Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]=[C:3]=[S:4].[F:5][C:6]([F:23])([F:22])[CH2:7][N:8]=[C:9]([NH2:21])[NH:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][S:17][CH2:18][CH2:19][NH2:20])[N:15]=1>CO>[F:23][C:6]([F:5])([F:22])[CH2:7][N:8]=[C:9]([NH2:21])[NH:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][S:17][CH2:18][CH2:19][NH:20][C:3]([NH:2][CH3:1])=[S:4])[N:15]=1
Reactant: CN=C=S
Reactant: NCCSCc1csc(NC(N)=NCC(F)(F)F)n1
Solvent: CO
Product: CNC(=S)NCCSCc1csc(NC(N)=NCC(F)(F)F)n1
Reaction time: 18 h
Yield: 22.8 %

Procedure:
Methyl isothiocyanate (80 mg.) was added to 2-[2-(2,2,2-trifluoroethyl)guanidino]-4-[(2-aminoethyl)thiomethyl]thiazole (320 mg.) dissolved in methanol (5 ml.) and the solution kept at room temperature for 18 hours and then evaporated to dryness. The residual gum was purified by preparative thin layer chromatography using ethyl acetate/methanol/ammonia 6:1:0.5 v/v/v as developing solvent to give 2-[2-(2,2,2-trifluoroethyl)guanidino]-4-[2-(3-methylthioureido)ethylthiomethyl]thiazole (90 mg.), characterised as the hydrogen maleate, m.p. 137°-139° (decomp.) (after crystallisation from acetonitrile.).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C@H:10]3[C:18]4[C:13](=[CH:14][C:15]([O:19][CH2:20][CH2:21][CH3:22])=[CH:16][CH:17]=4)[C:12](=[O:23])[CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[C:24](=O)([O:27]C)[O:25][CH3:26]>C(O)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C@H:10]3[C:18]4[C:13](=[CH:14][C:15]([O:19][CH2:20][CH2:21][CH3:22])=[CH:16][CH:17]=4)[C:12](=[O:23])[C@@H:11]3[C:24]([O:25][CH3:26])=[O:27])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CCCOc1ccc2c(c1)C(=O)C[C@H]2c1ccc2c(c1)OCO2
Reactant: COC(=O)OC
Solvent: CC(=O)O
Product: CCCOc1ccc2c(c1)C(=O)[C@H](C(=O)OC)[C@H]2c1ccc2c(c1)OCO2
Temperature: 0 °C
Yield: 62 %

Procedure:
A 250 mL three-necked flask under nitrogen was charged with (S)-3-(1,3-Benzodioxol-5-yl)-2,3-dihydro-6-propoxy-1H-inden-1-one (6.6 g, 21.3 mmol, 90% e.e.) and dimethyl carbonate (70 mL). To the solution was added sodium t-amylate (4.7 g, 42.5 mmol) in four portions over 20 minutes to maintain the temperature below 35° C. Upon complete addition of base, stir the solution until the temperature drops to 20° C. (˜1.5 h). Cool the solution to 0° C. and add a 50% acetic acid solution (50 mL) over 15 minutes to keep the temperature below 5° C. Concentrate the solution to ¼ volume, add toluene (100 mL), wash the organic phase with water (2×100 mL), sat. NaHCO3 (100 mL), brine (100 mL), dry over MgSO4 and concentrate in vacuo. Slurry the crude solid in cold MeOH (25 mL, 0° C.), filter and air dry to afford (1S-trans)-Methyl 1-(1,3-benzodioxol-5-yl)-2,3-dihydro-3-oxo-5-propoxy-1H-indene-2-carboxylate as a pale yellow solid (4.8 g, 62%): mp 103.0-105.5° C.; 1H NMR δ7.15 (d, J=2.3 Hz, 1H), 7.05 (d, J=8.4 Hz, 1H), 6.95 (dd, J=2.4, 8.3 Hz, 1H), 6.7 (m, 2H), 6.45 (d, J=1.2 Hz, 1H), 6.4 (m, 2H), 4.6 (s, 1H 3.9 (t, J=6.5 Hz, 2H), 3.7 (s, 3H), 1.8 (quintet, J=7.2 Hz, 2H), 1.05 (t, J=7.4 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11])[NH2:6].C(N(CC)CC)C.Cl[C:22](=[O:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24].Cl>ClCCl>[CH3:13][O:12][C:8]1[CH:7]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:9]=1[O:10][CH3:11])[NH:6][C:22](=[O:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)C(=O)Cl
Reactant: COc1cc(N)cc(OC)c1OC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=O)Nc1cc(OC)c(OC)c(OC)c1
Reaction time: 2 h

