Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4](Cl)=[O:5].[C:7]1([C:13]2[CH:14]=[C:15]3[C:21]([NH2:22])=[N:20][NH:19][C:16]3=[N:17][N:18]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl>N1C=CC=CC=1>[C:7]1([C:13]2[CH:14]=[C:15]3[C:21]([NH:22][C:4](=[O:5])[CH2:3][CH2:2][CH3:1])=[N:20][NH:19][C:16]3=[N:17][N:18]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCCC(=O)Cl
Reactant: Nc1n[nH]c2nnc(-c3ccccc3)cc12
Agent: Cl
Solvent: c1ccncc1
Product: CCCC(=O)Nc1n[nH]c2nnc(-c3ccccc3)cc12

Procedure:
n-Butyryl chloride (120 μl, 0.73 mmol) was added to a solution of 5-phenyl-1H-pyrazolo[3,4-c]pyridazin-3-ylamine (Description 8; 100 mg, 0.47 mmol) in pyridine (0.5 mL). The reaction mixture was stirred at reflux for 16 hours, then allowed to cool. The solution was acidified to pH 1 with 5N HCl, and the resulting solids were filtered and dried. Purification by column chromatography (5% MeOH/CHCl3) afforded the title compound as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:10][NH2:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)(C)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH2:10][NH:11][CH2:10][C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H](CN)Cc1ccccc1
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N[C@H](CNC[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)Cc1ccccc1
Temperature: 100 °C
Yield: 84.2 %

Procedure:
The product from Example 1B (0.54 g, 2.16 mmol) and the product from Example 1C (0.50 g, 2.14 mmol) in isopropanol (5 mL) were placed in a sealed tube and heated at 100° C. for 18 hours. The mixture was concentrated and the residue was purified by column chromatography on silica gel (24:1 CHCl3:methanol) to provide the title compound as a colorless solid (0.44 g, 42%). Rf=0.55 (CHCl3:methanol, 9:1); 1H NMR (CDCl3) δ 7.30-7.14 (m, 10H), 4.61 (br s, 2H), 3.87 (m, 2H), 2.87-2.77 (m, 2H), 2.72 (dd, J=7.4, 13.6 Hz, 2H), 2.57 (d, J=5.8 Hz, 4H), 1.41 (s, 18H); MS (APCl+) m/z 484 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:45])[NH:13][CH2:14][C:15]([N:17]2[CH:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:20]([CH3:28])[CH2:19][C:18]2([C:36](=[O:44])[NH:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:16])[CH:8]=[CH:9][CH:10]=1)=[O:4].[OH-].[K+]>O.CO>[C:32]([O:31][C:29]([C:18]1([C:36](=[O:44])[NH:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:19][CH:20]([CH3:28])[CH:21]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:17]1[C:15](=[O:16])[CH2:14][NH:13][C:12](=[O:45])[NH:11][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=1)[C:3]([OH:4])=[O:2])=[O:30])([CH3:33])([CH3:34])[CH3:35]
Reactant: COC(=O)c1cccc(NC(=O)NCC(=O)N2C(c3ccccc3)C(C)CC2(C(=O)Nc2ccccc2)C(=O)OC(C)(C)C)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1CC(C(=O)Nc2ccccc2)(C(=O)OC(C)(C)C)N(C(=O)CNC(=O)Nc2cccc(C(=O)O)c2)C1c1ccccc1
Yield: 31.3 %

Procedure:
A The reaction is carried out in a way analogous to that described in Example 3, but from 3.6 g of tert-butyl (2RS,4RS,5SR)-1-{2-[3-(3-(methoxycarbonyl)phenyl)ureido]acetyl}-4-methylphenylcarbamoyl-5-phenylpyrrolidine-2-carboxylate and 0.33 g of potassium hydroxide in a mixture of 20 cm3 of distilled water and 60 cm3 of methanol. After treatment, there are obtained 1.1 g of (2RS,4RS,5SR)-3-{3-[2-(2-tert-butoxycarbonyl-5-phenyl-4-methylphenylcarbamoyl-1-pyrrolidinyl)-2-oxoethyl]ureido}benzoic acid, melting at 238° C.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH2:7][CH2:8][OH:9])=[CH:4][CH:3]=1.CO[CH:12](OC)[CH2:13][NH2:14]>>[Br:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][O:9][CH:12]([CH2:13][NH2:14])[C:4]=2[CH:3]=1
Reactant: COC(CN)OC
Reactant: OCCc1ccc(Br)s1
Product: NCC1OCCc2sc(Br)cc21

