Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][N:35]([CH2:39][CH3:40])[CH2:34]1.O>CN(C)C=O>[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:32][CH:33]2[CH2:38][CH2:37][CH2:36][N:35]([CH2:39][CH3:40])[CH2:34]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCN1CCCC(CBr)C1
Reactant: CCCCNc1nc(N)c2nc(OC)[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CCCCNc1nc(N)c2nc(OC)n(CC3CCCN(CC)C3)c2n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 58.1 %

Procedure:
A stirring mixture of N2-butyl-8-methoxy-9H-purine-2,6-diamine trifluoroacetic acid salt (200 mg) and potassium carbonate (236 mg) in dry N,N-dimethylformamide (2 ml) was heated with stirring at 60° C. for 1 hour. 3-(Bromomethyl)-1-ethylpiperidine (141 mg) was added and the stirring mixture heated at 50° C. for 6 hours. After 72 hours at ambient temperature heating at 50° C. was continued for a further 6 hours to complete the reaction. Water was added and the mixture extracted three times with ethyl acetate. The combined extracts were washed with water then brine, dried by passing through a phase separation cartridge and stripped to give a brown oil. This was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid)-acetonitrile (containing 0.05% formic acid) as eluent (5-35%) and the appropriate fractions combined and evaporated to remove acetonitrile. The remaining aqueous mixture was made basic with saturated sodium hydrogen carbonate, extracted three times with dichloromethane and the combined extracts dried by passing through a phase separation cartridge then evaporated to afford the title compound as a clear oil (120 mg).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([O:6][C:7](=[O:10])[C:8]=1[CH3:9])=O)[CH3:2].[F:11][C:12]1[CH:18]=[C:17]([Cl:19])[C:16]([O:20][CH:21]([CH3:23])[CH3:22])=[CH:15][C:13]=1[NH2:14]>CN(C)C1C=CN=CC=1.C1(C)C(C)=CC=CC=1>[F:11][C:12]1[CH:18]=[C:17]([Cl:19])[C:16]([O:20][CH:21]([CH3:22])[CH3:23])=[CH:15][C:13]=1[N:14]1[C:7](=[O:10])[C:8]([CH3:9])=[C:3]([CH2:1][CH3:2])[C:4]1=[O:6]
Reactant: CCC1=C(C)C(=O)OC1=O
Reactant: CC(C)Oc1cc(N)c(F)cc1Cl
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1C
Product: CCC1=C(C)C(=O)N(c2cc(OC(C)C)c(Cl)cc2F)C1=O
Reaction time: 5 h

Procedure:
5 g of 2-ethyl-3-methylmaleic anhydride, 7.3 g of 2-fluoro-4-chloro-5-isopropoxyaniline and 0.61 g of 4-dimethylaminopyridine are combined in 100 ml of xylene in a distillation apparatus and the solvent is slowly distilled off. After 5 hours, the reaction is complete. The xylene still present is removed under a water-jet vacuum. The dark residue is taken up in ethyl acetate and extracted with 2M hydrochloric acid, water, 10% sodium bicarbonate solution and lastly with saturated sodium chloride solution. After drying over sodium sulphate, the ethyl acetate is distilled off in a rotary evaporator and the residue is chromatographed over a column of silica gel with hexane:ethyl acetate 1:1. After evaporating the solvent, 5 g of the title compound are obtained in the form of a red oil having a refractive index of nD22 =1.5351.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[S:9]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10]1.[Al].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)(Cl)Cl.Cl(O)(=O)(=O)=O>[Br:1][C:10]1[S:9][CH:13]=[CH:12][C:11]=1[CH2:14][CH2:15][OH:16]
Reactant: OCCc1ccsc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])[O-]
Agent: [Al]
Agent: [K+]
Solvent: ClC(Cl)(Cl)Cl
Product: OCCc1ccsc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
N-bromosuccinimide (33.8 g, 0.19 mmol) followed by perchloric acid (0.19 g, 0.002 mol) were added to a solution of 2-(thiophen-3-yl)ethanol )24.3 g, 0.19 mol) in carbon tetrachloride (250 mL) in a flask wrapped with aluminum foil at rt. The mixture was stirred in the dark at rt overnight and then potassium carbonate (40 g) was added. After stirring at rt for 1 h the mixture was filtered through Celite and washed with diethyl ether. The solvent was removed in vacuo and the product purified by flash chromatography eluting with ethyl acetate/hexane ((1:3) to give the title compound as an oil (25 g, 64%).
Reaction SMILES: [C:1]1([CH:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:8][C:9]([N:11]2[CH2:22][CH2:21][C:14]3[N:15]=[N:16][C:17]([NH:19][NH2:20])=[CH:18][C:13]=3[CH2:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:29][C:30]([CH3:32])=O>>[C:23]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][C:9]([N:11]2[CH2:22][CH2:21][C:14]3[N:15]=[N:16][C:17]([NH:19][N:20]=[C:30]([CH3:32])[CH3:29])=[CH:18][C:13]=3[CH2:12]2)=[O:10])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)=O
Reactant: NNc1cc2c(nn1)CCN(C(=O)CC(c1ccccc1)c1ccccc1)C2
Product: CC(C)=NNc1cc2c(nn1)CCN(C(=O)CC(c1ccccc1)c1ccccc1)C2

