Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:8]1[C:13]([CH2:14][C:15]([O:17]C)=O)=[C:12](Cl)[N:11]=[C:10]([CH3:20])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([CH2:28][NH2:29])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([CH2:28][NH:29][C:12]1[C:13]2[CH2:14][C:15](=[O:17])[N:1]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:8]=2[N:9]=[C:10]([CH3:20])[N:11]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)Cc1c(Cl)nc(C)nc1Nc1ccccc1
Reactant: NCCc1ccccc1
Product: Cc1nc(NCCc2ccccc2)c2c(n1)N(c1ccccc1)C(=O)C2
Temperature: 160 °C
Yield: 44.6 %

Procedure:
A mixture of 4-anilino-6-chloro-2-methylpyrimidine-5-acetic acid, methyl ester (5.0g, 17.2mM) and benzylmethylamine (2.22ml, 17.2mM) was heated at 160° C. for 3.5 hours. The mixture was cooled and then partitioned between methylene chloride (50ml) and 2M hydrochloric acid (50ml). The organic layer was separated, washed with a solution of sodium hydroxide (2M, 50ml), water, dried and the solvent evaporated. The residue was purified by flash column chromatography on silica (Merck 9385), eluting with ethyl acetate/hexane (20:80, v/v) to give 4-(N-benzylmethylamino)-2-methyl-6-oxo-7-phenyl-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidine (2.64g, 44.6%) m.p. 81°-84° C.; microanalysis, found; C, 73.0; H, 6.0; N, 16.3%; C21H20H40 requires C, 73.3; H, 5.8; N, 16.3%; NMR: DMSOd6 : 2.3(3H, s, pyrimidine-CH3), 3.2(3H,s,N-CH3), 3.95(2H,s,COCH2), 4.85(2H,s,N-CH2), 7.2-7.55(10H, complex, aromatic).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]2([CH2:23][NH2:24])[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:13]=1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:24][CH2:23][C:18]1([C:14]2[CH:13]=[N:12][CH:17]=[CH:16][CH:15]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: NCC1(c2cccnc2)CCCC1
Product: O=C(NCC1(c2cccnc2)CCCC1)c1cccc(Cl)c1Cl

Procedure:
From 2,3-dichlorobenzoic acid and C-(1-pyridin-3-yl-cyclopentyl)-methylamine. LCMS (MH+): m/z=348.9, tR (minutes, Method A)=1.16
Reaction SMILES: [OH:1][N:2]=[C:3]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:15])[CH3:14])=[CH:8][CH:7]=1)[CH2:4][CH3:5].C(=O)([O-])[O-].[Cs+].[Cs+].[F:22][C:23]([F:33])([F:32])[C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>CN(C=O)C>[F:22][C:23]([F:32])([F:33])[C:24]1[CH:31]=[CH:30][C:27]([CH2:28][O:1][N:2]=[C:3]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:15])[CH3:14])=[CH:8][CH:7]=2)[CH2:4][CH3:5])=[CH:26][CH:25]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: CCC(=NO)c1ccc(NC(C)=O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCC(=NOCc1ccc(C(F)(F)F)cc1)c1ccc(NC(C)=O)cc1
Reaction time: 3 h
Yield: 94.3 %

Procedure:
To a solution of N-(4-(1-(hydroxyimino)propyl)phenyl)acetamide (6 gm, 0.0291 moles) in DMF (60 mL), cesium carbonate (18.9 gm, 0.0582 moles) and 4-(trifluoromethyl)benzyl bromide (6.96 gm, 0.0291 moles) were added and the reaction mixture was srirred at 25° C. for 3 hours. The reaction mixture was poured into ice cold water and extracted with ethyl acetate. The combined ethyl acetate extract was washed with water & brine, dried over sodium sulphate and evaporated under reduced pressure to yield 10 gm (94%) of product as solid.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][N:6]([C:9]2[N:14]=[CH:13][C:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:11][CH:10]=2)[N:5]=1)([O-])=O>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:8]=[CH:7][N:6]([C:9]2[N:14]=[CH:13][C:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:11][CH:10]=2)[N:5]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-n2ccc([N+](=O)[O-])n2)nc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(-n2ccc(N)n2)nc1
Reaction time: 1 h
Yield: 99.4 %

