Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]([CH2:16][CH:17]([OH:22])[C:18]([F:21])([F:20])[F:19])[C:11](=[O:15])[CH:12](Br)[CH3:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>>[CH2:3]([N:10]1[CH2:16][CH:17]([C:18]([F:21])([F:20])[F:19])[O:22][CH:12]([CH3:13])[C:11]1=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(Br)C(=O)N(Cc1ccccc1)CC(O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Product: CC1OC(C(F)(F)F)CN(Cc2ccccc2)C1=O
Temperature: 0 °C

Procedure:
A solution of 3-(Benzylamino)-1,1,1-trifluoropropan-2-ol (2.68 g, 12.3 mmol) and triethylamine (1.7 mL, 12.2 mmol) in CH2Cl2 is cooled to 0° C. The solution is treated drop wise with 2-bromopropanoyl chloride (1.2 mL, 12 mmol, Aldrich) and stirred for 5 minutes. The solution is diluted to 100 mL with CH2Cl2 and washed sequentially with 1.0M HCl, saturated NaHCO3, and brine (100 mL each). The organic layer is dried over Na2SO4 and filtered. The solvent is removed by rotary evaporation yielding (N-benzyl-2-bromo-N-(3,3,3-trifluoro-2-hydroxypropyl)propanamide as a golden oil. Dry NaH is suspended in dry, inhibitor free THF (25 ml) in a flame dried flask and the mixture is cooled to 0° C. with stirring on an ice bath. The N-benzyl-2-bromo-N-(3,3,3-trifluoro-2-hydroxypropyl)propanamide (4.25 g, 12 mmol) is added as a solution in dry, inhibitor free THF (25 ml) and the resultant suspension is warmed to RT. After stirring for one hour the reaction is quenched with MeOH over an ice bath until no more gas evolved and the mixture is poured into 1.0M HCl (200 mL). The aqueous mixture is extracted into MTBE (200 mL) and the organic layer is washed with saturated NaHCO3 and brine (200 mL each). The organic layer is dried over Na2SO4 and filtered, and the solvent is removed by rotary evaporation yielding an amber oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N+:10]([O-:12])=[O:11])[C:6](O)=[N:7][CH:8]=1)#[N:2].C(N(CC)CC)C.CS(Cl)(=O)=O.[NH2:25][C@H:26]1[CH2:31][CH2:30][C@H:29]([OH:32])[CH2:28][CH2:27]1>ClCCl>[C:1]([C:3]1[CH:4]=[C:5]([N+:10]([O-:12])=[O:11])[C:6]([NH:25][C@H:26]2[CH2:31][CH2:30][C@H:29]([OH:32])[CH2:28][CH2:27]2)=[N:7][CH:8]=1)#[N:2]
Reactant: N#Cc1cnc(O)c([N+](=O)[O-])c1
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1cnc(N[C@H]2CC[C@H](O)CC2)c([N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
To a solution of 5-cyano-2-hydroxy-3-nitropyridine (600 mg) in 6 mL of dichloromethane containing triethylamine(0.557 mL) was added methanesulfonyl chloride (0.295 mL) under stirring at 0° C. The reaction mixture was stirred at the same temperature for 30 minutes, and then trans-4-aminocyclohexanol (1.26 g) was added to the mixture at 0° C. After stirring at room temperature for 2 hours, the mixture was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was subjected to a preparative silica gel column chromatography eluting with 5% methanol in chloroform. The obtained substance was triturated with diisopropyl ether to give 5-cyano-2-(trans-4-hydroxycyclohexylamino)-3-nitropyridine (198.9 mg) as a yellow solid.
Reaction SMILES: [CH2:1]([C:8]1[O:9][CH:10]=[N:11][N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CCOCC.[Mg+2].[Br-].[Br-].[Br:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[O:37][N:36]=[C:35]([CH3:38])[C:34]=2[CH:39]=[O:40])=[CH:29][CH:28]=1>C1COCC1>[CH2:1]([C:8]1[O:9][C:10]([CH:39]([C:34]2[C:35]([CH3:38])=[N:36][O:37][C:33]=2[C:30]2[CH:31]=[CH:32][C:27]([Br:26])=[CH:28][CH:29]=2)[OH:40])=[N:11][N:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Reactant: c1ccc(Cc2nnco2)cc1
Agent: [Br-]
Agent: [Li]CCCC
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1noc(-c2ccc(Br)cc2)c1C(O)c1nnc(Cc2ccccc2)o1
Temperature: -70 °C
Reaction time: 1.5 h

