Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:3]=1[CH2:4][N:5]1[C:10](=[O:11])[C:9]([CH3:12])=[N:8][N:7]=[C:6]1[N:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]([NH:19]C(=O)OC(C)(C)C)[CH2:14]1.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>ClCCl>[NH2:19][C@@H:15]1[CH2:16][CH2:17][CH2:18][N:13]([C:6]2[N:5]([CH2:4][C:3]3[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:2]=3[Cl:1])[C:10](=[O:11])[C:9]([CH3:12])=[N:8][N:7]=2)[CH2:14]1
Reactant: Cc1nnc(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)n(Cc2cc(F)ccc2Cl)c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nnc(N2CCC[C@@H](N)C2)n(Cc2cc(F)ccc2Cl)c1=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of (R)-tert-butyl 1-(4-(2-chloro-5-fluorobenzyl)-6-methyl-5-oxo-4,5-dihydro-1,2,4-triazin-3-yl)piperidin-3-ylcarbamate (31, 44 mg) in dichloromethane (1 mL) was added TFA (0.4 mL), and the mixture was stirred at RT for 1.5 h. The mixture was carefully neutralized with NaHCO3 (aq, saturated), and extracted with CH2Cl2 (10 mL×3). The combined extracts were dried over Na2SO4 and concentrated to give (R)-3-(3-aminopiperidin-1-yl)-4-(2-chloro-5-fluorobenzyl)-6-methyl-1,2,4-triazin-5(4H)-one (32). MS: m/z, 352 (100%, M+1), 354 (33%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:17][CH2:16][CH2:15][C@@H:14]3[N:9]2[C:10](=[O:18])[CH2:11][CH:12]=[CH:13]3)=[CH:4][CH:3]=1.[H][H]>CO.[Pt]=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:17][CH2:16][CH2:15][C@@H:14]3[N:9]2[C:10](=[O:18])[CH2:11][CH2:12][CH2:13]3)=[CH:4][CH:3]=1
Reactant: O=C1CC=C[C@@H]2CCC[C@H](c3ccc(F)cc3)N12
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CO
Product: O=C1CCC[C@@H]2CCC[C@H](c3ccc(F)cc3)N12
Yield: 99.2 %

Procedure:
Platinum oxide (10 mg) was added to a solution of (6R*,9aS*)-6-(4-fluorophenyl)-3,6,7,8,9,9a-hexahydroquinolizin-4-one (550 mg) in methanol (5 mL), and the reaction solution was stirred in a hydrogen stream at room temperature for three hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain 550 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13](=[O:54])[C@@H:14]([NH:24][C:25]([C:27]2[CH:36]=[C:35]([O:37][CH2:38][C:39]([N:41]3[CH2:45][CH2:44][CH2:43][C@H:42]3[C:46](=[O:52])[NH:47][CH:48]3[CH2:51][CH2:50][CH2:49]3)=[O:40])[C:34]3[C:29](=[CH:30][C:31]([CH3:53])=[CH:32][CH:33]=3)[N:28]=2)=[O:26])[CH2:15][CH2:16][C:17]([O:19][C:20](C)(C)[CH3:21])=[O:18])[CH2:9][CH2:8]1)=[O:6])[CH3:3].C1(C)C=CC=CC=1>C(O)C>[CH2:2]([O:4][C:5]([N:7]1[CH2:8][CH2:9][N:10]([C:13](=[O:54])[C@@H:14]([NH:24][C:25]([C:27]2[CH:36]=[C:35]([O:37][CH2:38][C:39]([N:41]3[CH2:45][CH2:44][CH2:43][C@H:42]3[C:46](=[O:52])[NH:47][CH:48]3[CH2:49][CH2:50][CH2:51]3)=[O:40])[C:34]3[C:29](=[CH:30][C:31]([CH3:53])=[CH:32][CH:33]=3)[N:28]=2)=[O:26])[CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:11][CH2:12]1)=[O:6])[CH3:3]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)c3ccc(C)cc3n2)CC1
Agent: Cl
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)CC[C@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)c2ccc(C)cc2n1)C(=O)N1CCN(C(=O)OCC)CC1
Reaction time: 2 h

