Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([OH:7])[CH:6]=CC=C[CH:2]=1.CNC(=NC)O[C:12]([CH3:15])([CH3:14])[CH3:13].[C:18](OCC)(=O)C.CCCCCC>>[C:12]([O:7][C:1]([CH3:2])([CH3:6])[CH3:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CN=C(NC)OC(C)(C)C
Reactant: CCOC(C)=O
Reactant: Oc1ccccc1
Solvent: CCCCCC
Product: CC(C)(C)OC(C)(C)C
Yield: 15 %

Procedure:
Following a procedure analogous to (3b), the phenol from (3a) (270 mg, 0.97 mmol) was reacted with N,N′-dimethyl-O-t-butylisourea. Silica gel chromatography (ethyl acetate-hexane, 20:80) gave the t-butyl ether (50.2 mg, 15%) as a 1:1 mixture of two isomers. MS found: (M+H)+=334.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14]([O-:16])=[O:15])=[C:12]([CH3:17])[NH:11][C:10]([CH3:18])=[C:9]2[C:19]([O:21][CH2:22][CH2:23][C:24]#[N:25])=[O:20])[CH:5]=[CH:6][CH:7]=1.[C:26]1([CH:32]2[CH2:34][CH:33]2[CH2:35]O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl.CN(C)CCCN=C=NCC.O>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14]([O:16][CH2:35][CH:33]3[CH2:34][CH:32]3[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:15])=[C:12]([CH3:17])[NH:11][C:10]([CH3:18])=[C:9]2[C:19]([O:21][CH2:22][CH2:23][C:24]#[N:25])=[O:20])[CH:5]=[CH:6][CH:7]=1
Reactant: OCC1CC1c1ccccc1
Reactant: CC1=C(C(=O)[O-])C(c2cccc(Cl)c2)C(C(=O)OCCC#N)=C(C)N1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CC1=C(C(=O)OCCC#N)C(c2cccc(Cl)c2)C(C(=O)OCC2CC2c2ccccc2)=C(C)N1

Procedure:
306 mg (0.85 mmol) of mono(2-cyanoethyl) 4-(3-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate, 188 mg (1.27 mmol) of 2-phenylcyclopropylmethanol, 243 mg (1.27 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 23 mg (0.18 mmol) of 4-dimethylaminopyridine were stirred together in 10 ml of dichloromethane at room temperature for one hour. Water was added to the reaction liquid. After the extraction with dichloromethane, the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by the silica gel chromatography (hexane/ethyl acetate=2/1) to obtain the title compound.
Reaction SMILES: [H-].[Na+].[CH2:3]([CH2:13][NH2:14])[CH2:4][C:5]([NH2:12])([C:9]([OH:11])=[O:10])[CH:6]([F:8])[F:7].O.[ClH:16]>C1COCC1>[OH2:10].[ClH:16].[F:7][CH:6]([F:8])[C@@:5]([C:9]([OH:11])=[O:10])([CH2:4][CH2:3][CH2:13][NH2:14])[NH2:12]
Reactant: NCCCC(N)(C(=O)O)C(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: NCCC[C@](N)(C(=O)O)C(F)F
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Into a dry 100 ml three necked RB flask equipped with a stirrer, gas inlet and outlet arrangement methyl-2,5-di[1-(3,4-chlorophenyl) methylidene amino] pentanoate (2.0 g) and sodium hydride (0.21 g) in dry THF (20 ml) were added. The resulting suspension was stirred at 50° C. under a nitrogen atmosphere for 2 hrs. The reaction mixture was then cooled to 5° C. and the nitrogen inlet was replaced with chlorodifluoromethane gas tube. The gas was passed for about 45 mts. The reaction was stirred at RT and allowed to stand overnight. The reaction mixture was worked up by quenching with water and the pH was adjusted to 2 with aqueous HCl. The reaction mixture was extracted with MDC twice. The water layer was concentrated and taken up in methanol and chilled. The crystallized inorganic material was removed. The filtrate was concentrated and the residue taken up in 6N HCl and hydrolyzed. The resulting aqueous layer was evaporated. The crude product was dissolved in ethanol, chilled again to remove any inorganic material and further purified by water-acetone to give a product with a melting point (mp) 223–225° C. with spectral data such as NMR matching with material obtained in Example 8.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[NH:16]1[CH:20]=[C:19](B(O)O)[CH:18]=[N:17]1.[C:24](=[O:27])([O-])[O-:25].[K+].[K+]>CC#N.O.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>[C:24]([OH:25])(=[O:27])[CH3:2].[CH2:12]([NH:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([C:20]3[CH:19]=[CH:18][NH:17][N:16]=3)=[CH:3][N:4]=2)[N:7]=1)[CH2:13][CH2:14][CH3:15]
Reactant: OB(O)c1cn[nH]c1
Reactant: O=C([O-])[O-]
Reactant: CCCCNc1ccc2ncc(Br)n2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(=O)O
Product: CCCCNc1ccc2ncc(-c3cc[nH]n3)n2n1
Temperature: 140 °C
Yield: 2.8 %