Procedure:
A solution of 1.5 g of 6-(3,3-diphenylpropionyl)-3-hydrazino-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine in 40 cc of absolute acetone is heated on a water bath for 35 minutes. The title compound has a M.P. of 172°-175° (decomp., from absolute ethanol).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][C:21]=3[CH3:28])=[C:10]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[S:11][CH:12]=2)=[CH:4][CH:3]=1.[BrH:29].N([O-])=O.[Na+]>O>[Br:29][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][C:21]=3[CH3:28])=[C:10]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[S:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCc1scc(-c2ccc(N)cc2)c1-c1ccc(C#N)cc1C
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CCc1scc(-c2ccc(Br)cc2)c1-c1ccc(C#N)cc1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of ethyl 3-(4-(4-aminophenyl)-3-(4-cyano-2-methylphenyl)thiophen-2-yl)propanoate (180 mg, 0.46 mmol) in a mixture solvent of HBr (48%, 3 mL) and water (1 mL) was added dropwise a solution of NaNO2 (32 mg, 0.46 mmol) in water (0.5 mL). Then the mixture was stirred at 0° C. for 1 hour. Then CuBr (66 mg, 0.46 mmol) was added and the mixture was stirred at 0° C. for additional 1 hour. The reaction mixture was extracted with EtOAc and the combined organic layer was dried over Na2SO4, concentrated in vacuo to give crude ethyl 3-(4-(4-bromophenyl)-3-(4-cyano-2-methylphenyl)thiophen-2-yl)propanoate, which was used in the next step directly.
Reaction SMILES: Br[CH2:2][CH3:3].[Cl:4][C:5]1[CH:6]=[C:7]([C:11]2[CH:12]=[CH:13][C:14](=[O:17])[NH:15][N:16]=2)[CH:8]=[CH:9][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C(OCC)(=O)C>[Cl:4][C:5]1[CH:6]=[C:7]([C:11]2[CH:12]=[CH:13][C:14](=[O:17])[N:15]([CH2:2][CH3:3])[N:16]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: CCBr
Reactant: O=c1ccc(-c2cccc(Cl)c2)n[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCn1nc(-c2cccc(Cl)c2)ccc1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 96 %

Procedure:
Under nitrogen atmosphere bromoethane (18.31 g, 0.168 mol) was added dropwise to a solution of 6-(3-chlorophenyl)-2H-pyridazin-3-one (4.96 g, 0.024 mol) and potassium carbonate (19.90 g, 0.144 mol) in N,N-dimethylformamide (100 ml). The mixture was stirred at room temperature for 4 hours and then water (150 ml) and ethyl acetate (300 ml) were added. The organic layer washed with water and brine, dried over sodium sulfate anhydride and evaporated. The oil obtained solidified in the vacuum oven to yield the title compound (96%).
Reaction SMILES: [F:1][C:2]1([F:43])[CH2:6][C@H:5]([O:7][C:8]2[CH:13]=[CH:12][C:11]([S:14]([N:17](CC3C=CC(OC)=CC=3OC)[C:18]3[CH:23]=[CH:22][N:21]=[CH:20][N:19]=3)(=[O:16])=[O:15])=[C:10]([F:35])[C:9]=2[F:36])[C@@H:4]([C:37]2[N:41]([CH3:42])[N:40]=[CH:39][CH:38]=2)[CH2:3]1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:43][C:2]1([F:1])[CH2:6][C@H:5]([O:7][C:8]2[CH:13]=[CH:12][C:11]([S:14]([NH:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][N:19]=3)(=[O:16])=[O:15])=[C:10]([F:35])[C:9]=2[F:36])[C@@H:4]([C:37]2[N:41]([CH3:42])[N:40]=[CH:39][CH:38]=2)[CH2:3]1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc(O[C@H]3CC(F)(F)C[C@@H]3c3ccnn3C)c(F)c2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nccc1[C@H]1CC(F)(F)C[C@@H]1Oc1ccc(S(=O)(=O)Nc2ccncn2)c(F)c1F
Yield: 96.6 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 4-{[(1S*,2R*)-4,4-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(2,4-dimethoxybenzyl)-2,3-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide (161 mg, 0.259 mmol) prepared in Example 132a, triethylsilane (0.30 mL), trifluoroacetic acid (2.0 mL) and dichloromethane (3.0 mL), to yield the title compound (118 mg, 97%) as a colorless solid.
Reaction SMILES: C([O:8][C@H:9]1[C@H:13]([O:14]CC2C=CC=CC=2)[CH2:12][N:11]([CH2:22][CH2:23][CH2:24][CH3:25])[C@@H:10]1[CH2:26][O:27]CC1C=CC=CC=1)C1C=CC=CC=1.[ClH:35]>[Pd].C(O)C>[ClH:35].[CH2:22]([N:11]1[CH2:12][C@@H:13]([OH:14])[C@H:9]([OH:8])[C@H:10]1[CH2:26][OH:27])[CH2:23][CH2:24][CH3:25]
Reactant: CCCCN1C[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1COCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCCCN1C[C@@H](O)[C@H](O)[C@H]1CO