Procedure:
To 100 ml of a saturated solution of hydrochloric acid in ethanol 5 g of 4-[(S)-4-tert-Butoxycarbonyl-2-({4-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester was added and the mixture was stirred for 2 h. Then, 30 ml of toluene was added and the solvents were removed under reduced pressure. The residue was filtered through a plug of silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. The residue was purified by re-crystallisation from n-heptane/ethyl acetate and dried under reduced pressure. Yield: 3.8 g MS (ES+): m/e=709.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15]([NH:21][CH2:22][CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[N:16][CH:17]=[N:18][C:19]=2[NH2:20])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[C:34](Cl)(=[O:37])[CH:35]=[CH2:36]>C1COCC1.O>[C:34]([N:26]1[CH2:27][CH2:28][CH:23]([CH2:22][NH:21][C:15]2[C:14]([C:11]3[CH:12]=[CH:13][C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:9][CH:10]=3)=[C:19]([NH2:20])[N:18]=[CH:17][N:16]=2)[CH2:24][CH2:25]1)(=[O:37])[CH:35]=[CH2:36]
Reactant: Nc1ncnc(NCC2CCNCC2)c1-c1ccc(Oc2ccccc2)cc1
Reactant: C=CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=CC(=O)N1CCC(CNc2ncnc(N)c2-c2ccc(Oc3ccccc3)cc2)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 36.8 %

Procedure:
Into a 20 mL reaction vial was added 5-(4-phenoxyphenyl)-N-(piperidin-4-ylmethyl)pyrimidine-4,6-diamine (70.00 mg; 0.19 mmol), sodium bicarbonate (23.49 mg; 0.28 mmol) suspended in THF (3.00 ml) and water (0.30 ml). The mixture was cooled to 0° C. Acryloyl chloride (0.02 ml; 0.22 mmol) was added. The ice bath was left to melt. The reaction mixture was then stirred at rt overnight. The crude mixture was purified using Biotage column chromatography eluting 0-50% MeOH/EtOAc. Fractions containing the desired product were combined and concentrated under reduced pressure. The residue was lyophilized overnight to afford N-[(1-acryloylpiperidin-4-yl)methyl]-5-(4-phenoxyphenyl)pyrimidine-4,6-diamine as a white solid (30.00 mg, 37% yield). HPLC purity: 97%, RT=3.665 min. MS: m/z=430 [M+H]+, RT=1.53 min. 1H-NMR (DMSO-d6) δ 7.93 (s, 1H), 7.40 (t, 2H), 7.21-7.08 (m, 8H), 6.76 (dd, 1H), 6.04 (d, 1H), 5.61 (d, 1H), 5.43 (s, 2H), 4.34 (d, 1H), 3.98 (d, 1H), 3.12 (t, 2H), 2.95 (t, 1H), 2.56 (t, 1H), 1.81 (m, 1H), 1.59 (m, 2H), 0.92 (m, 2H).
Reaction SMILES: O.[F:2][C:3]1[C:22]([N:23]2[C:28](=[O:29])[CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[N:25]([CH3:34])[C:24]2=[O:35])=[CH:21][C:6]([O:7][C:8]2[C:9]([O:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[N:10][C:11]([Cl:14])=[CH:12][CH:13]=2)=[C:5]([N+:36]([O-])=O)[CH:4]=1>C(O)(=O)C.[Fe]>[NH2:36][C:5]1[CH:4]=[C:3]([F:2])[C:22]([N:23]2[C:28](=[O:29])[CH:27]=[C:26]([C:30]([F:31])([F:33])[F:32])[N:25]([CH3:34])[C:24]2=[O:35])=[CH:21][C:6]=1[O:7][C:8]1[C:9]([O:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[N:10][C:11]([Cl:14])=[CH:12][CH:13]=1
Reactant: COC(=O)COc1nc(Cl)ccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)COc1nc(Cl)ccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1N
Temperature: 35 °C
Reaction time: 2 h