Procedure:
The title compound was synthesized from 2-(5-bromothiophen-2-yl)ethanol and aminoacetaldehyde dimethylacetal according to General Procedure A.
Reaction SMILES: [F:1][C:2](=[C:7]([F:9])[F:8])[CH2:3][C:4]([Cl:6])=[O:5].Cl.[NH2:11][CH2:12][CH2:13][SH:14]>CCOCC>[ClH:6].[F:1][C:2](=[C:7]([F:9])[F:8])[CH2:3][C:4](=[O:5])[S:14][CH2:13][CH2:12][NH2:11]
Reactant: O=C(Cl)CC(F)=C(F)F
Reactant: NCCS
Agent: Cl
Solvent: CCOCC
Product: NCCSC(=O)CC(F)=C(F)F
Temperature: 25 °C
Yield: 33.9 %

Procedure:
A mixture of 3,4,4-trifluoro-3-butenoyl chloride (2.5 g, 0.0158 mole) and 2-aminoethanethiol hydrochloride (1.14 g, 0.010 mole) is slowly heated to reflux for 15 min. The mixture is cooled to room temperature and treated with dry ether and filtered. The product is recrystallized from absolute ethanol to give 0.8 g of the title compound as a off-white solid, a 34% yield. m.p. 95°-115° C.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8])=[O:5].Br[CH2:16][C:17]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:18].C(OCC)(=O)C>[Cl-].[Na+].O>[CH2:2]([O:3][C:4](=[O:5])[CH:6]([C:7](=[O:8])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH2:16][C:17]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:18])[CH3:1]
Reactant: O=C(CBr)C1CCCCC1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C(CC(=O)C1CCCCC1)C(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a stirred slurry of 1.44 g (36 mmol) sodium hydride, obtained as a 60% dispersion in mineral oil, in 45 mL anhydrous THF, at 0° C., was added dropwise 6.48 g (33.75 mmol) ethyl benzoyl acetate. The resulting slurry was stirred at 0° C. for 0.5 hr, upon which time was added dropwise the entire sample of 2-bromo-1-cyclohexyl-ethanone obtained in Step 1. The reaction was stirred at room temperature for 24 hr and poured into 0.4 L brine. The brine was shaken with ethyl acetate twice and the combined organic extracts were dried over MgSO4 and concentrated to afford 14.37 g (45.4 mmol, >100% yield) of 2-benzoyl-4-cyclohexyl-4-oxo-butyric acid ethyl ester. The product was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]C(Cl)(Cl)Cl)=[CH:4][N:3]=1>CN(C=O)C.O.[Cu]I>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[S:15][C:4]=2[N:3]=1
Reactant: Clc1ncc(-c2ccccc2SC(Cl)(Cl)Cl)c(Cl)n1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ncc2c(n1)sc1ccccc12
Temperature: 110 °C
Yield: 38.4 %

Procedure:
A solution of 2,4-dichloro-5-(2-((trichloromethyl)thio)phenyl)pyrimidine (0.618 g, 1.650 mmol) and copper(I) iodide (0.031 g, 0.165 mmol) in DMF (24.63 ml) was degassed with nitrogen and heated at 110° C. overnight. The reaction solution was cooled to room temperature, diluted with water and filtered. The resulting brown solids were washed with water and a small volume of EtOH. The aqueous layer was extracted twice with EtOAc, combined with the solids, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel, eluted with 10-20% EtOAc/heptanes (v/v), affording 0.14 g (38% yield) of the 2-chlorobenzo[4,5]thieno[2,3-d]pyrimidine as white solids.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:13][CH2:14][CH2:15][CH2:16][OH:17]>O>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: NCCCO
Reactant: Clc1ccc2c(Cl)ccnc2c1
Solvent: O
Product: OCCCNc1ccnc2cc(Cl)ccc12
Temperature: 135 °C
Reaction time: 24 h
Yield: 90.1 %

