Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][OH:11])[C:2]1C=CC=C[CH:3]=1.[O:12]1C(COC)[CH2:13]1>>[CH3:13][O:12][CH2:3][CH:2]1[O:11][CH2:10][CH2:9][NH:8][CH2:1]1
Reactant: COCC1CO1
Reactant: OCCNCc1ccccc1
Product: COCC1CNCCO1
Temperature: 50 °C
Reaction time: 16 h
Yield: 98.3 %

Procedure:
N-Benzylethanolamine (459 g) is mixed with 1,2-epoxy-3-methoxypropane (422 g) and the mixture is stirred at 50° C. for 16 hours and thereafter the excess 1,2-epoxy-3-methoxypropane is distilled off under reduced pressure. The residue is dissolved in 1,4-dioxane (3 liters) and thereto are added powdery potassium hydroxide (692.5 g) and tris(3,6-dioxaheptyl)amine (11.4 g). To the mixture is added dropwise with stirring a solution of p-toluenesulfonyl chloride (809.4 g) in 1,4-dioxane (2 liters) over a period of 1.5 hour, during which the temperature of the reaction mixture raises and the solvent is refluxed. After the dropwise addition, the mixture is stirred for 2 hours, and the undissolved materials are filtered off and washed with ethyl acetate. The filtrate and the washing liquid are combined and distilled under reduced pressure to remove the solvent. To the residue are added water (600 ml) and conc. hydrochloric acid (300 ml) to make acidic. The aqueous layer is washed with ethyl acetate, made strongly basic by adding sodium hydroxide (160 g) under ice cooling and extracted with ethyl acetate. The ethyl acetate layer is washed with saturated saline solution, dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The obtained residue is distilled under reduced pressure to give the title compound (391.3 g) as colorless liquid.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[F:23][C:24]1[CH:25]=[C:26]([C:30]2[S:34][C:33]([CH3:35])=[N:32][C:31]=2[C:36]([OH:38])=O)[CH:27]=[CH:28][CH:29]=1.[C@H:39]12[CH2:44][C@H:43]1[CH2:42][C@@H:41]([CH2:45][NH:46][C:47](=[O:52])[C:48]([F:51])([F:50])[F:49])[NH:40]2.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:51][C:48]([F:49])([F:50])[C:47]([NH:46][CH2:45][C@@H:41]1[CH2:42][C@H:43]2[C@H:39]([CH2:44]2)[N:40]1[C:36]([C:31]1[N:32]=[C:33]([CH3:35])[S:34][C:30]=1[C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([F:23])[CH:25]=1)=[O:38])=[O:52]
Reactant: O=C(NC[C@@H]1C[C@@H]2C[C@@H]2N1)C(F)(F)F
Reactant: Cc1nc(C(=O)O)c(-c2cccc(F)c2)s1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(C(=O)N2[C@H](CNC(=O)C(F)(F)F)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1

