Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][C@@H:19]1[CH2:31][CH2:32][OH:33])=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl.C(=O)(O)[O-].[Na+]>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][C@@H:19]1[CH2:31][CH:32]=[O:33])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](CCO)C1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](CC=O)C1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Combine a solution of oxalyl chloride (0.238 mL, 2.72 mmol) in dichloromethane (25 mL) with dimethyl sulfoxide (0.322 mL, 4.54 mmol) at −78° C. and stir. After 15 minutes, add a solution of (S)-2-(2-hydroxyethyl)piperazine-1,4-dicarboxylic acid di-tert-butyl ester (0.60 g, 1.82 mmol) in dichloromethane at −78° C. via cannula and stir at −78° C. After one hour, add triethylamine (1.27 mL, 9.08 mmol) and warm to room temperature overnight. Dilute the mixture with saturated aqueous sodium bicarbonate and extract three times with dichloromethane. Combine the organic layers, dry over sodium sulfate and concentrate under reduced pressure to give the title compound: mass spectrum (APCI): m/z=129.1 (M+1-2BOC).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=1.[CH3:24][NH:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>C1COCC1.C(=O)([O-])O.[Na+]>[CH:26]1([N:25]([CH3:24])[C:2]2[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[N:3]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: CNC1CCCCC1
Reactant: CCCC(C(=O)OC)c1c(C)nc(Cl)nc1-c1ccc(C)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC(C(=O)OC)c1c(C)nc(N(C)C2CCCCC2)nc1-c1ccc(C)cc1
Temperature: 100 °C
Yield: 49.6 %

Procedure:
A mixture of methyl 2-(2-chloro-4-methyl-6-p-tolylpyrimidin-5-yl)pentanoate (100 mg; 0.30 mmol) and N-methylcyclohexanamine (0.158 mL; 1.202 mmol) in THF (1 mL) was placed in a sealed tube and heated at 100° C. for 18 h. The reaction mixture was diluted with a saturated sodium hydrogen carbonate solution and extracted twice with ethyl acetate. The organic layers were combined, washed with brine, dried over magnesium sulphate and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a linear gradient of ethylacetate (2-20%) in heptane to give 61 mg (49%) of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:20])[C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)=[O:10])=[CH:3][CH:2]=1.[N+:21]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1)([O-:23])=[O:22]>>[N:1]1[CH:2]=[CH:3][C:4]([NH:7][C:8](=[O:20])[C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:28][C:27]3[CH:30]=[CH:31][C:24]([N+:21]([O-:23])=[O:22])=[CH:25][CH:26]=3)[CH:12]=2)=[O:10])=[CH:5][CH:6]=1
Reactant: O=C(Nc1ccncc1)C(=O)c1c[nH]c2ccccc12
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Product: O=C(Nc1ccncc1)C(=O)c1cn(Cc2ccc([N+](=O)[O-])cc2)c2ccccc12
Yield: 64 %

Procedure:
The N-(pyridin-4-yl)-(indol-3-yl)glyoxylamide obtained according to the 1st Stage (Scheme 2) is reacted with 4-nitrobenzyl chloride according to the “benzylation procedure” (page 5) and the compound N-(pyridin-4-yl)-[1-(4-nitrobenzyl)indol-3-yl]glyoxylamide obtained is isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH3:19])=[C:6]([NH:8][C:9]2[S:10][C:11]([C:15](=[O:17])[CH3:16])=[C:12]([CH3:14])[N:13]=2)[CH:7]=1.[Br-:20].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>Br.CC(O)=O>[Br:20][CH2:16][C:15]([C:11]1[S:10][C:9]([NH:8][C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:18][CH3:19])=[N:13][C:12]=1[CH3:14])=[O:17]
Reactant: [Br-]
Reactant: COc1ccc(Cl)cc1Nc1nc(C)c(C(C)=O)s1
Agent: Br
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Product: COc1ccc(Cl)cc1Nc1nc(C)c(C(=O)CBr)s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 101.2 %

