Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:23]=[C:22]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[N:21]=[C:20]([C:30](O)=[O:31])[CH:19]=2)[CH2:14][CH2:13]1)=[O:10].Cl.[O:34]([NH2:36])[CH3:35]>>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:13][CH2:14][N:15]([C:18]2[N:23]=[C:22]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[N:21]=[C:20]([C:30]([NH:36][O:34][CH3:35])=[O:31])[CH:19]=2)[CH2:16][CH2:17]1)=[O:10]
Reactant: CON
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3cc(C(=O)O)nc(N4CCNCC4)n3)CC2)c(Cl)c1Cl
Agent: Cl
Product: CONC(=O)c1cc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)nc(N2CCNCC2)n1

Procedure:
The title compound was synthesized by an analogous method to Example 8 starting from 6-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-2-piperazin-1-ylpyrimidine-4-carboxylic acid (Example 194) and methoxylamine hydrochloride.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH2:14][C:15]([OH:17])=[O:16])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18]OC(=O)C(N)CCC.Cl.CN(C)C>C(Cl)Cl.C(Cl)CCl>[CH3:18][O:16][C:15](=[O:17])[CH2:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:9]=1
Reactant: CCCC(N)C(=O)OC
Reactant: O=C(O)Cc1cccc(Oc2ccccc2)c1
Agent: CN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: ClCCCl
Product: COC(=O)Cc1cccc(Oc2ccccc2)c1
Yield: 131.8 %

Procedure:
A mixture of (3-Phenoxy-phenyl)-acetic acid (10.00 g, 0.0438 mol), 2-amino-pentanoic acid methyl ester (7.34 g, 0.0438 mol.), HBOT (6.20 g, 0.046 mol), EDC. HCl (12.59 g, 0.067 mol) and a trimethylamine (30.45 ml, 0.22 mol) in methylene chloride (150 ml) was stirred at room temperature overnight. The mixture was quenched with water and extracted with methylene chloride. The organic layer was washed with 1N HCl, then brine, dried over sodium sulfate and the solvent was removed at reduced pressure to provide 13.99 g of (3-phenoxy-phenyl)-acetic acid methyl ester as a thick oil, LC-MS M+1=342.
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:15][C:16]2[CH:17]=[C:18]([CH:27]=[CH:28][CH:29]=2)/[CH:19]=[C:20]2/[C:21](=[O:26])[NH:22][C:23](=[O:25])[S:24]/2)=[N:4][CH:5]=[N:6][C:7]=1[O:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(N(CC)CC)C.[C:37](Cl)(=[O:39])[CH3:38]>ClCCl>[C:37]([N:12]1[CH2:11][CH2:10][CH:9]([O:8][C:7]2[N:6]=[CH:5][N:4]=[C:3]([O:15][C:16]3[CH:17]=[C:18]([CH:27]=[CH:28][CH:29]=3)/[CH:19]=[C:20]3/[C:21](=[O:26])[NH:22][C:23](=[O:25])[S:24]/3)[C:2]=2[CH3:1])[CH2:14][CH2:13]1)(=[O:39])[CH3:38]
Reactant: Cc1c(Oc2cccc(/C=C3\SC(=O)NC3=O)c2)ncnc1OC1CCNCC1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCC(Oc2ncnc(Oc3cccc(/C=C4\SC(=O)NC4=O)c3)c2C)CC1
Temperature: 30 °C
Reaction time: 5 h
Yield: 67.8 %

