Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]2[N:7](C(OCC3C4C=CC=CC=4C4C3=CC=CC=4)=O)[CH2:8][C@@H:9]([O:10][CH3:11])[C@H:5]2[O:4][CH2:3]1.[H][H]>[Pd].C(O)C>[CH3:11][O:10][C@@H:9]1[CH2:8][NH:7][C@@H:6]2[C@@H:2]([OH:1])[CH2:3][O:4][C@H:5]12
Reactant: CO[C@@H]1CN(C(=O)OCC2c3ccccc3-c3ccccc32)[C@H]2[C@@H]1OC[C@@H]2O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CO[C@@H]1CN[C@H]2[C@@H]1OC[C@@H]2O
Reaction time: 2.5 h

Procedure:
(3R,3aR,6R,6aS)— (9H-Fluoren-9-yl)methyl 3-hydroxy-6-methoxytetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate (5b). Ethanol (30 mL) was added dropwise to a mixture of 10% palladium on charcoal (200 mg) and syn-/anti-epoxides respectively (605 mg, 2.06 mmol) under an atmosphere of argon. The argon was replaced by hydrogen then the suspension was stirred for 2.5 hours then filtered through celite in vacuo. The filter cake was washed with ethanol then the solvents removed in vacuo from the filtrate to obtain the crude (3R,3aR,6R,6aS)-6-methoxyhexahydro-2H-furo[3,2-b]pyrrol-3-ol which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][CH:14]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:12]2)=[CH:7][C:3]=1[C:4](O)=[O:5].[C:25]12([CH2:35][NH2:36])[CH2:34][CH:29]3[CH2:30][CH:31]([CH2:33][CH:27]([CH2:28]3)[CH2:26]1)[CH2:32]2>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:12][CH2:13][CH:14]([NH:17][C:18](=[O:19])[O:20][C:21]([CH3:22])([CH3:24])[CH3:23])[CH2:15][CH2:16]2)=[CH:7][C:3]=1[C:4]([NH:36][CH2:35][C:25]12[CH2:34][CH:29]3[CH2:28][CH:27]([CH2:33][CH:31]([CH2:30]3)[CH2:32]1)[CH2:26]2)=[O:5]
Reactant: NCC12CC3CC(CC(C3)C1)C2
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(Cl)c(C(=O)O)c2)CC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(Cl)c(C(=O)NCC34CC5CC(CC(C5)C3)C4)c2)CC1

Procedure:
Prepared as described in Example 5c) using 2-chloro-5-[4-[[(1,1-dimethylethoxy)carbonyl]amino]-1-piperidinyl]-benzoic acid (Example 6b, 0.065 g), N,N′-carbonyldiimidazole (0.030 g), 1-adamantanemethylamine (0.032 ml) and dimethylformamide (3 ml) to give the subtitle compound as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:15]([O:17]C)=[O:16])[CH:11]=2)[CH:6]=1)=[O:4].[OH-].[Na+]>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([C:15]([OH:17])=[O:16])[CH:9]=[CH:8]2)=[O:4]
Reactant: COC(=O)c1ccc2cc(C(=O)OC)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2cc(C(=O)O)ccc2c1
Reaction time: 0.5 h
Yield: 59.8 %

Procedure:
2,6-naphthalenedicarboxylic acid dimethyl ester (26.0 g, 106 mmol) was dissolved in N,N-dimethylformamide (500 ml), and a 1N aqueous sodium hydroxide solution (106 ml) was added dropwise thereto at 100° C. over 30 minutes. After stirred for 3 hours, the solvent was distilled off under reduced pressure, water was added to the residue and the insolubles were filtered off. Concentrated hydrochloric acid (9 ml) was added to the filtrate, the precipitated crude product was filtered, washed with water, and recrystallized from hot methanol to obtain 6-(methoxycarbonyl)-2-naphthalenecarboxylic acid (14.6 g) as a white powder.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][O:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=1/[CH:29]=[CH:30]/[C:31](O)=[O:32]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:31](=[O:32])/[CH:30]=[CH:29]/[C:22]3[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:21]=3[O:20][CH3:19])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: COc1ccc(/C=C/C(=O)O)c(OC)c1
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Product: COc1ccc(/C=C/C(=O)Nc2ccn(Cc3ccc(C(C)=O)o3)n2)c(OC)c1