Procedure:
3,4,5-Trimethoxyaniline (3.0 g) and triethylamine (4.5 mL) were dissolved in dichloromethane (10 mL), ethyl chloroglyoxylate (1.89 mL) was added dropwise to the solution under ice cooling, and the mixture was stirred for 2 hours. 1 M Hydrochloric acid was added to the reaction mixture to conduct extraction with dichloromethane. The resultant organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain the title compound.
Reaction SMILES: [CH2:1]=[C:2]([CH3:4])[CH3:3].[C:5]([O:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)(=[O:9])[C:6]([CH3:8])=[CH2:7].C1(C)C=CC=CC=1>CS(O)(=O)=O.O>[C:5]([O:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][C:2]([CH3:4])([CH3:3])[CH3:1])=[CH:15][CH:16]=1)(=[O:9])[C:6]([CH3:8])=[CH2:7]
Reactant: C=C(C)C(=O)Oc1ccc(O)cc1
Reactant: C=C(C)C
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: C=C(C)C(=O)Oc1ccc(OC(C)(C)C)cc1
Yield: 65 %

Procedure:
Under ice cooling, isobutene was introduced into a mixture of 17.8 g of 4-hydroxyphenyl methacrylate, 0.3 g of methanesulfonic acid, and 100 g of toluene over 4 hours. To the reaction solution, 50 g of water was added to quench the reaction, from which the organic layer was recovered. The organic layer was washed with water, sodium bicarbonate water, and saturated saline solution in sequence and concentrated. The concentrate was purified by distillation, obtaining 152 g (yield 65%) of 4-tert-butoxyphenyl methacrylate, designated Monomer 1.
Reaction SMILES: NC(CCC)C#N.[NH2:8][CH:9]([CH2:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=1)[C:10]([NH2:12])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[F:20][C:18]1[CH:19]=[C:14]([CH2:13][CH:9]([NH2:8])[CH2:10][NH2:12])[CH:15]=[C:16]([F:21])[CH:17]=1
Reactant: NC(=O)C(N)Cc1cc(F)cc(F)c1
Agent: CCCC(N)C#N
Agent: [Al+3]
Agent: [H-]
Product: NCC(N)Cc1cc(F)cc(F)c1
Yield: 75 %

Procedure:
Following the procedure as described in Preparation 11, making variations as required to replace 2-aminopentanenitrile with 2-amino-3-(3,5-difluorophenyl)-propanamide to react with lithium aluminum hydride, 3-(3,5-difluorophenyl)propane-1,2-diamine was obtained as a colorless solid in 75% yield: The crude product was used for the next step.
Reaction SMILES: CN1CCOCC1.C(OC(Cl)=O)C(C)C.[C:16]([NH:19][C@H:20]([CH2:24][OH:25])[C:21]([OH:23])=O)(=[O:18])[CH3:17].[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O1CCCC1>[C:16]([NH:19][C@H:20]([CH2:24][OH:25])[C:21]([NH:33][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:23])(=[O:18])[CH3:17]
Reactant: NCc1ccccc1
Reactant: CC(=O)N[C@H](CO)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(=O)N[C@H](CO)C(=O)NCc1ccccc1
Temperature: 32.5 °C
Reaction time: 0.5 h