Procedure:
To a solution Trifluoro acetate salt of (Z)-5-(3-((5-methyl-6-(piperidin-4-yloxy)pyrimidin-4-yl)oxy)benzylidene)thiazolidine-2,4-dione prepared in step 1 of example 5 (524 mg, 0.000974 mol) in dichloromethane (20 ml), triethyl amine (1.35 ml, 0.00974 mol) was added followed by the addition of acetyl chloride (0.104 ml, 0.001461 mol) at 0° C. and the reaction mixture was stirred for 5 hrs at 30° C. Then reaction mixture was diluted with dichloromethane, washed with water, dried over calcium chloride and evaporated under reduced pressure to collect the crude product. The crude product was then purified by column chromatography using 1.5% methanol in chloroform as eluent to yield the 300 mg product as yellow solid.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1.[CH2:13]([NH:20][C:21]([C:23]1[S:27][C:26]([N:28]2[CH2:33][CH2:32][CH2:31][CH:30](Br)[C:29]2=[O:35])=[N:25][C:24]=1[CH3:36])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([NH:20][C:21]([C:23]1[S:27][C:26]([N:28]2[CH2:33][CH2:32][CH2:31][CH:30]([NH:10][CH2:9][C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:11])([F:12])[F:1])=[CH:8][CH:7]=3)[C:29]2=[O:35])=[N:25][C:24]=1[CH3:36])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1nc(N2CCCC(Br)C2=O)sc1C(=O)NCc1ccccc1
Reactant: NCc1ccc(C(F)(F)F)cc1
Product: Cc1nc(N2CCCC(NCc3ccc(C(F)(F)F)cc3)C2=O)sc1C(=O)NCc1ccccc1
Yield: 20 %

Procedure:
Following the procedure as described in Example 5, making variation as required to use (4-(trifluoromethyl)phenyl)methanamine in place of 2-cyclopropylethanamine to react with N-benzyl-2-(3-bromo-2-oxopiperidin-1-yl)-4-methylthiazole-5-carboxamide in place of 2-(3-bromo-2-oxopyrrolidin-1-yl)-N-(4-fluorobenzyl)-4-methylthiazole-5-carboxamide, the title compound was obtained as a white solid in 20% yield: mp 39-40° C. (diethyl ether); 1H NMR (300 MHz, CDCl3) δ 7.55 (d, J=8.1 Hz, 2H), 7.45 (d, J=8.1 Hz, 2H), 7.39-7.21 (m, 5H), 6.03 (t, J=5.6 Hz, 1H), 4.55 (d, J=5.6 Hz, 2H), 4.32-4.21 (m, 1H), 4.06-3.96 (m, 1H), 3.93 (s, 2H), 3.50-3.39 (m, 1H), 2.62 (s, 3H), 2.30-2.05 (m, 2H), 1.99-1.83 (m, 2H), 1.81-1.66 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 171.4, 162.5, 156.6, 152.0, 143.8, 137.9, 129.4, 128.8, 128.3, 127.9, 127.7, 125.5, 125.4, 119.7, 57.9, 50.9, 47.5, 44.1, 26.5, 20.4, 17.4; MS (ES+) m/z 503.3 (M+1).
Reaction SMILES: [OH:1][C@@H:2]([CH2:6][CH:7]1[CH2:10][CH2:9][CH2:8]1)[C:3]([OH:5])=[O:4].[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][CH:14]=1>>[OH:1][C@@H:2]([CH2:6][CH:7]1[CH2:10][CH2:9][CH2:8]1)[C:3]([O:5][CH2:17][C:16]1[CH:19]=[CH:20][C:13]([O:12][CH3:11])=[CH:14][CH:15]=1)=[O:4]
Reactant: COc1ccc(CCl)cc1
Reactant: O=C(O)[C@@H](O)CC1CCC1
Product: COc1ccc(COC(=O)[C@@H](O)CC2CCC2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 75 %