Procedure:
A mixture of 4,7-dichloroquinoline (25.35 g, 0.128 mol) and 3-aminopropanol (120 mL, 1.57 mol) were heated with stirring at 130-140° C. for 24 hours. After cooling, the reaction mixture was poured into water (500 mL) and filtered, and the solid residue was dried then boiled in ethyl acetate (250 mL) to give the title compound (27.3 g, 90%) as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:19]([O-:21])=[O:20])[C:5]([CH:8](C(OCC)=O)C(OCC)=O)=[N:6][CH:7]=1.Cl>O>[Br:1][C:2]1[CH:3]=[C:4]([N+:19]([O-:21])=[O:20])[C:5]([CH3:8])=[N:6][CH:7]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ncc(Br)cc1[N+](=O)[O-]
Agent: Cl
Solvent: O
Product: Cc1ncc(Br)cc1[N+](=O)[O-]
Temperature: 105 °C
Yield: 88.8 %

Procedure:
To diethyl (5-bromo-3-nitropyridin-2-yl)malonate (66 g, 0.18 mol) was added water (250 mL) and 12 M HCl (360 mL, 4.32 mol). The mixture was heated at 105° C. until TLC showed starting material was consumed. The reaction mixture was then allowed to cool to rt and brine (0.67 L) was added. The organic solution was separated and the aqueous solution was extracted with DCM (3×0.67 L). The organic solutions were combined, washed with brine, sat. aq. NaHCO3, and brine again, dried over Na2SO4, filtered and concentrated to give 5-bromo-2-methyl-3-nitropyridine (34.7 g, 75%) as a yellow solid.
Reaction SMILES: II.C(Br)C.Br[C:7]1[CH:24]=[CH:23][C:10]([O:11][CH2:12][CH2:13][N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:9][CH:8]=1.[OH:25][C:26]1[CH:27]=[CH:28][C:29]([C:32](N(OC)C)=[O:33])=[N:30][CH:31]=1>C1COCC1>[OH:25][C:26]1[CH:27]=[CH:28][C:29]([C:32]([C:7]2[CH:24]=[CH:23][C:10]([O:11][CH2:12][CH2:13][N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:9][CH:8]=2)=[O:33])=[N:30][CH:31]=1
Reactant: CON(C)C(=O)c1ccc(O)cn1
Reactant: CN(CCOc1ccc(Br)cc1)C(=O)OC(C)(C)C
Agent: II
Solvent: CCBr
Solvent: C1CCOC1
Product: CN(CCOc1ccc(C(=O)c2ccc(O)cn2)cc1)C(=O)OC(C)(C)C
Temperature: 55 °C
Reaction time: 0.5 h

Procedure:
Mg (3.5 eq) was added to a 3-neck round bottom flask containing 50 mL anhydrous THF. The mixture was heated to 55° C. Iodine chips (2 grains) were added in one lot followed by addition of 0.1 mL ethyl bromide. Tert-butyl 2-(4-bromophenoxy)ethyl(methyl)carbamate (3.0 eq) was dissolved in 30 mL anhydrous THF, 3 mL of this solution was added at once to Mg-THF suspension. The reaction was initiated after 30 min and reflux started. The remaining solution of tert-butyl 2-(4-bromophenoxy)ethyl(methyl)carbamate was added dropwise in such speed that the reaction mixture remained reflux. After addition, the reaction mixture was further reflux for 2 h and cooled to rt. 5-Hydroxy-N-methoxy-N-methylpicolinamide (1.0 eq) in 20 mL THF was added dropwise at rt, stirred for 30 min. at rt., quenched with sat NH4Cl (aq), and extracted with EtOAc. The extract was dried, concentrated, and purified by column chromatography to give the desired product.
Reaction SMILES: [C:1]([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Cl:15][S:16](O)(=[O:18])=[O:17]>ClCCl>[C:1]([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][C:13]([S:16]([Cl:15])(=[O:18])=[O:17])=[CH:14][C:7]=2[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: O=S(=O)(O)Cl
Reactant: CC(=O)N1CCc2ccccc2CC1
Solvent: ClCCl
Product: CC(=O)N1CCc2ccc(S(=O)(=O)Cl)cc2CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 45 %