Procedure:
TBTU (3.22 mmol, 1.05 eq) is added to a solution of 5-(3-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid (3.07 mmol, 1.0 eq), N-[(1S,3S,5S)-2-aza-bicyclo[3.1.0]hex-3-ylmethyl]-2,2,2-trifluoro-acetamide (3.07 mmol, 1.0 eq) and DIPEA (9.20 mmol, 3.0 eq) in DCM (15 mL). After 2 h the mixture is washed twice with water, once with sat. aqueous NaHCO3 solution, once with hydrochloric acid (0.2 M) and three times with water. The organic layer is dried over Na2SO4, the solvents are removed in vacuo and the residue is purified by flash chromatography (gradient: DCM to DCM/MeOH 19/1) and preparative TLC (DCM/MeOH 19/1) to give the desired product as an orange foam. LC-MS (acidic): tR=0.97 min; [M+H]+=428.1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:41])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:40]=[C:14]3[N:15](CC4C=CC(OC)=CC=4)[CH:16]=[N:17][C:18]([O:19][C:20]4[C:21]([F:30])=[C:22]5[C:26](=[CH:27][CH:28]=4)[NH:25][C:24]([CH3:29])=[CH:23]5)=[C:13]3[CH:12]=2)=[CH:7][CH:6]=1)[CH3:2]>C1COCC1.CN1CCN(C)C1=O.C1COCC1.O.[Pd]>[CH2:1]([O:3][C:4](=[O:41])[C:5]1[CH:6]=[CH:7][C:8]([C:11]2[NH:40][C:14]3[N:15]=[CH:16][N:17]=[C:18]([O:19][C:20]4[C:21]([F:30])=[C:22]5[C:26](=[CH:27][CH:28]=4)[NH:25][C:24]([CH3:29])=[CH:23]5)[C:13]=3[CH:12]=2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(-c2cc3c(Oc4ccc5[nH]c(C)cc5c4F)ncn(Cc4ccc(OC)cc4)c-3n2)cc1
Agent: [Pd]
Solvent: CN1CCN(C)C1=O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1ccc(-c2cc3c(Oc4ccc5[nH]c(C)cc5c4F)ncnc3[nH]2)cc1

Procedure:
Hydrogenation of 0.50 g (0.91 mMol) of 4-[4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-1-(4-methoxy-benzyl)-1H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzoic acid ethyl ester in 150 ml of THF and 15 ml of 1,3-dimethyl-2-imidazolidinone in the presence of 0.2 g of Pd/C (10%; “Engelhard 5125”), filtration and concentration gives the crude product. Stirring in THF/water, filtration and washing with water gives the title compound; MS-ES+: (M+H)+=431; elemental analysis for C, H, N and F within 0.4% of calculated value.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=5)=[C:34]([Cl:46])[CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:47]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:56])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38]([CH2:39][C:40]5[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=5)=[O:56])=[C:34]([Cl:46])[CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:47]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4cccnc4)c(Cl)c2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cccnc4)c(Cl)c2)CCN3CC(C)C)cc1
Reaction time: 0.25 h
Yield: 30.6 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[3-chloro-4-[(3-pyridinylmethyl)sulfanyl]phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (0.30 g) in methylene chloride (9.0 ml) was added dropwise a solution of m-chloroperbenzoic acid (93 g) in methylene chloride (6.0 ml) at −78° C., and the mixture was stirred for 15 minutes. To the reaction mixture was added an aqueous solution of saturated sodium thiosulfate. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[3-chloro-4-[(3-pyridinylmethyl)sulfinyl]phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 244) (94 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]#[C:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>C(Cl)Cl.N1C=CC=CC=1.C(OCC)(=O)C>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[C:9]#[C:10][C:11]2[CH:12]=[CH:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:19][CH:20]=2)(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: COC(=O)c1ccc(C#Cc2cc(Cl)ccc2N)cc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1ccc(C#Cc2cc(Cl)ccc2NS(=O)(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.5 %

Procedure:
To a solution of methyl 4-[2-(2-amino-5-chlorophenyl)ethynyl]benzoate (136 mg; prepared in Reference Example 16.) in methylene chloride (2 ml), pyridine (77 μl) and 4-chlorobenzenesulfonyl chloride (106 mg) were added at 0° C. under an atmosphere of argon. The mixture was stirred for 24 hours at room temperature. The reaction mixture was diluted with ethyl acetate, washed, dried over and concentrated under the reduced pressure. The residue was purified on silica gel column chromatography (hexane-AcOEt) to give the title compound (207 mg) having the following physical data.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:21])=[C:4]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[C:14]([C:16]#[N:17])[CH:13]=[CH:12][C:11]=2[CH2:18]O)[CH:5]=[CH:6][CH:7]=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.C(P(CCCC)CCCC)CCC>C1COCC1>[Br:1][C:2]1[C:3]([CH3:21])=[C:4]([N:8]2[C:9](=[O:20])[C:10]3[C:11](=[CH:12][CH:13]=[C:14]([C:16]#[N:17])[CH:15]=3)[CH2:18]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Br)cccc1NC(=O)c1cc(C#N)ccc1CO
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: Cc1c(Br)cccc1N1Cc2ccc(C#N)cc2C1=O
Temperature: 25 °C
Yield: 62.1 %