Procedure:
A mixture of 3-bromo-6-(butylamino)imidazo[1,2-b]pyridazine (100 mg, 0.38 mmol), (1H-pyrazol-4-yl)boronic acid (45 mg, 0.38 mmol), PdCl2(PPh3)2 (10 mg, 0.014 mmol) and potassium carbonate (98 mg, 0.71 mmol) was dissolved in CH3CN (3 mL) and water (1.5 mL). The reaction was heated at 140° C. for 30 min in the microwave. The catalyst was filtered off celite, then the filtrate was concentrated and purified by Prep HPLC (neutral) to give N-butyl-3-(1H-pyrazol-3-yl)imidazo[1,2-b]pyridazin-6-amine acetate salt as yellow solid (1.7 mg, 2% yield): 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.12 (s, 1H), 7.86-7.92 (m, 2H), 7.30 (d, J=2.53 Hz, 1H), 7.17 (d, J=9.85 Hz, 1H), 3.47 (t, J=7.20 Hz, 2H), 1.75 (quin, J=7.26 Hz, 2H), 1.52 (sxt, J=7.43 Hz, 2H), 1.02 (t, J=7.33 Hz, 3H); LRMS (ESI) m/e 257.2 [(M+H)+, calcd for C13H17N6 257.3].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5](Cl)=[O:6].C(N(CC)CC)C.[NH2:19][C:20]1[CH:42]=[CH:41][C:23]([C:24]([N:26]2[CH2:32][C:31]3[CH:33]=[CH:34][CH:35]=[CH:36][C:30]=3[CH2:29][C:28]3[CH:37]=[CH:38][CH:39]=[CH:40][C:27]2=3)=[O:25])=[CH:22][CH:21]=1>C(Cl)Cl>[CH:37]1[C:28]2[CH2:29][C:30]3[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=3[CH2:32][N:26]([C:24]([C:23]3[CH:22]=[CH:21][C:20]([NH:19][C:5](=[O:6])[C:4]4[CH:3]=[C:2]([Cl:1])[CH:10]=[C:9]([Cl:11])[CH:8]=4)=[CH:42][CH:41]=3)=[O:25])[C:27]=2[CH:40]=[CH:39][CH:38]=1
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.7 %

Procedure:
A mixture of 301.6 mg of 3,5-dichlorobenzoyl chloride and 145 mg of triethylamine is stirred in 2 ml of methylene chloride while 314 mg of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine in 5 ml of methylene chloride is added. The reaction mixture is stirred at room temperature for 2 hours and 100 mg of 3,5-dichlorobenzoyl chloride added. The reactants are heated at reflux for 36 hours. The cooled reaction mixture layer washed with 1N HCl, water, 1N NaOH, water and brine. The organic layer is dried with Na2SO4 and passed through a short pad of hydrous magnesium silicate and hexane added to the filtrate at the boil to give 242 mg of the desired product as a crystalline solid, m.p. 263°-265° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]2.Cl[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]([NH2:24])=[O:23])[CH:17]=1>>[C:22]([C:18]1[CH:17]=[C:16]([O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]3)[CH:21]=[CH:20][N:19]=1)(=[O:23])[NH2:24]
Reactant: NC(=O)c1cc(Cl)ccn1
Reactant: O=C(O)c1cccc2cc(O)ccc12
Product: NC(=O)c1cc(Oc2ccc3c(C(=O)O)cccc3c2)ccn1

