Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[Cl:22])[NH:15][CH:14]=1)([NH2:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.C=O.[CH:26]1C=C2C(C(O)(O)C(=O)C2=CC=1)=O>C1C=CC=CC=1>[ClH:22].[CH2:9]([O:8][C:6]([C:5]1([C:4]([OH:3])=[O:23])[CH2:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[Cl:22])[NH:15][C:14]=2[CH2:26][NH:11]1)=[O:7])[CH3:10]
Reactant: CCOC(=O)C(N)(Cc1c[nH]c2cccc(Cl)c12)C(=O)OCC
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Agent: C=O
Solvent: c1ccccc1
Product: CCOC(=O)C1(C(=O)O)Cc2c([nH]c3cccc(Cl)c23)CN1
Product: Cl

Procedure:
1.13 g of 2-(4-chloroindol-3-ylmethyl)-2-aminomalonic acid diethylester hydrochloric and 80 mg of paraformaldehyde are boiled at reflux for about 15 minutes in 30 ml of benzene until the Ninhydrin reaction has disappeared. After cooling, the crystalline precipitate is suction-filtered and recrystallized from benzene. 1.05 g of 5-chloro-1,2,3,4-tetrahydro-β-carbolin-3,3-dicarboxylic acid ethyl ester hydrochloride of melting point 157° C. is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=1)[CH3:2].C(N([CH2:18][CH3:19])CC)C.[CH:20]([P:22](=[O:27])(OCl)[O:23]Cl)=[CH2:21]>C(Cl)Cl>[CH:20]([P:22]([O:23][C:7]1[CH:6]=[C:5]([CH:10]=[CH:18][CH:19]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:12])([O:11][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:12])=[O:27])=[CH2:21]
Reactant: CCOC(=O)c1cccc(O)c1
Reactant: C=CP(=O)(OCl)OCl
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: C=CP(=O)(Oc1cccc(C(=O)OCC)c1)Oc1cccc(C(=O)OCC)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.5 %

Procedure:
A solution containing ethyl-3-hydroxybenzoate (8 mmol, 1.329 g) and triethylamine (8.3 mmol, 829 mg) in methylene chloride (50 mL) was added dropwise at 0° C. under stirring to a solution of dichloro vinylphosphonate (4 mmol, 0.58 g) in methylene chloride (20 mL). The reaction mixture was stirred at ambient temperature for 24 hours, washed twice with water (40 mL each). The separated organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated to dryness in vacuo to yield 1.61 g (86-99%) of the desired title compound. MS (APPI+): m/e 405 [M+H]+.
Reaction SMILES: C[O:2][C:3]([CH:5]([O:10][C:11]1[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=1[C:13]([O:15]C)=[O:14])[CH2:6][CH2:7][CH2:8][CH3:9])=[O:4].[OH-].[Na+]>CO.O>[C:3]([CH:5]([O:10][C:11]1[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=1[C:13]([OH:15])=[O:14])[CH2:6][CH2:7][CH2:8][CH3:9])([OH:4])=[O:2]
Reactant: CCCCC(Oc1ccccc1C(=O)OC)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCC(Oc1ccccc1C(=O)O)C(=O)O
Temperature: 40 °C
Reaction time: 1 h
Yield: 86.3 %

Procedure:
13.0 g of methyl 2-(1-methoxycarbonylpentoxy)benzoate were dissolved in methanol in a 250 ml flask, and a solution of 9.1 g of sodium hydroxide in 40 ml of water was added. The reaction mixture was stirred at 40° C. for one hour, during which a precipitate formed. This was dissolved after cooling to room temperature by adding further methanol and sodium hydroxide solution. The reaction mixture was washed with dichloromethane, and the aqueous phase was subsequently adjusted to pH 0 with concentrated hydrochloric acid while cooling in ice. A colourless solid precipitated during this and was filtered off and dried. 10.1 g (87% of theory) of 2-(1-carboxypentoxy)benzoic acid were obtained in this way.
Reaction SMILES: [OH-:1].[K+].[CH2:3]([CH:5]1[CH2:10][O:9][C:8]2[CH:11]=[CH:12][C:13]([C:15]#N)=[CH:14][C:7]=2[O:6]1)[CH3:4].C(O)C.Cl.[OH2:21]>>[CH2:3]([CH:5]1[CH2:10][O:9][C:8]2[CH:11]=[CH:12][C:13]([C:15]([OH:21])=[O:1])=[CH:14][C:7]=2[O:6]1)[CH3:4]
Reactant: [OH-]
Reactant: CCC1COc2ccc(C#N)cc2O1
Reactant: O
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: CCC1COc2ccc(C(=O)O)cc2O1
Temperature: 80 °C
Yield: 92 %