Procedure:
A solution of 3-acetyl-2,3,4,5-tetrahydro-1H-3-benzazepine (4.0 g, 0.021 mol) in dichloromethane (25 ml) was added dropwise to a stirred solution of chlorosulphonic acid in dichloromethane (25 ml) at −70° C. under argon. After warming to room temperature, the reaction was stirred for 18 h before being quenched in ice/water (200 ml). The resulting mixture was extracted with ethyl acetate (3×100 ml), dried (Na2SO4) and the solvent evaporated in vacuo to give the title compound (2.74 g, 45%) as a pale yellow solid.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([SH:20])[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]3[O:35][CH2:34][CH2:33][O:32][C:29]=3[CH:30]=2)[N:25]=[CH:24][N:23]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(O)(C)C>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:22]3[C:31]4[C:26](=[CH:27][C:28]5[O:35][CH2:34][CH2:33][O:32][C:29]=5[CH:30]=4)[N:25]=[CH:24][N:23]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(S)c2)no1
Reactant: Clc1ncnc2cc3c(cc12)OCCO3
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)O
Product: CC(C)(C)c1cc(NC(=O)Nc2cccc(Sc3ncnc4cc5c(cc34)OCCO5)c2)no1
Temperature: 60 °C

Procedure:
According to the procedure described in Example 50, a mixture of the intermediate 1-(5-tert-butylisoxazol-3-yl)-3-(3-mercaptophenyl)urea described in Example 44A (0.105 g, 0.36 mmol), 4-chloro-7,8-dihydro-[1,4]dioxino[2,3-g]quinazoline described in Example 14A (0.111 g, 0.5 mmol), and Cs2CO3 (0.326 g, 1 mmol) in isopropanol (7 mL) was heated at 60° C. for 2 hours, to afford 1-(5-tert-butylisoxazol-3-yl)-3-[3-(7,8-dihydro-[1,4]dioxino[2,3-g]quinazolin-4-ylthio]phenyl)urea as solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[C:4]([Br:10])[C:3]=1[O:11][C:12](=[O:16])[O:13][CH2:14]I.[CH3:17][O:18][C:19]([NH:21][O:22][CH2:23][C:24]([O-:26])=[O:25])=[O:20].[Na+].CCOCC>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[C:4]([Br:10])[C:3]=1[O:11][C:12]([O:13][CH2:14][O:26][C:24](=[O:25])[CH2:23][O:22][NH:21][C:19]([O:18][CH3:17])=[O:20])=[O:16]
Reactant: N#Cc1cc(Br)c(OC(=O)OCI)c(Br)c1
Reactant: COC(=O)NOCC(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)NOCC(=O)OCOC(=O)Oc1c(Br)cc(C#N)cc1Br
Reaction time: 16 h