Procedure:
6-Hydroxy-1-napthoic acid (2.5 g, 13 mmol) was reacted with 4-chloropicolinamide (WO 02/085857)(2.6 g, 15 mmol) under the conditions of Example 421 Step a to give the title compound as a brown solid. MS (ESI, pos. ion) m/z: 309.2 (M+1). Mass Calc'd for C17H12N2O4: 308.29.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([O:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[C:14]([CH3:17])[CH:13]=[CH:12]2)[CH3:5].[Se](=O)=[O:19]>O1CCOCC1.O>[CH3:1][O:2][CH2:3][CH:4]([O:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[C:14]([CH:17]=[O:19])[CH:13]=[CH:12]2)[CH3:5]
Reactant: O=[Se]=O
Reactant: COCC(C)Oc1cccc2ccc(C)nc12
Solvent: O
Solvent: C1COCCO1
Product: COCC(C)Oc1cccc2ccc(C=O)nc12
Yield: 82.5 %

Procedure:
To 8-(1-methoxypropan-2-yloxy)-2-methylquinoline (1.0 g, 4.32 mmol) in dioxane/water (10/1 mL) was added selenium dioxide (0.576 g, 5.19 mmol) and the reaction was heated to reflux for 2 hours. The reaction was concentrated to dryness and the residue purified by reverse phase chromatography (SP4, 25M, eluting with a gradient of water/ACN 100:0 to 0:100, 20 column volumes) to yield 8-(1-methoxypropan-2-yloxy)quinoline-2-carbaldehyde (874 mg, 82.4% yield) as a solid
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([F:17])=[C:5]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][C:11]2=[O:16])[CH:6]=[C:7]([F:9])[CH:8]=1.[CH3:18][N:19]1[CH:23]=[C:22]([NH:24][C:25]2[N:30]=[C:29]3[NH:31][N:32]=[CH:33][C:28]3=[CH:27][N:26]=2)[CH:21]=[N:20]1>>[F:17][C:4]1[C:3]([CH2:2][N:31]2[C:29]3=[N:30][C:25]([NH:24][C:22]4[CH:21]=[N:20][N:19]([CH3:18])[CH:23]=4)=[N:26][CH:27]=[C:28]3[CH:33]=[N:32]2)=[CH:8][C:7]([F:9])=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][O:13][CH2:12][C:11]1=[O:16]
Reactant: Cn1cc(Nc2ncc3cn[nH]c3n2)cn1
Reactant: O=C1COCCN1c1cc(F)cc(CBr)c1F
Product: Cn1cc(Nc2ncc3cnn(Cc4cc(F)cc(N5CCOCC5=O)c4F)c3n2)cn1

Procedure:
The title compound was prepared as in Example 1 (Step ii) using 4-(3-(bromomethyl)-2,5-difluorophenyl)morpholin-3-one and N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine. 1H NMR (d6-DMSO) δ 9.90 (s, 1H), 8.93 (s, 1H), 8.13-8.05 (m, 2H), 7.56 (s, 1H), 7.48-7.42 (m, 1H), 7.14 (s, 1H), 5.63 (s, 2H), 4.23 (s, 2H), 3.99-3.93 (m, 2H), 3.83 (s, 3H), 3.70-3.63 (m, 2H); LC-MS method B, (ES+) 441, RT=6.82 min.
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24](OCC)=[O:25])[C:6]1=[O:29])[CH2:2][CH2:3][CH3:4].[NH2:30][CH2:31][CH2:32][N:33]([CH3:38])[S:34]([CH3:37])(=[O:36])=[O:35]>>[CH2:1]([N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24]([NH:30][CH2:31][CH2:32][N:33]([CH3:38])[S:34]([CH3:37])(=[O:36])=[O:35])=[O:25])[C:6]1=[O:29])[CH2:2][CH2:3][CH3:4]
Reactant: CN(CCN)S(C)(=O)=O
Reactant: CCCCn1c(=O)c(C(=O)OCC)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Product: CCCCn1c(=O)c(C(=O)NCCN(C)S(C)(=O)=O)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Yield: 55 %