Procedure:
To a mixture of an iron powder, acetic acid and water is added a solution of 3-{4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)--1,2,3,6-tetrahydropyrimidin-1-yl]-2-nitrophenoxy}-6-chloro-2-(methoxycarbonyl)methoxypyridine in acetic acid dropwise while maintaining the temperature of the reaction solution at 35° C. or lower. After completion of the addition, the mixture is stirred for 2 hours, then, the reaction solution is filtrated through Celite, and diluted with ethyl acetate. The mixture is neutralized with saturated aqueous sodium bicarbonate solution, the organic layer is washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated, then, the resulted residue is subjected to silica gel chromatography to obtain 3-{2-amino-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-6-chloro-2-(methoxycarbonyl)methoxypyridine.
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[OH:6][C:7]1[CH:16]=[CH:15][C:14]2[NH:13][C:12](=O)[CH:11]=[CH:10][C:9]=2[C:8]=1[CH:18]=[O:19]>CN(C=O)C>[Cl:3][C:12]1[CH:11]=[CH:10][C:9]2[C:8]([CH:18]=[O:19])=[C:7]([OH:6])[CH:16]=[CH:15][C:14]=2[N:13]=1
Reactant: O=Cc1c(O)ccc2[nH]c(=O)ccc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: O=Cc1c(O)ccc2nc(Cl)ccc12
Temperature: 20 °C
Reaction time: 20 h
Yield: 80.3 %

Procedure:
POCl3 (973 μL, 10.4 mmol) was added dropwise to a DMF (5 mL) solution of 6-hydroxy-2-oxo-1,2-dihydroquinoline-5-carbaldehyde (658 mg, 3.48 mmol) at 0° C. The mixture was stirred for 20 hours at 20° C. then cooled to 0° C. Upon addition of ice water the product precipitated. It was filtered, washed with water and dried on air to afford 580 mg (88%) of the title compound. MS (ESI): 208 (M+H)+. 1H NMR (δ, DMSO (2.5 ppm)): 11.95 (s, 1H, OH), 10.70 (s, 1H, CHO), 9.38, 8.10, 7.67 and 7.55 (4d, 4×1H).
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH:15][C:16](=[O:24])OC3C=CC=CC=3)=[CH:9][CH:8]=2)[N:5]=[C:4]([C:25]([F:28])([F:27])[F:26])[C:3]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[OH:35][C:36]1[CH:37]=[C:38]([S:42]([NH2:45])(=[O:44])=[O:43])[CH:39]=[CH:40][CH:41]=1>>[OH:35][C:36]1[CH:37]=[C:38]([S:42]([NH:45][C:16]([NH:15][CH2:14][CH2:13][C:10]2[CH:11]=[CH:12][C:7]([N:6]3[C:2]([CH3:1])=[C:3]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:4]([C:25]([F:27])([F:26])[F:28])=[N:5]3)=[CH:8][CH:9]=2)=[O:24])(=[O:43])=[O:44])[CH:39]=[CH:40][CH:41]=1
Reactant: Cc1c(-c2ccccc2)c(C(F)(F)F)nn1-c1ccc(CCNC(=O)Oc2ccccc2)cc1
Reactant: NS(=O)(=O)c1cccc(O)c1
Product: Cc1c(-c2ccccc2)c(C(F)(F)F)nn1-c1ccc(CCNC(=O)NS(=O)(=O)c2cccc(O)c2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 42 from phenyl 2-{4-[5-methyl-4-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}ethylcarbamate (step 7 of Example 52) and 3-hydroxybenzenesulfonamide: MS (ESI) m/z 545 [M+H]+, 543 [M−H]−, 1H-NMR (CDCl3) δ 7.48-7.01 (13H, m), 6.32 ▪ 1H, br.s), 3.50 (2H, t, J=6.1 Hz), 2.85 (2H, t, J=6.1 Hz), 2.20 (3H, s).
Reaction SMILES: C([O-])(=O)C.[Na+].[CH3:6][C:7]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]2[C:8]=1[C:9](=O)[CH2:10][CH2:11][S:12]2.Cl.[NH2:20][OH:21]>O.C(O)C>[CH3:6][C:7]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]2[C:8]=1[C:9](=[N:20][OH:21])[CH2:10][CH2:11][S:12]2
Reactant: NO
Reactant: Cc1cc(C)c2c(c1)SCCC2=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cc(C)c2c(c1)SCCC2=NO
Yield: 69.5 %

