Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C@H:13]([CH3:21])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:20])[CH:18]=[CH2:19])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][O:23][C:24]([C@H:26]1[NH:30][CH2:29][C@H:28]([OH:31])[CH2:27]1)=[O:25].Cl.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:13]([CH3:21])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:20])[CH:18]=[CH2:19])[C:10]([N:30]1[CH2:29][C@H:28]([OH:31])[CH2:27][C@H:26]1[C:24]([O:23][CH3:22])=[O:25])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=CC(C)CCC[C@@H](C)C(NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1
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: ClCCl
Product: C=CC(C)CCC[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.5 %

Procedure:
To a slurry of (3R)-2-((tert-butoxycarbonyl)amino)-3,7-dimethylnon-8-enoic acid (6.5 g, 21.7 mmol), L-4-hydroxyproline methyl ester hydrochloride (3.9 g, 21.7 mmol) and O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (8.36 g, 21.7 mmol) in DCM (50 mL) at 0° C., N,N-diisopropylethylamine (11.5 mL, 66.6 mmol) was added dropwise. The resulting light yellow mixture was stirred at rt overnight, washed with 1M HCl (35 ml) and brine, dried over Na2SO4, filtered, concentrated in vacuo. The residual oil (12 g) was purified by conventional column chromatography (60-120 g silica gel column), eluted with 4%˜8% IPA-Hexane to afford the desired product (2S,4R)-methyl 1-((2S,3R)-2-(tert-butoxycarbonylamino)-3,7-dimethylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxylate (9a, 4.3 g, 46% yield) as a white foam and the undesired diastereomer (2S,4R)-methyl 1-((2R,3R)-2-(tert-butoxycarbonylamino)-3,7-dimethylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxylate (9b, 1.9 g, 20% yield) as a viscous oil. 1H NMR (400 MHz, CDCl3): δ ppm 5.73-5.64 (m, 1H), 5.19-5.17 (m, 1H), 4.97-4.88 (m, 2H), 4.70-4.66 (t, J=8.4 Hz, 1H), 4.53 (bs, 1H), 4.29-4.25 (m, 1H), 3.99-3.96 (d, J=10.8 Hz, 3H), 3.72 (s, 3H), 3.70-3.66 (m, 1H), 2.34-2.11 (m, 1H), 2.10-2.00 (m, 2H), 1.85-1.81 (m, 1H), 1.49-1.41 (m, 9H), 1.39-1.14 (m, 3H), 0.98-0.86 (m, 7H) MS: MS m/z 427.2 (M++1).
Reaction SMILES: N1C=CC=CC=1.Cl.[C:8]1(/[CH:14]=[CH:15]/[C:16]([NH:18][CH2:19][CH2:20][CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:23][CH2:22]2)=[O:17])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:34]([Cl:37])(=[O:36])[CH3:35]>O>[ClH:37].[C:8]1(/[CH:14]=[CH:15]/[C:16]([N:18]([C:34](=[O:36])[CH3:35])[CH2:19][CH2:20][CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:23][CH2:22]2)=[O:17])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(=O)Cl
Reactant: O=C(/C=C/c1ccccc1)NCCC1CCN(Cc2ccccc2)CC1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)N(CCC1CCN(Cc2ccccc2)CC1)C(=O)/C=C/c1ccccc1

