Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([O:18][C:19]([N:21]1[CH2:25][C@H:24]([CH2:26][OH:27])[C@H:23]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:22]1)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl.C(N(CC)CC)C>[CH2:11]([O:18][C:19]([N:21]1[CH2:25][CH:24]([CH:26]=[O:27])[C@H:23]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:22]1)=[O:20])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1CO
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1CN(C(=O)OCc2ccccc2)CC1C=O
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
Dimethyl sulfoxide (5.10 mL, 59.3 mmol) was added to a solution of oxalylchloride (5.00 mL, 57.3 mmol) in dichloromethane (100 mL), and the mixture was stirred at −78° C. for 20 minutes. Subsequently, a solution of (3S,4S)-1-benzyloxycarbonyl-3-(tert-butoxycarbonyl)amino-4-hydroxymethylpyrrolidine (8.00 g, 22.8 mmol) in dichloromethane (85 mL) was added dropwise slowly thereto, followed by stirring at the same temperature for 30 minutes, and further at −43° C. for 1 hour. Subsequently, triethylamine (30 mL) was added thereto, and the temperature of the resultant mixture was elevated to an ice cooling temperature, followed by stirring for 45 minutes. Thereafter, a 10% aqueous citric acid solution (100 mL) was added to the resultant mixture, followed by stirring for 10 minutes. The obtained aqueous layer was extracted with dichloromethane (200 mL×2). The combined organic layer was washed by saturated brine (100 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, to thereby yield a crude aldehyde as a pale yellow oily substance. Subsequently, triethylamine (0.50 mL, 3.59 mmol) was added to a solution of the crude aldehyde compound (2.5 g, 7.18 mmol) in dichloromethane (10 mL). The resultant mixture was stirred at room temperature for 24 hours, and triethylamine (0.50 mL, 3.59 mmol) was further added thereto, followed by stirring for another 24 hours. Thereafter, silica gel (100 g) was added to the reaction mixture, followed by stirring for 24 hours. The reaction mixture was concentrated under reduced pressure, and left to stand for 24 hours. The residue was purified through silica gel column chromatography (ethyl acetate:n-hexane=7:3), to thereby yield the title compound (an isomer mixture of (4S)-form and (4R)-form (1:3)) as a colorless oily substance (750 mg, 28%).
Reaction SMILES: [C:1]([F:6])(F)=[C:2](Cl)F.[NH:7]1C=C[C:11](N)=[N:10][C:8]1=[O:9].FF.[OH2:17]>>[F:6][C:1]1[C:2](=[O:17])[NH:7][C:8](=[O:9])[NH:10][CH:11]=1
Reactant: O
Reactant: Nc1cc[nH]c(=O)n1
Reactant: FC(F)=C(F)Cl
Agent: FF
Product: O=c1[nH]cc(F)c(=O)[nH]1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Into a "Daiflon" resin (polytriflurochloroethylene manufactured by Daikin Kogyo, Co., Ltd.) made flask equipped with a stirrer, a cooler, a gas inlet and a therometer, a solution of cytosine (1.11 g; 10 mmol) in water (50 ml) was charged, and fluorine gas (34%; diluted with nitrogen) was blown therein at 18° to 20° C. until the cytosine was consumed completely. The reaction was finished in 60 minutes, and the total amount of fluorine used was 35 mmol. The reaction mixture (pH, <1) was adjusted to pH 6.0 with an aqueous solution of sodium hydroxide and heated at 80° C. for 4 hours. After removal of the solvent while heating under reduced pressure, the residual pale brown solid was extracted with ethanol and recrystallized from water to give 5-fluorouracil (0.85 g). Yield, 65%. M.P. 282°-283° C. (decomp.). UV absorption spectrum: λmaxpH 2 266 nm; λmaxpH 10.5 269 nm. Thin layer chromatography: Rf 0.60. Paper chromatography: Rf 0.54.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9](Cl)=[N:10][OH:11].[Cl:13][CH:14]([Cl:26])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]#[CH:25])=[CH:20][CH:19]=1)=[O:16]>C1COCC1.C(N(CC)CC)C>[Cl:13][CH:14]([Cl:26])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[O:11][N:10]=[C:9]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])[CH:25]=2)=[CH:20][CH:19]=1)=[O:16]
Reactant: ON=C(Cl)c1c(Cl)cccc1Cl
Reactant: C#Cc1ccc(NC(=O)C(Cl)Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccc(-c2cc(-c3c(Cl)cccc3Cl)no2)cc1)C(Cl)Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,6-Dichloro-N-hydroxybenzenecarboximidoyl chloride (1.01 g, 4.5 mmol) and 2,2-dichloro-N-(4-ethynylphenyl)acetamide (1.01 g, 4.42 mmol) were dissolved in anhydrous THF (40 mL) and triethylamine (1.0 mL). The mixture was stirred at room temperature for 1 h then heated at reflux for 4 h to generate the 2,6-dichlorophenyl nitrile oxide intermediate, which reacted by a 1,3-dipolar cycloaddition reaction with 2,2-dichloro-N-(4-ethynylphenyl)acetamide. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed successively with water and brine. The ethyl acetate solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting solid was purified by column chromatography on silica gel, eluting with 8:2 hexanes-ethyl acetate. The appropriate fractions were combined to give 2,2-dichloro-N-[4-[3-(2,6-dichlorophenyl)-5-isoxazolyl]phenyl]acetamide as a tan solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][N:12]([CH3:34])[C:13]1[C:22](/[CH:23]=[CH:24]/[CH2:25][OH:26])=[C:21]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1.C(N(CC)CC)C.[Cl-].[NH4+]>ClCCl>[CH3:34][N:12]([CH3:11])[C:13]1[C:22](/[CH:23]=[CH:24]/[CH:25]=[O:26])=[C:21]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1
Reactant: CN(C)c1nc2ccccc2c(-c2ccc(F)cc2)c1/C=C/CO
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CN(C)c1nc2ccccc2c(-c2ccc(F)cc2)c1/C=C/C=O
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 91.6 %

