Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:9].[OH-:10].[Ba+2].[OH-]>O>[CH3:1][NH:2][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:9])=[O:10]
Reactant: [OH-]
Reactant: CN1CCCCCC1=O
Agent: [Ba+2]
Solvent: O
Product: CNCCCCCC(=O)O
Temperature: 110 °C
Yield: 102.3 %

Procedure:
N-methyl-caprolactam (15 g, 118 mmol) was combined with barium hydroxide (10.1 g, 72 mmol) and water (150 ml). The suspension was warmed to 110° C. for 18 hours then cooled over an ice bath. Gaseous carbon dioxide was bubbled through the solution for 20 minutes. The suspension was filtered through a celite pad and the filtrate was concentrated to dryness. The residue was triturated with acetonitrile, collected, rinsed with ether and dried in vacuo to yield 6-(methylamino)hexanoic acid as a white solid (10.7 g). 6-(Methylamino)hexanoic acid (5 g, 34.5 mmol), and potassium carbonate (18 g, 130 mmol) were suspended in water (50 ml) and dioxane (25 ml) then cooled to 0° C. Methyl chloroformate (13 ml, 168 mmol) was added over 1 minute, then the mixture was stirred and allowed to warm slowly to room temperature for 16 hours. Conc. HCl (20 ml) was added then the mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, evaporated and dried in vacuo to give 6-[(methoxycarbonyl)(methyl)amino]hexanoic acid as a thick clear oil (5.7 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:10](OC)=[O:11])=[CH:4][CH:3]=1.[Li]Cl.O.[BH4-].[Na+]>C(O)C.C1COCC1>[C:18]([O:17][C:15](=[O:16])[NH:14][CH:9]([CH2:10][OH:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)([CH3:19])([CH3:21])[CH3:20]
Reactant: COC(=O)C(Cc1ccc(Br)cc1)NC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Li]Cl
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NC(CO)Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.7 %

Procedure:
To a solution of compound 3e (15 g, 42 mmol) in ethanol (50 mL) and THF (50 mL) was added LiCl.H2O (10 g, 170 mmol) and NaBH4 (6.3 g, 170 mmol) at 0° C. The mixture was stirred at rt overnight. LCMS analysis indicated the total consumption of compound 3e. The precipitate was removed by filtration and the filtrate was concentrated in vacuo to give 3f as a white solid (13 g, 94% yield).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C([Li])CCC.CCCCCC.[Br:17][CH2:18][CH2:19][CH2:20][CH2:21]Br>O1CCCC1>[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][C:2]1[O:1][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccoc1
Reactant: BrCCCCBr
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: BrCCCCc1ccco1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of furan (23.8 g, 0.35 mol) in dry tetrahydrofuran (150 ml) was cooled to -15° C., after which a solution of n-butyllithium in hexane (150 ml, 2.2 M, 0.33 mol) was added dropwise under nitrogen. The whole was stirred for a further 21/2 hours at 0° C. The solution thus obtained was subsequently added under nitrogen blanket during a period of about 1 hour to a solution of 1,4-dibromobutane (150 g, 0.7 mol) in dry tetrahydrofuran (225 ml), cooled to -25° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:14]3[CH:13]=[C:12](Cl)[N:11]=[C:10]([F:22])[C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25](B(O)O)[CH:24]=1.Cl.[F:33][C:34]1([F:39])[CH2:38][CH2:37][NH:36][CH2:35]1>>[F:33][C:34]1([F:39])[CH2:38][CH2:37][N:36]([C:12]2[N:11]=[C:10]([F:22])[C:9]3[O:8][C:5]4[C:4]([C@@:15]5([CH2:19][O:18][C:17]([NH2:20])=[N:16]5)[C:14]=3[CH:13]=2)=[CH:3][C:2]([C:25]2[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=2)=[CH:7][CH:6]=4)[CH2:35]1
Reactant: FC1(F)CCNC1
Reactant: NC1=N[C@@]2(CO1)c1cc(Br)ccc1Oc1c2cc(Cl)nc1F
Reactant: OB(O)c1cccnc1
Agent: Cl
Product: NC1=N[C@@]2(CO1)c1cc(-c3cccnc3)ccc1Oc1c2cc(N2CCC(F)(F)C2)nc1F