Procedure:
Following general procedure B followed by T, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and (E)-3-(2,4-dimethoxy-phenyl)-acrylic acid. LC-MS-conditions 05b: tR=0.97 min; [M+H]+=396.15.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([NH:27][NH2:28])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[CH:29](OCC)(OCC)OCC>>[CH2:1]([C:5]1[N:6]2[CH:29]=[N:28][N:27]=[C:7]2[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(NN)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CCOC(OCC)OCC
Product: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2nncn12
Temperature: 100 °C
Reaction time: 16 h
Yield: 17 %

Procedure:
A mixture of 4′-[(4-butyl-2-hydrazino-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (2.6 g) and triethyl orthoformate (30 mL) was stirred at 100° C. for 16 hr. The reaction mixture was concentrated, and ethyl acetate and water were added to the obtained residue. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.46 g, 17%).
Reaction SMILES: [C:1]([Si:5]([CH3:30])([CH3:29])[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:16]([C:24]3([CH:27]=O)[CH2:26][CH2:25]3)[O:15][N:14]=2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:31][NH:32][CH3:33].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.O1CCCC1>[C:1]([Si:5]([CH3:30])([CH3:29])[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:16]([C:24]3([CH2:27][N:32]([CH3:33])[CH3:31])[CH2:26][CH2:25]3)[O:15][N:14]=2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2noc(C3(C=O)CC3)c2-c2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C)CC1(c2onc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)c2-c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture consisting of 1-{3-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-4-phenyl-isoxazol-5-yl}-cyclopropanecarbaldehyde (Examples 14-17 General Procedure, Step A, 0.51 g) in dichloromethane (20 mL) is added sequentially a solution consisting of dimethylamine in tetrahydrofuran (2.0 M, 2 mL) followed by sodium triacetoxyborohydride (0.75 g.) The mixture is agitated overnight at room temperature under a nitrogen atmosphere. The mixture is diluted with dichloromethane (20 mL) and is washed twice with brine solution. The organic layer is separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate is purified by flash silica gel column chromatography to afford the synthetic intermediate (1-{3-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-4-phenyl-isoxazol-5-yl}-cyclopropylmethyl)-dimethyl-amine (0.251 g)
Reaction SMILES: [CH3:1][NH2:2].[Br:3][C:4]1[C:8]([N+:9]([O-:11])=[O:10])=[C:7](Br)[N:6]([CH2:13][CH2:14][O:15][CH3:16])[N:5]=1>C(O)C>[Br:3][C:4]1[C:8]([N+:9]([O-:11])=[O:10])=[C:7]([NH:2][CH3:1])[N:6]([CH2:13][CH2:14][O:15][CH3:16])[N:5]=1
Reactant: COCCn1nc(Br)c([N+](=O)[O-])c1Br
Reactant: CN
Solvent: CCO
Product: CNc1c([N+](=O)[O-])c(Br)nn1CCOC
Temperature: 22.5 °C
Reaction time: 2 h

Procedure:
Aqueous 40% methylamine solution (300 ml, 8.71 mol) was added to a solution of 3,5-dibromo-1-(2′-methoxyethyl)4-nitropyrazole (15 g, 0.483 mol) in ethanol (300 ml). The reaction mixture was stirred at 20-25° C. for 2 hours and then cooled to 0-5° C. for 30 minutes. The precipitate formed was filtered off and washed with a cold mixture of water/ethanol (1/1, 30 ml). The final amine product was obtained in the form of a yellow solid (4.6 g, 36%) after drying under reduced pressure.
Reaction SMILES: [C:1]12([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([CH3:18])[CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>CN(C)C=O.C(OCC)(=O)C>[C:1]12([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:13]([CH3:18])[CH:12]=3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: Cc1cc(C23CC4CC(CC(C4)C2)C3)ccc1O
Reactant: CCOC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
To a solution of 4-(adamantan-1-yl)-2-methylphenol (2.0 g, 8.76 mmol) in N,N-dimethylformamide (10 mL) was added potassium carbonate (3.63 g, 23.29 mmol) and ethyl chloroacetate (1.29 g, 10.51 mmol), and stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with aqueous sodium bicarbonate. The organic layer was dried over anhydrous magnesium sulfate. The solvent was filtered and evaporated under reduced pressure to afford a crude solid, which was purified by silica gel column chromatography to give ethyl 2-(4-(adamantan-1-yl)-2-methylphenoxy)acetate as a white solid (2.6 g, 95.9% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[C:15](Br)[CH:14]=[C:13]3[Br:21])=[O:9])=[CH:4][CH:3]=1.[OH2:22]>C1(C)C=CC=CC=1.CCOC(C)=O>[Br:21][C:13]1[C:12]2[C:17](=[CH:18][CH:19]=[C:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[O:9])[CH:11]=2)[N:16]=[C:15]([O:22][C:5]([CH3:8])([CH3:6])[CH3:4])[CH:14]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc2nc(Br)cc(Br)c2c1
Reactant: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)Oc1cc(Br)c2cc(C(=O)c3ccc(Cl)cc3)ccc2n1
Temperature: 70 °C

