (SiO2, 12 g, [5% MeOH in EtOAc] in isohexane, 0-80%, gradient elution) to afford the title compound, Example 23, as a white solid (26 mg, 40%); Rt 2.22 min (Method 2); m/z 576 (M+H)+ (ES+); 1H NMR (400 MHz, DMSO-d6) δ: 1.04 (3H, t), 1.28 (9H, s), 2.39 (3H, s), 3.14 (2H, m), 4.33 (2H, s), 6.40 (1H, s), 6.76 (1H, dd), 7.16 (1H, s), 7.36 (2H, d), 7.39 (1H, d), 7.45 (2H, d), 7.53 (2H, m), 7.87 (1H, d), 7.92 (1H, d), 8.01-8.04 (2H, overlapping m), 8.15 (1H, br t), 8.78 (1H, s), 9.04 (1H, s), 9.07 (1H, s).
Reaction SMILES: C[O-].[Na+].[SH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1.[NH2:11][C:12]1[N:17]=[C:16]([CH2:18]Cl)[CH:15]=[C:14]([O:20][CH3:21])[N:13]=1>CO.O>[NH2:11][C:12]1[N:13]=[C:14]([O:20][CH3:21])[CH:15]=[C:16]([CH2:18][S:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=2)[N:17]=1
Reactant: COc1cc(CCl)nc(N)n1
Reactant: Sc1ccccn1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc(CSc2ccccn2)nc(N)n1

Procedure:
18 g of 30% methanolic sodium methylate solution are added to a solution of 11.1 g of 2-mercaptopyridine in 100 ml of methanol, and stirring is then maintained at 20°-25° C. for 1 hour. To this solution are added portionwise 17.4 g of 2-amino-4-chloromethyl-6-methoxy-pyrimidine, and the mixture is stirred at 20°-25° C. for a further 2 hours. In further processing, the mixture is diluted with 1 litre of water, and the precipitating crystalline product is separated and dried. The yield is 22.5 g (91% of theory) of 2-amino-4-methoxy-6-(pyridin-2-yl-thiomethyl)-pyrimidine, m.p. 115°-116° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:27]=[C:26]([CH2:28][CH3:29])[CH:25]=[CH:24][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][CH2:19][CH2:20][CH2:21][NH2:22])=[CH:14][C:13]=1[F:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[S:37](Cl)([CH3:40])(=[O:39])=[O:38]>ClCCl>[CH3:40][S:37]([N:18]([C:15]1[CH:16]=[CH:17][C:12]([O:11][C:10]2[CH:24]=[CH:25][C:26]([CH2:28][CH3:29])=[CH:27][C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:13]([F:23])[CH:14]=1)[CH2:19][CH2:20][CH2:21][NH2:22])(=[O:39])=[O:38]
Reactant: CS(=O)(=O)Cl
Reactant: CCc1ccc(Oc2ccc(NCCCN)cc2F)c(OCc2ccccc2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1ccc(Oc2ccc(N(CCCN)S(C)(=O)=O)cc2F)c(OCc2ccccc2)c1
Yield: 82.8 %

Procedure:
To a solution of N1-[4-(2-Benzyloxy-4-ethylphenoxy)-3-fluorophenyl]propan-1,3-diamine (90 mg, 0.23 mmol) in 5 ml of dry dichloromethane and 0.08 ml (0.57 mmol) of triethylamine, cooled to 0° C., was added mesyl chloride (26 mg, 0.23 mmol) taken in 0.5 ml of dichloromethane dropwise. The reaction was quenched after 5 minutes as the reaction was complete on TLC. The reaction mixture was diluted with water and the layers separated. The aqueous layer was extracted with dichloromethane and the combined dichloromethane fraction was washed with water, dried over anhydrous Na2SO4 and concentrated. The crude residue obtained was combined with the crude obtained from an earlier 20 mg batch and column purified over silica gel using 2% methanol in dichloromethane as eluant to get 90 mg, 68.3% of title compound.
Reaction SMILES: [S:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].[CH:8]([C:10]1[CH:28]=[CH:27][C:13]([O:14][C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][C:16]=2[C:23]([F:26])([F:25])[F:24])=[C:12]([O:29][CH3:30])[CH:11]=1)=O>>[CH3:30][O:29][C:12]1[CH:11]=[C:10]([CH:8]=[C:7]2[S:1][C:2](=[S:3])[NH:4][C:5]2=[O:6])[CH:28]=[CH:27][C:13]=1[O:14][C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][C:16]=1[C:23]([F:24])([F:26])[F:25]
Reactant: COc1cc(C=O)ccc1Oc1ccc(C#N)cc1C(F)(F)F
Reactant: O=C1CSC(=S)N1
Product: COc1cc(C=C2SC(=S)NC2=O)ccc1Oc1ccc(C#N)cc1C(F)(F)F