Procedure:
To a solution of tert-butyl 6-(3-nitropyrazol-1-yl)pyridine-3-carboxylate (0.505 gm, 1.74 mmol) in ethyl acetate (15 mL), 10% Pd/C (0.100 g, 20% w/w) was added under argon atmosphere. Argon gas was removed under vacuum and reaction flask was filled with hydrogen gas at 40 psi pressure. Reaction mixture was stirred for 1 hr on parr-apparatus. Reaction mixture was filtered through celite pad and concentrated under reduced pressure to give tert-butyl 6-(3-aminopyrazol-1-yl)pyridine-3-carboxylate (0.450 gm.)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][SH:4].[C:5]1(=[O:11])[O:10][CH2:9][CH2:8][CH2:7][CH2:6]1>[Zn].O>[OH:11][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([NH:1][CH2:2][CH2:3][SH:4])=[O:10]
Reactant: NCCS
Reactant: O=C1CCCCO1
Agent: [Zn]
Solvent: O
Product: O=C(CCCCO)NCCS
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture, stirred under an inert atmosphere, of 5 g of cysteamine and 6.05 cm3 of δ-valerolactone is brought to a temperature of about 60°-70° C. for 15 hours. The disappearance of the δ-valerolactone is followed by VPC. The reaction mixture is then poured into 100 cm3 of water and 10 g of acid resin, "Dowex 50" and 3 g of zinc powder are added. The resulting mixture is stirred for 4 hours at ambient temperature and then left overnight. The next day the mixture is filtered and the water is evaporated under reduced pressure.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[C:10](OC(=O)C)(=[O:12])[CH3:11]>C1(C)C=CC=CC=1>[C:10]([N:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][OH:1])[CH2:5][CH2:6]1)(=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: OCCN1CCNCC1
Solvent: Cc1ccccc1
Product: CC(=O)N1CCN(CCO)CC1
Temperature: 80 °C

Procedure:
To a solution of 1-(2-hydroxyethyl)piperazine (5.5 ml; 42.3 mmol) in toluene (50 ml) was added acetic anhydride (4.0 ml; 42.4 mmol). The mixture was heated to 80° C. overnight. The solvent was removed under reduced pressure and the residue was washed several times with a mixture of diethyl ether and petroleum ether (1:1 v/v) to leave 6q1 as an oil (5.2 g; 72%).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][CH:23]=O)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[NH:25]1[CH2:30][CH2:29][CH:28]([NH:31]C(=O)OC(C)(C)C)[CH2:27][CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>CO.O1CCOCC1.ClCCCl>[ClH:1].[NH2:31][CH:28]1[CH2:29][CH2:30][N:25]([CH2:23][CH2:22][C:19]2[CH:20]=[CH:21][C:2]([Cl:1])=[C:3]([CH:18]=2)[C:4]([NH:6][CH2:7][C:8]23[CH2:9][CH:10]4[CH2:11][CH:12]([CH2:13][CH:14]([CH2:16]4)[CH2:15]2)[CH2:17]3)=[O:5])[CH2:26][CH2:27]1
Reactant: O=CCc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Solvent: ClCCCl
Product: NC1CCN(CCc2ccc(Cl)c(C(=O)NCC34CC5CC(CC(C5)C3)C4)c2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 102.5 %

Procedure:
Prepared according to the method described in Example 66c from 2-chloro-5-(2-oxoethyl)-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (0.094 g, Example 66b), 4-piperidinyl-carbamic acid, 1,1-dimethylethyl ester (0.109 g), sodium triacetoxyborohydride (0.081 g) and 1,2-dichloroethane (2 ml). After work-up, the residue was purified by HPLC eluting with a gradient of 0-5% ethanol in dichloromethane. The white powder obtained was dissolved in methanol (2 ml) and a solution of hydrochloric acid in dioxane (4N, 1 ml) was added. The mixture was stirred for 14 h at room temperature. Solvents were then removed under reduced pressure and the product obtained was triturated with diethyl ether to afford the title compound as a white powder (0.065 g).
Reaction SMILES: O[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]([O:14]C)=O.[CH3:16][NH:17][C:18]([NH2:20])=[NH:19].NC(N)=N>>[CH3:16][NH:17][C:18]1[NH:20][C:12](=[O:14])[C:3]2[C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=3[CH2:10][CH2:11][C:2]=2[N:19]=1
Reactant: CNC(=N)N
Reactant: COC(=O)C1=C(O)CCc2ccccc21
Agent: N=C(N)N
Product: CNc1nc2c(c(=O)[nH]1)-c1ccccc1CC2