Procedure:
To a solution of 5z (0.15 g, 0.5 mmol) in HBr/HOAc (33% wt HBr in HOAc; 2.5 mL) was added pyridinium tribromide (0.18 g, 0.55 mmol). The reaction mixture was stirred at room temperature for 24 h and poured onto ice-water. The precipitated product was collected by filtration, washed with cold water, and dried to afford 6z (0.19 g, 99%). Rf=0.714 in Hexane:EtOAc:1:1. 1H NMR (600 MHz, DMSO-d6): δ 8.38 (d, J=2.4 Hz, 1H), 7.07-7.12 (m, 2H), 4.58 (s, 2H), 3.86 (s, 3H), 2.57 (s, 3H). 13C NMR (150 MHz, DMSO-d6): δ 183.1, 166.1, 158.1, 147.8, 129.8, 124.1, 123.1, 119.6, 119.4, 112.7, 56.2, 36.0, 18.7. MS m/z (ESI) 376.92 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH3:18][C:19]1[C:23]([CH2:24][CH2:25][C:26]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[O:27])=[C:22]([CH3:35])[NH:21][C:20]=1[CH:36]=O>C(O)C.N1CCCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[C:10](=[CH:36][C:20]2[NH:21][C:22]([CH3:35])=[C:23]([CH2:24][CH2:25][C:26]([N:28]4[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]4)=[O:27])[C:19]=2[CH3:18])[C:11](=[O:17])[NH:12]3)=[CH:6][CH:7]=1
Reactant: O=C1Cc2c(cccc2-c2ccc(Cl)cc2)N1
Reactant: Cc1[nH]c(C=O)c(C)c1CCC(=O)N1CCN(C)CC1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4ccc(Cl)cc4)c32)c(C)c1CCC(=O)N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 37.7 %

Procedure:
To a solution of 4-(4-chloro-phenyl)-1,3-dihydro-indol-2-one (60.9 mg, 0.25 mmol) and 3,5-dimethyl-4-[3-(4-methyl-piperazin-1-yl)-3-oxo-propyl]-1H-pyrrole-2-carbaldehyde (72.1 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 4-(4-chloro-phenyl)-3-{3,5-dimethyl-4-[3(4-methyl-piperazin-1-yl)-3-oxo-propyl]-1H-pyrrol-2-ylmethylene}-1,3-dihydro-indol-2-one as a yellow solid (47.4 mg, 38%).
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.B(O)(O)[C:10]1[C:15]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH3:8][C:7]1[C:2]([C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:15]=2[NH:16][C:17](=[O:18])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cccnc1Br
Reactant: CC(C)(C)OC(=O)Nc1ccccc1B(O)O
Product: Cc1cccnc1-c1ccccc1NC(=O)OC(C)(C)C
Yield: 132.3 %