Procedure:
The title compound was synthesized by steps analogous to those described in method CC4 above, but using (S)-7-bromo-3-chloro-1-fluoro-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-oxazol]-2′-amine (prepared by steps analogous to those described in Method BB33) and 3-pyridyl-boronic acid and 3,3-difluoropyrrolidine hydrochloride.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].[CH3:9][Si:10]([C:13]#[CH:14])([CH3:12])[CH3:11].Cl>C(N(CC)CC)C.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:9][Si:10]([CH3:12])([CH3:11])[C:13]#[C:14][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8]
Reactant: Cc1ccccc1I
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: Cc1ccccc1C#C[Si](C)(C)C
Temperature: 25 °C
Yield: 94.6 %

Procedure:
2-Iodotoluene (81.5 ml, 0.64 mol) and trimethylsilylacetylene (99 ml, 0.71 mol) were dissolved in triethylamine (250 ml). Triphenylphosphine (0.427 g, 1.6 mmol), copper (I) iodide (0.3 g, 1.6 mmol) and bistriphenyphosphinepalladium (II) dichloride (0.53 g, 0.71 mmol) were added and the mixture was heated under reflux for 18 h. The mixture was cooled to ambient temperature and carefully added to 10% hydrochloric acid (480 ml) and the product was extracted into hexane (3×200 ml). The extracts were washed with 10% hydrochloric acid (200 ml) and water (2×200 ml) then dried (MgSO4) and evaporated in vacuo to give trimethyl-(2-methylphenyl)ethynylsilane (114.06 g) as a yellow oil, which was used without further purification.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][CH:11]=2)[CH:6]=[CH:5]1.[C:21](OC(=O)C)(=[O:23])[CH3:22].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.C1COCC1>[C:21]([O:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][CH:11]=2)[CH:6]=[CH:5]1)(=[O:23])[CH3:22]
Reactant: OCCn1ccc2cc(OCc3ccccc3)ccc21
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)OCCn1ccc2cc(OCc3ccccc3)ccc21

Procedure:
Crude N-(2-hydroxyethyl)-5-benzyloxyindole (11.09 g, 42.1 mmol), acetic anhydride (4.36 mL, 46.3 mmol), triethylamine (6.50 mL,46.3 mmol), and DMAP (100 mg) were stirred together in THF for 1 hour before standard aqueous workup provided N-(2-acetoxyethyl)-5-benzyloxyindole in yield as a clear oil (13.0 g, 99%). 1H NMR (500 MHz, CDCl3) δ 7.51 (d, J=8.1 Hz, 2H), 7.42 (t, J=8.1 Hz, 2H), 7.35 (s, 1H), 7.27 (d, J=8.9 Hz, 1H), 7.21 (d, J=2.4 Hz, 1H), 7.09 (d, J=3.1 Hz, 1H), 7.01 (dd, J=2.4, 8.1 HZ, 1H), 6.47 (dd, J=0.8, 3.1 Hz, 1H), 5.14 (s, 2H), 4.37 (t, J=5.0 Hz, 2H), 4.31 (t, J=5.0 Hz, 2H), 2.02 (s, 3H). 13C NMR (50 MHz, CDCl3) δ 170.6, 153.3, 137.7, 131.6, 128.9, 128.5 (2 C's), 128.4, 127.7, 127.5 (2 C's), 112.8, 109.8, 104.,3 101.4, 70.9, 63.0, 45.0, 20.7. MS (EI, m/z) M+=309.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][C:3]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Cl:12][C:13]1[C:29]([CH3:30])=[CH:28][C:16]2[NH:17][C:18]([S:20][C:21]3[O:25][C:24]([CH:26]=O)=[CH:23][CH:22]=3)=[N:19][C:15]=2[CH:14]=1.[C:31]1(=O)[CH2:36][CH2:35][CH2:34][C:33](=[O:37])[CH2:32]1>C(O)CCC>[CH2:10]([O:9][C:7]([C:3]1[NH:4][CH:5]=[C:6]2[CH:26]([C:24]3[O:25][C:21]([S:20][C:18]4[NH:17][C:16]5[CH:28]=[C:29]([CH3:30])[C:13]([Cl:12])=[CH:14][C:15]=5[N:19]=4)=[CH:22][CH:23]=3)[C:32]3[C:33](=[O:37])[CH2:34][CH2:35][CH2:36][C:31]=3[NH:1][C:2]=12)=[O:8])[CH3:11]
Reactant: O=C1CCCC(=O)C1
Reactant: CCOC(=O)c1[nH]ccc1N
Reactant: Cc1cc2[nH]c(Sc3ccc(C=O)o3)nc2cc1Cl
Solvent: CCCCO
Product: CCOC(=O)c1[nH]cc2c1NC1=C(C(=O)CCC1)C2c1ccc(Sc2nc3cc(Cl)c(C)cc3[nH]2)o1
Temperature: 25 °C
Yield: 11 %