Procedure:
A mixture of 432 mg (3.0 mmol) of 2-(S)-hydroxy-3-cyclobutyl propanoic acid (from EXAMPLE 19, Step D), 0.61 mL of 4-(methoxy)benzyl chloride and 0.63 mL of TEA was stirred at rt for 20 h. The reaction mixture was partitioned between 100 mL of ether and 50 mL of H2O and the layers were separated. The organic layer was washed with 50 mL of sat'd NaHCO3, 50 mL of 2.0 N HCl, 2×50 mL of H2O and 50 mL of sat'd NaCl, dried over MgSO4 and concentrated. Flash chromatography on 30 g of silica gel using 4:1 v/v hexanes/ether as the eluant afforded 598 mg (75%) of the title compound: 1H NMR (500 MHz) δ 1.56-1.94 (6H), 1.98-2.12 (m, 2H), 2.44-2.56 (m, 1H),2.64 (br s, 1H), 3.82 (s, 3H), 4.11-4.13 (m, 1H), 5.19 (ABq, J=25.0, 2H), 6.90 (d, J=9.0, 2H), 7.30 (d, J=9.0, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([CH3:23])[CH:17]=2)=[CH:9][C:10]2[N:14]([CH3:15])[N:13]=[N:12][N:11]=2)=[CH:4][C:3]=1[CH3:24].C([Li])CCC.[CH:30](OCC)=[O:31]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([CH3:23])[CH:17]=2)=[C:9]([C:10]2[N:14]([CH3:15])[N:13]=[N:12][N:11]=2)[CH:30]=[O:31])=[CH:4][C:3]=1[CH3:24]
Reactant: CCOC=O
Reactant: Cc1cc(C(=Cc2nnnn2C)c2ccc(F)c(C)c2)ccc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(C(=C(C=O)c2nnnn2C)c2ccc(F)c(C)c2)ccc1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 56.4 %

Procedure:
A solution of 1,1-bis(4-fluoro-3-methylphenyl)-2-(1-methyltetrazol-5-yl)ethene (3.58 g, 11.0 mmoles)) in dry tetrahydrofuran (20 mL) at -78° C. was treated with n-butyllithium (5.3 ml of 2.5M solution in hexane; 13.25 mmoles) and the mixture stirred at -78° C. for 0.5 hours. Ethyl formate (1.33 ml; 1.22 g, 16.5 mmoles) was added and the mixture was allowed to warm up to 23° C. over 1 hour, then quenched with 2N HCl (250 mL). The aqueous phase was extracted with ethyl acetate (3×50 mL) and the combined organic layers were dried (MgSO4) and evaporated. The residue was purified by chromatography using 20% EtOAc-Hexane as eluent to afford 2.2 g (57%) of the title compound as a foam. MS (CI): m/e=355 for (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10](Cl)=[O:11])[CH2:3][CH2:2]1.[NH2:16][C:17]1[CH:18]=[CH:19][C:20]([Cl:36])=[C:21]([NH:23][C:24](=[O:35])[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=2)[CH:22]=1.O>N1C=CC=CC=1>[Cl:36][C:20]1[CH:19]=[CH:18][C:17]([NH:16][C:10](=[O:11])[C:9]2[CH:13]=[CH:14][CH:15]=[C:7]([N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[CH:8]=2)=[CH:22][C:21]=1[NH:23][C:24](=[O:35])[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=1
Reactant: COc1ccc(C(=O)Nc2cc(N)ccc2Cl)cc1OC
Reactant: O=C(Cl)c1cccc(N2CCOCC2)c1
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(C(=O)Nc2cc(NC(=O)c3cccc(N4CCOCC4)c3)ccc2Cl)cc1OC
Temperature: 115 °C
Yield: 36.4 %

Procedure:
3-Morpholinobenzoyl chloride (0.15 g) was added to a stirred solution of N-(5-amino-2-chlorophenyl)-3,4-dimethoxybenzamide (0.17 g) in pyridine (3 ml). The reaction mixture was stirred and heated to 115° C. for 18 hours. The mixture was allowed to cool and poured into water. The mixture was extracted with methylene chloride. The organic extract was dried (MgSO4) and evaporated. The resultant solid was azeotroped with toluene and triturated under diethyl ether to give the title compound (0.1 g), m.p. 147.9-148.3° C.;
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[S:12][N:11]=[C:10]([CH3:13])[N:9]=2)=[CH:6][CH:7]=1.Cl.[NH:15]1[CH2:20][CH2:19][C:18]2([C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22][CH2:21]2)[CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH3:13][C:10]1[N:9]=[C:8]([C:5]2[N:4]=[N:3][C:2]([N:15]3[CH2:20][CH2:19][C:18]4([C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[CH2:22][CH2:21]4)[CH2:17][CH2:16]3)=[CH:7][CH:6]=2)[S:12][N:11]=1
Reactant: c1ccc2c(c1)CCC21CCNCC1
Reactant: Cc1nsc(-c2ccc(Cl)nn2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nsc(-c2ccc(N3CCC4(CCc5ccccc54)CC3)nn2)n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 60.8 %