Procedure:
A mixture of (4-chlorophenyl)(2,4-dibromoquinolin-6-yl)methanone (5 g) and KOBut (1.1 eq. 12.93 mmol) in dry toluene (60 mL) was heated at 70° C. for 2 hr. and then cooled to room temperature. The reaction was diluted with EtOAc and water. The aqueous layer was extracted with ethyl acetate. The organics were combined and then washed with water, concentrated and subjected to chromatography (5-15% EtOAc/hexanes silica column) to yield (4-bromo-2-(tert-butoxy)quinolin-6-yl)(4-chlorophenyl)methanone.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[CH:16]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:14]=[C:13]([CH3:26])[N:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1.Br[C:28]1[CH:33]=[CH:32][N:31]=[C:30]([C:34]#[N:35])[CH:29]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([C:34]#[N:35])[CH:29]=3)[CH:14]=[C:13]([CH3:26])[N:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(NC(=O)c2cc(B3OC(C)(C)C(C)(C)O3)cc(C)n2)ccn1
Reactant: N#Cc1cc(Br)ccn1
Product: Cc1cc(NC(=O)c2cc(-c3ccnc(C#N)c3)cc(C)n2)ccn1

Procedure:
The title compound, was prepared from 6-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine-2-carboxylic acid (2-methyl-pyridin-4-yl)-amide in accordance with the general method of example 131, step 2 using 4-Bromo-2-cyanopyridine instead of 3-Trifluoromethyl-5-bromopyridine to yield the final compound as a white solid, MS (ISP): m/e=330.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[OH:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[CH3:18])[NH2:14]>>[OH:10][C:11]1[CH:12]=[C:13]([NH:14][C:2]2[N:7]=[C:6]([NH:14][C:13]3[CH:15]=[CH:16][C:17]([CH3:18])=[C:11]([OH:10])[CH:12]=3)[C:5]([F:9])=[CH:4][N:3]=2)[CH:15]=[CH:16][C:17]=1[CH3:18]
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Cc1ccc(N)cc1O
Product: Cc1ccc(Nc2ncc(F)c(Nc3ccc(C)c(O)c3)n2)cc1O

Procedure:
In like manner to N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 3-hydroxy-4-methylaniline were reacted to yield N2,N4-bis(-3-hydroxy-4-methylphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 7.83 (d, 1H J=4 Hz), 7.11 (m, 4H), 6.81 (m, 2H), 2.19 (m, 6H); LCMS: ret. time: 20.69 min.; purity: 98%; MS (m/e): 341 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:30]=[CH:29][C:13]([CH2:14][NH:15][C:16]3[CH:28]=[CH:27][C:19]4[O:20][C:21]([CH3:26])([CH3:25])[O:22][C:23](=[O:24])[C:18]=4[CH:17]=3)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH:31]1([C:37](Cl)=[O:38])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][C:10]2[CH:30]=[CH:29][C:13]([CH2:14][N:15]([C:16]3[CH:28]=[CH:27][C:19]4[O:20][C:21]([CH3:26])([CH3:25])[O:22][C:23](=[O:24])[C:18]=4[CH:17]=3)[C:37]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:38])=[CH:12][CH:11]=2)=[CH:6][CH:7]=1
Reactant: CC1(C)OC(=O)c2cc(NCc3ccc(C#Cc4ccc(Cl)cc4)cc3)ccc2O1
Reactant: O=C(Cl)C1CCCCC1
Product: CC1(C)OC(=O)c2cc(N(Cc3ccc(C#Cc4ccc(Cl)cc4)cc3)C(=O)C3CCCCC3)ccc2O1