Procedure:
A solution of carbonic acid iodomethyl ester 2,6-dibromo-4-cyanophenyl ester (0.20 g, 0.43 mmol) in DMF (2 mL) was added sodium methoxycarbonylaminooxyacetate (0.89 g, 0.52 mmol). The mixture was stirred for 16 h. Ether was added to the reaction and washed with water then brine then dried over sodium sulfate, filtered, and concentrated to an oil. Silica gel chromatography (2:1 EtOAc:hexanes) afforded the desired product as a clear oil. 1H-NMR (300 MHz, CDCl3) δ (ppm): 3.80 (s, 3H), 4.57 (s, 2H), 5.99 (s, 2H), 7.90 (s, 2H), 8.02 (bs, 1H). Mp=110-111° C.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:18]([O:20]CC)=[O:19])[C:7]3[C:12]([CH3:13])=[N:11][N:10]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:8]=3[N:9]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C>[CH:1]1([C:4]2[CH:5]=[C:6]([C:18]([OH:20])=[O:19])[C:7]3[C:12]([CH3:13])=[N:11][N:10]([C:14]([CH3:17])([CH3:15])[CH3:16])[C:8]=3[N:9]=2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cc(C2CC2)nc2c1c(C)nn2C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nn(C(C)(C)C)c2nc(C3CC3)cc(C(=O)O)c12
Reaction time: 1 h

Procedure:
The title compound was prepared in the same manner as described for intermediate 46 using ethyl 6-cyclopropyl-1-(1,1-dimethylethyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (240 mg, 0.796 mmol), sodium hydroxide (4 mL, 4.00 mmol), and ethanol (30 mL), wherein the stir time was 1 h. The final product was collected as 0.210 g (96%). LCMS E-S (M+H)=274.4. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.05 (m, 4H) 1.70 (s, 9H) 2.33 (m, 1H) 2.51 (s, 3H) 7.46 (s, 1H) 13.70 (br. s., 1H).
Reaction SMILES: C1(C[N:8]2[CH2:12][CH2:11][CH:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[CH2:9]2)C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].CO.O>[NH:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:9]1
Reactant: c1ccc(CN2CCC(c3ccccn3)C2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: c1ccc(C2CCNC2)nc1
Temperature: 25 °C
Yield: 74.9 %

Procedure:
To a suspension of 2-[1-(phenylmethyl)-3-pyrrolidinyl]pyridine (7.15 g, 30.0 mmol) and 10% palladium on charcoal catalyst (1.90 g) in methanol (120 mL) was added dropwise a solution of ammonium formate (7.57 g, 120 mmol) in water (30 mL). The mixture was heated at reflux for 30 minutes, allowed to cool to room temperature, and filtered. The filtrate was concentrated under reduced pressure, the residue was taken up in water (10 mL), and the solution was made basic with concentrated ammonia and extracted with dichloromethane (4×15 mL). The organic extracts were combined, dried over anhydrous potassium carbonate, and concentrated to a yellow oil. This crude product was chromatographed (silica gel, chloroform-methanol-ammonia 75:25:5) to give the title compound (3.33 g, 75%) as a faint yellow liquid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:6]([OH:8])=[O:7])#[N:2].[CH3:16][Si](C=[N+]=[N-])(C)C>ClCCl.CO>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:6]([O:8][CH3:16])=[O:7])#[N:2]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C#N
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1ccc(OC(C)C)c(C#N)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99.9 %

Procedure:
To 3-cyano-4-isopropoxybenzoic acid (0.3 g, 1.462 mmol) in a mixture of dichloromethane (4 mL) and MeOH (1.00 mL) was added trimethylsilyldiazomethane (0.950 mL, 1.9 mmol) dropwise over a period of 3 min at 0° C. The pale yellow solution was allowed to come to room temperature over a period of 15 min. and stirred at room temperature for 1.5 h. Excess trimethylsilyldiazomethane was quenched by the slow addition of acetic acid (˜0.5 ml) at room temperature until the yellow color was discharged. The reaction mixture was concentrated and partitioned between ether (20 mL) and sat. aq. sodium bicarbonate (10 mL). The ether layer was washed with brine (10 mL), dried over sodium sulfate and concentrated. The resulting oil was azeotroped with THF (5 mL) and dried under high vacuum to yield methyl 3-cyano-4-isopropoxybenzoate (0.32 g, 1.460 mmol, 100% yield) as an oil. LC/MS M+1=219.9.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[Br:9][CH:10]([CH2:18][CH3:19])[C:11](=O)[CH2:12][C:13](OC)=[O:14].[OH-].[Na+]>>[Br:9][CH:10]([C:11]1[N:8]=[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]2[C:13](=[O:14])[CH:12]=1)[CH2:18][CH3:19]
Reactant: CCC(Br)C(=O)CC(=O)OC
Reactant: Cc1cccc(N)n1
Agent: [Na+]
Agent: [OH-]
Product: CCC(Br)c1cc(=O)n2c(C)cccc2n1
Temperature: 110 °C
Reaction time: 5 h
Yield: 64.5 %