Procedure:
A mixture of 3-amino-2-ethoxycarbonyl-pyrrole (0.204 g, 1.32 mmol), 5-(5-chloro-6-methyl-1H-benzimidazol-2-ylsulfanyl)-furan-2-carbaldehyde (0.388 g, 1.32 mmol) and 1,3-cyclohexanedione (0.149 g, 1.32 mmol) in 10 ml of 1-butanol is heated at reflux temperature for 4 h. The reaction mixture is then concentrated under reduced pressure and purified on a silica gel column (34 g) eluted with a mixture of cyclohexane and ethylacetate (7/3, v/v). The fractions containing the expected product are concentrated under reduced pressure, and the residue is resuspended in 5 ml of acetonitrile and heated at reflux temperature for 15 minutes. After cooling to room temperature, the insoluble material is collected by filtration and dried under vacuum to yield 76 mg of 9-[5-(5-chloro-6-methyl-1H-benzimidazol-2-ylsulfanyl)-furan-2-yl]-8-oxo-4,5,6,7,8,9-hexahydro-2H-pyrrolo[3,4-b]quinoline-3-carboxylic acid ethyl ester. Yield=11%. Analytical LC/MS (method B): m/z=523 (positive ion mode, [M+H]+, 1 Cl present), m/z=521 (negative ion mode, [M−H]−, 1 Cl present).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[CH3:8].[Br:9][C:10]1[CH:15]=[C:14]([F:16])[C:13]([F:17])=[CH:12][C:11]=1[SH:18]>CN(C=O)C.C(OCC)(=O)C>[Br:9][C:10]1[CH:15]=[C:14]([F:16])[C:13]([F:17])=[CH:12][C:11]=1[S:18][CH3:8]
Reactant: Fc1cc(S)c(Br)cc1F
Reactant: CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSc1cc(F)c(F)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
Potassium carbonate (310 mg, 2.22 mmol) and iodomethane (0.138 mL, 2.22 mmol) were added to a solution (10 mL) of 2-bromo-4,5-difluorothiophenol (400 mg, 1.78 mmol) in DMF, and stirred at room temperature overnight. After diluted with ethyl acetate, the resultant was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled away, and the resulting residue was purified by silica gel chromatography (hexane/ethyl acetate) to thus obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH2:13][C:14]([CH3:17])([NH2:16])[CH3:15].[CH3:18][C:19]1[O:23][C:22]([CH:24]=O)=[CH:21][CH:20]=1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH2:13][C:14]([CH3:17])([NH:16][CH2:24][C:22]1[O:23][C:19]([CH3:18])=[CH:20][CH:21]=1)[CH3:15]
Reactant: CC(C)(N)COc1ccc2ccccc2c1Cl
Reactant: Cc1ccc(C=O)o1
Product: Cc1ccc(CNC(C)(C)COc2ccc3ccccc3c2Cl)o1
Yield: 41 %