Procedure:
2-Bromo-3-methylpyridine (0.65 g, 3.8 mmol) and N-(tert-butoxycarbonyl)-2-amino-1-phenylboronic acid (0.90 g, 3.8 mmol), prepared according to the method described by J. J. S. Lambda and J. M. Tour in J. Am. Chem. SDC., 1994,116,11723-11736, were coupled as in Example 70 (also see J. Org. Chem., 1995, 60, 292), to give 1.43 g of crude tert-butyl 2-(3-methyl-2-pyridinyl)phenylcarbamate, which was deprotected as in Example 75 to give 0.45 g of 2-(3-methyl-2-pyridinyl)aniline.
Reaction SMILES: Cl[C:2]1[N:24]=[CH:23][C:5]2[N:6]=[C:7]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[C:8](=[O:16])[N:9]([CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH3:15])[C:4]=2[CH:3]=1.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][N:28]=1>O1CCOCC1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:25][O:26][C:27]1[N:28]=[CH:29][C:30]([C:2]2[N:24]=[CH:23][C:5]3[N:6]=[C:7]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[C:8](=[O:16])[N:9]([CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH3:15])[C:4]=3[CH:3]=2)=[CH:31][CH:32]=1
Reactant: CCCOCCn1c(=O)c(N2CCNCC2)nc2cnc(Cl)cc21
Reactant: COc1ccc(B(O)O)cn1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: C1COCCO1
Product: CCCOCCn1c(=O)c(N2CCNCC2)nc2cnc(-c3ccc(OC)nc3)cc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 7-chloro-3-(piperazin-1-yl)-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2(1H)-one (72 mg, 0.18 mmol) in 1,4-dioxane (2.5 mL) was treated with tetrakis(triphenylphosphine) palladium(0) (19 mg, 0.016 mmol, Strem) and stirred at room temperature for five minutes. A warm solution of 2-methoxy-5-pyridineboronic acid (41 mg, 0.27 mmol, Frontier) in ethanol (0.5 mL) and 2.0 M aqueous sodium carbonate 1.5 mL) were added. The mixture was refluxed for 2.0 hours, filtered hot through celite and the filtrate was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water, and the layers were separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, concentrated under reduced pressure, and passed through a column of silica gel with 2% methanol/dichloromethane. Fractions were concentrated at reduced pressure and triturated with diethyl ether. The 7-(6-methoxypyridin-3-yl)-3-(piperazin-1-yl)-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2(1H)-one was obtained as a pink powder.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[C:7]([NH:16][CH:17]([C:19]3[CH:24]=[CH:23][C:22]([S:25]([NH2:28])(=[O:27])=[O:26])=[CH:21][CH:20]=3)[CH3:18])[N:8]=[C:9]([O:12][CH:13]3[CH2:15][CH2:14]3)[C:10]=2[N:11]=1.[C:29]([CH:31]1[CH2:33][CH2:32]1)#[CH:30].O>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH:13]1([O:12][C:9]2[C:10]3[N:11]=[C:2]([C:30]#[C:29][CH:31]4[CH2:33][CH2:32]4)[CH:3]=[CH:4][C:5]=3[N:6]=[C:7]([NH:16][C@@H:17]([C:19]3[CH:24]=[CH:23][C:22]([S:25]([NH2:28])(=[O:27])=[O:26])=[CH:21][CH:20]=3)[CH3:18])[N:8]=2)[CH2:15][CH2:14]1
Reactant: C#CC1CC1
Reactant: CC(Nc1nc(OC2CC2)c2nc(Cl)ccc2n1)c1ccc(S(N)(=O)=O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](Nc1nc(OC2CC2)c2nc(C#CC3CC3)ccc2n1)c1ccc(S(N)(=O)=O)cc1
Temperature: 80 °C
Yield: 77.7 %

Procedure:
A mixture of 4-[1-(6-Chloro-4-cyclopropoxy-pyrido[3,2-d]pyrimidin-2-ylamino)-ethyl]-benzenesulfonamide (300 mg, 0.71 mmol), PdCl2(PPh3)2 (25 mg, 0.035 mmol), CuI (13.5 mg, 0.07 mmol) in TEA (1 mL) and DMF (5 mL) was degassed for 10 min then purged with argon. Ethynyl-cyclopropane (0.3 mL, 3.5 mmol) was added and the reaction tube was sealed and heated at 80° C. for 3 hours. After cooling to room temperature, the reaction mixture was poured into water and extracted twice with EtOAc. The combined organic layers were washed with 5% LiCl solution and brine. Solvent was removed by concentration in vacuo and the residue was purified by RP HPLC using a C18 column with a gradient of H2O, 0.1% TFA-acetonitrile, to provide 248 mg (62%) of desired product. MS (m/z) 450.0 [M+H]+; HPLC Rt=2.16 min.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)#[N:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>CCOCC>[NH2:2][CH2:1][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: N#CCCCc1ccccn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: NCCCCc1ccccn1
Yield: 44.7 %