Procedure:
To a manually stirred polyphosphoric acid (80 g, 800 mmol) in a 1000 mL beaker at room temperature was added 6-methyl-2-pyridinamine (15 g, 140 mmol), followed by methyl 4-bromo-3-oxohexanoate (37.3 g, 167 mmol). The mixture was heated with stirring at 110° C. for 5 h. After cooling, the dark slurry was transferred into 300 g of ice. The pH of the mixture was adjust to 6-7 with 10% sodium hydroxide. The precipitate was collected by filtration under reduced pressure, washed with water, and air dried to yield the desired product (25.4 g, 64.8%). LCMS calculated for C12H14BrN2O (M+H)+: m/z=281.0. Found: 281.2. 1H NMR (DMSO-d6, 300 MHz) δ 7.66 (1H, d, J=9.0 and 6.9 Hz), 7.39 (1H, d, J=9.0 Hz), 6.90 (1H, d, J=6.9 Hz), 6.33 (1H, s), 4.91 (1H, t, J=7.5 Hz), 2.91 (3H, s), 2.15 (2H, qd, J=7.5 and 7.5 Hz), 0.93 (3H, t, J=7.5 Hz) ppm.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([CH2:9][NH2:10])=[N:5][CH:6]=[CH:7][N:8]=1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.ON1C2C=CC=CC=2N=N1.[CH2:42]([O:49][C:50]([NH:52][CH2:53][C@H:54]1[CH2:59][CH2:58][C@H:57]([C:60](O)=[O:61])[CH2:56][CH2:55]1)=[O:51])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>C(Cl)Cl>[CH2:42]([O:49][C:50](=[O:51])[NH:52][CH2:53][C@H:54]1[CH2:59][CH2:58][C@H:57]([C:60](=[O:61])[NH:10][CH2:9][C:4]2[C:3]([Cl:2])=[N:8][CH:7]=[CH:6][N:5]=2)[CH2:56][CH2:55]1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: O=C(NC[C@H]1CC[C@H](C(=O)O)CC1)OCc1ccccc1
Reactant: NCc1nccnc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC[C@H]1CC[C@H](C(=O)NCc2nccnc2Cl)CC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of C-(3-chloropyrazin-2-yl)methylamine hydrochloride salt (0.100 g, 0.533 mmol) in DCM (1.35 mL) was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.16 g, 0.83 mmol), N,N-diisopropylethylamine (0.14 mL, 0.83 mmol), 1-hydroxybenzotriazole (0.075 g, 0.56 mmol) and trans-4-({[(benzyloxy)carbonyl]amino}methyl)cyclohexanecarboxylic acid (0.21 g, 0.70 mmol). The reaction was stirred at rt overnight then diluted with DCM, washed with sat. NaHCO3 (aq) and brine, then dried over Na2SO4 and the solvent removed in vacuo. The residue thus isolated was chromatographed over silica gel eluting with EtOAc/hexane (1:1) to afford 0.173 g of the title compound. 1H NMR (400 MHz, CDCl3): δ 1.00-1.03 (m, 2H), 1.45-1.51 (m, 2H), 1.83-1.89 (m, 2H), 1.99-2.03 (m, 2H), 2.20 (m, 1H), 3.05-3.12 (m, 3H), 4.68 (d, J=4.4 Hz, 2H), 4.79 (br, 1H), 5.10 (s, 2H), 6.79 (br, 1H), 7.31-7.37 (m, 5H), 8.33 (d, J=2.8 Hz, 1H), 8.46 (d, J=2.8 Hz, 1H). MS (ES+): m/z 417.14 [MH+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH:6]=[O:7].[CH2:13](O)[CH2:14][CH2:15][OH:16].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C1C=CC=CC=1>C1C=CC=CC=1.O>[CH3:12][O:11][C:9]1[CH:8]=[C:5]([CH:6]2[O:16][CH2:15][CH2:14][CH2:13][O:7]2)[CH:4]=[C:3]([O:2][CH3:1])[CH:10]=1
Reactant: OCCCO
Reactant: COc1cc(C=O)cc(OC)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: c1ccccc1
Product: COc1cc(OC)cc(C2OCCCO2)c1