Procedure:
Prepared from 1-[(1-chloronaphthalen-2-yl)oxy]-2-methylpropan-2-amine and 5-methylfuran-2 carbaldehyde in 41% yield as a yellow oil.
Reaction SMILES: [C:1]([C:4]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]2[C:5]=1[O:6][C:7]1[CH:8]=[CH:9][C:10]([C:19]([O:21][CH3:22])=[O:20])=[CH:11][C:12]=1[CH2:13]2)(=[O:3])[CH3:2].CO.[BH4-].[Na+].O>C(O)(=O)C>[OH:3][CH:1]([C:4]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]2[C:5]=1[O:6][C:7]1[CH:8]=[CH:9][C:10]([C:19]([O:21][CH3:22])=[O:20])=[CH:11][C:12]=1[CH2:13]2)[CH3:2]
Reactant: COC(=O)c1ccc2c(c1)Cc1cc(C)cc(C(C)=O)c1O2
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc2c(c1)Cc1cc(C)cc(C(C)O)c1O2
Reaction time: 0.25 h

Procedure:
To a solution of 6 g. of methyl 5-acetyl-7-methyl-xanthene-2-carboxylate in 500 ml. of absolute methanol are added 1.1 g. of sodium borohydride in 50 ml. of water at a temperature of from 25° to 30° C with stirring, over a period of about 30 minutes. After 15 minutes under these conditions, 400 ml. of water and 20 ml. of acetic acid are added and the resultant mixture is stripped of solvent. The resultant mixture is extracted with methylene chloride and washed with bicarbonate and water. The washed extracts are concentrated to give methyl 5-(1-hydroxyethyl)-7-methylxanthene-2-carboxylate.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](=[S:21])[NH:18][C:17]3=[O:22])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.I[CH3:34]>>[F:32][C:2]([F:31])([F:1])[C:3]1[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([S:21][CH3:34])=[N:18][C:17]3=[O:22])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: O=C1NC(=S)SC1=Cc1ccc2c(cnn2Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1
Reactant: CI
Product: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1

Procedure:
5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-thioxo-thiazolidin-4-one and iodomethane following General Procedure B.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[CH:6]=1.[F:16][C:17]1[CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:20]=[CH:19][C:18]=1[C:32]1[CH:33]=[N:34][C:35]([NH2:38])=[N:36][CH:37]=1>>[NH2:11][C:7]1[CH:6]=[C:5]([O:4][C:3]2[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=2[C:21]2[CH:20]=[CH:19][C:18]([C:32]3[CH:37]=[N:36][C:35]([NH2:38])=[N:34][CH:33]=3)=[C:17]([F:16])[CH:22]=2)[CH:10]=[CH:9][N:8]=1
Reactant: Nc1cc(Oc2ccccc2Br)ccn1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Product: Nc1cc(Oc2ccccc2-c2ccc(-c3cnc(N)nc3)c(F)c2)ccn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 4-(2-bromophenoxy)pyridin-2-amine and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C21H16FN5O, 373.13; m/z found, 374.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.44 (s, 2H), 7.77 (d, J=6.3, 1H), 7.65-7.48 (m, 3H), 7.45-7.32 (m, 3H), 7.25 (d, J=8.0, 1H), 6.88 (s, 2H), 6.52 (s, 2H), 6.23 (dd, J=6.3, 2.2, 1H), 5.87 (d, J=2.2, 1H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[CH3:27][O:28][C:29]1[CH:39]=[CH:38][CH:37]=[C:36]([CH3:40])[C:30]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32]>C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:40][C:36]1[CH:37]=[CH:38][CH:39]=[C:29]([O:28][CH3:27])[C:30]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32]
Reactant: CCOC(=O)c1c(C)cccc1OC
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1c(CBr)cccc1OC
Temperature: 5 °C
Yield: 56.8 %