Procedure:
Step 2 A solution of N-(3-bromo-2-methylphenyl)-5-cyano-2-(hydroxymethyl)benzamide (170 mg, 0.492 mmol) in THF (20 mL) was treated with di-tert-butyl azodicarboxylate (113 mg, 0.492 mmol) and tributylphosphine (0.119 mL, 0.492 mmol) and stirred at rt. After 2 h the mixture was concentrated and the residue was column chromatography (eluting with a gradient from 90:10 to 50:50 hexane-EtOAc) to provide 2-(3-bromo-2-methylphenyl)-3-oxoisoindoline-5-carbonitrile (100 mg, 62%) as a white solid. 1H NMR (400 MHz, chloroform-d) δ 8.07 (1H, d, J=8.1 Hz), 7.82-7.89 (2H, m), 7.64 (1H, dd, J=7.8, 1.4 Hz), 7.13-7.25 (2H, m), 4.78 (2H, s), 2.30 (3H, s). Mass spectrum m/z 327, 329 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21].[CH3:22]C1(C)COC2=CC3OCC4(C=3C=C12)C1C(=CC=CC=1)NC4=O.IC.BrCC1OC(C(F)(F)F)=CC=1>>[CH3:22][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21]
Reactant: CC1(C)COc2cc3c(cc21)C1(CO3)C(=O)Nc2ccccc21
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Agent: FC(F)(F)c1ccc(CBr)o1
Solvent: CI
Product: CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21

Procedure:
Following the procedure described in EXAMPLE 10.21, and making non-critical variations using spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 5,5-dimethyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and iodomethane to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound was obtained (72%) as a white solid: mp 142-144° C.; MS (ES+) m/z 296.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[SH:9].[C:10]([OH:14])(=[O:13])[CH:11]=[CH2:12]>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9][CH2:12][CH2:11][C:10]([OH:14])=[O:13]
Reactant: C=CC(=O)O
Reactant: Sc1cccc(Cl)c1Cl
Product: O=C(O)CCSc1cccc(Cl)c1Cl
Temperature: 50 °C
Reaction time: 3 h
Yield: 55.2 %