Procedure:
Methyl 3,4-dihydro-2-hydroxy-1-naphthoate was reacted with methylguanidine in the same manner as for the analogous reaction using guanidine (example 1) to obtain 5,6-dihydro-3-(methylamino)benzo[f]quinazolin-1(2H)-one. 1H NMR (DMSO-d6, 200 MHz) δ: 2.52-2.64(m, 2H, CH2), 2.68-2.82(m, 2H, CH2), 2.81(d, J=5 Hz, 3H, NCH3), 6.54(br s, 1H, C3NH), 7.02 (ddd, J=8, 8, 2 Hz, 1H, Ar), 7.07-7.18(m, 2H, Ar), 8.42(dd, J=8,2 Hz, 1H, Ar), 10.98(br s, 1H, N2H).
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([O:13][CH3:14])=[CH:8][N:7]=1)(=O)C.[OH-].[Na+]>CO>[CH3:14][O:13][C:9]1[C:10]([CH3:12])=[CH:11][C:6]([CH2:5][OH:4])=[N:7][CH:8]=1
Reactant: COc1cnc(COC(C)=O)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cnc(CO)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.1 %

Procedure:
To a solution of 0.21 g of (5-methoxy-4-methylpyridin-2-yl)methyl acetate in 2 mL of methanol, 0.64 mL of a 20% aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, water and ethyl acetate were added to the resultant residue, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, the resultant solution was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 0.16 g of (5-methoxy-4-methylpyridin-2-yl)methanol as a white solid.
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.C(=O)(O)[O-].[Na+].[Na].[NH2:25][N:26]1[C:30]([SH:31])=[N:29][N:28]=[N:27]1.C.CS(O)(=O)=O>>[NH2:13][C@@H:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][S:31][C:30]3[N:26]([NH2:25])[N:27]=[N:28][N:29]=3)[CH2:15][S:14][C@H:9]12
Reactant: Nn1nnnc1S
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Product: N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnnn3N)CS[C@H]12
Yield: 52.6 %

Procedure:
27.2 g of 7β-amino-cephalosporanic acid are added to an aqueous solution of sodium bicarbonate (sodium bicarbonate content: 9.24 g/liter) under stirring, 27.8 g of 1-amino-5-mercapto-1H-tetrazole sodium salt are added thereto. The mixture is stirred at 52°-53° C. in argon gas atmosphere for 3 hours. The mixture is treated with an activated charcoal and adjusted to pH 4.6 with 6 ml of methanesulfonic acid under cooling. The resultant precipitates are collected by filtration, washed with water and then dried. 17.3 g of 7β-amino-3-(1-amino-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid are obtained as ocherous powder.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:19]=[CH:18][C:11]([O:12][CH2:13][C@@H:14]([CH3:17])[CH2:15][OH:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22].CCOC(C)=O.O>N1C=CC=CC=1.C1COCC1>[Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:19]=[CH:18][C:11]([O:12][CH2:13][C@@H:14]([CH3:17])[CH2:15][O:16][S:21]([CH3:20])(=[O:23])=[O:22])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: C[C@@H](CO)COc1ccc(-c2ccc(Cl)nn2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@H](COc1ccc(-c2ccc(Cl)nn2)cc1)COS(C)(=O)=O
Temperature: 0 °C
Reaction time: 20 h
Yield: 91.7 %