Procedure:
A suspension of 37.8 g of sodium acetate in water is added, at 50-60° C., to a suspension of 31.1 g (0.154 mol) of 5,7-dimethylthio-chroman-4-one and 18.5 g (0.261 mol) of hydroxylamine hydrochloride in 200 ml of ethanol. This mixture is subsequently refluxed for 30 minutes. After cooling, filtration with suction of the solid which has precipitated gives 22.2 g of 5,7-dimethylthiochroman-4-one oxime (66% of theory, purity approx. 95%) of melting point 170-174° C.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[C:17]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])[CH:16]=[CH:15][C:3]=1[C:4]([C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8](O)=[O:9])=[O:5].[CH2:24]([N:26]([CH2:38][CH3:39])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]([CH2:36][CH3:37])[CH2:34][CH3:35])[CH:28]=1)[CH3:25].C(OC(=O)C)(=O)C>O>[CH2:36]([N:33]([CH2:34][CH3:35])[C:29]1[CH:28]=[C:27]([N:26]([CH2:38][CH3:39])[CH2:24][CH3:25])[CH:32]=[CH:31][C:30]=1[C:4]1([C:3]2[CH:15]=[CH:16][C:17]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:18][C:2]=2[CH3:1])[C:6]2[C:7](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:8](=[O:9])[O:5]1)[CH3:37]
Reactant: CCN(CC)c1cccc(N(CC)CC)c1
Reactant: CCN(CC)c1ccc(C(=O)c2ccccc2C(=O)O)c(C)c1
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CCN(CC)c1ccc(C2(c3ccc(N(CC)CC)cc3N(CC)CC)OC(=O)c3ccccc32)c(C)c1
Temperature: 40 °C

Procedure:
A mixture of 2-(2-methyl-4-(diethylamino)benzoyl)-benzoic acid (12.48 g.), N,N,N',N'-tetraethyl-m-phenylenediamine (10.56 g.) and acetic anhydride (12 ml.) was warmed (at 40±8° C.) during one hour, diluted with water (50 ml., then 100 ml.), adjusted to pH 4.6 and filtered. The filtrate was clarified with water and adjusted to pH 5.5. Recrystallization of the resulting product (m.p. 134°-140° C.) from methanol afforded 3-(2,4-bis(diethylamino)phenyl)-3-(2-methyl-4-(diethylamino)phenyl)phthalide (I: X= Y4 = (CH3CH2)2N, Y2 = CH3, Z4 = Z5 = Z6 = Z7 = H) (m.p. 149°- 151° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:3]=1[CH2:4][NH:5][C:6]([N:8]1[CH2:11][C:10]2([CH2:14][NH:13][CH2:12]2)[CH2:9]1)=[O:7].C(N(CC)CC)C.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>ClCCl>[Cl:1][C:2]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:3]=1[CH2:4][NH:5][C:6]([N:8]1[CH2:11][C:10]2([CH2:14][N:13]([C:27](=[O:34])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:12]2)[CH2:9]1)=[O:7]
Reactant: O=C(NCc1ccc(Cl)cc1Cl)N1CC2(CNC2)C1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCc1ccc(Cl)cc1Cl)N1CC2(C1)CN(C(=O)c1ccccc1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
2,6-Diaza-spiro[3.3]heptane-2-carboxylic acid 2,4-dichloro-benzylamide (245 mg, 416 μmol) and triethylamine (200 mg, 198 mmol) were dissolved in dichloromethane (5 mL) followed by benzoyl chloride (70 mg, 499 μmol) and the reaction mixture was stirred for 1 h at ambient temperature. The crude reaction mixture was concentrated under reduced pressure. The residue was purified by chromatography (SiO2; methanol:dichloromethane 0:1 to 1:19) to give the title compound (106 mg, 63%) as a colorless solid. MS (EI) m/e: 404.1 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:11]2[CH2:16][CH2:15][N:14]([S:17]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH2:13][CH2:12]2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[CH3:27][N:28](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([C:27]#[N:28])=[CH:3][CH:4]=1)([N:11]1[CH2:16][CH2:15][N:14]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:13][CH2:12]1)[CH3:10]
Reactant: CN(C)C=O
Reactant: Cc1ccc(S(=O)(=O)N2CCN(C(C)(C)c3ccc(Br)cc3)CC2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1ccc(S(=O)(=O)N2CCN(C(C)(C)c3ccc(C#N)cc3)CC2)cc1
Yield: 47 %