Procedure:
The titled compound was prepared following the procedure E using 6-({4-[(4-chlorophenyl)ethynyl]benzyl}amino)-2,2-dimethyl-4H-1,3-benzodioxin-4-one and cyclohexanecarbonyl chloride as a yellow oil (79%). HPLC, Rt: 6.01 min (Purity: 98.2%).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([NH:21][CH2:22][CH2:23][CH3:24])=[N:8][C:9]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[N:10][CH:11]=1)=[O:5])C.C(O)C.[OH-].[Na+].Cl>O1CCCC1>[CH2:22]([NH:21][C:7]1[C:6]([C:4]([OH:5])=[O:3])=[CH:11][N:10]=[C:9]([NH:12][CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=2)[N:8]=1)[CH2:23][CH3:24]
Reactant: CCCNc1nc(NCCc2ccncc2)ncc1C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCNc1nc(NCCc2ccncc2)ncc1C(=O)O
Temperature: 40 °C
Reaction time: 4 h
Yield: 110.5 %

Procedure:
A mixture of 4-(propylamino)-2-((2-(pyridin-4-yl)ethyl)amino)pyrimidine-5-carboxylic acid ethyl ester (A2, 9.2 g), ethanol (115 mL), tetrahydrofuran (58 mL) and 2.0 mol/L aqueous sodium hydroxide (115 mL) was stirred at 40° C. for 4 hours, and then further stirred at 60° C. for 3 hours. The reaction mixture was cooled to room temperature, then 12 mol/L aqueous hydrochloric acid (19.5 mL) was added to the mixture (pH 5 to 6), and the organic solvent was evaporated under reduced pressure. The solid matter was taken by filtration, washed with water, and then dried under reduced pressure to obtain 4-(propylamino)-2-((2-(pyridin-4-yl)ethyl)amino)pyrimidine-5-carboxylic acid (A3, 9.3 g) as white solid.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH2:17][C:18]4[C:26]5[N:25]=[CH:24][N:23](C6CCCCO6)[C:22]=5[CH:21]=[CH:20][CH:19]=4)[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.CC1C=CC(S(O)(=O)=O)=CC=1.O>CO.O>[NH:23]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:17][NH:16][C:12]3[N:11]=[C:10]([NH:9][C:6]4[CH:5]=[C:4]([CH:1]5[CH2:2][CH2:3]5)[NH:8][N:7]=4)[CH:15]=[CH:14][N:13]=3)[C:26]=2[N:25]=[CH:24]1
Reactant: c1cc(CNc2nccc(Nc3cc(C4CC4)[nH]n3)n2)c2ncn(C3CCCCO3)c2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: c1cc(CNc2nccc(Nc3cc(C4CC4)[nH]n3)n2)c2nc[nH]c2c1
Temperature: 80 °C

Procedure:
A mixture of 60 (110 mg, 0.26 mmol) and p-TsOH.H2O (44 mg, 0.26 mmol) in MeOH (5 mL) and water (1 mL) was heated at 80° C. for 14 h. The solvent was removed in vacuo. The crude product was purified by preparative HPLC to afford 45 mg (51%) I-39 as white solid.
Reaction SMILES: Br[C:2]1[NH:22][C:5]2=[N:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[CH:13]=3)[N:9]=[C:4]2[CH:3]=1.[C:23]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][C:26]=1[F:34])#[N:24]>>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([CH:17]=[C:16]([O:18][CH3:19])[CH:15]=1)[CH2:11][CH2:10][C:8]1[N:9]=[C:4]2[CH:3]=[C:2]([C:29]3[CH:28]=[CH:27][C:26]([F:34])=[C:25]([CH:30]=3)[C:23]#[N:24])[NH:22][C:5]2=[N:6][CH:7]=1
Reactant: COc1cc(CCc2cnc3[nH]c(Br)cc3n2)cc(OC)c1
Reactant: N#Cc1ccc(B(O)O)cc1F
Product: COc1cc(CCc2cnc3[nH]c(-c4ccc(F)c(C#N)c4)cc3n2)cc(OC)c1