Procedure:
2-Benzyl-[1,3,4]oxadiazole (0.500 g, 3.12 mmol) was dissolved in THF and cooled to −70° C. then n-butyllithium (1.5M in THF, 2.1 mL, 3.12 mmol) was added and the reaction stirred for 1.5 hours. Magnesium bromide ethyl etherate (0.631 g, 3.43 mmol) was added and the reaction was allowed to warm to −45° C. After 45 minutes 5-(4-bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde (0.415 g, 1.56 mmol) in THF (2 mL) was added and the reaction was allowed to stir overnight. The reaction was quenched with aqueous ammonium chloride then submitted to standard workup and purification via silica gel chromatography (0-60% EtOAc in hexanes) to give the title compound.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:11][O:12][C:13](=[O:29])[CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=1.[CH:30](I)([CH3:32])[CH3:31]>C1COCC1>[CH3:11][O:12][C:13](=[O:29])[CH:14]([C:15]1[CH:16]=[C:17]([C:25]([F:28])([F:26])[F:27])[CH:18]=[C:19]([C:21]([F:23])([F:24])[F:22])[CH:20]=1)[CH:30]([CH3:32])[CH3:31]
Reactant: COC(=O)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(C)I
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium bis(trimethylsilyl) amide (1.0M in THF—177 μL) was added drop-wise to a solution of (3,5-bis-trifluoromethyl-phenyl)-acetic acid methyl ester (389 mg) in dry THF (2 mL) at 0° C., under nitrogen atmosphere. After ten minutes, isopropyl iodide (143 μL) was added and the reaction mixture was stirred at 0° C. for 30 min. Further isopropyl iodide (143 μL) was added and the solution stirred at r.t. for 1 hour. The reaction was quenched with a 2N hydrochloric acid solution (2 mL) and the product was extracted with Et2O (2×). The combined organic extracts were dried and concentrated in vacuo to a residue which was purified by flash chromatography (CH/AcOEt 95:5) to give the title compound (184 mg) as a colourless oil.
Reaction SMILES: Br[CH:2]1[CH2:17][CH2:16][C:5]2=[C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[S:7][C:8]([S:9][CH3:10])=[C:4]2[C:3]1=[O:18].[N-:19]=[N+:20]=[N-:21].[Na+]>CN(C)C=O.O>[N:19]([CH:2]1[CH2:17][CH2:16][C:5]2=[C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[S:7][C:8]([S:9][CH3:10])=[C:4]2[C:3]1=[O:18])=[N+:20]=[N-:21]
Reactant: CCOC(=O)c1sc(SC)c2c1CCC(Br)C2=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc(SC)c2c1CCC(N=[N+]=[N-])C2=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.7 %

Procedure:
Ethyl 5-bromo-4,5,6,7-tetrahydro-3-methylthio-4-oxobenzo[c]thiophene-1-carboxylate (5.24 g) was suspended in N,N-dimethylformamide (80 ml); a solution of sodium azide (1.95 g) in water (12 ml) was added at 0° C. After the reaction mixture was stirred at room temperature for 4 hours, it was poured over water (50 ml) and extracted with ethyl acetate. The organic layer was washed with water and dried (MgSO4), after which the solvent was distilled off. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:9 to 1:2, v/v) to yield ethyl 5-azido-4,5,6,7-tetrahydro-3-methylthio-4-oxobenzo[c]thiophene-1-carboxylate (3.77 g, 80.7%), which was then recrystallized from ethyl acetate-hexane. Colorless needles. Melting point 163-164° C. (decomposed).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:19]([N:21]1[C:29]2[C:24](=[N+:25]([O-:31])[CH:26]=[CH:27][C:28]=2[CH3:30])[N:23]([C:32]2[CH:37]=[CH:36][C:35]([O:38][Si](C(C)C)(C(C)C)C(C)C)=[CH:34][CH:33]=2)[C:22]1=[O:49])[CH3:20].[Cl-].[Cl-].[Ca+2]>C1COCC1>[CH2:19]([N:21]1[C:29]2[C:24](=[N+:25]([O-:31])[CH:26]=[CH:27][C:28]=2[CH3:30])[N:23]([C:32]2[CH:33]=[CH:34][C:35]([OH:38])=[CH:36][CH:37]=2)[C:22]1=[O:49])[CH3:20]
Reactant: CCn1c(=O)n(-c2ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc2)c2c1c(C)cc[n+]2[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Ca+2]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCn1c(=O)n(-c2ccc(O)cc2)c2c1c(C)cc[n+]2[O-]
Yield: 105.3 %