Procedure:
To a solution of 1-[1-(4-bromo-phenyl)-1-methyl-ethyl]-4-(toluene-4-sulfonyl)-piperazine (200 mg, 0.45 mmol) in DMF (3 mL) was added zinc cyanide (64.41 mg, 0.54 mmol) and tetrakis(triphenylphosphine)palladium(0) (52 mg, 0.045 mmol) and the reaction mixture degassed for 10 min under N2. The reaction mixture was then subjected to microwave irradiation for 30 min at 180° C., afterwhich time the reaction was diluted with 1:1 CH2Cl2/EtOAc (20 mL), washed with water (2×10 mL), passed through a phase separation cartridge and concentrated in vacuo. The crude residue was purified by reverse phase preparative HPLC-MS to afford 4-{1-methyl-1-[4-(toluene-4-sulfonyl)-piperazin-1-yl]-ethyl]-benzonitrile as a cream solid (70 mg, 47%).
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([Br:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(O[CH:18](OC(C)(C)C)[N:19]([CH3:21])[CH3:20])(C)(C)C>C1(C)C=CC=CC=1>[C:3]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([Br:12])[CH:9]=[C:10]([CH3:11])[C:2]=1[N:1]=[CH:18][N:19]([CH3:21])[CH3:20])([CH3:7])([CH3:4])[CH3:2]
Reactant: CN(C)C(OC(C)(C)C)OC(C)(C)C
Reactant: Cc1cc(Br)cc(C(=O)O)c1N
Solvent: Cc1ccccc1
Product: Cc1cc(Br)cc(C(=O)OC(C)(C)C)c1N=CN(C)C
Yield: 97.5 %

Procedure:
A mixture of 5.0 g (21.7 mmol) of the product of Example 132 and 20.8 ml (86.9 mmol) of N,N-dimethylformamide di-t-butylacetal in 30 ml of toluene was heated to reflux for 2 hr. The reaction mixture was cooled to room tenperature, washed with water and brine, dried over MgSO4 and concentrated in vacuo to provide 3.61 g (49%) of the desired product as an yellow oil. Electrospray Mass Spec 341(M+H).
Reaction SMILES: CC(C[AlH]CC(C)C)C.[CH3:10][C:11]1[CH:18]=[C:17]([C:19]2[S:20][C:21]3[C:26]([N:27]=2)=[CH:25][CH:24]=[C:23]([C:28]2([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH2:30][CH2:29]2)[N:22]=3)[CH:16]=[CH:15][C:12]=1[C:13]#N.C(C(C(C([O-])=O)O)O)([O-])=[O:38]>C(Cl)Cl>[CH3:10][C:11]1[CH:18]=[C:17]([C:19]2[S:20][C:21]3[C:26]([N:27]=2)=[CH:25][CH:24]=[C:23]([C:28]2([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH2:30][CH2:29]2)[N:22]=3)[CH:16]=[CH:15][C:12]=1[CH:13]=[O:38]
Reactant: Cc1cc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)ccc1C#N
Reactant: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: Cc1cc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)ccc1C=O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
DIBAL-H (1.0M in hexanes; 0.132 mL, 0.132 mmol) was added to a solution of 2-methyl-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)benzonitrile (44.2 mg, 0.120 mmol) in CH2Cl2 (2.0 mL) at 25° C., and the resulting solution was stirred at 25° C. for 45 min. Saturated aqueous Na/K tartrate solution (2.0 mL) was then added, and the resulting mixture was stirred for 15 min, then partitioned between CH2Cl2 (20 mL) and water (10 mL). The organic layer was separated, and the aqueous layer was extracted with CH2Cl2. The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 15% EtOAc/hexanes) provided 2-methyl-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)benzaldehyde as a light yellow solid. MS (ESI) m/z: Calculated: 370.1; Observed: 371.2 (M++1).
Reaction SMILES: [CH:1]([NH:3][C@@H:4]1[C:32](=[O:33])[N:6]2[C:7]([C:16]([O:18][CH:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])=[C:8](OS(C)(=O)=O)[CH2:9][S:10][C@H:5]12)=[O:2].[SH:34][CH2:35][C:36]1[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH:1]([NH:3][C@@H:4]1[C:32](=[O:33])[N:6]2[C:7]([C:16]([O:18][CH:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:17])=[C:8]([S:34][CH2:35][C:36]3[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=3)[CH2:9][S:10][C@H:5]12)=[O:2]
Reactant: SCc1ccncc1
Reactant: CS(=O)(=O)OC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC=O)[C@H]2SC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=CN[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(SCc3ccncc3)CS[C@H]12
Temperature: 0 °C
Reaction time: 1.9 h
Yield: 88.4 %