Procedure:
KOH (218 mg, 3.9 mmol) is added to a mixture of 3-ethyl-2,3-dihydro-1,4-benzodioxine-6-carbonitrile (247 mg, 1.3 mmol), ethanol (3 mL) and water (1 mL). The resulting mixture is heated to 80° C. for 24 hours. The reaction is allowed to cool, diluted with water (2 mL) and acidified to pH<2 with concentrated HCl. The resulting solid is filtered, washed with water and dried at 60° C. under vacuum to give 3-ethyl-2,3-dihydro-1,4-benzodioxine-6-carboxylic acid as a white solid (249 mg, 92%). 1H NMR (400 MHz, DMSO-d6) δ 12.66, 7.43, 7.37, 6.95, 4.38, 4.10, 3.95, 1.64, 1.01.
Reaction SMILES: [O:1]=[C:2]1[C:8]2=[CH:9][C:10]3[CH:11]=[CH:12][C:13]([C:16]([OH:18])=O)=[CH:14][C:15]=3[N:7]2[CH2:6][CH2:5][CH2:4][NH:3]1.CN(C([O:26][N:27]1N=N[C:29]2[CH:30]=[CH:31][CH:32]=[N:33][C:28]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N=P1N(C)CCCN1C)(C)(C)C.C(C1ON=C(N)C=1)C>C1COCC1.CN(C=O)C>[CH2:31]([C:30]1[O:26][N:27]=[C:28]([NH:33][C:16]([C:13]2[CH:12]=[CH:11][C:10]3[CH:9]=[C:8]4[C:2](=[O:1])[NH:3][CH2:4][CH2:5][CH2:6][N:7]4[C:15]=3[CH:14]=2)=[O:18])[CH:29]=1)[CH3:32]
Reactant: O=C(O)c1ccc2cc3n(c2c1)CCCNC3=O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CCc1cc(N)no1
Agent: CN1CCCN(C)[PH]1=NC(C)(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCc1cc(NC(=O)c2ccc3cc4n(c3c2)CCCNC4=O)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 4.8 %

Procedure:
To a solution of 1-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indole-8-carboxylic acid (Intermediate J, 75 mg, 0.31 mmol) in THF (2 mL) and DMF (0.5 mL) is added HATU (128 mg, 0.34 mmol). The mixture is stirred at room temperature for 1 h, after which polystyrene bound 2-tert-butylimino-1,3-dimethylperhydro-1,3,2-diazaphosphorine (419 mg, 0.92 mmol) is added. The mixture is stirred at room temperature for 10 min and 5-ethyl-3-aminoisoxazole (103 mg, 0.92 mmol) is added. The reaction is stirred at 60° C. for 16 h and is then cooled to room temperature. The mixture is filtered, washing with methanol and the filtrate is concentrated under reduced pressure. The residue is purified via preparative HPLC using a gradient elution from 10-90% acetonitrile/water with 0.1% TFA to obtain the title compound (5 mg, 5%). LCMS: 339.20 (M+H+). (System V1)
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[N:10]=2)[CH:3]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[O:17]([C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=1)[O:24][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[N:10]=2)[CH:3]=1)[CH3:16]
Reactant: Nc1cccc(Nc2cc(Cl)ncn2)n1
Reactant: COc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cccc(Oc2cc(Nc3cccc(N)n3)ncn2)c1
Temperature: 100 °C
Yield: 39.5 %