Procedure:
The title compound was synthesized as described for compound 9 using (2R,3R,4R)-3,4-dibenzyloxy-2-benzyloxymethyl-1-butylpyrrolidine (Compound 10) (0.243 g,0.53 mmol), ethanol (30 ml), 10% Pd/C (0.07 g) and excess of 1 M hydro-chloric acid to convert the amine to the hydrochloride salt. (2R,3R,4R)-1-Butyl-3,4-dihydroxy-2-hydroxymethylpyrrolidine, hydrochloride was obtained as a yellow syrup (0.098 g, yield: 82%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:11][C:12]1[CH:22]=[CH:21][C:15]([C:16]([N:18]=[C:19]=[S:20])=[O:17])=[CH:14][CH:13]=1>CCOCC>[NH2:6][C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[NH:1][C:19](=[S:20])[NH:18][C:16](=[O:17])[C:15]1[CH:21]=[CH:22][C:12]([CH3:11])=[CH:13][CH:14]=1)=[O:5]
Reactant: NC(=O)c1ccccc1N
Reactant: Cc1ccc(C(=O)N=C=S)cc1
Solvent: CCOCC
Product: Cc1ccc(C(=O)NC(=S)Nc2ccccc2C(N)=O)cc1
Reaction time: 48 h
Yield: 98.2 %

Procedure:
To a stirred mixture of 5.4 g of 2-aminobenzamide and 200 ml of ether was added dropwise, a solution of 7.5 g of 4-methylbenzoyl isothiocyanate in 100 ml of ether over 30 minutes. After 48 hours, the solid was collected, giving 12.2 g of the desired product as grey crystals, mp 208°-210° C. (dec.).
Reaction SMILES: [N:1]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[C:7](=[O:15])[C:6]3=[CH:16][CH:17]=[CH:18][C:4]([C:5]=23)=[CH:3][CH:2]=1>C(O)(=O)C.[Pt]>[OH:15][C:7]1[C:8]2[CH2:14][CH2:13][CH2:12][CH2:11][C:9]=2[C:10]2[N:1]=[CH:2][CH:3]=[C:4]3[CH2:18][CH2:17][CH2:16][C:6]=1[C:5]=23
Reactant: O=C1c2ccccc2-c2nccc3cccc1c23
Agent: [Pt]
Solvent: CC(=O)O
Product: Oc1c2c(c3nccc4c3c1CCC4)CCCC2
Temperature: 65 °C
Yield: 92 %