Procedure:
4-methylmorpholine (7.3 ml) followed by isobutylchloroformate (12.35 ml) was added to a suspension of (R)-2-acetamido-3-hydroxypropanoic acid (7 grams) in tetrahydrofuran (147 ml) at −78 to −75° C., benzylamine (10.4 ml) was added to it and the reaction mixture temperature was raised to 30-35° C. then stirred for 30 minutes. The reaction mixture was filtered and the filtrate was distilled off under reduced pressure. The obtained residue was dissolved in methylene chloride (35 ml) and washed with aqueous hydrochloric acid followed by sodium carbonate and then with water. The solvent from the methylene chloride layer was distilled off completely under reduced pressure to get the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11])[NH2:6].[S-:14][C:15]#[N:16].[NH4+].BrBr.O>C(O)(=O)C>[NH2:16][C:15]1[S:14][C:7]2[C:8]([O:12][CH3:13])=[C:9]([O:10][CH3:11])[C:3]([O:2][CH3:1])=[CH:4][C:5]=2[N:6]=1
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: N#C[S-]
Agent: BrBr
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc2nc(N)sc2c(OC)c1OC
Reaction time: 8 h
Yield: 47.1 %

Procedure:
In 200 ml of acetic acid were dissolved 22.0 g of 3,4,5-trimethoxyaniline and 30.0 g of ammonium thiocyanate. Under ice cooling, 20.0 ml of a solution of 20.0 g of bromine in acetic acid was dropwise added to the solution over one hour. After allowing to stand at room temperature overnight, 200 ml of water was added to the mixture. The mixture was concentrated at 60° C. to about half and rendered alkaline with ammonia water. The precipitated crystals, 30.1 g, were taken out by filtration. The crystals were refluxed in an aqueous ethanol solution of sodium sulfite for one hour to give 13.6 g of 2-amino-5,6,7-trimethoxybenzothiazole. The compound, 9.6 g, was reacted with 9.6 g of propargyl bromide to give 7.6 g of 2-imino-5,6,7-trimethoxy 3-propargylbenzothiazole hydrobromide. The hydrobromide, 5.4 g, was cyclized with sodium ethoxide (Na, 0.4 g), which was then reacted with hydrochloric acid to form the hydrochloride. The hydrochloride, 5.4 g, was added to a mixture of 6 ml of phosphorus oxychloride and 25 ml of dry dimethylformamide. After stirring at room temperature for one hour, the mixture was heated at 60° C for 7 hours. The reaction solution was evaporated to dryness and the residue was dissolved in water. The solution was alkalized with potassium carbonate and extracted with chloroform. From the chloroform phase, 3.21 g of 3-formyl-7-methoxy-2-methylimidazo[2,1-b]benzothiazole was obtained. The obtained formyl compound was dissolved in 50 ml of ethanol and 3.1 g of sodium borohydride was added to the solution. After stirring at room temperature for one hour, the reaction mixture was warmed at 50° C. for 15 minutes. The reaction mixture was evaporated to dryness and the residue was treated with water. The mixture was filtered and were recrystallized from isopropyl alcohol to give 2.5 g of the title compound.
Reaction SMILES: [CH2:1]([C:5]12[CH2:12][CH2:11][CH:8]([CH:9]=[CH:10]1)[CH2:7][C:6]2=[O:13])[CH2:2][CH2:3][CH3:4].C(C1C=CC=CC=1)(=O)C>C1CCCCC1>[CH2:1]([C:5]12[CH:9]3[CH:8]([CH2:7][C:6](=[O:13])[CH:10]13)[CH2:11][CH2:12]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC12C=CC(CC1)CC2=O
Solvent: CC(=O)c1ccccc1
Solvent: C1CCCCC1
Product: CCCCC12CCC3CC(=O)C1C32
Reaction time: 50 h