Procedure:
A pyridine solution (5 ml) of (E)-3-phenyl-N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-propenamide. hydrochloride (0.25 g) and acetyl chloride (0.3 ml) was stirred at 60° C. for 2 hours. Water was added to the reaction mixture after being left standing for cooling; the mixture was dried over anhydrous sodium sulfate. The solvent was distilled off. The oily residue was subjected to silica gel column chromatography (developing solvent : ethyl acetate). The solvent of the solution containing the object compound was distilled off. To the residue was added an ethanol solution of 3N hydrogen chloride. The solvent was then distilled off to obtain hydroscopic amorphous powder (0.16 g).
Reaction SMILES: N1(C2C=CC(CC3[C:12]([O:24]C)=NC4C(C=3Cl)=CC(Br)=CC=4C)=CC=2)C=CC=N1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([C:37]2[CH:38]=[C:39]3[C:44](=[CH:45][CH:46]=2)[N:43]=[C:42](Cl)[C:41]([CH2:48][C:49]2[CH:54]=[CH:53][C:52]([S:55]([CH3:58])(=[O:57])=[O:56])=[CH:51][CH:50]=2)=[C:40]3[Cl:59])=[O:36])=[CH:31][CH:30]=1.N1(C2C=CC(CC3C(OC)=NC4C(C=3Cl)=CC(Br)=CC=4)=CC=2)C=CC=N1>>[Cl:59][C:40]1[C:39]2[C:44](=[CH:45][CH:46]=[C:37]([C:35]([C:32]3[CH:33]=[CH:34][C:29]([Cl:28])=[CH:30][CH:31]=3)=[O:36])[CH:38]=2)[N:43]=[C:42]([O:24][CH3:12])[C:41]=1[CH2:48][C:49]1[CH:50]=[CH:51][C:52]([S:55]([CH3:58])(=[O:57])=[O:56])=[CH:53][CH:54]=1
Reactant: COc1nc2c(C)cc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Reactant: CS(=O)(=O)c1ccc(Cc2c(Cl)nc3ccc(C(=O)c4ccc(Cl)cc4)cc3c2Cl)cc1
Agent: COc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Product: COc1nc2ccc(C(=O)c3ccc(Cl)cc3)cc2c(Cl)c1Cc1ccc(S(C)(=O)=O)cc1

Procedure:
The title compound was prepared by substituting 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-2,4-dichloroquinoline (Intermediate 6: step c) with (4-chlorophenyl)(2,4-dichloro-3-(4-(methylsulfonyl)benzyl)quinolin-6-yl)methanone (Intermediate 22: step a) then following the procedure described for the preparation of 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-4-chloro-2-methoxyquinoline (Intermediate 16).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:23](Cl)(=[O:25])[CH3:24]>C(Cl)Cl>[C:1]1([S:7]([C:10]2[CH:11]=[CH:12][C:13]([O:16][C:23](=[O:25])[CH3:24])=[CH:14][CH:15]=2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)c1ccc(O)cc1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Oc1ccc(S(=O)(=O)c2ccccc2)cc1

Procedure:
In 150 ml of CH2Cl2 were dissolved 23 g of the compound obtained in step 2; and, 12.9 ml of pyridine and 7.8 ml of acetyl chloride was slowly added at room temperature thereto. The reaction solution was washed with 0.2N HCl and with saturated NaHCO3 aqueous solution, dried over Na2SO4 and concentrated under reduced pressure to obtain residue, which was used for subsequent reaction without further purification.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[N:8]=[CH:9][S:10][CH:11]=1.[CH3:12][Si:13](Cl)([CH3:15])[CH3:14]>C(OCC)C>[CH3:6][C:7]1[N:8]=[C:9]([Si:13]([CH3:15])([CH3:14])[CH3:12])[S:10][CH:11]=1
Reactant: C[Si](C)(C)Cl
Reactant: Cc1cscn1
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cc1csc([Si](C)(C)C)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (2.5M solution in hexane, 1.1 equivalents) was added dropwise to a solution of 4-methylthiazole (1.0 equivalent) in dry diethyl ether at -70° C. under an atmosphere of dry nitrogen. After 30 minutes, trimethylsilylchloride (1.0 equivalent) was added dropwise. The mixture was allowed to warm to room temperature and was then quenched by the addition of saturated aqueous sodium hydrogen carbonate. Work-up in the normal fashion and vacuum distillation then gave the title compound. B.p. 42° C. at 1 mmHg.
Reaction SMILES: C([N:4]1[C:12]2[CH:11]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[N:9]=[CH:8][C:7]=2/[C:6](=[C:17](\OCC)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)/[C:5]1=[O:27])(=O)C.[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([N:35]([CH3:46])[C:36](=[O:45])[CH2:37][N:38]2[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]2)=[CH:31][CH:30]=1.N1CCCCC1>CN(C=O)C>[CH3:46][N:35]([C:32]1[CH:31]=[CH:30][C:29]([NH:28]/[C:17](/[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[CH:11]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[N:9]=[CH:8][C:7]\2=3)=[CH:34][CH:33]=1)[C:36](=[O:45])[CH2:37][N:38]1[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]1
Reactant: CN1CCN(CC(=O)N(C)c2ccc(N)cc2)CC1
Reactant: CCO/C(=C1/C(=O)N(C(C)=O)c2cc(C(=O)OC)ncc21)c1ccccc1
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: COC(=O)c1cc2c(cn1)/C(=C(/Nc1ccc(N(C)C(=O)CN3CCN(C)CC3)cc1)c1ccccc1)C(=O)N2
Temperature: 110 °C
Reaction time: 2 h