Procedure:
To a solution of N2-(6-chloropyrimidin-4-yl)pyridine-2,6-diamine (200 mg, 0.90 mmol) in dry DMF (2 mL) was added 3-methoxyphenol (112 mg, 0.90 mmol) and anhydrous K2CO3 (186 mg, 1.353 mmol). The reaction mixture was heated at 100° C. for 16 h under N2 atmosphere. It was then cooled and DMF removed under reduced pressure to give a yellowish gummy residue that was taken in EtOAc (10 mL). It was washed with water (5 mL), brine (5 mL), dried over Na2SO4 and then concentrated under reduced pressure to give a crude product. This was further purified by column chromatography (SiO2, 60-120, hexane/EtOAc, 5/5) to give N2-(6-(3-methoxylphenoxy)pyrimidin-4-yl)pyridine-2,6-diamine (110 mg, 40.7%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12](=O)[CH:13]=[N+:14]=[N-:15])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.NN1[N:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]1=[O:32].C(N(CC)CC)C.CN(C=[O:44])C>CCOC(C)=O.C([O-])(=O)C1C=CC=CC=1.[Ag+]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:12][C:13]([NH:14][N:15]3[N:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:19]3=[O:32])=[O:44])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=CC(=O)C1(c2ccc(Cl)cc2)CCC1
Reactant: CN(C)C=O
Reactant: Nn1nc(C(F)(F)F)c2ccccc2c1=O
Agent: [Ag+]
Agent: O=C([O-])c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(CC1(c2ccc(Cl)cc2)CCC1)Nn1nc(C(F)(F)F)c2ccccc2c1=O

Procedure:
A solution of the above crude 1-(1-(4-chlorophenyl)cyclobutyl)-2-diazoethanone (65.6 mg, 0.280 mmol), the product from Example 11B (0.0503 g, 0.219 mmol), triethylamine (0.12 mL, 0.86 mmol), and silver benzoate (12.4 mg, 0.054 mmol) in DMF (1 mL) was stirred for 2 hours, diluted with EtOAc, washed with saturated aqueous NaHCO3 and brine, dried (Na2SO4), and filtered. The residue was chromatographed on SiO2 (4% EtOAc/dichloromethane) to give the title compound (33.5 mg) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 11.50 (s, 1H), 8.41 (dd, J=7.9, 1.4 Hz, 1H), 8.09-8.15 (m, 1H), 8.02-8.07 (m, 1H), 7.97-8.02 (m, 1H), 7.30-7.34 (m, 2H), 7.21-7.24 (m, 2H), 2.80 (s, 2H), 2.44-2.49 (m, 2H), 2.26-2.39 (m, 2H), 2.06-2.21 (m, 1H), 1.70-1.84 (m, 1H); MS (ESI+) M/Z 436 (M+H)+.
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Br:11])[C:3]=1[CH3:12].[Cu][C:14]#[N:15]>CN1CCCC1=O.ClCCl>[Br:11][C:4]1[C:3]([CH3:12])=[C:2]([C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1)[C:14]#[N:15]
Reactant: Cc1c(Br)ccc([N+](=O)[O-])c1Br
Reactant: N#C[Cu]
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: Cc1c(Br)ccc([N+](=O)[O-])c1C#N
Temperature: 150 °C

Procedure:
To a mixture of 2,6-dibromo-3-nitrotoluene (1.0 g, 3.4 mmol) in 14 ml of N-methylpyrrolidinone was added 0.323 g of freshly prepared copper (I) cyanide. The reaction was stirred and heated at a temperature of 150° C. under a nitrogen atmosphere for a period of three hours. After this period, the reaction mixture was cooled to room temperature, diluted with dichloromethane, and washed with 10% aqueous sodium thiosulfate solution. The organic layer was separated, dried, and concentrated under vacuum to remove the solvent. The residue was chromatographed on silica gel, eluting with 20% ethyl acetate/80% hexane, to afford 0.293 g of 3-bromo-2-methyl-6-nitrobenzonitrile as a yellow-white crystalline solid, mp 116°-118° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]#[N:10])=[N:6][C:7]=1[CH3:8].O.[NH2:12][NH2:13]>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9](=[N:12][NH2:13])[NH2:10])=[N:6][C:7]=1[CH3:8]
Reactant: NN
Reactant: Cc1nc(C#N)ccc1Br
Solvent: O
Solvent: CCO
Product: Cc1nc(C(N)=NN)ccc1Br
Temperature: 25 °C
Reaction time: 24 h
Yield: 93.2 %