Procedure:
3-Chloro-6-(3-methyl-1,2,4-thiadiazol-5-yl)pyridazine (51 mg), 2,3-dihydrospiro[indene-1,4′-piperidine] hydrochloride (78 mg) and potassium carbonate (70 mg) were suspended in N,N-dimethylformamide (3 mL), and the suspension was stirred at 80° C. overnight. The mixture was cooled to room temperature, diluted with ethyl acetate, and washed twice with aqueous sodium hydrogen carbonate solution. The organic layer was dried over sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (15% ethyl acetate/hexane to 50% ethyl acetate/hexane) and recrystallized from hexane/ethyl acetate to give the object product (53 mg, 60%).
Reaction SMILES: S(O)(=O)(=O)C.[NH2:6][C:7]1[CH:12]=[C:11]([Cl:13])[N:10]=[C:9]([SH:14])[N:8]=1.[H-].[Na+].[CH3:17][O:18][C:19]1[CH:20]=[N:21][C:22]([CH:27](Cl)[CH3:28])=[CH:23][C:24]=1[CH2:25][CH3:26]>CN(C)C=O.C(OCC)(=O)C>[NH2:6][C:7]1[CH:12]=[C:11]([Cl:13])[N:10]=[C:9]([S:14][CH:27]([C:22]2[CH:23]=[C:24]([CH2:25][CH3:26])[C:19]([O:18][CH3:17])=[CH:20][N:21]=2)[CH3:28])[N:8]=1
Reactant: CCc1cc(C(C)Cl)ncc1OC
Reactant: Nc1cc(Cl)nc(S)n1
Agent: CS(=O)(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1cc(C(C)Sc2nc(N)cc(Cl)n2)ncc1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.6 %

Procedure:
A solution of 4-amino-6-chloro-2-mercapto-pyrimidine mesylate salt (290 mg, 1.1 mmol) in 2 mL of N,N-dimethylformamide at 0° C. is treated with 92 mg (60% in oil, 2.3 mmol) of sodium hydride and warmed to room temperature for 1 h. A solution of 3-methoxy-4-ethyl-6-(1-chloroethyl)-pyridine (225 mg, 1.1 mmol) in 2×1 mL of N,N-dimethylformamide is added dropwise to the mixture and the reaction was stirred for 18 h. The reaction is diluted with 50 mL of ethyl acetate, was washed with 4×25 mL of 50% saturated sodium chloride and dried over potassium carbonate. The organics are concentrated in vacuo and the crude material is chromatographed over 20 g of silica gel (230-400 mesh), eluting with 50% ethyl acetate/hexanes to afford 256 mg of an oil which upon crystallization from ether gave 188 mg (53%) of Cpd #245 (Melting Pt. 136-137° C.).
Reaction SMILES: [OH:1]O.[CH3:3][N:4]([CH3:20])[S:5]([C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=1)(=[O:7])=[O:6].[OH-].[Na+].[Cl-].[Na+]>C(O)C.O>[CH3:3][N:4]([CH3:20])[S:5]([C:8]1[CH:15]=[CH:14][C:11]([C:12]([NH2:13])=[O:1])=[C:10]([C:16]([F:17])([F:19])[F:18])[CH:9]=1)(=[O:6])=[O:7]
Reactant: CN(C)S(=O)(=O)c1ccc(C#N)c(C(F)(F)F)c1
Reactant: OO
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CN(C)S(=O)(=O)c1ccc(C(N)=O)c(C(F)(F)F)c1