Procedure:
(S)-3-[4-(6-Chloro-pyridazin-3-yl)phenoxy]-2-methylpropan-1-ol (3.0 g, 10.76 mmol) was dissolved in a mixture of pyridine (10 mL) and THF (90 mL), and the solution cooled to 0° C. Methanesulfonyl chloride (2.863 g, 25 mmol) was introduced dropwise, and the reaction mixture was stirred at ambient temperature for 20 h. EtOAc (100 mL) and H2O (150 mL) were added, separated, and the aqueous layer was extracted further with EtOAc (2×100 mL). The combined extracts were dried (MgSO4) and evaporated to a solid which was purified by column chromatography on silica gel, eluting with a gradient of hexane/EtOAc to provide the intermediate methanesulfonic acid (R)-3-[4-(6-chloro-pyridazin-3-yl)-phenoxy]-2-methylpropyl ester (3.52 g, 91%). This intermediate (7 mmol) was treated with (R)-2-methylpyrrolidine, benzenesulfonic acid salt (3.65 g, 15 mmol) and dry, pulverized K2CO3 (4.15 g, 30 mmol) in dry CH3CN (200 mL). The reaction mixture was heated at reflux for 30 h and cooled, filtered and the filtrate evaporated. The residue was purified by column chromatography, eluting with a gradient mixture of CH2Cl12 and EtOH containing 10% of aqueous ammonia solution, to provide the title compound (1.46 g, 60%), m.p. 152-155° C., 1H NMR (CDCl3) 1.18 (d, 3H, —CH3), 1.27 (d, 3H, —CH3), 3.98 (m, 2H, —CH2—), 7.02 (d, 2H, Ar—H), 7.52 (d, 1H, C—H), 7.78 (d, 1H, C—H), 8.02 (d, 2H, Ar—H); HPLC retention time 7.530 min. (elution solvents CH3CN w/0.1% TFA and H2O w/0.1% TFA); 10-100% CH3CN over 20 min.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:6])[CH:4]=[CH2:5].[CH3:7][O:8][CH2:9][CH2:10][NH2:11].CCO>CO>[CH3:7][O:8][CH2:9][CH2:10][NH:11][CH2:5][CH2:4][C:3]([NH:2][CH3:1])=[O:6]
Reactant: C=CC(=O)NC
Reactant: COCCN
Solvent: CCO
Solvent: CO
Product: CNC(=O)CCNCCOC
Temperature: 140 °C
Yield: 64.6 %

Procedure:
N-Methylacrylamide (ABCR; 500 mg, 5.87 mmol), 2-Methoxyethylamine (Aldrich; 441 mg, 5.87 mmol), and EtOH (2 mL) were combined and heated in a microwave at 140° C. for 40 minutes. The reaction mixture was cooled and added to a 5 g SCX-2 column pre-wet with MeOH (2 column volumes), flushed with MeOH (2 column volumes) then the product eluted with 2M ammonia in MeOH. Product containing fractions were evaporated in vacuo to give the title compound as a clear oil (608 mg, 65%)
Reaction SMILES: [NH:1]1[C:8](=[O:9])[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].[F:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]=[C:18]=[O:19])=[CH:13][CH:12]=1>N1C=CC=CC=1>[F:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:7]2[C:8](=[O:9])[NH:1][C:2](=[S:3])[NH:4][C:5]=2[OH:6])=[O:19])=[CH:13][CH:12]=1
Reactant: O=C1CC(=O)NC(=S)N1
Reactant: O=C=Nc1ccc(F)cc1
Solvent: c1ccncc1
Product: O=C(Nc1ccc(F)cc1)c1c(O)[nH]c(=S)[nH]c1=O
Temperature: 90 °C
Reaction time: 8 h

Procedure:
2-thiobarbituric acid (14.4 g) was suspended in pyridine and 4-fluorophenyl isocyanate (13.7 g) was added thereto. The reaction mixture was maintained at 90° C. for one hour, and thereafter left overnight at room temperature. The solids formed were collected, washed with pyridine, re-suspended in ethanol, and again collected and dried. A pale pink powder product was thereby obtained, mp >250° C. (dec.), NMR (DMSO) 7.0-7.7δ (multiplet, integral 4); 10.7-11.4δ (overlapping broad singlets, combined integral 4). MS, M/e 281 (Calc., 281).
Reaction SMILES: [CH:1]([S:4]Cl)([CH3:3])[CH3:2].[OH:6][C:7]1[CH:12]=[C:11]([CH3:13])[O:10][C:9](=[O:14])[CH:8]=1>C(Cl)Cl>[CH:1]([S:4][C:8]1[C:9](=[O:14])[O:10][C:11]([CH3:13])=[CH:12][C:7]=1[OH:6])([CH3:3])[CH3:2]
Reactant: CC(C)SCl
Reactant: Cc1cc(O)cc(=O)o1
Solvent: ClCCl
Product: Cc1cc(O)c(SC(C)C)c(=O)o1
Temperature: 40 °C
Reaction time: 17 h