Procedure:
2,3-Dichlorothiophenol (4.94 g, 28 mmol) was placed in a flask with acrylic acid (2.11 g, 29 mmol) and stirred at 50° C. for 3 hours. The reaction mixture was poured into 10% Na2Cl3 and extracted with ether. The aqueous layer was acidified with concentrated hydrochloric acid, extracted with ether, washed with brine, dried over MgSO4, and concentrated in vacuo to give the 3-(2,3-dichlorophenylthio)propanoic acid (3.88 g), contaminated with some acrylic acid, as a clear oil which was used without further purification in the next step.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([OH:16])=O)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:18][NH:19][O:20][CH3:21].ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.C(N=C=NCCCN(C)C)C.Cl>C1COCC1>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C@H:12]([C:14](=[O:16])[N:19]([O:20][CH3:21])[CH3:18])[CH3:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)[C@H](C)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
N-Benzyloxycarbonyl-L-alanine (6.5 g, 28.5 mmol), N,O-dimethylhydroxylamine hydrochloride (3.4 g, 36.2 mmol), and N-hydroxybenzotriazole (4.8 g, 34.8 mmol) were dissolved in THF (32 mL) and cooled to 0° C. under N2. Diisopropylethylamine (12.3 mL, 71.3 mmol) was slowly added, maintaining the temperature below 25° C. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (7.0 g, 36.2 mmol) was then added slowly, maintaining the temperature at 15-25° C. The slurry was stirred overnight at room temperature, and then cooled to 0° C. 1N Aqueous HCl (36 mL) was added slowly, and the mixture was warmed to room temperature and extracted with EtOAc. The combined organic layers were washed with 10% aqueous HCl, saturated aqueous NaHCO3, and brine, and then concentrated and purified by silica gel chromatography to give the title compound.
Reaction SMILES: [C:1]1([C:13]2[N:17]([CH:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)[N:16]=[N:15][N:14]=2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1.[ClH:31]>>[ClH:31].[NH:21]1[CH2:22][CH2:23][CH:18]([N:17]2[C:13]([C:1]3[C:11]4=[C:12]5[C:7](=[CH:8][CH:9]=[CH:10]4)[CH2:6][CH2:5][CH2:4][N:3]5[CH:2]=3)=[N:14][N:15]=[N:16]2)[CH2:19][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2nnnc2-c2cn3c4c(cccc24)CCC3)CC1
Agent: Cl
Product: c1cc2c3c(c1)c(-c1nnnn1C1CCNCC1)cn3CCC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-1-carboxylic acid (200 mg, 1.00 mmol) in dry N,N-dimethylformamide (3 mL) were added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU) (417 mg, 1.10 mmol) and disopropylethyl amine (0.35 mL, 2.0 mmol), and tert-butyl 4-aminopiperidine-1-carboxylate (1.00 mmol). The reaction was stirred at room temperature and monitored by LC-MS. Upon completion, the mixture was diluted with ethyl acetate (50 mL) and washed with water (25 mL), sat. NaHCO3 solution (25 mL) and brine. The organic phase was separated and dried over sodium sulfate. After removing solvent, the crude product was purified by silica gel chromatography (EtOAc/Hexanes) to give the desired product tert-butyl 4-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-1-carboxamido)piperidine-1-carboxylate (77) as a white solid. Mp=187-189° C., LC/MS [M+H]: 384.22. Step 2: Amide (77) (1 eq), was dissolved in dicholoromethane (15 mL/1 mmol) and phosphorus pentachloride (1 eq) was added. The mixture was stirred at ambient temperature for 2 hours then trimethylsilyl azide (8 eq) was added. Mixture was stirred at room temperature for additional 4 hours and reaction progress was followed by LC-MS. Upon completion, saturated NaHCO3 solution was added and the mixture was extracted with dicholoromethane (30 mL/mol), Combined organics were combined and dried Na2SO4 Solvent was removed and the crude product was purified by silica gel chromatography (EtOAc/Hexanes, 25-40% gradient) to give the desired product tert-butyl 4-(5-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-1H-tetrazol-1-yl)piperidine-1-carboxylate (78) as a solid. LC/MS [M+H]: 409.23. Step 3: Carbamate (78) (1 equivalent) was dissolved in dicholoromethane and HCl (20 equivalent, 4 M in dioxane) was added and stirred at room temperature for 2 to 4 hours. Concentration of the solution under reduced pressure gave the pure desired product 1-(1-(piperidin-4-yl)-1H-tetrazol-5-yl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline hydrochloride (79) as a white solid Mp=198-200° C., LC/MS [M+H]: 309.18.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[F:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[C@@:18]1([CH2:22][N:23]2[CH:27]=[N:26][CH:25]=[N:24]2)[C@H:20]([CH3:21])[O:19]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.C(OCC)(=O)C>[F:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[C@:18]([OH:19])([C@H:20]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1)[CH3:21])[CH2:22][N:23]1[CH:27]=[N:26][CH:25]=[N:24]1
Reactant: c1ccc2[nH]ncc2c1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H](N1NCc2ccccc21)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 180 °C
Reaction time: 0.08 h
Yield: 44 %