Procedure:
The compound was prepared by using procedures analogous to those described for the synthesis of Example 53, Step 2 starting from 6-bromo-2-[2-(3,5-dimethoxyphenyl)ethyl]-5H-pyrrolo[2,3-b]pyrazine and (4-cyano-3-fluorophenyl)boronic acid (from Aldrich). LCMS calculated for C23H20FN4O2(M+H)+: m/z=403.2. Found 403.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](F)[C:6]([Cl:10])=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12].C([O-])([O-])=O.[K+].[K+].[N:20]1([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.O>CS(C)=O>[Cl:10][C:6]1[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[C:3]([O:2][CH3:1])=[CH:8][C:7]=1[N:29]1[CH2:30][CH2:31][CH:26]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:27][CH2:28]1
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: COc1cc(F)c(Cl)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(N2CCC(N3CCCCC3)CC2)c(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
4-Chloro-5-fluoro-2-nitrophenyl methyl ether (2.19 g, 10.7 mmol) was dissolved in DMSO (10 mL). K2CO3 (2.2 g, 16 mmol) and 1,4′-bipiperidine (1.8 g, 11 mmol) were added and the reaction mixture was allowed to stir overnight at rt. The mixture was then poured into H2O and extracted with EtOAc (2×) and then the combined organics were extracted with H2O (5×). The organic layer was dried with MgSO4, filtered, and concentrated in vacuo. The resulting residue was adsorbed onto silica gel and flash chromatographed to give the title compound of step C (2.69 g, 71%). MS (M+H, ES+) 354.
Reaction SMILES: CC1C[O:5][C:4]2([CH2:11][C:10]([CH3:13])([CH3:12])[C:9](=[O:14])[C:8]([CH3:15])=[CH:7]2)O1.[CH2:16]([Li])[CH2:17][CH2:18][CH3:19].O.[Li]>CCCCCC>[CH2:16]([C:9]1([OH:14])[C:10]([CH3:12])([CH3:13])[CH2:11][C:4](=[O:5])[CH:7]=[C:8]1[CH3:15])[CH2:17][CH2:18][CH3:19]
Reactant: CC1=CC2(CC(C)(C)C1=O)OCC(C)O2
Reactant: [Li]CCCC
Agent: [Li]
Solvent: O
Solvent: CCCCCC
Product: CCCCC1(O)C(C)=CC(=O)CC1(C)C
Reaction time: 0.25 h

Procedure:
A solution of 20 g of 2,7,9,9-tetramethyl-1,4-dioxaspiro-[4,5]dec-6-en-8-one (prepared by the method of Example III) in hexane is stirred while a solution of n-butyl lithium in hexane is added dropwise. When no additional exotherm occurred the addition is stopped and the mixture is stirred for about 15 minutes. Water is added with stirring to hydrolyze the lithium salt. The organic layer is separated and the hexane is allowed to evaporate, leaving oily crystals which are recrystallized from cyclohexane yielding 10 g of 4-butyl-4-hydroxy-3,5,5-trimethyl-2-cyclohexen-1-one, m.p. 90°-93° C. The compound exhibits the following spectral characteristics:
Reaction SMILES: [CH2:1]([S:3]([C:6]1[N:10]=[CH:9][NH:8][N:7]=1)(=[O:5])=[O:4])[CH3:2].[CH2:11]([N:14]([CH2:18][CH3:19])[C:15](Cl)=[O:16])[CH:12]=[CH2:13].C(N(CC)CC)C>O1CCCC1>[CH2:11]([N:14]([CH2:18][CH3:19])[C:15]([N:8]1[CH:9]=[N:10][C:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[N:7]1)=[O:16])[CH:12]=[CH2:13]
Reactant: CCS(=O)(=O)c1nc[nH]n1
Reactant: C=CCN(CC)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCN(CC)C(=O)n1cnc(S(=O)(=O)CC)n1

Procedure:
A mixture of 6.45 g. 3-ethylsulphonyl-1,2,4-triazole, 5.9 g. N-allyl-N-ethylcarbamoyl chloride, 6.5 ml. dry triethylamine and 80 ml. dry tetrahydrofuran was refluxed under anhydrous conditions for 6 hours. The reaction mixture was worked up as described in Example 1 to produce a solid residue which was recrystallized from benzene/petroleum ether, b.p. 40° - 60°C. to give 1-(N-allyl-N-ethylcarbamoyl)-3-ethylsulphonyl-1,2,4-triazole, m.p. 41° - 43°C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][N:27]3[C:32](=[O:33])[C:31]4[CH:34]=[C:35]([CH3:37])[S:36][C:30]=4[NH:29][C:28]3=S)[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.[OH-].[K+].C([OH:43])C.OO>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:20][CH2:21][N:22]([CH2:25][CH2:26][N:27]3[C:32](=[O:33])[C:31]4[CH:34]=[C:35]([CH3:37])[S:36][C:30]=4[NH:29][C:28]3=[O:43])[CH2:23][CH2:24]2)=[CH:6][CH:7]=1
Reactant: CCO
Reactant: Cc1cc2c(=O)n(CCN3CCC(Nc4nc5ccccc5n4Cc4ccc(F)cc4)CC3)c(=S)[nH]c2s1
Agent: OO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1cc2c(=O)n(CCN3CCC(Nc4nc5ccccc5n4Cc4ccc(F)cc4)CC3)c(=O)[nH]c2s1
Reaction time: 8 h
Yield: 55 %