Procedure:
Step-2: To a solution of (E)-methyl 1-acetyl-3-(ethoxy(phenyl)methylene)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine-6-carboxylate (40 mg, 0.109 mmol) in DMF (0.2 mL) was added N-(4-aminophenyl)-N-methyl-2-(4-methylpiperazin-1-yl)acetamide (28 mg, 0.109 mmol) at room temperature, and the reaction mixture was stirred at 110° C. for 2 h. The reaction mixture was cooled to RT, piperidine (0.2 mL) was added and stirred for 10 minutes at room temperature. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography using 5% CH3OH in dichloromethane as eluent to afford (Z)-methyl 3-(((4-(N-methyl-2-(4-methylpiperazin-1-yl)acetamido)phenyl)amino)(phenyl)methylene)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine-6-carboxylate as yellow solid. MS (ES+): m/z 541.3 (MH+).
Reaction SMILES: Cl[C:2]1[C:3]2[S:18][C:17]([NH2:19])=[N:16][C:4]=2[N:5]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]=1.[NH2:20][C@H:21]([CH3:31])[CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[NH2:19][C:17]1[S:18][C:3]2[C:2]([NH:20][C@H:21]([CH3:31])[CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[N:7][C:6]([S:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N:5][C:4]=2[N:16]=1
Reactant: Nc1nc2nc(SCc3ccccc3)nc(Cl)c2s1
Reactant: C[C@@H](N)CNC(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: C[C@H](CNC(=O)OC(C)(C)C)Nc1nc(SCc2ccccc2)nc2nc(N)sc12
Temperature: 110 °C

Procedure:
The product from example 1 step c) (2.0 g) and the product from example 25 step d) (1.3 g) in a solvent of NMP (10 ml) containing Hunigs base (3 ml) was heated at 110° C. for 10 hours. The mixture was evaporated to dryness and purified (SiO2, (1:1) dichloromethane:ethyl acetate as eluant) to give the subtitle compound (1.9 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][N:15]3[CH:19]=[CH:18][N:17]=[N:16]3)[O:11][C:10]2=[O:20])[CH:5]=[CH:6][C:7]=1I.C[Sn](C)(C)[C:23]1[S:27][C:26]([C:28]2[CH2:32][CH:31]([CH2:33][OH:34])[O:30][N:29]=2)=[CH:25][CH:24]=1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd]>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][N:15]3[CH:19]=[CH:18][N:17]=[N:16]3)[O:11][C:10]2=[O:20])[CH:5]=[CH:6][C:7]=1[C:23]1[S:27][C:26]([C:28]2[CH2:32][CH:31]([CH2:33][OH:34])[O:30][N:29]=2)=[CH:25][CH:24]=1
Reactant: C[Sn](C)(C)c1ccc(C2=NOC(CO)C2)s1
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(I)c(F)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: ClC(Cl)Cl
Product: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(-c2ccc(C3=NOC(CO)C3)s2)c(F)c1
Temperature: 90 °C
Yield: 53.1 %