Procedure:
To a suspension of indazole (0.059 g, 0.5 mmol), 1-(((2R,3S)-2-(2,4-difluorophenyl)-3-methyloxiran-2-yl)methyl)-1H-1,2,4-triazole (0.105 g, 0.416 mmol) in N,N′-dimethylformamide (2.5 ml) was added anhydrous potassium carbonate (0.069 g, 0.5 mmol), followed by radiating microwaves thereon with stirring at 180° C. for 5 min. Thereafter, the addition of water (0.5 ml) at 0° C. terminated the reaction. The reaction solution was diluted with ethyl acetate (10 ml) and washed with saturated ammonium chloride solution (10 ml) and then with brine (10 ml). The organic layer was dried over anhydrous magnesium sulfate and concentrated in a vacuum. The crude product was purified by chromatography on silica gel to give the title compound (Yield 44%).
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.N1C=CC=CC=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>O>[C:24]([O:1][CH2:2][C:3]1([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)[CH2:4][CH2:5][C:6](=[O:9])[CH2:7][CH2:8]1)(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(C2(CO)CCC(=O)CC2)cc1
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(C2(COC(C)=O)CCC(=O)CC2)cc1
Reaction time: 20 h
Yield: 68 %

Procedure:
The 4-hydroxymethyl-4-(4-methoxyphenyl)cyclohexanone is dissolved in 12 ml. of pyridine and 6 ml. of acetic anhydride. After about 20 hours of standing at room temperature, the mixture is poured into ice and water. The gum that precipitates is extracted with ether. The organic layer is washed successively with water, 2.5 N hydrochloric acid, water, sodium bicarbonate solution and brine, and evaporated to dryness. The solid residue is recrystallized from a mixture of ether and Skellysolve B to give 2.95 g. (68% yield) of 4-acetoxymethyl-4-(4-methoxyphenyl)cyclohexanone, having a melting point of 86.5° to 88°C.
Reaction SMILES: C([O:5][C:6]([NH:8][CH2:9][C:10]1[S:11][CH:12]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:14]=1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(OC(=O)C)(=O)C>C(O)=O>[CH:6]([NH:8][CH2:9][C:10]1[S:11][CH:12]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:14]=1)=[O:5]
Reactant: CCOC(=O)c1csc(CNC(=O)OC(C)(C)C)n1
Solvent: CC(=O)OC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: O=CO
Product: CCOC(=O)c1csc(CNC=O)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 102.5 %

Procedure:
To 1.50 g of the above-obtained ethyl 2-(tert-butoxycarbonylamino)methylthiazole-4-carboxylate was added 5 ml of trifluoroacetic acid, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure. A saturated aqueous solution of sodium hydrogencarbonate was added to the residue to adjust the pH of the mixture to approximately 8. To this was added 30 ml of dichloromethane. To the mixture was added with vigorous stirring a mixture which had been prepared by reacting 1 ml of formic acid with 1 ml of acetic anhydride at 50° C. for 30 minutes, and the resulting mixture were stirred for an additional one hour. The organic layer was separated, and the aqueous layer was extracted twice with dichloromethane. The combined organic layers were dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure to give 1.15 g of crude ethyl 2-(formylamino)methylthiazole-4-carboxylate. This compound was dissolved in 30 ml of dichloromethane. To the solution was added 1.2 ml of phosphorus oxychloride at -20 C., and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure. To this was added 12 ml of phosphorus oxychloride, and the mixture was stirred at 100° C. for 30 minutes. The reaction solution was cooled to room temperature, and then concentrated to dryness under reduced pressure. The residue was dissolved in 30 ml of water, and the solution was washed with 20 ml of dichloromethane. To this was added sodium hydrogencarbonate to adjust the pH of the solution to 8, and the mixture was extracted with dichloromethane (30 ml×2). The combined organic layers were dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure to give 0.885 g (yield 85%) of the title compound as light brown crystals.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[C:10]([S:12][CH3:13])[N:9]=[C:8]([NH2:14])[N:7]=1.[Br:15]N1C(=O)CCC1=O>C(O)(=O)C>[Br:15][C:11]1[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[N:7][C:8]([NH2:14])=[N:9][C:10]=1[S:12][CH3:13]
Reactant: CSc1cc(-c2ccco2)nc(N)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Product: CSc1nc(N)nc(-c2ccco2)c1Br
Reaction time: 48 h
Yield: 34.2 %