Procedure:
Hydrogen peroxide (30%, 100 ml) was added to a stirred mixture of 4-(N,N-dimethylaminosulphonyl)-2-trifluoromethylbenzonitrile (20.37 g) and sodium hydroxide (1.0 g) in ethanol under an inept atmosphere maintaining the temperature at 40°-45° C. The mixture was stirred and heated at that temperature for 3.5 hours. It was cooled, poured into water, sodium chloride was added and it was extracted with ethyl acetate, washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was re-crystallized from a mixture of ethyl acetate and toluene to give 4-(N,N-dimethylaminosulphonyl)-2-trifluoromethylbenzamide (16.44 g) as white crystals, m.p. 149°-156° C.
Reaction SMILES: [Cl:1][C:2]1[N:23]=[CH:22][CH:21]=[CH:20][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:8]=1)=[O:5].[H-].[Na+].[CH3:26][O:27][CH2:28]Cl>CN(C)C=O>[Cl:1][C:2]1[N:23]=[CH:22][CH:21]=[CH:20][C:3]=1[C:4]([N:6]([C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:12]=1)[CH2:26][O:27][CH3:28])=[O:5]
Reactant: CCOC(=O)CCc1ccc(NC(=O)c2cccnc2Cl)cc1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1ccc(N(COC)C(=O)c2cccnc2Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
The compound (100 mg, 0.31 mmol) prepared in step 2 was dissolved in N,N-dimethylformamide (3 ml), added with sodium hydride (407 mg, 10.02 mmol) at 0° C. After stirring for 30 minutes, chloromethyl methyl ether was added dropwise and the resulting mixture was stirred for 8 hours. The mixture was poured into ice water and extracted with chloroform. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated to dryness. The residue was then purified by flash column chromatography (hexane:ethyl acetate=2:1) to obtain title compound (57 mg, yield: 50%, yellow liquid).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[CH:3]=1.Cl[C:10]1[C:11]2[C:18]([C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:20])=[CH:17][N:16]([CH3:27])[C:12]=2[N:13]=[CH:14][N:15]=1.FC(F)(F)C(O)=O>C(OCC)C>[NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:10]2[C:11]3[C:18]([C:19]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[O:20])=[CH:17][N:16]([CH3:27])[C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cn1cc(C(=O)c2ccccc2)c2c(Cl)ncnc21
Reactant: Nc1cccc(N)c1
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(C(=O)c2ccccc2)c2c(Nc3cccc(N)c3)ncnc21

Procedure:
(4-((3-aminophenyl)amino)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(phenyl)methanone was synthesized according to general procedure A step 2 using 1,3-diaminobenzene and (4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(phenyl)methanone. A white solid was obtained. M.p: 170-173° C.; 400 MHz 1H NMR (DMSO-d6) δ: 8.53 (s, 1H), 8.12 (s, 1H), 8.06 (s, 1H), 7.86 (d, J=6.6 Hz, 2H), 7.71 (d, J=4.3 Hz, 2H), 7.68 (d, J=4.3 Hz, 2H), 7.43 (d, J=7.8 Hz, 1H), 7.13 (t, J=7.8 Hz, 1H), 6.95 (d, J=5.8 Hz, 1H), 6.69 (s, 1H), 6.57 (d, J=1.9 Hz, 1H), 3.68 (s, 3H); LCMS [M+H]: 344; Calc. C20H17N5O.1.6 trifluoroacetic acid.0.1 diethyl ether: C, 53.16; H, 3.70; N, 13.13. Found C, 50.79; H, 3.73; N, 12.93.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[OH:19].Br[CH2:21][CH2:22][CH2:23][C:24]#[N:25].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:14]1([C:7]2([CH3:13])[CH2:6][C:5]3[C:9](=[C:10]([Cl:11])[C:2]([Cl:1])=[C:3]([O:19][CH2:21][CH2:22][CH2:23][C:24]#[N:25])[CH:4]=3)[C:8]2=[O:12])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CC1(C2CCCC2)Cc2cc(O)c(Cl)c(Cl)c2C1=O
Reactant: N#CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C2CCCC2)Cc2cc(OCCCC#N)c(Cl)c(Cl)c2C1=O
Reaction time: 4 h