Procedure:
2-(3-cyanopropyl)pyridine (14.6 g) in dry ether (100 ml) is added dropwise to a stirred suspension of lithium aluminium hydride (9.5 g) in dry ether (300 ml). The mixture is heated under reflux for 3 hours, cooled and treated successively with water, aqueous sodium hydroxide and water. Extraction with chloroform, followed by fractionation affords 2-(4-aminobutyl)pyridine (6.7 g), b.p. 100°-101° C/1.0 mm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[CH:14]=3)[C:9]=2[O:20][C:21]2[CH:35]=[CH:34][C:24]([O:25][CH2:26][CH2:27][N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:23][CH:22]=2)[CH:5]=[CH:6][CH:7]=1.Cl.N(=CCCl)[CH2:38]CCCCC[Cl:44]>>[ClH:44].[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[CH:14]=3)[C:9]=2[O:20][C:21]2[CH:22]=[CH:23][C:24]([O:25][CH2:26][CH2:27][N:28]3[CH2:29][CH2:30][CH2:38][CH2:31][CH2:32][CH2:33]3)=[CH:34][CH:35]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: ClCC=NCCCCCCCl
Reactant: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3cccc(F)c3)ccc2c1
Agent: Cl
Product: COc1ccc2c(Oc3ccc(OCCN4CCCCCC4)cc3)c(-c3cccc(F)c3)ccc2c1

Procedure:
Prepare this compound following the procedure to make 1-(2-{4-[2-(3-fluoro-phenyl)-6-methoxy-naphthalen-1-yloxy]-phenoxy}-ethyl)-piperidine above, using 2-(hexamethyleneimino)-ethyl chloride hydrochloride to get a 100% yield of the free base of the title compound after radial chromatography. Form the hydrochloride salt by adding 0.8 mL of a 1 M HCl in Et2O solution: mass spectrum (ion spray) m/z=4.86 (M−Cl).
Reaction SMILES: S(Cl)(Cl)=O.CN(C1C=CC=CN=1)C.[F:14][C:15]([F:24])([CH2:19][CH2:20][CH2:21][O:22][CH3:23])[CH:16]=[N:17]O.CC1C=CN=C(N)C=1C>ClCCl>[F:14][C:15]([F:24])([CH2:19][CH2:20][CH2:21][O:22][CH3:23])[C:16]#[N:17]
Reactant: COCCCC(F)(F)C=NO
Agent: CN(C)c1ccccn1
Agent: Cc1ccnc(N)c1C
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COCCCC(F)(F)C#N
Temperature: -15 °C
Reaction time: 1 h
Yield: 67.1 %

Procedure:
Thionyl chloride (809 mg, 6.8 mmoles) in ice cold dry dichloromethane (7 ml) is added to a solution of dimethylamino pyridine (903 mg, 7.4 mmoles) in dichloromethane (15 ml) kept under nitrogen and cooled at -15° C. The oxime 34 (1.04 g, 6.2 mmoles), dissolved in dichloromethane (20 ml) is added, followed by addition of dimethyl aminopyridine as a solid (903 mg, 7.4 mmoles). The reaction mixture is then allowed to rise to room temperature, kept at 25° C. for 1 hour, diluted with dichloromethane, washed with 1N HCl, and finally with water. Concentration of the organic phase, previously dried over sodium sulfate, (30° C., 100 mm Hg) affords the title compound (620 mg) which is purified by bulb to bulb distillation (50° C., 30 mm Hg): 485 mg (52%).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][O:11][C:12]([NH:14][C@H:15]([C@@H:23]([OH:47])[CH2:24][C@@H:25]([NH:33][C:34]([O:36][CH2:37][CH2:38][O:39][Si](C(C)(C)C)(C)C)=[O:35])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:13])(C(C)(C)C)(C)C>CO.C[Si](Cl)(C)C>[OH:8][CH2:9][CH2:10][O:11][C:12]([NH:14][C@H:15]([C@@H:23]([OH:47])[CH2:24][C@@H:25]([NH:33][C:34]([O:36][CH2:37][CH2:38][OH:39])=[O:35])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:13]
Reactant: CC(C)(C)[Si](C)(C)OCCOC(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCCO[Si](C)(C)C(C)(C)C
Agent: C[Si](C)(C)Cl
Solvent: CO
Product: O=C(N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCCO)OCCO
Reaction time: 2 h
Yield: 578.2 %