Procedure:
To a solution of diphenylmethyl 7β-formamido-3-methanesulfonyloxy-3-cephem-4-carboxylate (14.66 g, 30 m mol) in DMF (103 ml) was added 4-(mercaptomethyl)pyridine (4.13 g, 33 m mol) at −20° C., followed by dropwise addition of N,N-diisopropylethylamine (3.88 g, 30 m mol). The mixture was stirred at the same temperature for 1.9 hours and poured into ice water (500 ml). The resulting precipitates were collected by filtration and washed with water. The powder was dissolved in THF, and ethyl acetate and water were added respective. The separated organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give diphenylmethyl 7β-formamido-3-[(4-pyridyl)methylthio]-3-cephem-4-carboxylate (13.73 g).
Reaction SMILES: [CH3:1][N:2]([CH3:34])[C:3]1[CH:33]=[CH:32][CH:31]=[CH:30][C:4]=1[CH2:5][N:6]1[CH2:10][CH2:9][C@@H:8]([NH:11][C:12]2[N:13]=[CH:14][C:15](/[CH:18]=[CH:19]/[C:20]([NH:22][O:23]C3CCCCO3)=[O:21])=[N:16][CH:17]=2)[CH2:7]1.[ClH:35]>CO.CCO>[ClH:35].[ClH:35].[ClH:35].[CH3:34][N:2]([CH3:1])[C:3]1[CH:33]=[CH:32][CH:31]=[CH:30][C:4]=1[CH2:5][N:6]1[CH2:10][CH2:9][C@@H:8]([NH:11][C:12]2[N:13]=[CH:14][C:15](/[CH:18]=[CH:19]/[C:20]([NH:22][OH:23])=[O:21])=[N:16][CH:17]=2)[CH2:7]1
Reactant: CN(C)c1ccccc1CN1CC[C@@H](Nc2cnc(/C=C/C(=O)NOC3CCCCO3)cn2)C1
Agent: Cl
Solvent: CCO
Solvent: CO
Product: CN(C)c1ccccc1CN1CC[C@@H](Nc2cnc(/C=C/C(=O)NO)cn2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2E)-3-[5-({(3R)-1-[2-(dimethylamino)benzyl]-3-pyrrolidinyl}amino)-2-pyrazinyl]-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (236 mg) in MeOH (3.5 mL) was added 2N—HCl solution in EtOH (1.27 mL), which was stirred at room temperature for 1 hour. To the reaction mixture was dropwised IPE (9.4 mL), which was stirred further more 1 hour. The prepicitate was filtered to give (2E)-3-[5-({(3R)-1-[2-(dimethylamino) benzyl]-3-pyrrolidinyl}amino)-2-pyrazinyl]-N-hydroxyacrylamide trihydrochloride as a yellow powder (241 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH2:13][CH2:14][CH3:15])=[C:5]2[NH:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)=[N:22][CH:23]=1.[Cl:37][C:38]1[CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH:41]=[C:40]([F:53])[C:39]=1[OH:54]>>[C:12]([C:6]1[CH:7]=[N:8][C:9]2[C:4]([C:5]=1[NH:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]3[CH2:25][CH2:26][N:27]([C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])[CH2:28][CH2:29]3)=[N:22][CH:23]=1)=[CH:3][C:2]([C:42]1[CH:41]=[C:40]([F:53])[C:39]([OH:54])=[C:38]([Cl:37])[CH:43]=1)=[CH:11][CH:10]=2)(=[O:16])[CH2:13][CH2:14][CH3:15]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CCCC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Product: CCCC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1Nc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Yield: 73.9 %