Procedure:
A 500-mL, three-neck, round-bottom flask was equipped with 5-bromo-6-methylpicolinonitrile (101.5 g, 0.515 mol), ethanol (122 mL) and hydrazine hydrate (50 mL, 1.03 mol). The resulting very thick mixture was allowed to stir at ambient temperature for 24 h. More ethanol (50 mL) was added and the mixture was allowed to stir over the weekend. The mixture was filtered and washed with cold ethanol (100 mL) and cold hexanes (50 mL). The solids were dried in a vacuum oven to afford the product (110 g, 93% yield) as an off-white solid.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[CH:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([NH:17][C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19])[CH:10]=2)=[O:5])C.[CH2:27]([C:30]([OH:32])=[O:31])[CH2:28][NH2:29].C[O-].[Na+].CO>>[OH:16][C:15]1[C:14]2[C:9](=[CH:10][C:11]([NH:17][C:18]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:19])=[CH:12][CH:13]=2)[CH:8]=[N:7][C:6]=1[C:4]([NH:29][CH2:28][CH2:27][C:30]([OH:32])=[O:31])=[O:5]
Reactant: NCCC(=O)O
Reactant: CCOC(=O)c1ncc2cc(NC(=O)Nc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CCNC(=O)c1ncc2cc(NC(=O)Nc3ccccc3)ccc2c1O
Reaction time: 24 h
Yield: 57 %

Procedure:
4-Hydroxy-7-(3-phenyl-ureido)-isoquinoline-3-carboxylic acid ethyl ester (75 mg, 0.2135 mmol) and B-alanine (191 mg, 2.135 mmol) were combined in a dry flask. 0.5M sodium methoxide in methanol (4.2 mL, 2.135 mmol) was added with stirring and the solution brought to reflux and held for 24 h. The mixture was cooled, concentrated in vacuo and the residue dissolved in water. The solution was acidified to pH 3 with 1M hydrochloric acid and the precipitate isolated by filtration. The crude product was purified by trituration with a minimal volume of methanol to provide the title compound in 57% yield. MS ESI(+) m/e: 395.1345 (M+1).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[O:9])[S:8][C:4]=2[CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1>>[Cl:12][C:13]1[CH:18]=[C:17]([C:2]2[CH:11]=[CH:10][C:5]3[NH:6][C:7](=[O:9])[S:8][C:4]=3[CH:3]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: O=c1[nH]c2ccc(Br)cc2s1
Reactant: OB(O)c1cccc(Cl)c1
Product: O=c1[nH]c2ccc(-c3cccc(Cl)c3)cc2s1

Procedure:
Prepared from 6-bromo-2-benzothiazolinone, 3-chlorophenyl boronic acid according to the procedure of example 12. A white solid: mp 195-196° C.; 1H-NMR (DMSO-d6) δ 11.95 (s, 1H), 7.96 (d, 1H, J=1.17 Hz), 7.7 (t, 1H, J=1.76 Hz) 7.62-7.59 (m, 2H), 7.46 (t, 1H, J=7.65 Hz), 7.4-7.38 (m, 1H), 7.18 (d, 1H, J=8.24 Hz); MS (EI) m/z (M+, 30%); Anal. Calc. For C13H8ClNOS.H2O: C, 57.67, H, 3.35, N, 5.17. Found: C, 57.98, H, 3.11, N, 4.98.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].O>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:5]=1
Reactant: CCCCCBr
Reactant: COC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCOc1cccc(C(=O)OC)c1
Temperature: 80 °C
Reaction time: 7 h