Procedure:
A 4% solution of (+)-1-butyl-bicyclo[2.2.2]oct-5-en-2-one (1.5 g.) in cyclohexane was irradiated in a Pyrex apparatus under argon and in the presence of 200 mg. of acetophenone with a 250 nm medium pressure mercury lamp. After 50 hours, a conversion of 98% was achieved. The solution was concentrated by evaporation and the residue subjected to chromatography on 100 g. of silica gel (70 to 230 mesh) with toluene to remove the acetophenone and with toluene/1% diethyl ether. Pure (-)-8-butyl-tricyclo[3.3.0.02,8 ]octan-3-one was obtained.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][C:6]1[N:7]=[C:8]([NH:12][C:13]([C:15]2[N:16]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=3[F:32])[CH:17]=[C:18]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH:19]=2)=[O:14])[S:9][C:10]=1[Cl:11])C.CO.O.[OH-].[Li+]>C1COCC1.O>[Cl:11][C:10]1[S:9][C:8]([NH:12][C:13]([C:15]2[N:16]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=3[F:32])[CH:17]=[C:18]([CH2:20][CH:21]([CH3:22])[CH3:23])[CH:19]=2)=[O:14])=[N:7][C:6]=1[CH2:5][C:4]([OH:33])=[O:3]
Reactant: CCOC(=O)Cc1nc(NC(=O)c2cc(CC(C)C)cn2Cc2ccc(F)cc2F)sc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Cc1cc(C(=O)Nc2nc(CC(=O)O)c(Cl)s2)n(Cc2ccc(F)cc2F)c1
Reaction time: 17 h

Procedure:
(5-Chloro-2-{[1-(2,4-difluoro-benzyl)-4-isobutyl-1H-pyrrole-2-carbonyl]-amino}-thiazol-4-yl)-acetic acid ethyl ester was taken in THF and methanol and to it lithium hydroxide monohydrate in water was added and stirred for 16-18 hrs. at room temperature. After completion of the reaction, the solvent was evaporated; the residue was diluted with water and was washed with diethyl ether. The aqueous layer was acidified with 1N HCl and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated the solvent to get the title compound (5-Chloro-2-{[1-(2,4-difluoro-benzyl)-4-isobutyl-1H-pyrrole-2-carbonyl]amino}-thiazol-4-yl)-acetic acid (E1).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][CH2:11][O:12][C:6]=2[CH:5]=[C:4]([CH2:13][NH:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH:3]=1.[CH2:19]([N:26]1[CH2:29][CH:28]([C:30]([OH:32])=O)[CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl.C(N=C=NCCCN(C)C)C.CC1C=CN=C(N)C=1C>ClCCl.O>[CH2:19]([N:26]1[CH2:27][CH:28]([C:30]([N:14]([CH2:13][C:4]2[CH:3]=[C:2]([Cl:1])[C:7]3[O:8][CH2:9][CH2:10][CH2:11][O:12][C:6]=3[CH:5]=2)[CH2:15][CH:16]([CH3:17])[CH3:18])=[O:32])[CH2:29]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(O)C1CN(Cc2ccccc2)C1
Reactant: CC(C)CNCc1cc(Cl)c2c(c1)OCCCO2
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccnc(N)c1C
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CC(C)CN(Cc1cc(Cl)c2c(c1)OCCCO2)C(=O)C1CN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
40 mg of N-(9-chloro-3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-2-methylpropan-1-amine was combined with 28 mg of 1-benzyl-azetidine-3-carboxylic acid in 5 ml dichloromethane. 38 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 26 mg of dimethyl aminopyridine were added. The reaction solution was stirred at room temperature overnight. 5 ml of water was added and the mixture was extracted with 5 ml ethyl acetate three times. The organic layer was washed with saturated sodium bicarbonate, water and brine, dried over anhydrous sodium phosphate and concentrated under reduced pressure. The product was purified by column chromatography using 75% ethyl acetate in hexane as a resin: MS (m+1)=443.3; 1H NMR (500 MHz, CDCl3) 0.95 (m, 6H), 1.95 (m, 1H), 2.05 (m, 1H), 2.25 (m, 2H), 2.95 (d, 1H), 3.00 (d, 1H), 3.40 (m, 1H), 3.45 (m, 1H), 3.50 (m, 1H), 3.65 (m, 2H), 3.75 (m, 2H), 4.25 (m, 2H), 4.35 (m, 2H), 4.50 (s, 1H), 6.5-7.0 (m, 2H), 7.1-7.4 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:12]([CH3:28])[C@@H:13]2[CH2:22][CH2:21][C:16]3(OCC[O:17]3)[CH2:15][C@H:14]2[N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:12]([CH3:28])[C@@H:13]2[CH2:22][CH2:21][C:16](=[O:17])[CH2:15][C@H:14]2[N:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN(C(=O)Cc1ccc(Cl)c(Cl)c1)[C@@H]1CCC2(C[C@H]1N1CCCC1)OCCO2
Solvent: CC(C)=O
Product: CN(C(=O)Cc1ccc(Cl)c(Cl)c1)[C@@H]1CCC(=O)C[C@H]1N1CCCC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
A mixture of trans-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidinyl)-1,4-dioxaspiro[4.5]dec-8-yl]benzeneacetamide (12.3 g, 0.029 mol) 3N HCl solution (288 ml), and 432 ml of acetone was stirred at 60° C. under N2 atmosphere for one hour. Acetone was removed on a rotary evaporator and the mixture was extracted with chloroform. The chloroform extracts were dried (Na2SO4), concentrated in vacuo and diluted with ether. Refrigeration overnight gave white crystals which were dried at 60° C. in vacuo for two days to give 10.5 g (87%) of the titled compound, mp 148.0°-148.9° C. The mass spectrum indicated ion fragments at m/e 382-384 (M+, chlorine isotopic peaks). The ir and nmr spectra were consistent with the structure assignment.
Reaction SMILES: C1(C=C(C2C=CN=CC=2)C(=[O:11])C)C=CC=CC=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]=[C:26]([C:43]2[CH:48]=[CH:47][N:46]=[CH:45][CH:44]=2)[C:27](=[O:42])[CH2:28][CH:29]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]2)=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]2[O:11][C:26]2([C:27](=[O:42])[CH2:28][CH:29]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]2)[C:43]2[CH:44]=[CH:45][N:46]=[CH:47][CH:48]=2)=[CH:21][CH:20]=1
Reactant: CC(=O)C(=Cc1ccccc1)c1ccncc1
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)C(=Cc2ccc(F)cc2)c2ccncc2)CC1
Product: CC(C)(C)OC(=O)N1CCC(CC(=O)C2(c3ccncc3)OC2c2ccc(F)cc2)CC1