Procedure:
In two batches, 81.4 mg (0.016 mmol) of the compound from Example 335B above was dissolved in 2 mL of methanol to which 14.9 μL of trimethylsilyl chloride was added and stirred for 2 hours. The solvent was removed and the crude product chromatographed on silica gel, eluting with 2% and 5% methanol in methylene chloride. The solvent was removed and the product dried to afford 42.6 mg of the title compound. MS M/Z (DCI/NH3): 461 (M+H), 478 (M+NH4). Proton NMR (DMSO): δ1.46 (t, 2H), 2.53-2.77 (4H), 3.45 (m, 3H), 3.55 (d, 1H), 3.64-3.92 (6H), 4.64 (m, 2H), 6.65 (d, 1H), 6.94 (d, 1H), 7.07-7.27 (10H). Anal calc. for C24H32N2O7 ·H2O: C, 60.25; H, 7.11; N, 5.86; found: C, 60.38; H, 6.56; N, 5.86.
Reaction SMILES: COC1C=CC(N2CCN(CCC3C=CC=CC=3)CC2)=CC=1.[CH2:23]([CH:30]1[CH2:35][CH2:34][N:33]([C:36]2[CH:41]=[C:40]([F:42])[C:39]([O:43]C)=[CH:38][C:37]=2[F:45])[CH2:32][CH2:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([CH:30]1[CH2:31][CH2:32][N:33]([C:36]2[C:37]([F:45])=[CH:38][C:39]([OH:43])=[C:40]([F:42])[CH:41]=2)[CH2:34][CH2:35]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COc1cc(F)c(N2CCC(Cc3ccccc3)CC2)cc1F
Agent: COc1ccc(N2CCN(CCc3ccccc3)CC2)cc1
Product: Oc1cc(F)c(N2CCC(Cc3ccccc3)CC2)cc1F
Yield: 48.1 %

Procedure:
Production Example 2 was repeated except that 1-(4-methoxyphenyl)-4-phenethylpiperazine was replaced with 4-benzyl-1-(2,5-difluoro-4-methoxyphenyl)piperidine (300 mg). The resulting crude product was purified on silica gel column chromatography (eluent, hexane: ethyl acetate=4:1) to provide 4-(4-benzylpiperidino)-2,5-difluorophenol (138 mg).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][N:29]2[C:37]3[C:32](=[CH:33][C:34]([C:38](O)=[O:39])=[CH:35][CH:36]=3)[C:31]([CH3:41])=[C:30]2[CH3:42])=[CH:24][CH:23]=1)=[O:15])(C)(C)C>>[CH2:1]([NH:8][C:38]([C:34]1[CH:33]=[C:32]2[C:37](=[CH:36][CH:35]=1)[N:29]([CH2:28][C:25]1[CH:24]=[CH:23][C:22]([C:17]3[C:16]([C:14]([OH:15])=[O:13])=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:27][CH:26]=1)[C:30]([CH3:42])=[C:31]2[CH3:41])=[O:39])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)NCc3ccccc3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Steps 8-9, Example 1, using benzylamine and 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][OH:13])=[CH:5][CH:4]=1.B(Br)(Br)Br.Cl>ClCCl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][OH:13])=[CH:7][CH:8]=1
Reactant: COc1ccc(CCCCO)cc1
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: OCCCCc1ccc(O)cc1
Temperature: 15 °C
Yield: 86 %