Procedure:
(5R)-3-(3-Fluoro-4-iodophenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (280 mg, 0.72 mM), {3-[5-(trimethylstannyl)thien-2-yl]-4,5-dihydroisoxazol-5-yl}methanol (250 mg, 0.72 mM), tris(dibenzylideneacetone)dipalladium (0)-chloroform adduct (75 mg, 0.072 mM) and tri-2-furylphosphine (34 mg, 0.145 mM) were placed in a flask. The solids were degassed and placed under nitrogen. Anhydrous dioxane (5 ml) was added and the suspension was heated at 90° C. for 16 hours. The reaction mixture was cooled and the solvent was evaporated. The residue was chromatographed on silica gel eluting with 5% methanol in dichloromethane to give the title compound (170 mg).
Reaction SMILES: P([O-])(OC1C=CC=CC=1)OC1C=CC=CC=1.[NH:17]1[CH:21]=[CH:20][N:19]=[CH:18]1.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)O>C1C=CC=CC=1>[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: c1c[nH]cn1
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1Cl
Agent: [O-]P(Oc1ccccc1)Oc1ccccc1
Solvent: c1ccccc1
Product: Clc1ccccc1C(c1ccccc1)(c1ccccc1)n1ccnc1
Yield: 72.8 %

Procedure:
A mixture of benzene (20 ml), diphenyl phosphite (5.62 g, 24 mmole), imidazole (2.45 g, 36 mmole) and o-chlorophenyldiphenylmethanol (2.95 g, 10 mmole) obtained in Example 1 (A) was refluxed for 8 hours. After cooling, the reaction mixture was washed with a 5% aqueous potassium hydroxide solution (20 ml). The benzene layer was separated, washed with water, dried over magnesium sulfate and evaporated. Recrystallization of the crystalline residue from acetonitrile gave 2.51 g of 1-(o-chlorophenyldiphenylmethyl)imidazole. Yield, 73%. M.P., 142°-143° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)[CH3:2].C([O:13][CH:14]=[C:15]([C:21](OCC)=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17])C>>[CH2:1]([O:3][C:4]1[CH:10]=[C:9]2[C:7](=[CH:6][CH:5]=1)[N:8]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:14]2[OH:13])[CH3:2]
Reactant: CCOc1ccc(N)cc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)c1cnc2ccc(OCC)cc2c1O

Procedure:
Prepared as in Example 1c from 4-ethoxyaniline and diethyl 2-(ethoxymethylene)malonate as a white solid (26%). 1H NMR (400 MHz, DMSO-d6) δ 1.24-1.37 (m, 6H), 4.09 (q, J=6.8 Hz, 2H), 4.19 (q, J=7.2 Hz, 2H), 7.29-7.32 (m, 1H), 7.52-7.56 (m, 2H), 8.47 (s, 1H), 12.27 (s, 1H). MS 262 (MH+).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]([CH3:14])[CH:3]=1.[CH3:15][CH:16]([CH2:19][CH:20]1[CH2:25][CH2:24][CH:23]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:22][CH2:21]1)[CH2:17][NH2:18]>>[CH3:13][C:6]1[N:5]=[C:4]([CH3:14])[CH:3]=[C:2]([NH:18][CH2:17][CH:16]([CH3:15])[CH2:19][CH:20]2[CH2:21][CH2:22][CH:23]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:24][CH2:25]2)[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CC(CN)CC1CCC(C(C)(C)C)CC1
Reactant: CCOC(=O)c1c(Cl)cc(C)nc1C
Product: CCOC(=O)c1c(NCC(C)CC2CCC(C(C)(C)C)CC2)cc(C)nc1C