Procedure:
7H-Dibenzo[de,h]quinol-7-one (48.4 g) and Adams platinum (16 g) suspended in acetic acid (800 cc) are placed under an initial hydrogen pressure of 30 bars at 25° C. The mixture is stirred and heated at 65° C. for 17 hours. After cooling to about 25° C., the catalyst is filtered off and washed twice with acetic acid (total 150 cc). The combined organic filtrates are evaporated to dryness. The residue is taken up in water (1000 cc) and adjusted to pH 9 by the addition of 5N sodium hydroxide. The resulting precipitate is filtered off, washed twice with distilled water (total 2000 cc) and four times with ethanol (total 100 cc) and then dried under reduced pressure (20 mm Hg) at 20° C. Crude 7-hydroxy-5,6,8,9,10,11-hexahydro-4H-dibenzo[de,h]quinoline (46.1 g), melting at 224° C., is thus obtained, which is recrystallised successively from butyl acetate and from propanol as described in Example 3.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[Br:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Cl>>[Br:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29][N:14]1[C:15]2[CH2:16][CH2:17][NH:8][CH2:9][CH2:10][C:11]=2[C:12]([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[N:13]1
Reactant: ClCc1cccc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Product: Clc1ccc(-c2nn(Cc3cccc(Br)c3)c3c2CCNCC3)cc1
Yield: 48 %

Procedure:
The title compound (0.04 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.2 mmol) using 3-bromobenzyl chloride (0.3 mmol) in place of 2-chloromethyl-thiophene. MS (ESI): exact mass calculated for C20H19BrClN3, 415.05; found, m/z 416.0 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.50-6.86 (m, 8H), 5.36 (s, 2H), 3.30-3.27 (br m, 4H), 3.06-3.04 (m, 4H).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[CH3:23][Si:24]([CH3:46])([CH3:45])[C:25]1[CH:33]=[C:32]2[C:28]([CH:29]=[C:30]([C:42](O)=[O:43])[N:31]2[CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=2)=[CH:27][CH:26]=1.[NH2:47][C:48]1[CH:49]=[N:50][C:51]([N:54]2[CH2:57][CH:56]([OH:58])[CH2:55]2)=[CH:52][CH:53]=1.C([O-])(O)=O.[Na+]>CN(C=O)C.C(OCC)(=O)C>[OH:58][CH:56]1[CH2:57][N:54]([C:51]2[N:50]=[CH:49][C:48]([NH:47][C:42]([C:30]3[N:31]([CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=4)[C:32]4[C:28]([CH:29]=3)=[CH:27][CH:26]=[C:25]([Si:24]([CH3:23])([CH3:46])[CH3:45])[CH:33]=4)=[O:43])=[CH:53][CH:52]=2)[CH2:55]1
Reactant: Nc1ccc(N2CC(O)C2)nc1
Reactant: C[Si](C)(C)c1ccc2cc(C(=O)O)n(Cc3cccc(F)c3)c2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[Si](C)(C)c1ccc2cc(C(=O)Nc3ccc(N4CC(O)C4)nc3)n(Cc3cccc(F)c3)c2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 60.7 %

Procedure:
114 mg (0.59 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDAC) and 81 mg (0.59 mmol) of 1-hydroxybenzotriazole (HOBT) are added to a solution, stirred at 20° C. under an inert atmosphere, of 0.2 g (0.59 mmol) of 6-trimethylsilyl-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxylic acid, prepared in stage 1.4, in 5 ml of DMF. The reaction mixture is stirred at ambient temperature for 15 minutes. 145 mg (0.88 mmol) of 3-amino-6-(3-hydroxyazetidin-1-yl)pyridine, prepared in stage 2.2, are subsequently added to the reaction mixture. After stirring at 20° C. for 20 hours, the reaction mixture is poured into a mixture of 30 ml of a saturated aqueous solution of NaHCO3 and 30 ml of ethyl acetate. The resulting mixture is separated by settling out and the aqueous phase is extracted with 20 ml of ethyl acetate. The combined organic phases are washed three times with 30 ml of water, dried over sodium sulphate and then concentrated under reduced pressure. The product obtained is purified by silica column chromatography, elution being carried out with a mixture of dichloromethane and methanol. The solid obtained after evaporation of the solvent under reduced pressure is recrystallized from isopropyl ether. 175 mg of the expected product are thus isolated.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH2:7][N:8]2[C:16]3[C:11](=[C:12]([N+:17]([O-])=O)[CH:13]=[CH:14][CH:15]=3)[C:10]([CH:20]=[CH2:21])=[N:9]2)[S:5][CH:6]=1>C(O)C.[OH-].[OH-].[Pd+2]>[CH2:20]([C:10]1[C:11]2[C:12]([NH2:17])=[CH:13][CH:14]=[CH:15][C:16]=2[N:8]([CH2:7][C:4]2[S:5][CH:6]=[C:2]([CH3:1])[N:3]=2)[N:9]=1)[CH3:21]
Reactant: C=Cc1nn(Cc2nc(C)cs2)c2cccc([N+](=O)[O-])c12
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCc1nn(Cc2nc(C)cs2)c2cccc(N)c12
Temperature: 25 °C
Reaction time: 14 h
Yield: 82.8 %