Procedure:
To 3-hydroxybenzoic acid methyl ester (25 g) and potassium carbonate (25 g) in N,N-dimethylformamide (300 ml) were added 1-bromopentane (25 ml) and the mixture was stirred for 7 hours at 80° C. the reaction mixture was added to a mixture of water and ethyl acetate. The organic layer was taken and dried over magnesium sulfate. The magnesium sulfate was filtered off and the filtrate was evaporated under reduced pressure to give 3-amyloxybenzoic acid methyl ester (35 g).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([C:10]2[NH:14][N:13]=[CH:12][CH:11]=2)[CH:7]=[C:6]([F:15])[C:3]=1[C:4]#[N:5].O[CH2:17][CH2:18][NH:19]C(=O)OC(C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>>[NH2:19][CH2:18][CH2:17][N:13]1[CH:12]=[CH:11][C:10]([C:8]2[CH:7]=[C:6]([F:15])[C:3]([C:4]#[N:5])=[C:2]([F:1])[CH:9]=2)=[N:14]1
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: N#Cc1c(F)cc(-c2ccn[nH]2)cc1F
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: N#Cc1c(F)cc(-c2ccn(CCN)n2)cc1F
Yield: 19.8 %

Procedure:
The title compound was prepared from 2,6-difluoro-4-(1H-pyrazol-5-yl)-benzonitrile (1.50 g, 7.31 mmol) and tert-butyl N-(2-hydroxyethyl)carbamate (0.96 ml, 6.09 mmol), triphenylphosphine (1.918 g, 7.31 mmol) and DIAD (1.200 ml, 6.09 mmol) using the method of Example 34 (c) affording 0.30 g of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.60 (m, 2H), 2.94 (t, 2H), 4.14 (t, 2H), 7.01 (d, 1H), 7.79 (m, 2H), 7.88 (d, 1H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:18])[C:11]2[CH:16]=[CH:15][N:14]=[C:13](Cl)[CH:12]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[NH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>>[I:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:18])[C:11]2[CH:16]=[CH:15][N:14]=[C:13]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:12]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: C1CCNC1
Reactant: Cc1ccc(NC(=O)c2ccnc(Cl)c2)cc1I
Product: Cc1ccc(NC(=O)c2ccnc(N3CCCC3)c2)cc1I

Procedure:
A solution of N-(3-iodo-4-methylphenyl)-2-chloro-isonicotinamide (Intermediate 20)(7.00 g, 18.8 mmol) in pyrrolidine (20 ml) was heated at 80° C. under an atmosphere of nitrogen for 16 hours. Excess pyrrolidine was removed in vacuo and the residue was titurated with dietheyl ether (20 ml). The resulting solid was collected by filtration and dried in vacuo to give N-(3-iodo-4-methylphenyl)-2-pyrrolidin-1-yl-isonicotinamide as a pale yellow solid (7.73 g, 18 mmol). LCMS: retention time 2.77 min MH+ 408. NMR: δH [2H6]-DMSO 10.29 (1H, s), 8.29 (1H, d), 8.20 (1H, d), 7.71 (1H, dd), 7.72 (1H, dd), 6.97 (1H, brd), 6.88 (1H, b), 3.45 (2H, apparent t), 3.09 (2H, m), 2.35 (3H, s), 1.98 (2H, m), 1.82 (2H, m).
Reaction SMILES: [OH-:1].[Na+].[CH3:3][O:4][C:5]1[CH:19]=[CH:18][C:8]([O:9][C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[CH:13]=[O:14])=[CH:7][CH:6]=1>O.[Ag]=O>[CH3:3][O:4][C:5]1[CH:19]=[CH:18][C:8]([O:9][C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[C:13]([OH:1])=[O:14])=[CH:7][CH:6]=1
Reactant: [OH-]
Reactant: COc1ccc(Oc2cccc(C=O)c2)cc1
Agent: O=[Ag]
Agent: [Na+]
Solvent: O
Product: COc1ccc(Oc2cccc(C(=O)O)c2)cc1
Yield: 61.7 %