Procedure:
was synthesized analogously to Example 8 using ethyl 4-chloro-2,6-dimethylnicotinate and 2-methyl-3-(4-tert-butylcyclohexyl)propylamine nD23 :1.4738.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[NH:20]1[CH:24]=[C:23](B(O)O)[CH:22]=[N:21]1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][C:9]2[N:10]=[C:3]3[C:2]([C:23]4[CH:24]=[N:20][NH:21][CH:22]=4)=[CH:7][CH:6]=[CH:5][N:4]3[N:8]=2)=[CH:13][CH:14]=1
Reactant: COc1ccc(Nc2nc3c(Br)cccn3n2)cc1
Reactant: OB(O)c1cn[nH]c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: COc1ccc(Nc2nc3c(-c4cn[nH]c4)cccn3n2)cc1

Procedure:
(4-Methoxy-phenyl)-[8-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amine was prepared from (8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-(4-methoxy-phenyl)-amine (200.0 mg, 0.6266 mmol) and 1H-pyrazole-4-boronic acid (75.0 mg, 0.670 mmol) with Pd(dppf)Cl2 (50.0 mg) as the catalyst in a manner analogous to Step 2c and was isolated as a brown solid (0.065 g, 34%). MP=224-226° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 13.03 (br s, 1H), 9.38 (s, 1H), 8.59 (d, J=6.5 Hz, 1H), 8.49 (s, 2H), 7.85 (d, J=7.2 Hz, 1H), 7.64 (d, J=8.0 Hz, 2H), 7.11 (t, J=7.2 Hz, 1H), 6.91 (d, J=8.4 Hz, 2H), 3.73 (s, 3H). MS=307 (MH)+.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)=[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:4][N:3]=1.CN(C)CCN(C)C.C([Li])CCC.[Cl:36][C:37]1[CH:44]=[CH:43][C:40]([CH:41]=[O:42])=[CH:39][CH:38]=1>O1CCCC1.O>[Cl:36][C:37]1[CH:44]=[CH:43][C:40]([CH:41]([OH:42])[CH2:1][C:2]2[C:6]([C:7]3[CH:8]=[CH:9][C:10]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:11][CH:12]=3)=[C:5]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[O:4][N:3]=2)=[CH:39][CH:38]=1
Reactant: Cc1noc(-c2ccccc2)c1-c1ccc(S(N)(=O)=O)cc1
Reactant: O=Cc1ccc(Cl)cc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(-c2c(CC(O)c3ccc(Cl)cc3)noc2-c2ccccc2)cc1
Temperature: -40 °C
Yield: 45.3 %

Procedure:
To a cold (-70° C.) solution of 4-[3-methyl-5-phenylisoxazol-4-yl]benzenesulfonamide (Example 13) (250 mg, 0.8 mmol) and tetramethylethylenediamine (277 mg, 2.4 mmol) in tetrahydrofuran (5 mL) under an argon atmosphere was added n-butyllithium (1.3 mL of 1.84M in hexane, 2.4 mmol). The solution was warmed to -40° C. for 15 minutes, recooled to -70° C., and a solution of 4-chlorobenzaldehyde (337 mg, 2.4 mmol) in tetrahydrofuran (3 mL) was added. The mixture was warmed to room temperature over 30 minutes, poured into water (25 mL) and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and the filtrate was concentrated in vacuo. The crude product was chromatographed on silica gel using mixtures of acetone and hexane as eluents to give 165 mg of desired product as a crystalline solid: mp 165°-167° C. Anal. Calc'd. for C23H19ClN2O4S(454.93): C, 60.72; H, 4.21; N, 6.16; S, 7.05. Found: C, 60.33; H, 4.34; N, 5.87; S, 6.74.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[Cl:19][C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:24]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:19])[C:25]=3[Cl:26])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: OB(O)c1cccc(Cl)c1Cl
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Product: CCCNC(=O)c1nnc2c(-c3cccc(Cl)c3Cl)cccc2c1N
Yield: 80.6 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (100 mg, 0.33 mmol) and 2,3-dichlorophenyl boronic acid (185 mg, 0.97 mmol) were reacted to afford the title compound (99.8 mg, 83.1% yield) as a pale-yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.52 (br, 1H), 7.96 (dd, J=7.6 Hz, J′=2.1 Hz, 1H), 7.66-7.78 (m, 2H), 7.53 (dd, J=6.3 Hz, J′=3.3 Hz, 1H), 7.28-7.35 (m, 2H), 3.45 (q, J=6.7 Hz, 2H), 1.64 (m, J=7.3 Hz, 2H), 0.99 (t, J=7.4 Hz, 3H) MS APCI, m/z=375/377 (M+H) HPLC 2.19 min.
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][C:5]2[C:6]([CH3:9])=[CH:7][O:8][C:4]=2[CH:3]=1.[CH2:13]([O:16][CH2:17][CH2:18]Br)[CH2:14]Br.C(N(C(C)C)C(C)C)C>C(O)C>[CH3:9][C:6]1[C:5]2[CH:10]=[C:11]([CH3:12])[C:2]([N:1]3[CH2:18][CH2:17][O:16][CH2:13][CH2:14]3)=[CH:3][C:4]=2[O:8][CH:7]=1
Reactant: Cc1cc2c(C)coc2cc1N
Reactant: BrCCOCCBr
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2c(C)coc2cc1N1CCOCC1