Procedure:
A solution of 4-methyl-2-((4-nitro-3-vinyl-1H-indazol-1-yl)methyl)thiazole (0.249 g, 0.829 mmol) in hot ethanol (8 mL) was purged with argon and treated with Pearlman's catalyst (124 mg). The mixture was purged with argon, purged with hydrogen gas and allowed to stir at ambient temperature under hydrogen gas for 14 hours. The mixture was filtered through glass fiber filter paper, washed with methanol and concentrated to afford 3-ethyl-1-((4-methylthiazol-2-yl)methyl)-1H-indazol-4-amine (187 mg, 83%) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[N:32]1[C:37]2[CH:38]=[CH:39][S:40][C:36]=2[C:35]([N:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)=[N:34][CH:33]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:29])([F:31])[F:30])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([N:44]4[CH2:45][CH2:46][N:41]([C:35]5[C:36]6[S:40][CH:39]=[CH:38][C:37]=6[N:32]=[CH:33][N:34]=5)[CH2:42][CH2:43]4)=[O:23])=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: c1nc(N2CCNCC2)c2sccc2n1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Product: O=C(c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1)N1CCN(c2ncnc3ccsc23)CC1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-(4-thieno[3,2-d]pyrimidinyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z=648.99 (M+H+); retention time=0.64 minutes.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][C:7]1[CH:16]=[C:15]([B:17]2[O:21][C:20]([CH3:23])([CH3:22])[C:19]([CH3:25])([CH3:24])[O:18]2)[CH:14]=[C:13]([CH3:26])[C:8]=1[O:9][CH2:10][CH2:11][OH:12].C(N(CC)CC)C.O>C(Cl)Cl.C(OCC)(=O)C>[CH3:1][S:2]([O:12][CH2:11][CH2:10][O:9][C:8]1[C:13]([CH3:26])=[CH:14][C:15]([B:17]2[O:21][C:20]([CH3:22])([CH3:23])[C:19]([CH3:25])([CH3:24])[O:18]2)=[CH:16][C:7]=1[CH3:6])(=[O:4])=[O:3]
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C)c1OCCO
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C)c1OCCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methanesulfonyl chloride (0.14 mL) was added to a mixture of 2-[2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxa-borolan-2-yl)phenoxy]ethanol (0.5 g) and triethylamine (0.29 mL) in methylene chloride (10 mL), and the mixture was stirred for 1 hr at room temperature. Water and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed with water and brine, and dried over an hydrous magnesium sulfate. The solvent was evaporated under reduced pressure to afford the title compound (0.632 g).
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][C:4]#[CH:5].[CH2:7]([O:9][N:10]=[CH:11][C:12]1[CH:17]=[C:16]([CH3:18])[C:15]([OH:19])=[C:14]([CH3:20])[CH:13]=1)[CH3:8]>>[CH2:7]([O:9][N:10]=[CH:11][C:12]1[CH:17]=[C:16]([CH3:18])[C:15]([O:19][CH2:5][CH2:4][CH2:3][C:2]#[CH:1])=[C:14]([CH3:20])[CH:13]=1)[CH3:8]
Reactant: C#CCCCO
Reactant: CCON=Cc1cc(C)c(O)c(C)c1
Product: C#CCCCOc1c(C)cc(C=NOCC)cc1C

Procedure:
Condensation of 4-pentyn-1-ol and 4-hydroxy-3,5-dimethylbenzaldehyde O-ethyloxime using Mitsunobu Reaction conditions (see for example J. Med. Chem., 36, 3240, 1993 and references cited therein) gave 3,5-dimethyl4-(4-pentyn-1-yloxy)benzaldehyde O-ethyl oxime in good yield.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:3]=1[CH2:12][CH2:13][CH3:14].[C:15](OCC)(=[O:20])[CH2:16][C:17]([CH3:19])=O>C(O)(=O)C>[CH3:19][C:17]1[NH:1][C:2]2[N:6]([N:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:3]=2[CH2:12][CH2:13][CH3:14])[C:15](=[O:20])[CH:16]=1
Reactant: CCCc1c(C(=O)OCC)n[nH]c1N
Reactant: CCOC(=O)CC(C)=O
Solvent: CC(=O)O
Product: CCCc1c(C(=O)OCC)nn2c(=O)cc(C)[nH]c12
Yield: 96.4 %