Procedure:
A solution of 62.7 g. (0.57 mole) of isopropanesulfenyl chloride in 300 ml. of methylene chloride was added dropwise to a suspension of 84.5 g. (0.57 mole) of 4-hydroxy-6-methyl-2-pyrone in 200 ml. of methylene chloride while the reaction mixture was maintained at 20°C. The mixture was then warmed to 40°C. for 1.5 hours and finally stirred at room temperature for 17 hours. The by-product sodium chloride was removed by filtration and the filtrate evaporated to dryness, leaving a red liquid (85.5 g.) which solidified upon cooling in an ice bath. The crude product was recrystallized from cyclohexane to give 33.1 g. (28 percent) of the product as off-white crystals, m. 89°-91°C. A second recrystallization from cyclohexane gave white crystals, m. 91°-92°C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[C:9](Cl)[C:5]=1[C:6]([OH:8])=O.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([SH:25])[CH:22]=[CH:23][CH:24]=1.Cl>O1CCCC1.CCCCC>[Cl:3][C:4]1[C:5]2[C:6](=[O:8])[C:22]3[C:21](=[CH:20][C:19]([O:18][CH3:17])=[CH:24][CH:23]=3)[S:25][C:9]=2[C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=1
Reactant: O=C(O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Reactant: COc1cccc(S)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCC
Product: COc1ccc2c(=O)c3c(Cl)ccc([N+](=O)[O-])c3sc2c1
Reaction time: 20 h

Procedure:
The requisite 1-chloro-6-methoxy-4-nitrothioxanthone was prepared as follows: To a prewashed (pentane) suspension of NaH in 500 ml of tetrahydrofuran cooled to 0° was added dropwise over about 25 minutes a solution of 35.4 g of 2,6dichloro-5-nitrobenzoic acid in 200 ml of tetrahydrofuran. After about five minutes a solution of 20 g of m-methoxybenzenethiol in 50 ml of tetrahydrofuran was added, and the mixture was stirred for 20 hours as it gradually came to ambient temperature. The mixture was treated with a 10% aqueous hydrochloric acid solution, extracted into ethyl acetate, dried, and the solvent was removed in vacuo. The orange gum was purified by flash chromatography on SiO2 with a 90:5:0.5 mixture of methylene chloride:methanol:acetic acid. The resulting oil was sufficiently pure for use in the next step. A solution of this material (24.8 g) in 120 ml of trifluoroacetic acid was treated with 60 ml of trifluoroacetic anhydride and allowed to stir at room temperature for 30 minutes. The solution was diluted with acetonitrile, and the precipitate was collected and triturated with boiling acetonitrile to give 15.8 g of the product, mp 254°-258°.
Reaction SMILES: [NH:1]([C:19]([O:21]CC1C=CC=CC=1)=O)[C@H:2]([C:7]([NH:9][C@H:10]([C:15]([CH2:17][F:18])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].Br.[C:30](O)(=O)[CH3:31]>>[NH:1]([C:19]([CH2:7][CH2:2][CH2:3][CH2:4][CH2:5][CH2:30][CH3:31])=[O:21])[C@H:2]([C:7]([NH:9][C@H:10]([C:15]([CH2:17][F:18])=[O:16])[CH2:11][CH:12]([CH3:13])[CH3:14])=[O:8])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: CC(=O)O
Reactant: CC(C)C[C@H](NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)C(=O)CF
Agent: Br
Product: CCCCCCCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)CF
Temperature: 25 °C
Reaction time: 3 h
Yield: 52 %

Procedure:
The Z-Leu-Leu-CH2F (0.39 g) obtained in Example 3 was dissolved in acetic acid (5 ml) including a 25% anhydrous hydrogen bromide and the mixture was agitated at room temperature for 3 hours. After the end of the reaction, the solvent was distilled off and the resultant residue was dissolved in anhydrous methylene chloride (5 ml). To this, under ice water, were added triethylamine (0.23 g) and octanoylchloride (0.2 g) to dissolve it, then this was washed with a 10% aqueous citric acid solution, a 5% sodium hydrogencarbonate, then a saturated saline water in this order, then was dried on anhydrous sodium sulfate and the solvent distilled off under reduced pressure. The residue was purified by silica gel medium pressure column chromatography to obtain the above-referenced compound Octanoyl-Leu-Leu-CH2F (200 mg, 0.52 mmole) at a yield of 52%.
Reaction SMILES: C(O[C:6]([N:8]1[C:20]2[C:11](=[C:12]3[C:17](=[C:18]([OH:21])[CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)[CH:10]([CH2:22][Cl:23])[CH2:9]1)=[O:7])(C)(C)C.Cl.[CH3:25][O:26][C:27]1[CH:37]=[CH:36][C:30]([CH:31]=[CH:32]C(O)=O)=[CH:29][CH:28]=1.CCN=C=NCCCN(C)C>O1CCOCC1.CC(N(C)C)=O>[Cl:23][CH2:22][CH:10]1[C:11]2=[C:12]3[C:17](=[C:18]([OH:21])[CH:19]=[C:20]2[N:8]([C:6](=[O:7])/[CH:32]=[CH:31]/[C:30]2[CH:36]=[CH:37][C:27]([O:26][CH3:25])=[CH:28][CH:29]=2)[CH2:9]1)[N:16]=[CH:15][CH:14]=[CH:13]3
Reactant: COc1ccc(C=CC(=O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CC(CCl)c2c1cc(O)c1ncccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: C1COCCO1
Product: COc1ccc(/C=C/C(=O)N2CC(CCl)c3c2cc(O)c2ncccc32)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 17 %

Procedure:
A suspension of 16 (0.10 g, 0.30 mmol) in dioxane (5 mL) was saturated with HCl, stirred at r.t. over 5 h and evaporated. 4-Methoxycinnamic acid (predominantly trans) (0.064 g, 0.36 mmol), EDCI (0.29 g, 1.50 mmol) and DMA (3 mL) were added to the remaining yellow solid, and the red mixture was stirred at r.t. for 3 h. The mixture was partitioned between CH2Cl2 and cold 5% KHCO3 solution. The aqueous layer was extracted with CH2Cl2 (×3). The CH2Cl2 extracts were dried (brine, Na2SO4). Flash chromatography (CH2Cl2/MeOH; 93:7) followed by recrystallisation (CH2Cl2/Et2O) gave 18e (0.02 g, 17%) as a yellow solid: mp 208–211° C.; 1H NMR [(CD3)2SO]δ 9.96 (bs, 1 H), 8.73 (d, J=3.3, 1 H), 8.35 (d, J=7.7, 1 H), 8.18 (bs, 1 H), 7.78 (d, J=8.7, 2 H), 7.67 (d, J=15.3, 1 H), 7.54 (dd, J=8.5, 4.1, 1 H), 7.08 (d, J=15.4, 1 H), 7.01 (d, J=8.7, 2 H), 4.54 (dd, J=10.3, 9.5, 1 H), 4.45 (m, 1 H), 4.27 (m, 1 H), 3.99 (dd, J=11.1, 3.2, 1 H), 3.88 (dd, J=11.1, 7.3, 1 H), 3.82 (s, 3 H). C22H20ClN2O3 requires M+H 395.1163, 397.1133. Found (FAB) 395.1161, 397.1169.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:21][C:22](O)=[O:23])[CH2:9][C:10]([N:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13]1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.O[C:38]1[C:46]2[N:45]=N[NH:43][C:42]=2C=[CH:40][CH:39]=1.Cl.N1CCC[C@H]1C#N>CN(C)C=O.C(N(CC)CC)C>[C:42]([C@@H:46]1[CH2:38][CH2:39][CH2:40][N:45]1[C:22](=[O:23])[CH2:21][N:8]([CH2:9][C:10]([N:12]1[CH2:13][C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:20]1)=[O:11])[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])#[N:43]
Reactant: Oc1cccc2[nH]nnc12
Reactant: CC(C)(C)OC(=O)N(CC(=O)O)CC(=O)N1Cc2ccccc2C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N#C[C@@H]1CCCN1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N(CC(=O)N1Cc2ccccc2C1)CC(=O)N1CCC[C@H]1C#N
Temperature: 25 °C
Reaction time: 21 h
Yield: 90.4 %

Procedure:
{t-Butoxycarbonyl-[2-(1,3-dihydroisoindol-2-yl)-2-oxoethyl]amino}acetic acid (260 mg), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (150 mg) and hydroxybenzotriazole (120 mg) were dissolved in N,N-dimethylformamide (5.0 ml). Triethylamine (110 μl) and (S)-pyrrolidine-2-carbonitrile hydrochloride (100 mg) were added thereto, and the mixture was stirred for 21 hours at room temperature. The reaction mixture was concentrated under reduced pressure, then ethyl acetate and 10% citric acid solution were added to the residue, and the organic phase was separated. The organic phase was washed with 4% sodium bicarbonate solution and a saturated saline solution and dried over sodium sulfate anhydrous. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (eluting solvent; dichloromethane:methanol 20:1) to give t-butyl (S)-[2-(cyanopyrrolidin-1-yl)-2-oxoethyl]-[2-(1,3-dihydrois oindol-2-yl)-2-oxoethyl]carbamate (290 mg, Y.:90%).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][C:8]1[C:16]2[C:11](=[N:12][CH:13]=[N:14][C:15]=2[NH2:17])[NH:10][N:9]=1.[Cl:18][C:19]1[C:24]([C:25]#[N:26])=[C:23]([N:27]2[CH2:30][CH:29]([O:31][CH3:32])[CH2:28]2)[C:22]([O:33][CH2:34][CH3:35])=[C:21]([CH:36](Cl)[CH3:37])[CH:20]=1.CN(C)C=O>CCOC(C)=O>[NH2:17][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[N:10]([CH:36]([C:21]3[CH:20]=[C:19]([Cl:18])[C:24]([C:25]#[N:26])=[C:23]([N:27]4[CH2:30][CH:29]([O:31][CH3:32])[CH2:28]4)[C:22]=3[O:33][CH2:34][CH3:35])[CH3:37])[N:9]=[C:8]([CH3:7])[C:16]=12
Reactant: CCOc1c(C(C)Cl)cc(Cl)c(C#N)c1N1CC(OC)C1
Reactant: Cc1n[nH]c2ncnc(N)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1N1CC(OC)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 17.6 %

Procedure:
Cesium carbonate (50 mg, 0.2 mmol) was added to a mixture of 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (16 mg, 0.10 mmol) and 6-chloro-4-(1-chloroethyl)-3-ethoxy-2-(3-methoxyazetidin-1-yl)benzonitrile (30 mg, 0.09 mmol) in N,N-dimethylformamide (3 mL, 40 mmol) and the reaction was stirred at 80° C. overnight. The mixture was diluted with EtOAc, washed with water, brine, dried over Na2SO4, filtered and concentrated the crude product. The product was purified was purified by prep HPLC on a C-18 column eluting water:acetonitrile gradient buffered pH 10 to give the title compound as a white amorphous solid (0.007 g, 20%). The product was isolated as a racemic mixture. LCMS calculated for C21H25ClN7O2(M+H)+: m/z=442.1; found: 442.1. 1H NMR (400 MHz, DMSO-d6) δ 8.11 (s, 1H), 6.80 (s, 1H), 6.18 (d, J=7.1 Hz, 1H), 4.58-4.44 (m, 2H), 4.18 (m, 1H), 4.13-4.01 (m, 2H), 3.81-3.62 (m, 2H), 3.23 (s, 3H), 2.55 (s, 3H), 1.69 (d, J=7.1 Hz, 3H), 1.35 (t, J=7.0 Hz, 3H).