Procedure:
To a solution of oxalyl chloride (1.21 ml, 1.3 equivalents), in 40 ml of dichloromethane at -78° C. under an atmosphere of nitrogen, is added a solution of 2.0 ml (2.6 equivalents) of dimethylsulfoxide in 25 ml of dichloromethane. The reaction is stirred at -78° C. for 15 minutes and 3.45 g of (E)-3-[2-(dimethylamino)-4-(4-fluorophenyl)-3-quinolinyl]-2-propen-1-ol in 40 ml of dichloromethane added dropwise. The reaction is stirred for one hour at -78° C. and then quenched by adding 7.46 ml (5.0 equivalents) of triethylamine and warming to room temperature. A saturated aqueous solution of ammonium chloride, 20 ml, is added and the reaction is washed with water, dried (magnesium sulfate), and evaporated to give 3.14 g of (E)-3-[2-(dimethylamino)-4-(4-fluorophenyl)-3-quinolinyl]-2-propenal as an orange solid; 1H NMR (chloroform-d): δ 9.35 (d, 1H), 7.75 (d, 1H), 7.58-6.98 (m, 8H), 6.32 (dd, 1H), 2.99 (s, 6H) ppm.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:21][CH2:22]CCCCC=CCCC.C([N:34]1[CH2:38][CH2:37][CH:36]([NH2:39])[CH2:35]1)C>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:34]4[CH2:38][CH2:37][CH:36]([NH:39][CH2:21][CH3:22])[CH2:35]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCCC=CCCCCCC
Reactant: CCN1CCC(N)C1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Solvent: CC#N
Product: CCNC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Reaction time: 8 h

Procedure:
To 0.80 g (2.8 mmol) of the 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in 10 ml of acetonitrile and 0.43 g (2.8 mmol) of 1,8-diazobicyclo [5.4.0], undec-7-ene was added 0.35 g (3.1 mmol) of the N-ethyl-3-aminopyrrolidine. The mixture was refluxed for one hour and stirred overnight. The solids were filtered and washed with ether: acetonitrile (6:1), to give 0.81 g of the title compound, mp 236°-238° C.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[H][H]>[Ni]>[OH:12][CH2:11][C@@H:9]([C@H:7]([C@@H:5]([C@@H:3]([CH2:2][OH:1])[OH:4])[OH:6])[OH:8])[OH:10].[CH2:11]([OH:12])[C@H:9]([C@H:7]([C@@H:5]([C@@H:3]([CH2:2][OH:1])[OH:4])[OH:6])[OH:8])[OH:10]
Reactant: [H][H]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Ni]
Product: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Product: OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
A mixture of 60 ml of a 45 percent aqueous solution of glucose containing 6 g of a 10 percent nickel on titanium dioxide catalyst, reduced at 250° C., was reacted with hydrogen at 700 psig and 120° C. for 5 hours. The cooled reaction mixture was then analyzed by high pressure liquid chromatography which showed that 98 percent of the glucose had reacted to afford as the only two products sorbitol and mannitol with selectivity of 95 percent and 3 percent respectively.
Reaction SMILES: CCN=C=[N:5][CH2:6][CH2:7][CH2:8]N(C)C.Cl.[C:13]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][C:20]([OH:22])=O)[CH:14]=1.C(N)CC.C1C=CC2N(O)N=NC=2C=1>CC#N.CCOC(C)=O>[C:13]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][C:20]([NH:5][CH2:6][CH2:7][CH3:8])=[O:22])[CH:14]=1
Reactant: O=C(O)Cc1cccc(-c2ccccc2)c1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCCN
Product: CCCNC(=O)Cc1cccc(-c2ccccc2)c1
Reaction time: 72 h