Procedure:
A mixture of 22.8 g (0.141 mole) of 6-amino-3,5-dimethylbenzofuran, 65.8 g (0.283 mole) of 2,2'-dibromodiethyl ether, 36.1 g (0.279 mole) of N-ethyldiisopropylamine and 210 ml of ethanol is boiled under reflux for 16 hours. The residue obtained after removal of the ethanol in vacuo is taken up in methylene chloride and washed twice with dilute sodium bicarbonate solution. The organic phase is dried, concentrated by evaporation and the crude product is chromatographed over silica gel with petroleum ether/ether. The excess 2,2'-dibromodiethyl ether is removed in a water-jet vacuum over a Vigreux column and the residue is purified by means of solid distillation (110°-115°/4.10-2 torr). 3,5-dimethyl-6-morpholinobenzofuran is obtained having a melting point of 69°-70°.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:10]O.P(Cl)(Cl)(Cl)(Cl)[Cl:13].O>C(Cl)(Cl)(Cl)Cl>[Cl:13][CH2:10][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([O:8][CH3:9])[C:2]=1[F:1]
Reactant: COc1cccc(CO)c1F
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: COc1cccc(CCl)c1F
Temperature: 90 °C
Reaction time: 1 h
Yield: 79.2 %

Procedure:
To a solution of (2-fluoro-3-methoxyphenyl)methanol (13 g, 83.2 mmol) in CCl4 (75 mL), PCl5 (26 g, 128.7 mmol) was added. The resulting mixture was heated at 90° C. for 30 min and then stirred at room temperature for 1 h. The mixture was poured into water (160 mL) and extracted with dichloromethane (2×150 mL). The combined organic layers were washed with brine (200 mL), dried (Na2SO4), and concentrated in vacuo. The residue was purified by silica gel column chromatography (1:15 EtOAc/petroleum ether) to give the title compound (11.5 g). 1H NMR (CDCl3): δ 7.10-6.91 (m, 3H), 4.63 (s, 2H), 3.89 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].[OH:26][CH2:27][CH2:28][N:29]([CH2:40][CH2:41][OH:42])[S:30]([C:33]1[CH:34]=[N:35][CH:36]=[C:37](Br)[CH:38]=1)(=[O:32])=[O:31]>>[OH:26][CH2:27][CH2:28][N:29]([CH2:40][CH2:41][OH:42])[S:30]([C:33]1[CH:34]=[N:35][CH:36]=[C:37]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)[CH:38]=1)(=[O:32])=[O:31]
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: O=S(=O)(c1cncc(Br)c1)N(CCO)CCO
Product: O=S(=O)(c1cncc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1)N(CCO)CCO