Procedure:
19.56 g of N-bromosuccinimide and 4.84 g of benzoyl peroxide were added to a solution of 19.40 g of ethyl 2-methoxy-6-methylbenzoate in 150 ml of carbon tetrachloride. The reaction medium was refluxed for 6 hours (no further change). The reaction medium was cooled to 5° C. and the succinimide was filtered. The organic phase was washed with a saturated sodium hydrogen carbonate solution (2×150 ml), dried over magnesium sulfate and evaporated. The residue was purified by chromatography on silica gel (column puriFlash, IR-50SI/800G, Spot II) eluted with heptane/ethyl acetate (gradient). 15.5 g of ethyl 2-bromomethyl-6-methoxybenzoate were obtained in the form of a yellow oil which later crystallizes. Yield=56%.
Reaction SMILES: [C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][C:4]([CH:7]=[CH:8][C:9]([OH:11])=O)=[CH:3][CH:2]=1.[CH3:18][O:19][C:20](=[O:41])[C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:22]=1[NH:28]C(C1C2C(=CC=CC=2)C=CC=1)=O.C([O-])(O)=O.[Na+]>O=S(Cl)Cl.CC(C)=O>[CH3:18][O:19][C:20](=[O:41])[C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:22]=1[NH:28][C:9](=[O:11])/[CH:8]=[CH:7]/[C:4]1[CH:3]=[CH:2][C:1]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1
Reactant: O=C(O)C=Cc1ccc(-c2ccccc2)cc1
Reactant: COC(=O)c1ccc(O)cc1NC(=O)c1cccc2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CC(C)=O
Product: COC(=O)c1ccc(O)cc1NC(=O)/C=C/c1ccc(-c2ccccc2)cc1
Reaction time: 18 h
Yield: 79.2 %

Procedure:
A mixture of 3-biphenyl-4-yl-acrylic acid (0.449 g, 2.004 mmol) in SOCl2 (5 ml) was refluxed for 2 h. After cooling, the solvent was removed. The residue was dissolved in acetone and added into a stirred solution of 4-hydroxy-2-(naphthoylamino)-benzoic acid methyl ester (0.335 g, 2.004 mmol) in acetone (10 ml) with NaHCO3 (0.202 g, 2.405 mmol). After 18 h, the reaction mixture was concentrated. The residue was triturated with water, filtered and the solids rinsed with ether and dried to give 2-{[(2E)-3-(1,1′-biphenyl-4-yl)prop-2-enoyl]amino}-4-hydroxybenzoic acid methyl ester (0.593 g, 1.588 mmol, 79%) as an off-white solid, mp 292-296° C. 1H NMR (DMSO-d6) δ 3.88 (s, 3H), 6.57 (dd, 1H), 6.95 (d, 1H), 7.37-7.54 (m, 3H), 7.67 (d, 1H), 7.70-7.80 (m, 4H), 7.80-7.90 (m, 3H), 8.20 (dd, 1H), 10.55 (s, 1H), 11.20 (s, 1H); mass spectrum [ES(−)], m/z 372 (M−H)−.
Reaction SMILES: C[O:2][C:3]([C:5]1([NH:11][C:12]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]=2[O:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)=[O:13])[CH2:10][CH2:9][S:8][CH2:7][CH2:6]1)=[O:4].Cl>C1COCC1.[OH-].[Na+].CO>[F:34][C:32]([F:33])([F:35])[C:29]1[CH:28]=[CH:27][C:26]([CH2:25][O:24][C:15]2[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:22]=[CH:23][C:14]=2[C:12]([NH:11][C:5]2([C:3]([OH:4])=[O:2])[CH2:6][CH2:7][S:8][CH2:9][CH2:10]2)=[O:13])=[CH:31][CH:30]=1
Reactant: COC(=O)C1(NC(=O)c2ccc3ccccc3c2OCc2ccc(C(F)(F)F)cc2)CCSCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(NC1(C(=O)O)CCSCC1)c1ccc2ccccc2c1OCc1ccc(C(F)(F)F)cc1
Yield: 93.9 %