Procedure:
1,1-Dimethylethyl 4-(2-[3-(4-fluorophenyl)-2-(4-pyridinyl)oxiranyl]-2-oxoethyl]-1-piperidinecarboxylate was prepared by the same method as described for step 3 of Example A-2 by replacing 4-phenyl-3-(4-pyridyl)-3-butene-2-one with the α,β unsaturated ketone of step 3 of the present Example.
Reaction SMILES: C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.S(=O)(=O)(O)O.Cl[C:53]1[N:58]=[C:57]([C:59]2[CH:60]=[N:61][CH:62]=[C:63]([Cl:65])[CH:64]=2)[C:56]2[N:66]([CH:69]([C@H:71]3[CH2:76][CH2:75][C@H:74]([CH3:77])[CH2:73][CH2:72]3)[CH3:70])[CH:67]=[N:68][C:55]=2[CH:54]=1.[CH3:78][N:79](C)C(=O)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[C-]#N.[Zn+2].[C-]#N.[Zn]>[Cl:65][C:63]1[CH:64]=[C:59]([C:57]2[C:56]3[N:66]([CH:69]([C@H:71]4[CH2:76][CH2:75][C@H:74]([CH3:77])[CH2:73][CH2:72]4)[CH3:70])[CH:67]=[N:68][C:55]=3[CH:54]=[C:53]([C:78]#[N:79])[N:58]=2)[CH:60]=[N:61][CH:62]=1
Reactant: CC(=O)N(C)C
Reactant: CC([C@H]1CC[C@H](C)CC1)n1cnc2cc(Cl)nc(-c3cncc(Cl)c3)c21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Product: CC([C@H]1CC[C@H](C)CC1)n1cnc2cc(C#N)nc(-c3cncc(Cl)c3)c21
Temperature: 80 °C