Procedure:
To a stirred mixture of 4.1 parts of 3-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-2,3-dihydro-6-methyl-2-thioxothieno[2,3-d]pyrimidin-4(1H)-one, 5.6 parts of potassium hydroxide, 81 parts of ethanol and 8 parts of water were added dropwise 60 parts of a hydrogen peroxide solution 3%. The whole was stirred overnight. The reaction mixture was evaporated. the residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2-propanone. The product was filtered off and dried, yielding 2.2 parts (55%) of 3-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-6-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione; mp. 187.6° C. (compound 135).
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH3:15])[C:13]4[CH:16]=[CH:17][C:18]([C:20]([OH:22])=O)=[CH:19][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.[CH3:25][O:26][CH2:27][CH2:28][NH2:29].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:25][O:26][CH2:27][CH2:28][NH:29][C:20]([C:18]1[CH:17]=[CH:16][C:13]2[N:14]([CH3:15])[C:10]([NH:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([F:1])[CH:24]=[CH:23][C:5]=4[N:6]=3)=[N:11][C:12]=2[CH:19]=1)=[O:22]
Reactant: COCCN
Reactant: Cn1c(Nc2nc3ccc(F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COCCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(F)cc3s1)n2C

Procedure:
2-(6-Fluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylic acid (2-methoxy-ethyl)-amide (29 mg) was prepared by following General Procedure F using 2-(6-fluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylic acid (34 mg), 2-methoxy-ethylamine (0.1 ml), HBTU (38 mg), and DIEA (0.1 ml). LCMS: m/z 401; and 1H NMR (DMSO-d6, 400 MHz): δ 8.44 (m, 1H), 8.06 (br, 1H), 7.76-7.70 (m, 2H), 7.66 (br, 1H), 7.45 (d, 1H), 7.20 (t, 1H), 3.61 (s, 3H), 3.44 (m, 4H), and 3.26 (s, 3H), —NH proton signal was not observed.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:14].[C:15](=[O:18])([O-])[O-:16].[K+].[K+]>CN(C)C=O>[NH2:14][C:3]1[CH:4]=[CH:5][C:6]([CH:8]2[CH2:13][CH2:12][N:11]([C:15]([O:16][C:6]([CH3:8])([CH3:7])[CH3:5])=[O:18])[CH2:10][CH2:9]2)=[CH:7][C:2]=1[Cl:1]
Reactant: Nc1ccc(C2CCNCC2)cc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(N)c(Cl)c2)CC1
Temperature: 25 °C

Procedure:
A mixture of the product of Example 60D (77 mg, 0.36 mmol), di-tert-butyl bicarbonate (80 mg, 0.37 mmol) and potassium carbonate (117 mg, 0.85 mmol) in N,N-dimethylformamide (4 mL) was stirred at ambient temperature until TLC indicated no starting material remained. The mixture was concentrated and the residue was purified by flash chromatography on silica gel (200-300 mesh) eluting with 8/1 petroleum/ethyl acetate to provide the title compound. MS: 310 (M+H+).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[OH-].[K+].[C:18]1([OH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCOCC>[O:24]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[CH:5]=[CH:4][N:3]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Oc1ccccc1
Reactant: FC(F)(F)c1ccc2ccnc(Cl)c2c1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Product: FC(F)(F)c1ccc2ccnc(Oc3ccccc3)c2c1
Temperature: 25 °C

Procedure:
A mixture of 1-chloro-7-(trifluoromethyl)isoquinoline (1.5 g, 6.5 mmol), from above step C, KOH (0.73 g, 13 mmol) and phenol (6.1 g, 65 mmol) were heated at 100° C. for 72 h. The resulting mixture was cooled to room temperature and taken in Et2O and extracted with 4N NaOH (x3). The organic fraction was washed with water, saturated NaCl, dried over Na2SO4 and evaporated to give the title compound.