Procedure:
EDAC.HCl (114 mg, 0.59 mmol) was added to a mixture of compound 91C (125 mg, 0.59 mmol), propylamine (49 μL, 0.59 mmol) and HOBT (80 mg, 0.59 mmol) in 1 mL of CH3CN. The reaction was stirred for 72 hours. After this time, the mixture was diluted with AcOEt. The organic layer was washed three times with HCl 2N, three times with NaOH 2N, dried over MgSO4 and concentrated. A with solid was obtained (100 mg, 67%). NMR 1H (ppm, CDCl3): 7.57 (d., J3=7.05 Hz, 2H), 7.52-7.32 (m, 6H), 7.23 J3=7.94 Hz, 1H), 5.65 (br. s., 1H), 3.62 (s, 2H), 3.20-3.13 (m, 2H), 1.44 (sex. J3=7.21 Hz, 2H), 0.83 (t, J3=7.43 Hz, 3H). NMR 13C (ppm, CDCl3): 170.9, 141.9, 140.5, 135.5, 129.3, 128.8, 128.2, 127.5, 127.0, 126.0, 43.8, 41.3, 22.7, 11.2. MS (+ESI): M+H+: 254.3.
Reaction SMILES: [CH3:1][S:2]([C:4]1[S:8][C:7]([N:9]=[C:10]=[O:11])=[N:6][N:5]=1)=[O:3].[CH2:12]([NH:16][CH:17]([CH2:20][O:21][CH3:22])[CH:18]=[O:19])[CH2:13][CH2:14][CH3:15]>C1C=CC=CC=1>[CH2:12]([N:16]([CH:17]([CH2:20][O:21][CH3:22])[CH:18]=[O:19])[C:10]([NH:9][C:7]1[S:8][C:4]([S:2]([CH3:1])=[O:3])=[N:5][N:6]=1)=[O:11])[CH2:13][CH2:14][CH3:15]
Reactant: CS(=O)c1nnc(N=C=O)s1
Reactant: CCCCNC(C=O)COC
Solvent: c1ccccc1
Product: CCCCN(C(=O)Nc1nnc(S(C)=O)s1)C(C=O)COC

Procedure:
5-Methylsulfinyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the dimethyl acetal of 2-butylamino-3-methoxypropionaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux for a period of about 30 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. This residue is then recrystallized to yield the desired product the dimethyl acetal of 2-[1-butyl-3-(5-methylsulfinyl-1,3,4-thiadiazol-2-yl)ureido]-3-methoxypropionaldehyde.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]=O)=[CH:10][C:5]=2[C:4]([CH3:14])([CH3:13])[O:3]1.[NH2:15][OH:16].Cl.CC([O-])=O.[Na+]>C1COCC1.O>[OH:1][B:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]=[N:15][OH:16])=[CH:10][C:5]=2[C:4]([CH3:14])([CH3:13])[O:3]1
Reactant: NO
Reactant: CC1(C)OB(O)c2ccc(C=O)cc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)OB(O)c2ccc(C=NO)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 102.5 %

Procedure:
To a mixture of 1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbaldehyde (560 mg, 2.95 mmol) and NH2OH.HCl (246 mg, 3.54 mmol) in THF (6 mL) and H2O (1.5 mL) at rt was added NaOAc (339 mg, 4.13 mmol). The reaction mixture was stirred at rt for 16 h, diluted with H2O and extracted with EA (10 mL×2). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the desired product (620 mg, 100% yield) as a white solid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([Cl:12])[CH:3]=1.[CH3:13][C:14]([CH3:18])([CH3:17])[C:15]#[CH:16]>CCN(CC)CC.CN(C=O)C.[Cu]I.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>[Cl:12][C:4]1[CH:3]=[C:2]([C:16]#[C:15][C:14]([CH3:18])([CH3:17])[CH3:13])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: C#CC(C)(C)C
Reactant: COC(=O)c1ccc(Br)cc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C#CC(C)(C)C)cc1Cl
Temperature: 100 °C
Yield: 82.3 %