Procedure:
To a suspension of 10.6 g of silver oxide in 75 ml of water were added 7 g of sodium hydroxide. Ten grams of 3-(4-methoxyphenoxy)benzaldehyde were added in dropwise fashion and the reaction mixture was heated to 60°-70° C. for one hour. The mixture was filtered, the filtrate was acidified to pH 2 with hydrochloric acid, and the resulting precipitate was recovered by filtration. Crystallization from ethanol/water afforded 6.6 g of the desired subtitle intermediate, m.p. 141°-143° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@H:13]2[CH2:22][CH2:21][C:20]3[C:15](=[C:16](Br)[CH:17]=[C:18]([F:23])[CH:19]=3)[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@H:13]2[CH:22]=[CH:21][C:20]3[C:15](=[C:16]([C:30]4[CH:31]=[C:26]([Cl:25])[CH:27]=[CH:28][C:29]=4[Cl:32])[CH:17]=[C:18]([F:23])[CH:19]=3)[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCc3cc(F)cc(Br)c3O2)cc1
Reactant: OB(O)c1cc(Cl)ccc1Cl
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OC[C@H]2C=Cc3cc(F)cc(-c4cc(Cl)ccc4Cl)c3O2)cc1
Yield: 88 %

Procedure:
To a solution of [(R)-8-bromo-6-fluoro-3,4-dihydro-2H-chromen-2-yl)methyl 4-methylbenzenesulfonate, prepared in Example 38, step 2 (0.40 g, 0.97 mmol) and 2,5-dichlorophenylboronic acid (0.56 g, 2.9 mmol) in dioxane (10 ml) was added a solution of potassium carbonate (0.34 g, 2.4 mmol) in water (2 mL) and the mixture purged with nitrogen for 20 minutes. Dichlorobis(tri-o-tolylphosphine)palladium (II) (20 mg, 0.029 mmol) was added and the reaction mixture heated to reflux for 1 hour. The cooled reaction mixture was then partitioned between ethyl acetate (100 mL) and 2.0 M aqueous sodium hydroxide (100 mL). The organic layer was separated, washed with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford a yellow syrup. Purification by flash chromatography using a solvent gradient of 5 to 20% ethyl acetate in hexane gave 0.41 g (88%) of ((R)-8-(2,5-dichlorophenyl)-6-fluoro-2H-chromen-2-yl)methyl 4-methylbenzenesulfonate as a colorless oil. MS (ES) m/z 496.0 ([M+NH4]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10](Br)[CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.[CH2:13]([O:15][C:16](=[O:25])[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)[CH3:14].C(OC(=O)C=C(C1C=CC=C2C=1C(C#N)=CN2)C1C=CC=CC=1)C>>[CH2:13]([O:15][C:16](=[O:25])[CH:17]=[C:18]([C:10]1[CH:9]=[C:8]2[C:4]([CH:5]=[CH:6][NH:7]2)=[C:3]([O:2][CH3:1])[CH:11]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)[CH3:14]
Reactant: CCOC(=O)C=Cc1ccccn1
Reactant: COc1cc(Br)cc2[nH]ccc12
Agent: CCOC(=O)C=C(c1ccccc1)c1cccc2[nH]cc(C#N)c12
Product: CCOC(=O)C=C(c1cc(OC)c2cc[nH]c2c1)c1ccccn1

Procedure:
3-(4-Methoxy-1H-indol-6-yl)-3-pyridin-2-yl-acrylic acid ethyl ester CLXXIV was prepared from 4-methoxy-6-bromo-1H-indole and 3-pyridin-2-yl-acrylic acid ethyl ester using the procedure described for preparation of 3-(3-Cyano-1H-Indol-4-yl)-3-phenyl-acrylic acid ethyl ester LVIII (Example 14).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:13]1[NH:18][CH2:17][CH2:16][N:15]2[CH2:19][CH2:20][CH2:21][CH2:22][CH:14]12.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>C(OCC)(=O)C.CS(C)=O>[ClH:1].[CH3:12][O:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([N:18]3[CH2:17][CH2:16][N:15]4[CH2:19][CH2:20][CH2:21][CH2:22][CH:14]4[CH2:13]3)[S:3][C:4]=2[CH:10]=1
Reactant: C1CCN2CCNCC2C1
Reactant: COc1ccc2nc(Cl)sc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COc1ccc2nc(N3CCN4CCCCC4C3)sc2c1
Product: Cl
Temperature: 115 °C
Reaction time: 8 h
Yield: 56.8 %