Procedure:
A mixture of 11.5 g of ethyl 5-amino-4-propylpyrazole-3-carboxylate, 11.3 g of ethyl acetoacetate, and 100 mL of acetic acid is refluxed overnight. The solvent is removed in vacuo, and the residue triturated with hexane/ether (1:1) to give 14.8 g of off-white solid. 1H NMR (CD3OD) δ: 0.97 (t, 3H), 1.40 (t, 3H), 1.61 (m, 2H), 2.42 (s, 3H), 2.85 (t, 2H), 4.40 (q, 2H), 5.73 (s, 1H). LC-MS (APCI, m/z): 264 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CC(C)=O.C(=O)=O.C([O:35][B:36](OC(C)C)[O:37]C(C)C)(C)C.Cl>O1CCCC1.C(OCC)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=1[B:36]([OH:37])[OH:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: FC(F)(F)c1ccc(OCc2ccccc2)c(Br)c1
Agent: Cl
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: OB(O)c1cc(C(F)(F)F)ccc1OCc1ccccc1
Temperature: 25 °C
Yield: 38.2 %

Procedure:
A solution of 4-benzyloxy-3-bromobenzotrifluoride (4.48 g, 13.54 mmol) in tetrahydrofuran (100 ml) was cooled to −100° C. (diethyl ether/liquid nitrogen) with stirring under nitrogen. 1.6 M n-butyllithium in hexanes (9.3 ml, 14.89 mmol) was added over 20 mins. at −100° C. and the mixture warmed to −78° C. (acetone/Drikold) and stirred for 1 h. Triisopropylborate (7.64 g, 9.38 ml, 40.66 mmol) was added dropwise at −78° C. and the reaction stirred and allowed to warm to room temperature over 1.5 h. 1M Hydrochloric acid (100 ml) was added and the mixture stirred vigorously for 1 h. The layers were separated and the aqueous layer extracted with diethyl ether (50 ml). The combined organic phases were washed with water, dried (MgSO4) and the solvent removed in vacuo. The yellow waxy solid was flash chromatographed (silica gel, 4-20% EtOAc-isohexane) and the product triturated with hexane. The white solid was filtered and dried in vacuo to give the title compound (1.53 g, 38%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[F:9].CCCCCC.C([Li])CCC.[I:21]I.[Cl-].[NH4+]>C1COCC1.CCCCCC>[F:9][C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[I:21]
Reactant: II
Reactant: Cc1ccc(Br)c(F)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1ccc(I)c(F)c1
Temperature: -72 °C
Reaction time: 1 h
Yield: 104.1 %

Procedure:
Under dry nitrogen, a solution prepared by dissolving 4-bromo-3-fluorotoluene (10 g) in THF (50 mL) was cooled to −72° C. Then, a 1.6 mol/L n-butyl lithium hexane solution (35 mL) was added at −72° C. to the solution such a rate that the inside temperature was not more than −65° C., followed by further stirring at −72° C. for 1 hour. A solution prepared by dissolving iodine (14.8 g) in THF (30 mL) was added at −72° C. to the resultant mixture such a rate that the inside temperature was not more than −60° C., and the temperature was slowly increased to room temperature. Then, a saturated aqueous ammonium chloride solution and hexane were added at room temperature to separate an organic layer, and the organic layer was washed with a 10% aqueous sodium sulfite solution two times and saturated brine in that order, and then dried with sodium sulfate. The sodium sulfate was filtered off, and the organic solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to yield 13.0 g of 3-fluoro-4-iodotoluene as a yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([Cl:12])=[CH:7][C:6]=2[C:13]#[N:14].C(N(CC)CC)C.N1C=CC=CC=1.[SH2:28]>O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([Cl:12])=[CH:7][C:6]=2[C:13](=[S:28])[NH2:14]
Reactant: S
Reactant: N#Cc1cc(Cl)cc2cc(Cl)cnc12
Solvent: O
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: NC(=S)c1cc(Cl)cc2cc(Cl)cnc12
Temperature: 40 °C

Procedure:
22 parts of 3,6-dichloro-8-cyanoquinoline (prepared by a method similar to that in Example 8) in 80 parts of triethylamine and 80 parts of pyridine were heated at 40° C., and H2S gas was slowly passed in for 4 hours. Water was then added and the solid was filtered off with suction, washed with water and acetone and recrystallized from ethyl acetate. 17 parts of 3,6-dichloroquinoline-8-thiocarboxylic acid amide of melting point 226° C. were obtained. The yield corresponds to 66% of theory.