Procedure:
A mixture of 6,7-dichloro-2-cyclopentyl-5-hydroxy-2-methyl-2,3-dihydro-1H-inden-1-one (6.0 g, 20 mmole), 4-bromobutanenitrile (3.28 g, 22 mmole), and potassium carbonate (3.1 g, 22 mmole) in dimethylformamide (50 ml) was stirred at 60°-65° for four hours. The reaction mixture was poured into water and extracted with diethyl ether. The organic layer was washed successively with water and brine, dried over magnesium sulfate, and concentrated in vacuo to a solid residue (4.7 g). Recrystallization from butyl chloride-hexane afforded the analytically pure title compound, m.p. ca. 112°.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH3:7][O:8][C:9]1[C:10]([CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])([CH:19]=O)[C:11]2[C:16]([CH2:17][CH:18]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH3:7][O:8][C:9]1[C:10]([CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])([CH:19]=[CH2:1])[C:11]2[C:16]([CH2:17][CH:18]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2
Reactant: COC1=CCc2ccccc2C1(C=O)CCC(C)C
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CC1(CCC(C)C)C(OC)=CCc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To a suspension of methyltriphenylphosphonium bromide (0.62 g, 1.7 mmol) in tetrahydrofuran (3 mL) at 0° C. was added a solution of 1.0 M potassium t-butoxide in tetrahydrofuran (1.5 mL, 1.5 mmol). The mixture was allowed to warm to room temperature and stirred for 1 h. After which, the solution was cooled to −40° C. and a solution of Example 181A (0.15 g, 0.6 mmol) in tetrahydrofuran (3 mL) was added dropwise. The reaction mixture was stirred at −40° C. for 1 h, and then allowed to warm to room temperature and stirred for 2 h. The solution was quenched with saturated NH4Cl solution (15 mL) and extracted with ethyl acetate (3×10 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. Column chromatography on silica (hexane) afforded product as a colorless oil (0.13 g, 87%). 1H NMR (300 MHz, CDCl3) δ ppm 0.63 (m, 1 H), 0.77 (dd, J=12.87, 6.62 Hz, 6 H), 0.90 (m, 1 H), 1.40 (m, 1 H), 1.79 (m, 1 H), 2.17 (m, 1 H), 3.50 (d, J=3.68 Hz, 2 H), 3.59 (s, 3 H), 4.99 (m, 3 H), 6.00 (dd, J=17.65, 10.66 Hz, 1 H), 7.16 (m, 4 H).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)O1.Br[C:20]1[CH:21]=[C:22]([F:26])[CH:23]=[CH:24][CH:25]=1.[OH-].[Na+]>C1COCC1.[Pd].C(OCC)(=O)C>[F:26][C:22]1[CH:21]=[C:20]([N:13]2[C:14]3[C:10](=[CH:9][CH:17]=[CH:16][CH:15]=3)[CH:11]=[CH:12]2)[CH:25]=[CH:24][CH:23]=1
Reactant: Fc1cccc(Br)c1
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Fc1cccc(-n2ccc3ccccc32)c1
Temperature: 70 °C
Reaction time: 15 h
Yield: 89 %

Procedure:
To a mixture of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl) 1H-indole (3, 2.43 g, 10 mmol), and 3-bromofluorobenzene (1.09 mL, 10 mmol) in THF (34 mL)) were added Palladium catalyst Pd(PPh3)4 (347 mg, 0.3 mmol) and the freshly prepared sodium hydroxide solution (1.20 g, 30 mmol in 14 mL water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 70° C. oil bath for 15 hours. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed by brine, dried over Na2SO4, and concentrated. The crude product was purified by a silica gel column eluting with hexanes-EtOAc (9:1) to provide 1.88 g (88%) of the product 4-(3-fluoro-phenyl)-1H-indole as a colorless syrup.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][C:7](=[O:13])[CH:6]=[C:5]2[CH2:14]Cl.[OH2:16]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][C:7](=[O:13])[CH:6]=[C:5]2[CH2:14][OH:16]
Reactant: O=c1cc(CCl)c2cc(Br)c(O)cc2o1
Reactant: O
Product: O=c1cc(CO)c2cc(Br)c(O)cc2o1
Yield: 98 %