Procedure:
126 mg 4-{[1-(4-trifluoromethyl-benzyloxy)-naphthalene-2-carbonyl]-amino}-tetrahydro-thiopyran-4-carboxylic acid methyl ester in 2.5 ml THF, 0.25 ml 2 M sodium hydroxide and 0.25 ml methanol were reacted at room temperature for 16 h. The reaction was then acidified with 2 M hydrochloric acid and extracted with ethyl acetate twice. The combined organic layers were dried over magnesium sulphate, and concentrated to yield 115 mg of 4-{[1-(4-trifluoromethyl-benzyloxy)-naphthalene-2-carbonyl]-amino}-tetrahydro-thiopyran-4-carboxylic acid.
Reaction SMILES: O1CCCCC1[O:7][CH:8]1[C:16]2[S:15][CH:14]=[N:13][C:12]=2[O:11][CH2:10][CH2:9]1.CC1C=CC(S(O)(=O)=O)=CC=1>C1COCC1.O.C(Cl)Cl>[S:15]1[C:16]2[CH:8]([OH:7])[CH2:9][CH2:10][O:11][C:12]=2[N:13]=[CH:14]1
Reactant: c1nc2c(s1)C(OC1CCCCO1)CCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: OC1CCOc2ncsc21

Procedure:
A soln. of 7-((tetrahydro-2H-pyran-2-yl)oxy)-6,7-dihydro-5H-pyrano[2,3-d]thiazole (895 mg, 3.71 mmol) and PTSA (141 mg, 0.74 mmol) in THF/H2O (7.4 mL, 1:1) was stirred at RT overnight. The mixture was diluted with DCM, dried over Na2SO4, and conc. in vacuo. Purification by means of CC (40-100% EtOAc/Hept) provided a yellow oil.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][N:11]([CH2:16][CH:17]([OH:28])[CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH3:27])[C:12](=[O:15])[CH2:13]Cl)=O)(C)(C)C.C(N(C(C)C)CC)(C)C>C(O)(C(F)(F)F)=O>[OH:28][CH:17]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH3:27])[CH2:16][N:11]1[CH2:10][CH2:9][NH:8][CH2:13][C:12]1=[O:15]
Reactant: COc1ccccc1OCC(O)CN(CCNC(=O)OC(C)(C)C)C(=O)CCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1OCC(O)CN1CCNCC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Compound 12 (0.5 g, 1.5 mmol) was dissolved in 10 mL TFA. The mixture was allowed to stir at RT for 2 h. TFA was removed under reduced pressure. The residue was dissolved in 20 mL EtOH and treated with diisopropylethyl amine (0.76 g, 4.5 mmol). The mixture was heated at reflux for 24 h. The solvent was removed under reduced pressure to afford compound 13 which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH:14][CH3:15])=[CH:10][N:11]=[N:12][CH:13]=2)=[C:4]([O:16][CH3:17])[CH:3]=1.[CH3:18][S:19]([C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[C:25](Cl)=[O:26])(=[O:21])=[O:20].C(N(CC)C(C)C)(C)C.[Cl-].[NH4+]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([N:14]([CH3:15])[C:25](=[O:26])[C:24]3[CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=[C:22]([S:19]([CH3:18])(=[O:21])=[O:20])[CH:23]=3)=[CH:10][N:11]=[N:12][CH:13]=2)=[C:4]([O:16][CH3:17])[CH:3]=1
Reactant: CNc1cnncc1-c1ccc(F)cc1OC
Reactant: CS(=O)(=O)c1cc(C(=O)Cl)cc(C(F)(F)F)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(F)ccc1-c1cnncc1N(C)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 1.75 h
Yield: 26.7 %