Procedure:
3,5-dimethoxybenzaldehyde (5.00 g,30.12 mmole), 1,3-propanediol (9.15 g, 120.5 mmole), pyridinium para-toluenesulfonate (3.02 g, 12.05 mmole) and 80 ml dry benzene were refluxed with Dean-Stark removal of the benzene-water azeotrope for 12 hours. The benzene was removed in vacuo and the remaining oil redissolved in dichloromethane and was washed with 10% NaHCO3 and H2O. The organic layer was washed over Na2SO4 and concentrated to an oil in vacuo which was purified by flash column chromatography using 2:1 hexane/ethyl acetate containing 0.5% triethylamine as eluent. (5.731 g, 85%).
Reaction SMILES: [C:1]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].[C-:17]#[N:18].[Na+].Cl>CCOCC.O>[OH:3][C:1]([CH3:2])([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=1)[C:17]#[N:18]
Reactant: [C-]#N
Reactant: CC(=O)c1ccc2c(c1)Cc1ccccc1-2
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CC(O)(C#N)c1ccc2c(c1)Cc1ccccc1-2

Procedure:
A mixture of 2-acetylfluorene (5.32g.) in ether (20ml.) and water (40ml.) is cooled to 5° and agitated vigorously. Sodium cyanide (2.45g.) is added portionwise and the solution is then treated with conc. HCl (4.8ml.) while maintaining the temperature between 5°-10°. The mixture is then stirred for 2 hr. at room temperature, diluted with water and extracted with ether. The ether extracts are dried (MgS04) and evaporated to give the titled compound.
Reaction SMILES: [CH2:1]([S:8][CH2:9][C@@H:10]([C:12]([OH:14])=[O:13])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-:15][C:16]#[N:17].[K+]>>[C:16]([NH:11][C@H:10]([C:12]([OH:14])=[O:13])[CH2:9][S:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:15])[NH2:17]
Reactant: N#C[O-]
Reactant: N[C@@H](CSCc1ccccc1)C(=O)O
Agent: [K+]
Product: NC(=O)N[C@@H](CSCc1ccccc1)C(=O)O

Procedure:
The desired compound was synthesized from S-benzyl-L-cysteine (2 g, 9.48 mmol) (Fluka) and potassium cyanate (1.7 g, 21 mmol) by a modification of published protocols [see Coll. Czech Chem. Commun. 33:2918 (1968)]. Instead of isolating the N-carbamyl-S-benzylcysteine intermediate, after an initial reflux of 1 h, 25 ml of 10% hydrochloric acid was added and reflux was continued for 1.5 h. Upon cooling, the desired product precipitated as a white solid 1.7 g (77% yield), melting point 119.5°-120.5° C.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[C:15]2[C:14]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=3)=[N:13][CH:12]=[N:11][C:10]=2[S:9][C:8]=1[CH3:27]>>[N:1]1([C:12]2[N:13]=[C:14]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=3)[C:15]3[CH:7]=[C:8]([CH3:27])[S:9][C:10]=3[N:11]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: Cc1sc2ncnc(NCc3cccc([N+](=O)[O-])c3)c2c1Cl
Product: Cc1cc2c(NCc3cccc([N+](=O)[O-])c3)nc(-n3cncn3)nc2s1

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