Procedure:
A mixture of 2-chloro-6-methoxybenzothiazole (0.17 g, 1.0 mmol), octahydropyrido[1,2-a]-pyrazine (0.21 g, 1.0 mmol), DIPEA (0.51 mL) and dimethylsulfoxide (1 mL) was stirred at 115° C. overnight. The reaction mixture was allowed to cool and dissolved in a mixture of ethyl acetate and a NaHCO3 solution. The phases were separated and the organic phase was washed with water (3×) and then extracted with 0.25 M hydrochloric acid (20 mL). The acidic aqueous extract was concentrated and re-evaporated with ethanol. The residue was crystallized from a mixture of ethanol and ethyl acetate to give 193 mg (57%) of 2-(6-methoxybenzothiazol-2-yl)octahydropyrido[1,2-a]pyrazine, hydrochloride.
Reaction SMILES: [S:1]1([C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:5](=O)[NH:4]1)(=[O:3])=[O:2].[CH3:13][O-:14].[Na+].[CH3:16][N:17]([CH3:20])[CH:18]=[O:19]>>[OH:14][C:13]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[S:1](=[O:2])(=[O:3])[NH:4][C:5]=1[C:18]([N:17]([CH3:20])[C:16]1[CH:11]=[CH:12][CH:7]=[CH:8][CH:9]=1)=[O:19]
Reactant: C[O-]
Reactant: CN(C)C=O
Reactant: O=C1NS(=O)(=O)c2ccccc21
Agent: [Na+]
Product: CN(C(=O)C1=C(O)c2ccccc2S(=O)(=O)N1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 9.9g (0.03 mole) of 2- (N-methyl-N-phenylcarbamoyl)!saccharin in 125ml of dimethylformamide at 35° C is added all at once 4.9g (0.09 mole) of sodium methoxide. A considerable amount of heat is evolved and the mixture turns purple in color. Stirring is continued for one hour and it is poured into ice-water containing excess hydrochloric acid to cause precipitation of 5.5g of a tan solid, mp. 138°-144° C. This is dissolved in dichloromethane and extracted with aqueous sodium carbonate solution. Neutralization of the alkaline layer gives a precipitate which is collected and recrystallized from methanol to give 4.0g of product, mp. 148°-152° C dec.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]=[C:21]([NH2:26])[CH:20]=[CH:19]2.[F:27][C:28]1[C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=[CH:30][N:29]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]=[C:21]([NH:26][C:34]([C:33]1[C:28]([F:27])=[N:29][CH:30]=[CH:31][CH:32]=1)=[O:35])[CH:20]=[CH:19]2
Reactant: O=C(O)c1cccnc1F
Reactant: COc1cc2nccc(Oc3ccc4cc(N)ccc4c3)c2cc1OC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2nccc(Oc3ccc4cc(NC(=O)c5cccnc5F)ccc4c3)c2cc1OC

Procedure:
6-(6,7-Dimethoxy-4-quinolyloxy)-2-naphthylamine (69.2 mg, 0.2 mmol, Example 1c), 2-fluoropyridine-3-carboxylic acid (33.8 mg, 0.24 mmol, Maybridge), DIEA (31 mg, 0.24 mmol, Aldrich) and TBTU (91.2 mg, 0.24 mmol, Advanced ChemTech) were stirred in 6 mL of dry DMF at RT for 24 h. The solution was diluted with 50 mL of EtOAc and washed with saturated aqueous NaHCO3 and brine. The organic layer was dried over MgSO4 and concentrated. The residue was purified by silica gel column chromatography (EtOAc) to give title compound as a white solid. MS (ESI, pos. ion) m/z: 470.0 (M+1). Mass Calc'd for C27H20FN3O4: 469.14.