Procedure:
To a stirred solution of 197 mg (0.95 mmol) 4-furan-2-yl-6-methylsulfanyl-pyrimidin-2-ylamine in 15 ml acetic acid was added 178 mg (1.00 mmol) N-bromosuccinimide and stirring continued at room temperature for 48 h. The reaction mixture was then concentrated in vacuo and the residue partitioned between ether and water. The organic phase was dried over, sodium sulfate and concentrated in vacuo. Chromatography (ethyl acetate/hexane 1/2) followed by trituration in ether/hexane then afforded 93 mg (34%) 5-bromo-4-furan-2-yl-6-methylsulfanyl-pyrimidin-2-ylamine as a yellow crystalline solid. EI-MS m/e (%): 287 (M{81Br}+, 44), 285 (M{79Br}+, 42), 206 ([M—Br]+, 100).
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH2:9][CH2:10][N:11]1[C:15]([CH3:16])=[CH:14][C:13]([C:17]([NH2:19])=O)=[N:12]1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl>[OH:8][CH2:9][CH2:10][N:11]1[C:15]([CH3:16])=[CH:14][C:13]([C:17]#[N:19])=[N:12]1
Reactant: Cc1cc(C(N)=O)nn1CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Cc1cc(C#N)nn1CCO
Reaction time: 0.17 h
Yield: 183.8 %

Procedure:
Under a nitrogen atmosphere, triethylamine (17.9 g, 177 mmol) was added to a slurry of 1-(2-hydroxyethyl)-5-methyl-1H-pyrazole-3-carboxamide (7.0 g, 41.4 mmol) in dichloromethane (70 mL). The mixture was cooled in an ice bath and then a solution of trifluoroacetic anhydride (15.6 g, 74.2 mmol) in dichloromethane (70 mL) was added over a period of 10 minutes. All of the solids dissolved to provide a cloudy solution. After 1 hour additional triethylamine (70.6 mmol) was added and the reaction mixture was cooled in an ice bath. Trifluoroacetic anhydride (35.3 mmol) was added neat over a period of 5 minutes. The reaction mixture was stirred for 10 minutes then the ice bath was removed and the reaction mixture was stirred for 30 minutes. The reaction mixture was diluted with 2 M aqueous sodium carbonate (100 mL) and water (100 mL) then extracted with chloroform (×3). The extracts were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 11.5 g of 1-(2-hydroxyethyl)-5-methyl-1H-pyrazole-3-carbonitrile a brown oil.
Reaction SMILES: C1(S([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:19]3[N:20]=[C:21]4[C:27]([C:28]([C:30]5([CH3:36])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]5)=[O:29])=[CH:26][NH:25][C:22]4=[N:23][CH:24]=3)=[CH:11]2)(=O)=O)C=CC=CC=1>C(Cl)Cl>[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([C:19]2[N:20]=[C:21]3[C:27]([C:28]([C:30]4([CH3:36])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]4)=[O:29])=[CH:26][NH:25][C:22]3=[N:23][CH:24]=2)=[CH:11]1
Reactant: CC1(C(=O)c2c[nH]c3ncc(-c4cn(S(=O)(=O)c5ccccc5)c5ccccc45)nc23)CCCCC1
Solvent: ClCCl
Product: CC1(C(=O)c2c[nH]c3ncc(-c4c[nH]c5ccccc45)nc23)CCCCC1

Procedure:
[2-(1H-Indol-3-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-(1-methyl-cyclohexyl)-methanone was prepared following the same procedure by using [2-(1-benzenesulfonyl-1H-indol-3-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-(1-methyl-cyclohexyl)-methanone as starting material. The product was obtained in 70% after SiO2 chromatography (DCM/[DCM/MeOH 9.5/1] 10/0 to 0/10).