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (388 mg, 1.1 mmol) and 5-bromo-pyridine-3-sulfonic acid bis-(2-hydroxy-ethyl)-amide (example B.5) (325 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (160 mg, 29%). MS (ISP) 600.2 [(M+H)+]; mp 173-178° C.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][N+:5]([O-])=[C:4]([CH3:10])[CH:3]=1.C(OP([C:19]#[N:20])(OCC)=O)C.C(N(CC)CC)C>CC#N>[Br:1][C:2]1[CH:3]=[C:4]([CH3:10])[N:5]=[C:6]([C:19]#[N:20])[C:7]=1[CH3:8]
Reactant: CCOP(=O)(C#N)OCC
Reactant: Cc1c[n+]([O-])c(C)cc1Br
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(Br)c(C)c(C#N)n1
Temperature: 80 °C
Yield: 69.8 %

Procedure:
To a Smith microwave vial was added 4-bromo-2,5-dimethyl-1-oxido-pyridin-1-ium (which may be prepared as described in Description 136), (300 mg, 1.48 mmol), diethoxyphosphorylformonitrile (0.9 mL, 5.94 mmol) and triethylamine (0.41 mL, 2.97 mmol) in anhydrous MeCN (1 mL). The reaction mixture was heated by microwave at 80° C. for 1 h. The reaction mixture was evaporated and the crude dark oil was purified on silica gel chromatography (10 g SiO2) eluting with ethyl acetate in iso-hexane (0-80%). Evaporation of desired fractions gave 4-bromo-3,6-dimethyl-pyridine-2-carbonitrile (D137) (218 mg, 1.0329 mmol, 69.6% yield) as colourless solid;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][CH:26]=1)[CH2:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[C:10]([CH2:21][C:22]#[N:23])=[CH:9][N:8]=1.[Se](=O)=[O:28]>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][CH:26]=1)[C:6]([C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[C:10]([CH2:21][C:22]#[N:23])=[CH:9][N:8]=1)=[O:28]
Reactant: COc1cccc(Cc2ncc(CC#N)c3cc(OC)c(OC)cc23)c1
Reactant: O=[Se]=O
Solvent: CCOC(C)=O
Product: COc1cccc(C(=O)c2ncc(CC#N)c3cc(OC)c(OC)cc23)c1
Yield: 42.8 %

Procedure:
The above 1-(3-methoxybenzyl)-4-cyanomethyl-6,7-dimethoxyisoquinoline (152.7 mg, 0.438 mmol) was dissolved in 10 ml of ethyl acetate, then selenium dioxide (48.8 mg, 58.8 mg, 0.529 mmol) was added. The mixture was refluxed for 1 hr. The crude mixture was filtered through a thin layer of silica gel and washed with ethyl acetate. After the evaporation of solvents, the residue was purified through a flash column chromatography using ethyl acetate and hexane (2/1) to give 1-(3-methoxybenzoyl)-4-cyanomethyl-6,7-dimethoxyisoquinoline as a solid (68 mg, 42.8%).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[O:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].C1(C)C(S(O[CH2:30][CH:31]2[CH2:35][CH:34]=[CH:33][CH2:32]2)(=O)=O)=CC=CC=1>>[CH:31]1([CH2:30][N:7]2[C:8]([O:9][C:10]3[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=3)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]2=[O:18])[CH2:35][CH:34]=[CH:33][CH2:32]1
Reactant: CCc1c(Oc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Reactant: Cc1ccccc1S(=O)(=O)OCC1CC=CC1
Product: CCc1c(Oc2cc(C)cc(C)c2)n(CC2CC=CC2)c(=O)[nH]c1=O
Yield: 49.9 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and (cyclopent-3-en-1-yl)methyl toluenesulfonate were reacted by the same method with the example 1 to obtain the titled compound (68 mg).