Procedure:
The title compound was prepared using rhodanine and 4-(4-Formyl-2-methoxy-phenoxy)-3-trifluoromethyl-benzonitrile according to General Procedure B. 1H NMR (400 Hz, CDCl3) δ 9.31 (bs, NH), 7.98 (bs, 1H), 7.68 (dd, 1H), 7.64 (s, 1H), 7.18 (m, 3H), 6.77 (d, 1H), 3.83 (s, 3H).
Reaction SMILES: IC.[CH2:3]([C:5]1[CH:14]=[C:13]2[C:8]([C:9]([OH:20])=[C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:11]=[N:12]2)=[CH:7][CH:6]=1)[CH3:4].[C:21](=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:3]([C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:20])[C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][N:12]2[CH3:21])=[CH:7][CH:6]=1)[CH3:4]
Reactant: CCOC(=O)c1cnc2cc(CC)ccc2c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)c1cn(C)c2cc(CC)ccc2c1=O
Reaction time: 30 h

Procedure:
Iodomethane (7.7 g) was added dropwise to a stirred mixture of ethyl 7-ethyl-4-hydroxyquinoline-3-carboxylate (12.1 g), anhydrous potassium carbonate (6.8 g) and dimethylformamide (125 ml) at ambient temperature. Stirring was continued for 30 hours. The solution was cooled in ice, diluted with 2 volumes of water and extracted with dichloromethane (3×100 ml). The extracts were combined, washed with water, dried over anhydrous sodium sulphate and evaporated. The residual oil was triturated with cold ethyl acetate. The resulting solid was collected, washed with ethyl acetate and recrystallised from ethyl acetate to give the novel compound ethyl 7-ethyl-1-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylate, m.p. 92°-94°.
Reaction SMILES: OC[C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][C:9]1[S:13][CH:12]=[C:11]([C:14]2[CH:15]=[C:16]3[C:20](=[C:21]([C:23]([NH2:25])=[O:24])[CH:22]=2)[NH:19][CH:18]=[C:17]3[CH:26]2[CH2:31][CH2:30][N:29]([S:32]([CH:35]([CH3:37])[CH3:36])(=[O:34])=[O:33])[CH2:28][CH2:27]2)[CH:10]=1.N1CCC[C@@H]1C[OH:44]>>[OH:44][C@H:6]1[CH2:7][CH2:3][N:4]([CH2:8][C:9]2[S:13][CH:12]=[C:11]([C:14]3[CH:15]=[C:16]4[C:20](=[C:21]([C:23]([NH2:25])=[O:24])[CH:22]=3)[NH:19][CH:18]=[C:17]4[CH:26]3[CH2:27][CH2:28][N:29]([S:32]([CH:35]([CH3:37])[CH3:36])(=[O:34])=[O:33])[CH2:30][CH2:31]3)[CH:10]=2)[CH2:5]1
Reactant: OC[C@H]1CCCN1
Reactant: CC(C)S(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN5CCC[C@@H]5CO)c4)cc23)CC1
Product: CC(C)S(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN5CC[C@H](O)C5)c4)cc23)CC1
Yield: 53.1 %

Procedure:
The title compound was prepared according to the general procedure of 5-(5-{[(2R)-2-(hydroxymethyl)-1-pyrrolidinyl]methyl}-3-thienyl)-3-{1-[(1-methylethyl)sulfonyl]-4-piperidinyl}-1H-indole-7-carboxamide, substituting (3S)-3-pyrrolidinol (90.13 mg, 1.20 mmol) for (2R)-2-pyrrolidinylmethanol to afford 12.8 mg of the title compound (53.1%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C[O-].[Na+].[CH2:11](Br)[C:12]#[CH:13]>CN(C)C=O>[CH2:13]([O:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)[C:12]#[CH:11]
Reactant: Oc1cccnc1
Reactant: C#CCBr
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCOc1cccnc1
Yield: 33.8 %

Procedure:
To a mixture of 9.5 g (0.1 mole) 3-hydroxypyridine, 5.2 g (0.1 mole) sodium methylate and 150 ml N,N-dimethylformamide, there was added 12.0 g (0.1 mole) propargyl bromide at room temperature over a two hour period. Most of the solvent was removed under reduced pressure. The residue was taken up with 200 ml methylene chloride and 100 ml water, the layers were separated and the methylene chloride evaporated to give 4.5 g 3-(2-propynyloxy)pyridine, yield 34%.