Procedure:
Following general procedure F, tert-butyl 4-[5-(6-bromo-3-butyrylquinolin-4-ylamino)pyridin-2-yl]piperazine-1-carboxylate (80 mg, 0.144 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (59 mg, 0.216 mmol) to afford the crude product (66 mg) as an orange solid: ESI MS m/z 620 [C33H35ClFN5O4+H]+.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][N:13]1[C:21]2[C:20]([CH3:22])=[C:19]([Cl:23])[N:18]=[C:17]([N:24](CC3C=CC(OC)=CC=3)CC3C=CC(OC)=CC=3)[C:16]=2[N:15]=[C:14]1[CH2:43][CH2:44][CH3:45])(C)(C)C>FC(F)(F)C(O)=O>[NH2:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][N:13]1[C:21]2[C:20]([CH3:22])=[C:19]([Cl:23])[N:18]=[C:17]([NH2:24])[C:16]=2[N:15]=[C:14]1[CH2:43][CH2:44][CH3:45]
Reactant: CCCc1nc2c(N(Cc3ccc(OC)cc3)Cc3ccc(OC)cc3)nc(Cl)c(C)c2n1CCOCCNC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc2c(N)nc(Cl)c(C)c2n1CCOCCN
Reaction time: 8 h
Yield: 30.8 %

Procedure:
Trifluoroacetic acid (40 mL) was added to [2-(2-{4-[bis-(4-methoxybenzyl)amino]-6-chloro-7-methyl-2-propyl-1H-imidazo[4,5-c]pyridin-1-yl}ethoxy)ethyl]carbamic acid tert-butyl ester (1 g, 1.5 mmol). The reaction was swirled until it became homogeneous and was allowed to stand at room temperature overnight. The reaction was concentrated under reduced pressure, and dichloromethane was added and removed under reduced pressure (5×40 mL) to provide a white solid. The solid was triturated in chloroform, isolated by filtration, and dried under reduced pressure with heating. The solid was dissolved in concentrated hydrochloric acid (5 mL) and stirred for three hours. Aqueous sodium hydroxide was then added. A white solid formed, which was isolated by filtration, washed with water and diethyl ether, and dried for five hours under high vacuum at 70° C. to provide 0.144 g of 1-[2-(2-aminoethoxy)ethyl]-6-chloro-7-methyl-2-propyl-1H-imidazo[4,5-c]pyridin-4-amine as a white solid, mp 158.0–161.0° C.
Reaction SMILES: [C:1]1([C:7]2([CH:17]=[O:18])[CH2:16][CH2:15][C:10]3([O:14][CH2:13][CH2:12][O:11]3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:19]([Mg]Br)=[CH2:20]>>[CH:19]([CH:17]([C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9][C:10]2([O:14][CH2:13][CH2:12][O:11]2)[CH2:15][CH2:16]1)[OH:18])=[CH2:20]
Reactant: O=CC1(c2ccccc2)CCC2(CC1)OCCO2
Reactant: C=C[Mg]Br
Product: C=CC(O)C1(c2ccccc2)CCC2(CC1)OCCO2

Procedure:
Prepared from 8-phenyl-1,4-dioxaspiro[4.5]decane-8-carboxaldehyde (J. Med. Chem. 1975, 18, 593-599) and vinylmagnesium bromide according to the method of Description 22. 1H NMR (400 MHz, CDCl3) δ 1.31 (1H, br s), 1.42-1.69 (4H, m), 1.76-1.89 (2H, m), 2.23-2.28 (1H, m), 2.45-2.51 (1H, m), 3.85-3.96 (5H, m), 5.09-5.14 (2H, m), 5.55-5.63 (1H, m), and 7.21-7.39 (5H, m).