Procedure:
In a similar manner to that described in example 196, from ethyl 1-butyl-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (30 mg, 0.075 mmol) and N-(2-aminoethyl)-N-methylmethanesulfonamide (excess) was prepared 1-butyl-7-[(4-fluorophenyl)methyl]-4-hydroxy-N-{2-[methyl(methylsulfonyl)amino]ethyl}-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (21 mg, 55% yield) as a white solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.41 (br s, 1 H), 8.55 (s, 1 H), 7.27 (s, 1 H), 7.17-7.13 (m, 2 H), 7.05-7.00 (m, 2 H), 4.13 (s, 2 H), 4.08 (m, 2 H), 3.65 (m, 2 H), 3.39 (m, 2 H), 2.94 (s, 3 H), 2.82(s, 3 H), 1.50 (m, 2 H), 1.33 (m, 2 H), 0.89 (m, 3 H); MS m/z 505 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=[C:5]2[N:4]=[C:3]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21][C:22]([F:25])([F:24])[F:23].ClC1C=CC=C(C(OO)=[O:34])C=1.C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[C:9]([C:11]([F:13])([F:14])[F:12])[CH:10]=[C:5]2[N:4]=[C:3]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([C:22]([F:25])([F:23])[F:24])=[O:34]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cn1c(-c2ccccc2SC(F)(F)F)nc2cc(C(F)(F)F)cnc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cn1c(-c2ccccc2S(=O)C(F)(F)F)nc2cc(C(F)(F)F)cnc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 52.8 %

Procedure:
To a mixture of 3-methyl-6-trifluoromethyl-2-(2-trifluoromethylsulfanylphenyl)-3H-imidazo[4,5-b]pyridine (0.80 g) and chloroform (7 ml), 3-chloroperbenzoic acid (purity: not less than 65%) (0.49 g) was added under ice-cooling. The mixture was heated to room temperature, stirred for 20 minutes, and then heated to 62° C., and stirred under reflux for 2 hours. Into the reaction mixture cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium thiosulfate solution were poured, and extracted with chloroform. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 0.44 g of 3-methyl-6-trifluoromethyl-2-(2-trifluoromethylsulfinylphenyl)-3H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 19).
Reaction SMILES: O.O.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].S(=O)(=O)(O)O.O.[OH:20][CH:21]1[CH2:26][CH2:25][CH:24]([CH:27]([C:32]([O:34][CH3:35])=[O:33])[C:28]([O:30][CH3:31])=[O:29])[CH2:23][CH2:22]1>C(OCC)C>[O:20]=[C:21]1[CH2:26][CH2:25][CH:24]([CH:27]([C:28]([O:30][CH3:31])=[O:29])[C:32]([O:34][CH3:35])=[O:33])[CH2:23][CH2:22]1
Reactant: COC(=O)C(C(=O)OC)C1CCC(O)CC1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: COC(=O)C(C(=O)OC)C1CCC(=O)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
At 5° C., a mixture of 22.7 g of sodium dichromate dihydrate, 17 ml of concentrated sulfuric acid and 113 ml of water was added dropwise to a solution of 47.7 g of dimethyl (4-hydroxycyclohexyl)malonate in 250 ml of diethyl ether. The mixture was stirred at room temperature for 4 hours, the organic phase was separated off and the aqueous phase was once more extracted with diethyl ether. The combined organic phases were dried and concentrated to give the title product as a yellow oil which was used without any further purification for the next step.
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)(=[O:5])=[O:4].Cl[C:27]1[N:32]=[CH:31][C:30]([CH2:33][CH3:34])=[CH:29][N:28]=1.C(N(C(C)C)CC)(C)C>CN1C(=O)CCC1.CCOC(C)=O>[CH2:33]([C:30]1[CH:29]=[N:28][C:27]([N:23]2[CH2:24][CH2:25][CH:20]([CH2:19][O:18][C:15]3[CH:16]=[CH:17][C:12]([C:9]4[CH:8]=[CH:7][C:6]([S:3]([CH3:2])(=[O:5])=[O:4])=[CH:11][CH:10]=4)=[CH:13][CH:14]=3)[CH2:21][CH2:22]2)=[N:32][CH:31]=1)[CH3:34]
Reactant: CS(=O)(=O)c1ccc(-c2ccc(OCC3CCNCC3)cc2)cc1
Reactant: CCc1cnc(Cl)nc1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cnc(N2CCC(COc3ccc(-c4ccc(S(C)(=O)=O)cc4)cc3)CC2)nc1
Temperature: 80 °C
Yield: 34.4 %