Procedure:
To a solution of 5-(4-fluoro-2-methoxyphenyl)-N-methylpyridazin-4-amine (27 mg, 116 μmol) in dichloromethane (1 mL) were added 3-(methylsulfonyl)-5-(trifluoromethyl)benzoyl chloride (66.4 mg, 232 mmol) and N,N-diisopropylethylamine (60 mg, 80.9 μL, 463 μmol). The clear, light brown solution was stirred at room temperature for 1.75 h and then poured on saturated aqueous ammonium chloride solution and dichloromethane and the layers were separated. The aqueous layer was extracted three times with dichloromethane. The organic layers were dried over magnesium sulfate, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 10 g column using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 0:100) to give the desired compound as a light brown solid (15 mg; 25%). MS (ESI+): m/z=483.09 ([M+H]+).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:12]=[C:11]2[C:6]([N:7]=[CH:8][C:9](=O)[NH:10]2)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:16])=O>ClCCl>[Cl:16][C:9]1[CH:8]=[N:7][C:6]2[C:11](=[CH:12][C:3]([S:2][CH3:1])=[CH:4][CH:5]=2)[N:10]=1
Reactant: CSc1ccc2ncc(=O)[nH]c2c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: CSc1ccc2ncc(Cl)nc2c1
Temperature: 25 °C
Yield: 33.7 %

Procedure:
A solution of 7-methylsulfanyl-1H-quinoxalin-2-one (9.23 g, 48.0 mmol, 1.0 eq) in phosphorus oxychloride (36 mL, 384.0 mmol, 8.0 eq) is heated under reflux for 30 minutes. Then the reaction mixture is cooled down to room temperature and the solvent is evaporated. The residue is poured into ice water, the resulting mixture is basified with saturated sodium hydrogen carbonate to pH=8-9 and extracted with ethyl acetate (3×50 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a crude product that is purified by column chromatography (silica gel, eluent: petroleum ether:dichloromethane, 4:1 to 1:1, v/v) to afford 2-chloro-7-methylsulfanyl-quinoxaline as a green solid (3.41 g, 33% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:9][CH:10]([CH3:21])[C:11](=[O:20])[CH2:12][C:13](=[O:19])[C:14]([O:16]CC)=O.[CH2:22]=O>C(O)C.CC(C)=O>[OH:19][C:13]1[C:14](=[O:16])[N:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:22][C:12]=1[C:11](=[O:20])[CH:10]([CH3:9])[CH3:21]
Reactant: C=O
Reactant: Nc1ccccc1
Reactant: CCOC(=O)C(=O)CC(=O)C(C)C
Agent: Cl
Solvent: CCO
Solvent: CC(C)=O
Product: CC(C)C(=O)C1=C(O)C(=O)N(c2ccccc2)C1
Temperature: 25 °C
Yield: 31.7 %

Procedure:
To a stirred mixture of aniline (0.50 g, 5.4 mmole) and concentrated HCl (0.46 ml) in ethanol (2.5 ml) was added ethyl 5-methyl-2,4-dioxohexanoate (1.0 g, 5.4 mmole) and paraformaldehyde (0.25 g). After heating at reflux over 3 hours hot acetone (13 ml) was added and the resulting solution was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in 1N NaOH and extracted with methylene chloride. The aqueous layer was acidified to pH 1 with 3N HCl, extracted with methylene chloride, dried over sodium sulfate, filtered and concentrated under reduced pressure. Recrystallization from 10% ether in pet. ether gives 0.42 g of the title compound as a pale yellow solid. M.P. 162°-170° C.; 1H NMR (250 MHz, CDCl3) δ 1.21 (d, J=6.8 Hz, 6H), 3.24 (heptet, J=6.8 Hz, 1H), 4.52 (s, 2H), 7.23 (m, 1H), 7.43 (t, J=8.0 Hz, 2H), 7.77 (d, J=7.8 Hz); MS m/z 246.