Procedure:
In an oven-dried, nitrogen cooled flask were placed palladium(II) acetate (286 mg, 1.27 mmol) and (R)-(+)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (793 mg, 1.27 mmol). N,N-dimethylacetamide (76 mL) was added and degassed for three minutes with nitrogen (sparge). Sulfuric acid (0.068 mL, 1.27 mmol) was added and degassed for three minutes with nitrogen (sparge). The flask was sealed and heated to 80° C. for 30 minutes. The mixture was cooled to room temperature and added to a separate nitrogen purged flask containing racemic 6-chloro-4-(5-chloropyridin-3-yl)-3-[1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridine (4.96 g, 12.7 mmol), zinc cyanide (748 mg, 6.37 mmol), and zinc (83 mg, 1.27 mmol). The flask was purged with nitrogen for five minutes and sealed and heated to 80° C. for 16 hours. The reaction mixture was cooled to room temperature, filtered, diluted with ethyl acetate, and washed with water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-100% ethyl acetate/hexanes, linear gradient) to afford racemic 4-(5-chloropyridin-3-yl)-3-[1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile. MS ESI calc'd. for C21H22ClN5 [M+H]+ 380. found 380.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[C:6]([CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1.Cl>CC(O)=O>[N:1]1[C:10]2[C:5](=[C:6]([CH2:11][C:12]([OH:14])=[O:13])[CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)Cc1cccc2nccnc12
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)Cc1cccc2nccnc12
Temperature: 80 °C

Procedure:
To a stirring mixture of tert-butyl 2-(quinoxalin-5-yl)acetate (200 mg) in HOAc (5 mL) was added 6N HCl (5 mL). The reaction mixture was warmed to 80° C. for 2 h. The crude product mixture was concentrated under reduced pressure to give 2-(quinoxalin-5-yl)acetic acid, which was used in the next reaction without further purification. Method[1], MS(ESI) 189.0 [M+H], Retention time=0.722 min.
Reaction SMILES: [Li]CCCC.[Br:6][C:7]1[CH:12]=[C:11]([F:13])[C:10](Br)=[CH:9][C:8]=1[CH3:15].CN([CH:19]=[O:20])C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CCCCCCC.C1(C)C=CC=CC=1.C1COCC1>[Br:6][C:7]1[C:8]([CH3:15])=[CH:9][C:10]([CH:19]=[O:20])=[C:11]([F:13])[CH:12]=1
Reactant: CN(C)C=O
Reactant: Cc1cc(Br)c(F)cc1Br
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]CCCC
Solvent: CCCCCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1cc(C=O)c(F)cc1Br
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88 %