Procedure:
A mixture of 4-({[4′-(methylsulfonyl)-4-biphenylyl]oxy}methyl)piperidine hydrochloride (70 mg, 0.18 mmol), 2-chloro-5-ethylpyrimidine (30 μL, 0.24 mmol) and diisopropylethylamine (0.10 mL, 0.55 mmol) in NMP (3 mL) was heated at 80° C. overnight. After more 2-chloro-5-ethylpyrimidine (0.1 mL) was added, the reaction mixture was heated at 80° C. for 4 h. The mixture was cooled to ambient temperature, and was diluted with EtOAc, washed with water and brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as a brown oil. The crude product was purified by chromatography on a silica gel column eluted with 50% EtOAc/hexane followed by trituration with hot hexanes containing 1% MeOH to give 28 mg (34%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.18 (bs, 2H), 7.96 (d, 2H, J=8.3 Hz), 7.72 (d, 2H, J=8.5 Hz), 7.54 (d, 2H, J=8.8 Hz), 6.99 (d, 2H, J=8.8 Hz), 4.85-4.70 (m, 2H), 3.88 (d, 2H, J=6.3 Hz), 3.08 (s, 3H), 3.00-2.85 (m, 2H), 2.55-2.40 (m, 2H), 2.20-2.05 (m, 1H), 2.00-1.90 (m, 2H), 1.45-1.30 (m, 2H), 1.19 (t, 3H, J=7.5 Hz); LRMS (ESI), m/z 452 (M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1.[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][C:26]=2[OH:28])[CH:21]=[CH:20][N:19]=1>>[F:15][C:14]([F:17])([F:16])[C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:5]=[CH:4][N:3]=[C:2]([O:28][C:26]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:27]=3[CH:18]=[N:19][CH:20]=[CH:21]4)[CH:7]=2)=[CH:9][CH:10]=1
Reactant: Oc1cccc2ccncc12
Reactant: FC(F)(F)c1ccc(-c2cc(Cl)ncn2)cc1
Product: FC(F)(F)c1ccc(-c2cc(Oc3cccc4ccncc34)ncn2)cc1

Procedure:
The title compound was prepared from 4-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine (Example 2(a), Method A) and isoquinolin-8-ol (MonomerChem) under the conditions of Example 6. Mp: 194-195° C. MS (ESI, pos. ion) m/z: 368.2 (M+1).
Reaction SMILES: N1C=CN=C1.Cl[Si:7]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9].[F:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([O:27][CH3:28])[C:25]=1[OH:26])[CH:21]=[O:22].O>CN(C=O)C.C(OCC)(=O)C>[F:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([O:27][CH3:28])[C:25]=1[O:26][Si:7]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])[CH:21]=[O:22]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: COc1cc(C=O)cc(F)c1O
Agent: c1c[nH]cn1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(C=O)cc(F)c1O[Si](C(C)C)(C(C)C)C(C)C

Procedure:
After adding 0.52 g of imidazole and 1.49 ml of chlorotriisopropylsilane to a solution of 1.0 g of 3-fluoro-5-methoxy-4-hydroxybenzaldehyde [CAS No. 79418-78-3] in 15 ml of DMF, the mixture was stirred at room temperature for 17 hours. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with dilute hydrochloric acid and saturated brine, and then dried over anhydrous sodium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (1.67 g) as a colorless oil.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:15])([F:14])[C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11]([NH2:13])=[O:12].[CH2:16]([N:23]=[C:24]=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Br[CH2:27][C:28](OC)=[O:29]>CN(C)C=O.O.C(OCC)(=O)C>[CH2:16]([N:23]1[C:28](=[O:29])[CH2:27][N:13]([C:11]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[C:4]([F:3])([F:14])[F:15])=[O:12])[C:24]1=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C=NCc1ccccc1
Reactant: COC(=O)CBr
Reactant: NC(=O)c1cnccc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1CN(C(=O)c2cnccc2C(F)(F)F)C(=O)N1Cc1ccccc1
Reaction time: 1 h

Procedure:
Sodium hydride (0.090 g, 60% dispersion in mineral oil) was added to a solution of 4-trifluoromethyl-3-pyridinecarboxamide (0.40 g) in N,N-dimethylformamide at 20° C., and stirred for 1 hour. Benzyl isocyanate (0.31 ml) was added and the mixture stirred at 20° C. for 2 hours, then methyl bromoacetate (0.30 ml) added and stirring continued for 5 hours. Ethyl acetate and water were added to the solution and the organic phase dried (magnesium sulfate), evaporated and the residue purified by column chromatography on silica gel, eluting with n-hexane/ethyl acetate (2:1), to give 3-benzyl-1-(4-trifluoromethyl-3-pyridylcarbonyl)hydantoin (0.50 g, Compound S-132).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)=O)(C)(C)C.[ClH:34].CCOCC>O1CCOCC1>[ClH:34].[NH:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)=[CH:24][CH:23]=2)=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Cc2ccc(-c3ccncc3)cc2)cc1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: c1cc(-c2ccc(Cc3ccc(OC[C@H]4CCCN4)cc3)cc2)ccn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
To a 20 mL vial which contained a solution of (R)-2-[4-(4-Pyridin-4-yl-benzyl)-phenoxymethyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (65 mg, 0.15 mmol) in dioxane (1 mL) was added HCl (4 N in dioxane 2 mL) at 0° C. The mixture was allowed to warm to rt and stir at rt for 16 h. The solvent was reduced to 1 mL and ether (15 mL) was added to this vial. the resulting solid was filtered out and dried in vacuo to yield the title product (35 mg, 80%); LCMS; 97%, APCI+, Calcd: 344.5; Found m/z: 345.8 (M+1); 1H NMR (500 MHz, DMSO-d6); δ 1.66-1.76 (m, 1H), 1.84-2.02 (m, 2H), 2.06-2.15 (m, 1H), 3.14-3.26 (m, 2H), 3.87 (br, 1H), 4.00 (s, 2H), 4.09-4.19 (m, 1H), 4.21 (dd, J1=11.0, J2=4.0, 1H), 6.93 (d, J=8.5 Hz, 2H), 7.23 (d, J=8.5 Hz, 2H), 7.45 (d, J=8.0 Hz, 2H), 7.94 (d, J=8.5 Hz, 2H), 8.27 (d, J=6.0 Hz, 2H), 8.89 (d, J=6.0 Hz, 2H):
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:9])=[CH:6][N:5]=[C:4]([Cl:16])[C:3]=1[Cl:17].[CH:18]([O-])([O-])[O:19][CH2:20][CH3:21].C(OC(=O)C)(=O)C>>[Cl:1][C:2]1[C:7]([C:8]([C:10](=[CH:18][O:19][CH2:20][CH3:21])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:9])=[CH:6][N:5]=[C:4]([Cl:16])[C:3]=1[Cl:17]
Reactant: CCOC(=O)CC(=O)c1cnc(Cl)c(Cl)c1Cl
Reactant: CCOC([O-])[O-]
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)C(=O)c1cnc(Cl)c(Cl)c1Cl

Procedure:
87.0 g (0.29 mol) of ethyl 2-(4,5,6-trichloronicotinoyl)acetate are heated with 56.2 g of (0.38 mol) of ethyl orthoformate and 65.2 g of acetic anhydride at 150°-160° C. for two hours. All volatile components are removed, initially in vacuo and then under a high vacuum up to 100° C.
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][C:5]([C:15]([OH:17])=O)=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1.ClC([N:23](C)C)=C(C)C.NC[CH2:28][C:29]([CH:32]1[CH2:34][CH2:33]1)([OH:31])[CH3:30].C(N(C(C)C)C(C)C)C>ClCCl>[CH:32]1([C:29]([OH:31])([CH3:30])[CH2:28][NH:23][C:15]([C:5]2[CH:4]=[N:3][C:2]([Br:1])=[C:7]([C:8]3[CH:9]=[CH:10][C:11]([F:14])=[CH:12][CH:13]=3)[N:6]=2)=[O:17])[CH2:34][CH2:33]1
Reactant: O=C(O)c1cnc(Br)c(-c2ccc(F)cc2)n1
Reactant: CC(O)(CCN)C1CC1
Reactant: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(O)(CNC(=O)c1cnc(Br)c(-c2ccc(F)cc2)n1)C1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.9 %

Procedure:
To a solution of 0.78 g of 5-bromo-6-(4-fluoro-phenyl)-pyrazine-2-carboxylic acid in 15.0 ml dichloromethane was added at room temperature 0.39 g (1-chloro-2-methyl-propenyl)-dimethyl-amine and the mixture was stirred for 0.5 hours at room temperature. To the resulting white suspension was added 0.333 g 4-amino-2-cyclopropyl-butan-2-ol and 0.45 ml N-ethyldiisopropylamine and the mixture was stirred for 2 hours at room temperature. The resulting mixture was partitioned between 10% aqueous citric acid and dichloromethane. The phases were separated and the organic layer was dried over magnesium sulfate and evaporated. The residue was purified by chromatography on silica gel using a gradient of heptane to 25% ethyl acetate in heptane to yield 0.70 g of the title compound as white crystals. MS (ISP) (M+H+)=394.1 and 396.0.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:10][C:11]1[C:12]([Cl:29])=[N:13][C:14]([N:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C@@H:19]2[CH3:28])=[N:15][C:16]=1[CH3:17]>CN(C)C=O>[ClH:29].[CH3:10][C:11]1[C:12]([NH:4][C:3]2[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:2]=2[CH3:1])=[N:13][C:14]([N:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C@@H:19]2[CH3:28])=[N:15][C:16]=1[CH3:17]
Reactant: Cc1nc(N2CCc3ccccc3[C@@H]2C)nc(Cl)c1C
Reactant: Cc1cc(F)ccc1N
Solvent: CN(C)C=O
Product: Cc1cc(F)ccc1Nc1nc(N2CCc3ccccc3[C@@H]2C)nc(C)c1C
Product: Cl
Yield: 69.2 %

Procedure:
After 2-methyl-4-fluoroaniline(0.82 ml, 7.35 mmol) was added to a mixture solution of (S)-5,6-dimethyl-2-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-4-chloropyrimidine(1.0 g, 3.5 mmol) obtained in the above Step 2 and dimethylformamide (10 ml), 1.0 g of the titled compound was obtained in accordance with the same procedure as in Step 4 of Example 57.