Procedure:
A mixture of methyl 4-bromo-2-chlorobenzoate (400 mg, 0.0016 mol), copper(I) iodide (30 mg, 0.00016 mol), 3,3-dimethyl-1-butyne (0.29 mL, 0.0024 mol) and bis(triphenylphosphine)palladium(II) chloride (110 mg, 0.00016 mol) in Et3N (5 mL) and DMF (2 mL) was heated at 100° C. in a 50 mL sealed reaction vessel for 32 hours. After cooling, the mixture was filtered through Celite® and the filter cake was washed repeatedly with ethyl acetate. The organic phase was washed with brine, dried (Na2SO4), and concentrated under vacuum. The residue was purified by column chromatography on silica gel to give the product (330 mg, 82%) as a light yellow oil.
Reaction SMILES: Cl.[F:2][C:3]([F:15])([F:14])[C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][NH:10][CH2:11]2)=[CH:6][CH:5]=1.[O:16]=[C:17]1[C:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:20][CH2:19][N:18]1[CH2:34][CH:35]=O.C([BH3-])#N.[Na+]>CO>[C:28]1([C:21]2([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:20][CH2:19][N:18]([CH2:34][CH2:35][N:10]3[CH2:9][CH2:8][C:7]4[C:12](=[CH:13][C:4]([C:3]([F:2])([F:14])[F:15])=[CH:5][CH:6]=4)[CH2:11]3)[C:17]2=[O:16])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=CCN1CCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: FC(F)(F)c1ccc2c(c1)CNCC2
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: O=C1N(CCN2CCc3ccc(C(F)(F)F)cc3C2)CCC1(c1ccccc1)c1ccccc1
Reaction time: 8 h

Procedure:
A solution of 7-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (0.153 g, 0.644 mmol), the product from Example 67B (0.120 g, 0.430 mmol) and sodium cyanoborohydride (0.040 g, 0.644 mmol) were stirred together in methanol (0.5 mL) at room temperature. After stirring overnight, the reaction was concentrated, dissolved in minimal dichloromethane and was loaded directly onto a SF15-12 column (Analogix®, Burlington, Wis.), and the title compound was eluted using a gradient of 5% to 100% ethyl acetate/hexanes over 20 minutes (flow=30 mL/minute). 1H NMR (300 MHz, CDCl3) δ ppm 7.36-7.42 (m, 1H), 7.29-7.34 (m, 4H), 7.18-7.26 (m, 2H), 7.12-7.18 (m, 6H), 3.66 (s, 2H), 3.63 (t, J=6.2 Hz, 2H), 3.44 (t, J=6.4 Hz, 2H), 2.69-2.84 (m, 8H); MS (ESI+) m/z 465 (M+H)+.
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:15][CH:16]1[CH:21]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([Cl:29])[CH:23]=2)[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]1>>[Cl:29][C:24]1[CH:23]=[C:22]([CH:21]2[CH2:20][CH2:19][NH:18][CH2:17][CH:16]2[NH:15][C:2]2[C:3]3[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH:27]=[CH:26][C:25]=1[F:28]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(F)c(Cl)c2)C(N)C1
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Product: NC(=O)c1ccnc2c(NC3CNCCC3c3ccc(F)c(Cl)c3)ncnc12

Procedure:
Compound 23 was prepared following general synthesis scheme 9 wherein 4-hydroxy-pyrido[3,2-d]pyrimidine-8-carboxylic acid amide was reacted with tert-butyl 3-amino-4-(3-chloro-4-fluoro-phenyl)piperidine-1-carboxylate to give the title compound. LC-MS [401 (M+H)].
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[S:22][CH:21]=[CH:20][N:5]2[C:6](=[O:19])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1.[CH3:23][O:24][C:25]1[C:26]([O:33][CH2:34][CH2:35][CH3:36])=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH:28]=O.[O-]CC.[Na+]>C(O)C>[CH3:23][O:24][C:25]1[C:26]([O:33][CH2:34][CH2:35][CH3:36])=[C:27](/[CH:28]=[CH:1]/[C:2]2[N:3]=[C:4]3[S:22][CH:21]=[CH:20][N:5]3[C:6](=[O:19])[C:7]=2[C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:17])([F:18])[F:16])=[CH:10][CH:9]=2)[CH:30]=[CH:31][CH:32]=1
Reactant: Cc1nc2sccn2c(=O)c1-c1ccc(OC(F)(F)F)cc1
Reactant: CCCOc1c(C=O)cccc1OC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCOc1c(/C=C/c2nc3sccn3c(=O)c2-c2ccc(OC(F)(F)F)cc2)cccc1OC
Yield: 47.9 %