Procedure:
n-BuLi (5.0 ml, 8.0 mmol, 1.6 M in hexane) was added dropwise to a solution of n-Bu2Mg (8.0 ml, 8.0 mmol, 1.0 M in heptane) at room temperature for 10 minutes. The mixture was stirred at room temperature for 15 minutes and then cooled to −10±2° C. A solution of 2,5-dibromo-4-fluorotoluene (5.466 g, 19.59 mmol) in toluene (30 ml)-THF (6 ml) was added dropwise to this mixed reaction solution over 30 minutes, and the mixture was then stirred at 0° C. for one hour. The reaction mixture was added dropwise to a solution cooled to −10° C. of DMF (2.1 ml, 27 mmol) in toluene (7.6 ml) over 15 minutes. Further, this mixture was stirred at −10 to −5° C. for 30 minutes, and then quenched with an aqueous citric acid solution (2.3 M, 16 ml, 37 mmol) and extracted with Et2O. The organic layer was washed with water, and then dried over MgSO4 and concentrated under reduced pressure to give 4-bromo-2-fluoro-5-methyl-benzaldehyde (3.74 g, 88%).
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([OH:12])=O)[CH:4]=[N:3][CH:2]=1.O=S(Cl)Cl.[Cl:20][C:21]([F:31])([F:30])[O:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1>C(Cl)Cl>[Cl:20][C:21]([F:30])([F:31])[O:22][C:23]1[CH:24]=[CH:25][C:26]([NH:27][C:10](=[O:12])[C:9]2[CH:13]=[CH:14][CH:15]=[C:7]([C:5]3[CH:4]=[N:3][CH:2]=[N:1][CH:6]=3)[CH:8]=2)=[CH:28][CH:29]=1
Reactant: O=C(O)c1cccc(-c2cncnc2)c1
Reactant: Nc1ccc(OC(F)(F)Cl)cc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cccc(-c2cncnc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-pyrimidin-5-yl-benzoic acid (100 mg, 0.50 mmol) and SOCl2 (73 μL, 1.0 mmol) was heated under reflux for 4 h. The solvent was evaporated off under reduced pressure and the residue was dissolved in DCM (5 mL) and slowly added to a mixture of 4-(chlorodifluoromethoxy)aniline (106 mg, 0.55 mmol) and TEA (140 μL, 1.0 mmol) in DCM (5 mL). The mixture was stirred at RT overnight. The solvent was evaporated off under reduced pressure and the residue was suspended in EtOAc (10 mL), filtered through a 10 μm Isolute® fritted cartridge and the filtrate was evaporated to dryness under reduced pressure to give the crude product which was purified by preparative HPLC to afford the title compound. LC-MS (Condition 4) tR=1.15 min, m/z=375.8 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 7.40 (d, J=9.05 Hz, 2H) 7.73 (t, J=7.82 Hz, 1H) 7.92 (m, 2H) 8.06 (t, J=6.97 Hz, 2H) 8.37 (t, J=1.96 Hz, 1H) 9.24-9.29 (m, 3H) 10.52 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:13])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[C:14]1([CH3:23])[CH:19]=[CH:18][CH:17]=[C:16](B(O)O)[CH:15]=1.C([O-])([O-])=O.[K+].[K+].CCO>[Pd].C(Cl)Cl.O>[F:10][C:9]([F:12])([F:11])[CH:8]([C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][C:4]=1[C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([CH3:23])[CH:15]=1)[OH:13]
Reactant: Cc1cccc(B(O)O)c1
Reactant: OC(c1ccc(Br)cc1)C(F)(F)F
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: Cc1cccc(-c2ccccc2C(O)C(F)(F)F)c1
Temperature: 80 °C
Yield: 71.5 %

Procedure:
1-(4-Bromophenyl)-2,2,2-trifluoroethanol (0.13 g, 0.525 mmol), m-tolylboronic acid (0.1 g, 0.736 mmol), Fibercat (4.28% Pd, 47 mgs, 0.0157 mmol Pd), K2CO3 (0.22 g, 1.576 mmol), EtOH (3 mls), and H2O (0.5 mls) were combined and heated at 80° C. for 4 hours. The reaction was shown complete by TLC (CH2Cl2). The mixture was cooled, filtered, concentrated, slurried in CH2Cl2, and chromatographed over silica gel (CH2Cl2) to give 0.1 g of 2,2,2-trifluoro-1-(3′-methylbiphenyl-2-yl)ethanol. Yield: 72%.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>CN(C=O)C>[O:4]1[CH2:5][CH2:6][N:1]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:2][CH2:3]1
Reactant: C1COCCN1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCOCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.4 %

Procedure:
To a solution of morpholine (1.4 g, 16.3 mmol, 1.0 eq) in DMF were added K2CO3 (5.63 g, 40.7 mmol, 2.5 eq.) and ethyl 2-bromoacetate (4.07 g, 24.4 mmol, 1.5 eq.). The mixture was stirred at RT for 16 h and quenched and extracted as in Intermediate Example 5(a). The solvent was distilled off to afford the product in 71.4% yield (2 g). LC-MS (ESI): Calculated mass: 173.2; Observed mass: 174.0 [M+H]+ (rt: 0.20 min).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[C:10]2[C:15]([Cl:16])=[C:14]([CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[C:10]3[C:15]([Cl:16])=[C:14]([CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: Cc1sc2nc(Cl)nc(NCc3ccc(F)cc3)c2c1Cl
Product: Cc1sc2nc(-n3cccn3)nc(NCc3ccc(F)cc3)c2c1Cl

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2,5-dichloro-6-methyl-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-5-chloro-6-methyl-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine.