Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C:8]1[C:13]([CH3:14])=[CH:12][N:11]=[C:10]([NH:15][C:16]2[S:17][C:18]([C:21]#[N:22])=[CH:19][N:20]=2)[CH:9]=1)(C)(C)C.C1C=CN=CC=1.F.C([O-])([O-])=O.[K+].[K+]>C1COCC1.O>[OH:6][CH2:7][C:8]1[C:13]([CH3:14])=[CH:12][N:11]=[C:10]([NH:15][C:16]2[S:17][C:18]([C:21]#[N:22])=[CH:19][N:20]=2)[CH:9]=1
Reactant: Cc1cnc(Nc2ncc(C#N)s2)cc1C(C)(C)O[SiH2]C(C)(C)C
Agent: F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1cnc(Nc2ncc(C#N)s2)cc1CO
Temperature: 25 °C

Procedure:
2-[4-(tert-Butyl-dimethyl-silanyloxymethyl)-5-methyl-pyridin-2-ylamino]-thiazole-5-carbonitrile (9-7, 0.650 g, 1.80 mmol) was dissolved in 5 mL THF. HF-pyridine (Aldrich), 0.5 mL, was added and the reaction was stirred at room temperature. After 4 hours the reaction was diluted with water and the pH was adjuted to 7 with K2CO3 (s). The resulting precipitate was filtered and washed with water to afford 9-8 as an orange solid which was used in the next step without further purification. 1H NMR (DMSO-d6) δ 12.15 (s, 1H), 8.24 (s, 1H), 8.10 (s, 1H), 7.26 (s, 1H), 5.48 (bs, 1H), 4.52 (s, 2H), 2.13 (s, 3H).
Reaction SMILES: [OH2:1].CC(C)=[O:4].C1C=CC=CC=1.[C:12]1([CH3:19])[C:13]([CH3:18])=[CH:14][CH:15]=[CH:16][CH:17]=1>C1(=O)OC(=O)C=C1.N1C=CC=CC=1.C(Cl)(Cl)Cl>[C:12]1([CH3:19])[C:13]([OH:4])=[CH:14][CH:15]=[CH:16][CH:17]=1.[C:12]1([OH:1])([CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]1[CH3:18]
Reactant: Cc1ccccc1C
Reactant: O
Reactant: CC(C)=O
Agent: O=C1C=CC(=O)O1
Solvent: c1ccncc1
Solvent: c1ccccc1
Solvent: ClC(Cl)Cl
Product: CC1C=CC=CC1(C)O
Product: Cc1ccccc1O

Procedure:
The resinous or gelous materials which were formed from phenol, hydroquinone, or p-benzoquinone by the reactions in Example 1 described above were practically insoluble not only in hot water but also in solvents such as acetone, benzene, xylene, chloroform, and pyridine, and were insoluble in molten maleic anhydride at 150° C. Incidentally, the resinous or gelatinous materials which were formed from cresol or xylenol were insoluble in hot water, but soluble in solvents such as acetone. These resinous or gelous materials showed considerable adhesiveness, and it may be readily presumed that once resinous materials are formed in and deposited on the apparatus, they will cause to bring scales by a rapid formation of fumaric acid and will result cloggings of apparatuses and pipes.
Reaction SMILES: CC(C)=[O:3].C1OC1CCCCCCC.C1OC1CCCCCCCC.[CH2:26]1[O:37][CH:27]1[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].S(=O)(=O)(O)O>>[CH2:26]([OH:37])[CH:27]([OH:3])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CC(C)=O
Reactant: CCCCCCCCCC1CO1
Agent: CCCCCCCC1CO1
Agent: CCCCCCCCC1CO1
Agent: O=S(=O)(O)O
Product: CCCCCCCCCC(O)CO

Procedure:
A homogeneous clear solution is prepared by adding 3 moles of acetone to a (1:1:1) mixture of 1-nonene oxide, 1-decene oxide, and 1-undecene oxide at room temperature. After adding 50 grams of 5% aqueous sulfuric acid to the solution, the acetone is evaporated off and the resulting solution is neutralized by adding an aqueous sodium hydroxide. The neutralized solution is extracted with pet ether and the extract dried over anhydrous magnesium sulfate. The pet ether is stripped off and a mixture of 1,2-nonanediol, 1,2-decanediol and 1,2 undecanediol is obtained by distilling under vacuo.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Br:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[N:29]([CH2:33][CH2:34][CH2:35][O:36][CH3:37])[CH:28]=[C:27]2[CH2:38][NH:39][CH:40]1[CH2:42][CH2:41]1.[C:43]([O:47][C:48]([N:50]1[CH2:55][CH2:54][O:53][C@@H:52]([C:56](O)=[O:57])[CH2:51]1)=[O:49])([CH3:46])([CH3:45])[CH3:44]>CN(C)C=O.C(OCC)(=O)C>[Br:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[N:29]([CH2:33][CH2:34][CH2:35][O:36][CH3:37])[CH:28]=[C:27]2[CH2:38][N:39]([CH:40]1[CH2:42][CH2:41]1)[C:56]([C@@H:52]1[O:53][CH2:54][CH2:55][N:50]([C:48]([O:47][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:49])[CH2:51]1)=[O:57]
Reactant: COCCCn1cc(CNC2CC2)c2cc(Br)ccc21
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCCn1cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CCO2)C2CC2)c2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-Hydroxybenzotriazole (162 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (288 mg) were added successively to a solution of N-{[5-bromo-1-(3-methoxypropyl)indol-3-yl]methyl}cyclopropanamine (a compound of Reference Example 127(2), 405 mg) and (2R)-4-(tert-butoxycarbonyl)morpholin-2-carboxylic acid (231 mg) in N,N-dimethylformamide (12.5 ml) and the mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate, washed with water, a saturated aqueous solution of sodium bicarbonate and saturated brine successively and dried over magnesium sulfate. The solvent was evaporated in vacuo and the resulted residue was purified with a silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=50/50 to 10/90) to give tert-butyl(2R)-2-{[{[5-bromo-1-(3-methoxypropyl)indol-3-yl]methyl}(cyclopropyl)amino]carbonyl}morpholin-4-carboxylate (581 mg) as a colorless oil.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[C:10]([O:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:9]([O:21][CH3:22])[C:8]([Cl:23])=[C:7]([CH3:24])[C:6]=1[C:25](=[O:27])[CH3:26].Cl.[OH:29][CH:30]1[CH2:33][NH:32][CH2:31]1>>[Cl:23][C:8]1[C:7]([CH3:24])=[C:6]([C:25](=[O:27])[CH3:26])[C:5]([O:4][CH2:3][CH2:2][N:32]2[CH2:33][CH:30]([OH:29])[CH2:31]2)=[C:10]([O:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]=1[O:21][CH3:22]
Reactant: OC1CNC1
Reactant: COc1c(Cl)c(C)c(C(C)=O)c(OCCBr)c1OCCCc1ccccc1
Agent: Cl
Product: COc1c(Cl)c(C)c(C(C)=O)c(OCCN2CC(O)C2)c1OCCCc1ccccc1
Yield: 16 %

Procedure:
Example 34b (207 mg, 0.46 mmol), CsCO3 (2.48 eq.) and 3-hydroxyazetidine hydrochloride (1.4 eq.) were reacted as described under General Procedure L and the crude product was purified by flash chromatography (silica gel, hexane/Et2O 1:1) to afford the title compound as a pale yellow oil (34 mg, 16%). 1H NMR (300 MHz, CDCl3) δ 7.33-7.20 (m, 5H), 4.40 (quintet, J=5.7 Hz, 1H), 4.07 (t, J=6.5 Hz, 2H), 3.98 (t, J=5.7 Hz, 2H), 3.88 (s, 3H), 3.67-3.62 (m, 2H), 2.96-2.91 (m, 2H), 2.85-2.80 (m, 2H), 2.73 (t, J=5.7 Hz, 2H), 2.51 (s, 3H), 2.19 (s, 3H), 2.13-2.03 (m, 2H). MS (ES+) m/z 448.2 (M+H+).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][CH2:7][CH3:8])=[S:5])[CH3:2].[Br:9][CH2:10][C:11](=[O:25])[CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CC(C)=O>[BrH:9].[C:13]1([CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:11]2([OH:25])[CH2:10][S:5][C:4](=[N:3][CH2:1][CH3:2])[N:6]2[CH2:7][CH3:8])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(CBr)C(c1ccccc1)c1ccccc1
Reactant: CCNC(=S)NCC
Solvent: CC(C)=O
Product: Br
Product: CCN=C1SCC(O)(C(c2ccccc2)c2ccccc2)N1CC

Procedure:
To a filtered solution of 1.32 g. of 1,3-diethyl-2-thiourea in 25 ml. of acetone is added a filtered solution of 3-bromo-1,1-diphenyl-2-propanone in 25 ml. of acetone. The mixture is allowed to stand, then the solid is collected by filtration, washed with acetone and dried in vacuo, giving 3.73 g. of the desired product, m.p. 174°-176° C. (dec.).
Reaction SMILES: C1(S([C:10]2([CH3:17])[CH:12]([C:13]([F:16])([F:15])[F:14])O2)(=O)=O)C=CC=CC=1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31](=[S:33])[NH2:32])[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].N1(C(OC(C)(C)C)=O)CCNCC1.C(N1C=CN=C1)(N1C=CN=C1)=S.N>CN(C)C=O>[C:18]([O:22][C:23]([N:25]1[CH2:26][CH2:27][N:28]([C:31]2[S:33][C:12]([C:13]([F:14])([F:15])[F:16])=[C:10]([CH3:17])[N:32]=2)[CH2:29][CH2:30]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC1(S(=O)(=O)c2ccccc2)OC1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCN(C(N)=S)CC1
Agent: CC(C)(C)OC(=O)N1CCNCC1
Agent: N
Agent: S=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: Cc1nc(N2CCN(C(=O)OC(C)(C)C)CC2)sc1C(F)(F)F
Yield: 30 %

Procedure:
A mixture of 4.92 mmol rac-2-benzenesulfonyl-2-methyl-3-trifluoromethyl-oxirane and 5.41 mmol 4-thiocarbamoyl-piperazine-1-carboxylic acid tert-butyl ester (prepared from tert-butyl 1-piperazinecarboxylate, 1,1′-thiocarbonyldiimidazole and ammonia according to the procedure of J. Med. Chem. 1998, 41, 5037–5054) in 15 ml N,N-dimethylformamide was heated at 100° C. for 4.5 h. The reaction mixture was then concentrated in vacuo and the residue purified by chromatography (SiO2, ethyl acetate/heptane) to afford the title compound as a yellow crystalline solid (yield 30%). MS (m/e): 352.3 (M+H+, 100%).
Reaction SMILES: Br[CH2:2][CH:3]([Br:8])[CH2:4][CH2:5][CH2:6][CH3:7].[S:9]([O-:12])([O-:11])=[O:10].[Na+:13].[Na+].O>C(O)C>[Br:8][CH:3]([CH2:4][CH2:5][CH2:6][CH3:7])[CH2:2][S:9]([O-:12])(=[O:11])=[O:10].[Na+:13]
Reactant: CCCCC(Br)CBr
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCCC(Br)CS(=O)(=O)[O-]
Yield: 50 %

Procedure:
1,2-Dibromohexane (1.22 g, 5.0 mmol) was added to a solution of 0.6 g (5 mmol) of sodium sulfite in 20 mL of a 1:1 mixture of water and ethanol, and the resulting mixture was refluxed for 24 hours with vigorous stirring. The ethanol was then removed by distillation and the residual solution was allowed to stand at room temperature, whereupon white crystals precipitated. The crystals were filtered off under reduced pressure, washed with ether and dried to give 0.67 g (2.5 mmol) of the desired substance, namely sodium 2-bromohexylsulfonate (yield 50%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH2:8][N:9]2[CH:13]=[CH:12][N:11]=[C:10]2[CH3:14])[CH:7]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19](B2OC(C)(C)C(C)(C)O2)=[CH:18][C:17]=1[C:31]([F:34])([F:33])[F:32]>>[ClH:15].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([CH2:8][N:9]3[CH:13]=[CH:12][N:11]=[C:10]3[CH3:14])[CH:7]=2)=[CH:18][C:17]=1[C:31]([F:32])([F:33])[F:34]
Reactant: Cc1nccn1Cc1cncc(Br)c1
Reactant: CC1(C)OB(c2ccc(Cl)c(C(F)(F)F)c2)OC1(C)C
Product: Cc1nccn1Cc1cncc(-c2ccc(Cl)c(C(F)(F)F)c2)c1
Product: Cl

Procedure:
The title compound, MS: m/e=352.3 (M+H+) was obtained as a beige foam (49% yield) by the reaction of 3-bromo-5-(2-methyl-imidazol-1-yl-methyl)-pyridine with 2-(4-chloro-3-trifluoromethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2] dioxaborolane.
Reaction SMILES: [N:1]1[C:8]([NH2:9])=[N:7][C:5]([NH2:6])=[N:4][C:2]=1[NH2:3].[C:10](O[C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[N:22][CH:21]=1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[N:13][CH:12]=1>N1C=CC=CC=1>[C:10]([NH:3][C:2]1[N:4]=[C:5]([NH2:6])[N:7]=[C:8]([NH2:9])[N:1]=1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[N:13][CH:12]=1.[C:10]([NH:3][C:2]1[N:4]=[C:5]([NH:6][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[N:22][CH:21]=2)[N:7]=[C:8]([NH2:9])[N:1]=1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[N:13][CH:12]=1
Reactant: O=C(OC(=O)c1cccnc1)c1cccnc1
Reactant: Nc1nc(N)nc(N)n1
Solvent: c1ccncc1
Product: Nc1nc(N)nc(NC(=O)c2cccnc2)n1
Product: Nc1nc(NC(=O)c2cccnc2)nc(NC(=O)c2cccnc2)n1
Reaction time: 3 h

Procedure:
4.9 g of melamine and 17 g of nicotinic acid anhydride are refluxed in 300 ml of pyridine with stirring for 3 hours. After cooling, the pyridine is removed by evaporation to dryness under vacuum and the residue is washed with 3% aqueous potassium carbonate and then with water. The residue is fractionated and recrystallized from methanol to yield 2-nicotinamido-4,6-diamino-s-triazine [monomicotinoylmelamine], melting point 252° - 254° C in a yield of 2.4 g and 2,4-bis(nicotinamido)-6-amino-s-triazine [dinicotinoylmelamine], melting point 265° - 270° C (dec) in a yield of 0.15 g.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:45]=[CH:46][CH:47]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[CH:23][C:24]([O:32][CH3:33])=[C:25]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH:26]=4)[CH:19]=3)[N:14](S(C3C=CC(C)=CC=3)(=O)=O)[CH:13]=2)[C:8]([CH3:44])=[N:7]1.[OH-].[Li+]>C1COCC1.CO.O>[F:1][C:2]1[CH:3]=[C:4]([CH:45]=[CH:46][CH:47]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[CH:23][C:24]([O:32][CH3:33])=[C:25]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH:26]=4)[CH:19]=3)[NH:14][CH:13]=2)[C:8]([CH3:44])=[N:7]1
Reactant: COc1ccc(-c2cnc3c(c2)c(-c2c(C)nn(Cc4cccc(F)c4)c2C)cn3S(=O)(=O)c2ccc(C)cc2)cc1NS(C)(=O)=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(-c2cnc3[nH]cc(-c4c(C)nn(Cc5cccc(F)c5)c4C)c3c2)cc1NS(C)(=O)=O
Yield: 8.4 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, N-(5-(3-(1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-methoxy phenyl)methanesulfonamide was hydrolyzed with lithium hydroxide (65 mg, 1.56 mmol) in THF/Methanol/water (10/3/2 mL). This yielded 22 mg (8.4% yield) of pure compound after purification by flash chromatography. 1H NMR (DMSO-d6, 300 MHz): δ 11.9 (s, 1H), 9.07 (s, 1H), 8.519-8.515 (d, 2H), 7.827-8.23 (d, 2H), 7.56-7.43 (m, 3H), 7.21-7.04 (m, 4H), 5.36 (s, 2H), 3.90 (s, 3H), 3.03 (s, 3H), 2.21-2.17 (d, 6H). MS: m/z=520.1 (M+1), HPLC: 95.74% (Method-B).
Reaction SMILES: Br[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[N:5]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[N:3]=1.[C-:21]#[N:22].[K+]>CN(C)C=O.C(OCC)(=O)C.O>[F:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[CH2:7][N:6]1[C:2]([C:21]#[N:22])=[N:3][C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[N:5]1
Reactant: [C-]#N
Reactant: Fc1ccccc1Cn1nc(-c2ccccn2)nc1Br
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1nc(-c2ccccn2)nn1Cc1ccccc1F
Temperature: 100 °C

Procedure:
To a solution of 2-(5-bromo-1-(2-fluorobenzyl)-1H-1,2,4-triazol-3-yl)pyridine (I-16, e.g., about 0.95 g, 2.9 mmol) in N,N-dimethylformamide (e.g., 9.5 mL) is added potassium cyanide (e.g., about 0.928 g, 14.3 mmol). After heating the solution at about 100° C. for about 22 h, the solution is diluted with ethyl acetate (e.g., about 125 mL) and water (e.g., about 100 mL). The layers are separated, and the aqueous layer is extracted with ethyl acetate (e.g., about 2×50 mL). The organics are combined, washed with water (e.g., about 50 mL) and brine (e.g., about 50 mL), dried, e.g., over sodium sulfate or magnesium sulfate, filtered, and the solvent is removed in vacuo to give the crude product, I-33. Purification by silica gel chromatography (0-15% ethyl acetate in dichloromethane) yields 1-(2-fluorobenzyl)-3-(pyridin-2-yl)-1H-1,2,4-triazole-5-carbonitrile I-33 (I-33) as a solid.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](Cl)=[O:19]>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:18](=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][Cl:13])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2ccccc21
Reactant: O=C(Cl)CCCCCl
Product: CC(=O)N1CCc2cc(C(=O)CCCCCl)ccc21
Yield: 45.4 %

Procedure:
Using 1-acetylindoline (1.60 g) and 5-chlorovaleryl chloride (1.70 g) according to the same method as that of Reference Example 1, the title compound (1.26 g) was obtained as colorless crystals having a melting point of 90 to 91° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:16])[C@H:10]([CH2:12][CH:13]([CH3:15])[CH3:14])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]1[CH2:23][S:20](=[O:22])(=[O:21])[O:19][CH2:18]1>O1CCCC1.O1CCOCC1.CO>[CH2:1]([O:8][C:9]([C@@H:10]([NH:11][CH2:18][CH2:17][CH2:23][S:20]([OH:22])(=[O:21])=[O:19])[CH2:12][CH:13]([CH3:14])[CH3:15])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C[C@H](N)C(=O)OCc1ccccc1
Reactant: O=S1(=O)CCCO1
Solvent: CO
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CC(C)C[C@H](NCCCS(=O)(=O)O)C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 47.3 %

Procedure:
To a solution of L-Leucine benzylester (2.81 g, 12.7 mmol) in tetrahydrofuran (6 mL), 1,4-dioxane (6 mL) and MeOH (6 mL) was added 1,3-propane sultone (1.40 g, 11.5 mmol). The solution was stirred at reflux for 2.5 hours. The reaction mixture was cooled to room temperature. The solid was filtered and washed with acetone (2×20 mL). The filtrate was evaporated under reduced pressure. The residue was dissolved in acetone (20 mL). The product was precipitated with Et2O (200 mL). The solid material was filtered. Both solids were combined and dissolved in 50% EtOH/water (200 mL). Dowex Marathon C ion exchange resin (strongly acidic) was added to the solution. The suspension was stirred for 15 minutes before the resin was removed by filtration. The filtrate was evaporated under reduced pressure and lyophilized, affording the title compound (1.87 g, 47%). 1H NMR (DMSO, 500 MHz) δ ppm 9.34 (s (broad), 1H), 7.39 (m, 5H), 5.25 (s, 2H), 4.10 (m, 1H), 3.09 (m, 2H), 2.60 (m, 2H), 1.95 (m, 2H), 1.64 (m, 3H), 0.86 (m, 6H). 13C (DMSO, 125 MHz) δ ppm 168.90, 134.91, 128.53, 128.50, 128.41, 67.38, 57.37, 49.17, 45.79, 38.06, 24.07, 22.79, 21.78, 21.33. [α]D=+1.8° (c=0.0017 in water), ES-MS 344 (M+1).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:14][CH2:15][CH3:16])[CH2:5][NH:6][CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)[CH3:2].[CH:17]1[C:29]2[CH:28]([CH2:30][O:31][C:32]([NH:34][C@@H:35]([CH2:39][C:40]3[CH:45]=[CH:44][C:43]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[CH:42][CH:41]=3)[C:36](O)=[O:37])=[O:33])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]=2[CH:20]=[CH:19][CH:18]=1>>[C:47]([O:46][C:43]1[CH:42]=[CH:41][C:40]([CH2:39][C@H:35]([NH:34][C:32](=[O:33])[O:31][CH2:30][CH:28]2[C:29]3[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=3[C:22]3[C:27]2=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:36]([N:6]([CH2:5][CH:4]([O:3][CH2:1][CH3:2])[O:14][CH2:15][CH3:16])[CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[O:37])=[CH:45][CH:44]=1)([CH3:50])([CH3:48])[CH3:49]
Reactant: CCOC(CNCc1ccncc1)OCC
Reactant: CC(C)(C)Oc1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Product: CCOC(CN(Cc1ccncc1)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21)OCC
Yield: 85.8 %

Procedure:
According to the procedure described in the synthesis method of Compound III-5, 2,2-diethoxy-N-(pyridin-4-ylmethyl)ethanamine (Compound IX-15) (70.8 g, 315 mmol) was coupled with (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-tert-butoxyphenyl)propanoic acid (128.6 g, 280 mmol) and the obtained residue was purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate=1:1 to 0:100) to obtain the title compound (160.0 g, 76%).
Reaction SMILES: O=C1N2C[C@@H](CC[C@H]2C([NH:12][O:13][C@H:14]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]2)=O)N1OS(O)(=O)=O.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:12][O:13][C@@H:14]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OS(=O)(=O)O)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@@H](ON)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 62.6 %

Procedure:
To a mixture of tert-butyl (3S)-3-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]pyrrolidine-1-carboxylate 10 (0.11 g, 0.24 mmol) in DCM (4.0 mL) was added trifluoroacetic acid (0.20 mL) at 0° C. The mixture was stirred at 0° C. for 1 h, concentrated and washed with ether. The white solid was collected by centrifugation. The crude product was purified by preparative HPLC to provide Compound 2 (Table 1) (30.4 mg, 36%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH3:24])[C:12]2[N:13]=[C:14](S(C)(=O)=O)[N:15]=[CH:16][C:11]=2[CH:10]=1.[NH2:25][C:26]1[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[N:30][CH:31]=1>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH3:24])[C:12]2[N:13]=[C:14]([NH:25][C:26]3[CH:31]=[N:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(S(C)(=O)=O)nc21
Reactant: COc1ccc(N)cn1
Solvent: O
Product: COc1ccc(Nc2ncc3cc(-c4c(Cl)cccc4Cl)c(=O)n(C)c3n2)cn1
Temperature: 160 °C

Procedure:
A mixture of 0.155 g (0.40 mmol) of 6-(2,6-dichlorophenyl)-2-methanesulfonyl-8-methyl-8H-pyrido[2,3-d]pyrimidin-7-one of Example 39 and 0.50 g (4.00 mmol) of 5-amino-2-methoxypyridine was heated, with stirring, in a 160° C. oil bath. The resulting solution was heated for 10 minutes and cooled to room temperature. Water (10 mL) was added to precipitate a gum. The mixture was decanted, and the remaining gum was triturated with 5 mL of water. The brown solid that developed was filtered, washed well with water, and dried; wt 0.135 g. Purification was effected by silica gel chromatography eluting with chloroform and then with ethyl acetate to obtain the fraction containing pure product. The eluent was concentrated to 2 mL volume. The crystals that separated on inducement were filtered and washed with 0.2 mL of ethyl acetate and then 0.5 mL of ether; wt 0.045 g; mp 233°-235° C.
Reaction SMILES: [H-].[Na+].O[C:4]1[CH:5]=[C:6]([C:10]2[CH:11]=[C:12]([C:18]#[N:19])[C:13](=[O:17])[NH:14][C:15]=2[CH3:16])[CH:7]=[CH:8][CH:9]=1.BrCCC[C:24]([O:26][CH2:27][CH3:28])=[O:25]>CN(C=O)C>[C:24]([C:4]1[C:5]([O:17][CH2:13][CH2:12][CH3:11])=[C:6]([C:10]2[CH2:11][CH:12]([C:18]#[N:19])[C:13](=[O:17])[NH:14][C:15]=2[CH3:16])[CH:7]=[CH:8][CH:9]=1)([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)CCCBr
Reactant: Cc1[nH]c(=O)c(C#N)cc1-c1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCOc1c(C(=O)OCC)cccc1C1=C(C)NC(=O)C(C#N)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 116.8 %

Procedure:
A dispersion of 337 mg (14.0 mmol) of 60% sodium hydride in mineral oil and 5 ml of DMF is treated, dropwise, with a solution of 1.60 g (7.0 mmol) of 5-(3-hydroxyphenyl)6-methyl-2-oxo-1,2-dihydro-3-pyridinecarbonitrile. The reaction is stirred 30 min at RT, then cooled in an ice bath and 1.36 g (7.0 mmol) of ethyl 4-bromobutyrate in 5 ml of DMF is added dropwise. The reaction is allowed to slowly come to RT and stirred over night. The mixture is concentrated under vacuum, the residue is taken up in 80 ml of water, extracted with EtOAc, acidified to pH=5 with IN HCl, and the aqueous phase extracted with EtOAc (4×80 ml). The EtOAc is dried (MgSO4) and the solvent removed to leave a light yellow solid. This solid is triturated with hot ether and filtered to give 1.40 g of 5-(3-carboethoxy-propyloxyphenyl)-6-methyl-2-oxo-1,3-dihydro-3-pyridinecarbonitrile as a pale yellow solid, m.p. 168°-169° C. 1H-NMR (d6 -DMSO): δ1.20 (t,3H); 1.95 (m,2H); 2.15 (s,3H); 2.50 (t,2H); 4.03 (q,2H); 4.05 (t,2H); 6.95 (m,3H); 7.30 (m,1H); 8.10 (s,1H).
Reaction SMILES: [C:1]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]([OH:18])=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C([N:21](CC)CC)C.ClC(OCC(C)C)=O>C(Cl)(Cl)Cl>[C:1]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]([NH2:21])=[O:18])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: CCN(CC)CC
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: ClC(Cl)Cl
Product: NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.8 %

Procedure:
To a solution of the resulting (S)-1-carbobenzoxypyrrolidine-2-carboxylic acid (52.2 g:0.21 mole) and triethylamine (21.2 g:0.21 mole) in 525 ml of chloroform was added isobutyl chloroformate (28.7 g:0.21 mole) with stirring under cooling on ice, followed by continuing the stirring for 15 minutes. Dried ammonia gas was bubbled into the mixture for 1 hour and then the mixture was allowed to warm to room temperature and stand overnight. The resulting white precipitate was removed by the filtration, and the filtrate was evaporated under reduced pressure. The residue was dissolved in 200 ml of chloroform and was washed with diluted aqueous hydrochloric acid and water, and dried over magnesium sulfate. Chloroform was distilled off to give 45.8 g of (S)-1-carbobenzoxypyrrolidine-2-carboxamide. Yield: 88%.