Procedure:
A suspension of 291.7 mg (1.008 mmol) of compound 11 in water (50 mL) was refluxed for 14 hours. The resulting solution was cooled and evaporated to give 268.7 mg (0.9913 mmol, 98% yield) of compound 14 as a solid, pure enough to use in the next step without further purification. 1H NMR (CD3OD) δ 7.83 (1H, s), 6.86 (1H, s), 6.40 (1H, s), 4.78 (2H, s).
Reaction SMILES: C1(OC2C=CC=CC=2)C=CC=CC=1.C(O[C:17](=[O:33])[C:18](=[CH:24][NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[N:27]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])C>CCCCCC>[CH2:22]([O:21][C:19]([C:18]1[C:17](=[O:33])[C:31]2[C:26](=[N:27][C:28]([CH3:32])=[CH:29][CH:30]=2)[NH:25][CH:24]=1)=[O:20])[CH3:23]
Reactant: CCOC(=O)C(=CNc1cccc(C)n1)C(=O)OCC
Solvent: CCCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1c[nH]c2nc(C)ccc2c1=O
Temperature: 250 °C
Yield: 70.3 %

Procedure:
A solution of diphenyl ether was heated to 250° C. and the product of Example 1a (2.50 g, 9.0 mmol) was added in several small portions over a period of about 5 min then heated at 250° C. for 30 min. After cooling to room temperature diluted with hexane. The resulting solid was filtered and was dried under vacuum giving the title compound as a tan solid (1.47 g, 71%).
Reaction SMILES: Br[C:2]1[C:3]([CH3:11])=[C:4]([C:7]([F:10])=[CH:8][CH:9]=1)[C:5]#[N:6].[CH2:12](O)[CH3:13]>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].C(Cl)Cl>[CH:12]([C:2]1[C:3]([CH3:11])=[C:4]([C:7]([F:10])=[CH:8][CH:9]=1)[C:5]#[N:6])=[CH2:13]
Reactant: CCO
Reactant: Cc1c(Br)ccc(F)c1C#N
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: C=Cc1ccc(F)c(C#N)c1C

Procedure:
3-Bromo-6-fluoro-2-methylbenzonitrile (23.6 g, 110 mmol), potassium vinyl trifluoroborate (29.5 g, 221 mmol), PdCl2(dppf)-CH2Cl2 Adduct (4.03 g, 5.51 mmol), and TEA (30.7 mL, 221 mmol) were added to 250 mL of ethanol. The reaction mixture was degassed then stirred at reflux for 4 h. LC-MS confirmed the presence of product. The reaction mixture was diluted with ethyl acetate, washed twice with brine, dried, and evaporated to dryness. The crude material was then purified by MPLC chromatography using a 330 g Redi-sep column and eluting with a 10% EtOAc/Hexane solvent system to yield 3-ethenyl-6-fluoro-2-methylbenzonitrile.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[CH3:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[NH:25][CH2:24][CH2:23][CH2:22]2>CN(C=O)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([N:25]2[C:26]3[C:21](=[CH:20][C:19]([CH3:18])=[CH:28][CH:27]=3)[CH2:22][CH2:23][CH2:24]2)[N:7]=1
Reactant: Cc1ccc2c(c1)CCCN2
Reactant: Clc1ncnc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)CCCN2c1ncnc(Cl)n1
Temperature: 0 °C

Procedure:
2,4-Dichloro-1,3,5-triazine (1.95 g, 13 mmol) was dissolved in DMF (50 mL) under N2 and cooled to 0° C. DIEA (1.68 g, 13 mmol) was added, followed by the addition of 6-methyl-1,2,3,4-tetrahydroquinoline (1.91 g, 13 mmol). The reaction was stirred with gradual warming to RT. The reaction was quenched after 3 h with water, which causes a sticky precipitate to form. The mixture was extracted 3× with EtOAc. The EtOAc extracts were washed brine, combined, dried over Na2SO4, filtered, and concentrated, then dried under high vacuum to remove residual traces of DMF. The recovered material was purified by elution through a 17×2.5 cm column of silica gel (5%, 10%, 20% and 40% EtOAc/Hexane step gradient) giving 1-(4-chloro-[1,3,5]triazin-2-yl)-6-methyl-1,2,3,4-tetrahydro-quinoline as a white solid.