Procedure:
The title compound was prepared by condensation of Intermediate 15 (400 mg, 1.225 mmol) with 3-methoxy-2-propoxybenzaldehyde (333 mg, 1.716 mmol) in the presence of sodium ethoxide (176 mg, 2.301 mmol) in ethanol (25 ml) according to the procedure outlined in Example 24 to give 295 mg of the desired product as a light yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 0.94 (t, J=7.2 Hz, 3H), 1.53 (q, J=6.9 Hz, 2H), 3.31 (s, 1H), 3.77 (s, 3H), 3.80 (s, 1H), 6.91-6.99 (m, 4H), 7.40-7.46 (m, 4H), 7.50 (d, J=4.8 Hz, 1H), 7.95-8.07 (m, 2H); ESI-MS (m/z) 503.51 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=O)=[CH:12][CH:13]=2)[C:8]([Cl:17])=[N:7]1.[OH:28][CH2:29][C@H:30]1[O:35][CH2:34][CH2:33][N:32]([C:36]2[S:37][CH2:38][C:39](=[O:41])[N:40]=2)[CH2:31]1>>[F:27][C:2]([F:1])([F:26])[C:3]1[CH:21]=[C:20]([C:22]([F:23])([F:25])[F:24])[CH:19]=[CH:18][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:38]3[S:37][C:36]([N:32]4[CH2:33][CH2:34][O:35][C@H:30]([CH2:29][OH:28])[CH2:31]4)=[N:40][C:39]3=[O:41])=[CH:12][CH:13]=2)[C:8]([Cl:17])=[N:7]1
Reactant: O=C1CSC(N2CCO[C@H](CO)C2)=N1
Reactant: O=Cc1ccc2c(c1)c(Cl)nn2Cc1ccc(C(F)(F)F)cc1C(F)(F)F
Product: O=C1N=C(N2CCO[C@H](CO)C2)SC1=Cc1ccc2c(c1)c(Cl)nn2Cc1ccc(C(F)(F)F)cc1C(F)(F)F

Procedure:
5-[1-(2,4-Bis-trifluoromethyl-benzyl)-3-chloro-1H-indazol-5-ylmethylene]-2-(2-(S)-hydroxymethyl-morpholin-4-yl)-thiazol-4-one was prepared from 1-(2,4-Bis-trifluoromethyl-benzyl)-3-chloro-1H-indazole-5-carbaldehyde and 2-(2-(S)-Hydroxymethyl-morpholin-4-yl)-thiazol-4-one following general procedure D.
Reaction SMILES: Br[C:2]1[C:3]([CH3:10])=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[Li]CCCC.CN(C)[CH:18]=[O:19]>O1CCCC1>[CH3:9][O:8][C:5]1[CH:4]=[C:3]([CH3:10])[C:2]([CH:18]=[O:19])=[CH:7][N:6]=1
Reactant: CN(C)C=O
Reactant: COc1cc(C)c(Br)cn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(C)c(C=O)cn1

Procedure:
In Route C, commercially available 5-bromo-2-methoxy-4-methylpyridine in anhydrous tetrahydrofuran is metallated with n-BuLi and then treated with N,N-dimethylformamide to afford 6-methoxy-4-methylnicotinaldehyde. This was converted to the tert-butylimine with tert-butylamine in dichloromethane. Metallation with lithium 2,2,6,6-tetramethylpiperidide (Li-TMP) (cf. J. Org. Chem. 1993, 58, 2463-2467) and addition of N,N-dimethylformamide affords the iminoacetaldehyde which is reduced with sodium cyanoborohydride in methanol to give 2-tert-butyl-6-methoxy-1,2,3,4-tetrahydro-2,7-naphthyridine. Cleavage of the methyl group with refluxing 48% hydrobromic acid and treatment with triflic anhydride in the presence of base gives (VIIb) protected as the tert-butylamine.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][N:7]([CH3:37])[CH:8]1[CH2:11][N:10]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([NH:20][C:21]3[N:26]=[C:25]([C:27]4[CH:28]=[N:29][N:30]5[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=45)[CH:24]=[CH:23][N:22]=3)=[CH:14][C:13]=2[NH2:36])[CH2:9]1>C(Cl)Cl.CO.C(Cl)Cl>[CH3:37][N:7]([CH3:6])[CH:8]1[CH2:9][N:10]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([NH:20][C:21]3[N:26]=[C:25]([C:27]4[CH:28]=[N:29][N:30]5[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=45)[CH:24]=[CH:23][N:22]=3)=[CH:14][C:13]=2[NH:36][C:1](=[O:4])[CH:2]=[CH2:3])[CH2:11]1
Reactant: C=CC(=O)Cl
Reactant: COc1cc(N2CC(N(C)C)C2)c(N)cc1Nc1nccc(-c2cnn3ccccc23)n1
Solvent: CO
Solvent: ClCCl
Product: C=CC(=O)Nc1cc(Nc2nccc(-c3cnn4ccccc34)n2)c(OC)cc1N1CC(N(C)C)C1
Reaction time: 0.5 h
Yield: 65.9 %