Procedure:
To a solution of 4-(4-methoxyphenyl)butanol (100 g, 0.55 mole) in dichloromethane, cooled to -75° C. in a dry ice-acetone bath, a solution of boron tribromide (278 g; 2.0 mole) was added slowly over one hour. The cooling bath was then removed and the reaction mixture allowed to warm to 15° C. slowly. The reaction was shown to be complete by thin layer chromatography (TLC). The reaction mixture was again cooled in an ice-water bath; 10% sodium hydroxide solution was added until pH of about 9 was obtained. The resulting mixture was then acidified with concentrated HCl to a pH of about 2. The organic layer was separated, the aqueous layer was extracted once with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and concentrated to give 90 g of crude product. The crude product was purified by dry filtration chromatography using 10% ethyl acetate/dichloromethane as eluent giving an 86% yield of pure 4-(4-hydroxyphenyl)butanol. The 1H NMR was consistent with the assigned structure.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:31])=[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][CH:25]3[CH2:27][CH2:26]3)[CH:17]=[C:16]4[C:28](O)=[O:29])[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.O1CCCC1.B>C1COCC1>[CH:1]1([NH:4][C:5](=[O:6])[C:7]2[CH:8]=[CH:9][C:10]([CH3:31])=[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][CH:25]3[CH2:26][CH2:27]3)[CH:17]=[C:16]4[CH2:28][OH:29])[CH:12]=2)[CH2:2][CH2:3]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(C(=O)O)c2c1
Agent: B
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(CO)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the product of Example 37 step v) (500 mg) in THF (12 mL) at 0° C. was added borane tetrahydrofuran complex (1M/THF) (1.6 mL) dropwise. The ice bath was removed once gas evolution had ceased, and the reaction was stirred at room temperature for 1 hour. The reaction mixture was cooled to 0° C. and further borane tetrahydrofuran complex (1M/THF, 750 uL) was added, and the reaction was slowly warmed to room temperature and stirred for 1 hour. The reaction mixture was quenched with water (50 mL) and extracted into ethyl acetate (2×50 mL). The combined organics were dried over magnesium sulfate, filtered and evaporated in vacuo. Purification (SiO2 chromatography, 3% methanol in dichloromethane) gave the sub-titled compound (300 mg).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([N:9]2[C:13]([CH3:14])=[C:12]([C:15]([OH:17])=O)[CH:11]=[N:10]2)[CH:6]=[CH:7][CH:8]=1.[NH2:20][C:21]1[CH:22]=[CH:23][C:24]([O:29][CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[C:25]([CH:28]=1)[C:26]#[N:27].C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>O.CN(C)C=O>[C:26]([C:25]1[CH:28]=[C:21]([NH:20][C:15]([C:12]2[CH:11]=[N:10][N:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:19])[F:18])[CH:4]=3)[C:13]=2[CH3:14])=[O:17])[CH:22]=[CH:23][C:24]=1[O:29][CH2:30][C:31]([CH3:33])([CH3:32])[CH3:34])#[N:27]
Reactant: Cc1c(C(=O)O)cnn1-c1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)COc1ccc(N)cc1C#N
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C(=O)Nc2ccc(OCC(C)(C)C)c(C#N)c2)cnn1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.4 %

Procedure:
1-(3-Trifluoromethylphenyl)-5-methylpyrazole-4-carboxylic acid (2 g), 5-amino-2-neopentyloxybenzonitrile (1.8 g), triethylamine (1.6 g) and diethyl cyanophosphate (1.4 g) were added to dimethylformamide (20 ml) and the mixture was stirred at room temperature for 1 h. The reaction mixture was added into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. n-Hexane was added to the residue to allow crystallization. The crystals were recrystallized from hydrous ethanol to give the title compound (1.4 g), melting point: 116–118° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([NH2:18])(Cl)[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][S:8][C:6]=2[N:7]=1.N[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1.C(O)C>O>[CH3:1][C:2]1[N:3]=[C:4]([NH:18][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][S:8][C:6]=2[N:7]=1
Reactant: NCc1ccccn1
Reactant: CC1=Nc2scc(-c3ccccc3)c2C(N)(Cl)N1
Solvent: O
Solvent: CCO
Product: Cc1nc(NCc2ccccn2)c2c(-c3ccccc3)csc2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 842.3 %

Procedure:
In a 10 ml glass tube were placed 2-methyl-4-chloro-5-phenylthieno[2,3-d]pyrimidin-4-ylamine (0.076 g, 0.293 mmol), 2-(aminomethyl)pyridine (0.0364 g, 0.03 mmol) and ethanol (2.5 ml). The vessel was sealed with a septum and placed in the microwave cavity. Microwave irradiation of 200 W was used, the temperature being ramped from room temperature to 150° C. Once 150° C. was reached, the reaction mixture was held at this temperature for 10 minutes. After cooling to ambient temperature, water (4 ml) was added and the mixture stirred for 2.5 hours. The resulting solid was collected by filtration, washed with water and dried in vacuo to give 2-methyl-N-(2-pyridyl)methyl-5-phenylthieno[2,3-d]pyrimidin-4-ylamine (0.084 g) as an off white solid, m.pt. 110-112° C.