Procedure:
A solution of acryloyl chloride (49 μL, 0.60 mmol) in CH2Cl2 (2.77 mL) was added dropwise over 5 minutes to 4-(3-dimethylaminoazetidin-1-yl)-6-methoxy-N-(4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)benzene-1,3-diamine (Intermediate 156, 246 mg, 0.57 mmol) in CH2Cl2 (8.3 mL), which was cooled in an ice/CH3OH bath. The mixture was stirred for 0.5 h asn was then diluted with 10% CH3OH/CH2Cl2. The resulting solution was washed with sat. NaHCO3, dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 0-5% methanolic ammonia in CH2Cl2 gave the title compound (182 mg, 66%) as a yellow solid after trituration with diethyl ether; 1H NMR: 2.09 (6H, s), 3.04-3.12 (1H, m), 3.55-3.60 (2H, m), 3.83 (3H, s), 3.96 (2H, t), 5.67 (1H, dd), 6.18 (1H, dd), 6.26 (1H, s), 6.48 (1H, dd), 7.05 (1H, td), 7.20 (1H, d), 7.41-7.46 (1H, m), 7.71 (1H, s), 8.00 (1H, s), 8.29 (1H, d), 8.43 (1H, br d), 8.75 (1H, s), 8.77 (1H, d), 9.29 (1H, s); m/z: ES+ MH+ 485.69.
Reaction SMILES: [O-]CC.[Na+].[CH3:5][CH2:6][CH2:7][C:8]1[C:13]([OH:14])=[C:12]([C:15]([CH3:17])=[O:16])[CH:11]=[CH:10][C:9]=1[OH:18].[CH2:19]([O:21][C:22](=[O:28])[C:23](OCC)=O)[CH3:20].Cl>C(O)C.CCOCC>[OH:18][C:9]1[CH:10]=[CH:11][C:12]2[C:15](=[O:16])[CH:17]=[C:23]([C:22]([O:21][CH2:19][CH3:20])=[O:28])[O:14][C:13]=2[C:8]=1[CH2:7][CH2:6][CH3:5]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: CCCc1c(O)ccc2c(=O)cc(C(=O)OCC)oc12
Temperature: 25 °C

Procedure:
To a solution of sodium ethoxide (from 19 gm. of sodium and 260 ml of absolute ethanol) under nitrogen atmosphere, add dropwise a solution of 40 gm of 2,4-dihydroxy-3-propylacetophenone and 68 gm of diethyloxalate in 55 ml of absolute ethanol and 55 ml of absolute ether. Heat under reflux for 3.5 hours. Cool to room temperature and pour the mixture into 500 ml of 5% aqueous hydrochloric acid. Extract the mixture twice with ether. Wash the combined organic fractions with water, dry over sodium sulfate and strip to a residue. Reflux the residue for 30 minutes in 150 ml absolute ethanol containing 2.5 ml of concentrated hydrochloric acid. Evaporate most of the ethanol and partition the residue between water and ethyl acetate. Wash the organic fraction with water, aqueous sodium bicarbonate solution and again with water. Dry over sodium sulfate and strip to a residue. Crystallize the residue from ethyl acetate-hexane to obtain a first crop (mp 155°-162° C.). Strip the mother liquors to dryness and chromatograph the residue over silica gel, eluting with a mixture of ethylacetate-hexane (1:1). Crystallize the resulting product from ethyl acetate to obtain a second crop. (mp 165°-167° C. lit. 166°-167° C.).