Procedure:
Tetrabutylammonium fluoride (0.566 mL) was added to a solution of 1-ethyl-7-methyl-3-(4-{[tris(1-methylethyl)silyl]oxy}phenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one 4-oxide (250 mg) in THF (5 mL) at room temperature. The mixture was stirred at room temperature under a dry atmosphere (CaCl2 tube) for 30 min. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0%-100% EtOAc in hexane) to give 1-ethyl-3-(4-hydroxyphenyl)-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one 4-oxide (170 mg) as a colorless solid. 3-Methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (126 mg) was added to a solution of 1-ethyl-3-(4-hydroxyphenyl)-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one 4-oxide (170 mg) and NaH (23.83 mg) in DMA (1 mL) at room temperature. The mixture was stirred at 150° C. under a dry atmosphere (CaCl2 tube) for 30 min. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 50%-100% EtOAc in hexane) to give 1-ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one 4-oxide as colorless crystals.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([CH2:7][S:8][CH2:9][CH2:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[N:6]=1.[CH3:19][C:20]([CH3:23])([O-:22])[CH3:21].[Na+]>C(O)(C)C.C(O)(C)(C)C>[C:20]([O:22][C:12]([NH:11][CH2:10][CH2:9][S:8][C:2]1[S:3][CH:4]=[C:5]([CH2:7][S:8][CH2:9][CH2:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[N:6]=1)=[O:13])([CH3:23])([CH3:21])[CH3:19]
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)OC(=O)NCCSCc1csc(Br)n1
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)NCCSCc1csc(SCCNC(=O)OC(C)(C)C)n1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of 2-bromo-4-[(2-tert-butoxycarbonylaminoethyl)thiomethyl]-1,3-thiazole (421 mg, 1.2 mmol) and 2-(tert-butoxycarbonylamino)ethylthiol (234 mg, 1.3 mmol) in isopropyl alcohol (5 mL) was added 1.0 M sodium t-butoxide in t-butanol (1.2 mL) and stirred at 80° C. for 1 h. After cooling, the mixture was concentrated and partitioned between ethyl acetate and water. The ethyl acetate extract was concentrated. The residue was chromatographed on silica gel (1% methanol/dichloromethane), affording 364 mg of the title compound. 1H NMR (CDCl3) δ 1.63 (18H), 2.78 (t, 2H), 3.42 (m, 4H), 3.61 (t, 2H), 3.90 (s, 2H), 5.18 (br s, 1H), 7.13 (1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:22])[C:9]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:23])[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[C:30]([C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)([OH:32])=[O:31]>O1CCOCC1.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>[Cl:23][C:4]1[CH:3]=[C:2]([C:36]2[CH:37]=[CH:38][C:33]([C:30]([OH:32])=[O:31])=[CH:34][CH:35]=2)[CH:7]=[CH:6][C:5]=1[CH:8]([CH3:22])[C:9]([OH:14])([C:15]1[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=1)[C:10]([F:13])([F:12])[F:11]
Reactant: Cc1cc(C(O)(C(C)c2ccc(Br)cc2Cl)C(F)(F)F)ccn1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Cc1cc(C(O)(C(C)c2ccc(-c3ccc(C(=O)O)cc3)cc2Cl)C(F)(F)F)ccn1

Procedure:
A mixture of 3-(4-bromo-2-chloro-phenyl)-1,1,1-trifluoro-2-(2-methyl-pyridin-4-yl)-butan-2-ol (10 mg), Pd(PPh3)4 (3 mg), Cs2CO3 (24 mg) and 4-carboxybenzeneboronic acid (CAS Reg. No. 14047-29-1, 8 mg) in dioxane (2 ml) was heated for 30 min at 160° C. in a microwave oven. The mixture was purified by prep. HPLC (C18-column, solvent gradient 30-98% CH3CN in 0.1% HCOOH[aq]) to give the title compound (3 mg) as a light yellow solid. MS (m/e)=450.1 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH:12]1[CH2:14][CH2:13]1)[C:7](=[C:15]=[O:16])[CH2:6][C:5]2=[O:17].CO[CH:20](OC)[N:21]([CH3:23])[CH3:22].C(N(CC)CC)C>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH:12]1[CH2:13][CH2:14]1)[C:7](=[C:15]=[O:16])[C:6](=[CH:20][N:21]([CH3:23])[CH3:22])[C:5]2=[O:17]
Reactant: COC(OC)N(C)C
Reactant: O=C=C1CC(=O)c2cc(Cl)ccc2N1C1CC1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CN(C)C=c1c(=O)c2cc(Cl)ccc2n(C2CC2)c1=C=O
Reaction time: 0.5 h
Yield: 99.6 %

Procedure:
A solution of 6-chloro-1-cyclopropyl-carbonyl-4-oxo-1,2,3,4-tetrahydroquinoline (1.996 g), N,N-dimethylformamide dimethyl acetal (3.808 g), and triethylamine (1.212 g) in benzene (16 ml) was refluxed with stirring for 30 minutes and then about three-fourths of the solvent was distilled slowly at atmospheric pressure over a period of approximately 30 minutes. To the residue was added benzene (16 ml) and the solvent was distilled again. The residue was dissolved in ethyl acetate, treated with activated charcoal, and evaporated in vacuo. The residual solid was washed with diethyl ether to give 6-chloro-1-cyclopropyl-carbonyl-3-dimethylaminomethylene-4-oxo-1,2,3,4-tetrahydroquinoline (2.43 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:14]2[CH2:13][CH2:12][O:11][CH2:10][C:9]=2[S:8][C:7]=1[NH:15][C:16]([C:18]12[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:26][CH:20]([CH2:21]3)[CH2:19]1)[CH2:25]2)=[O:17])=[O:5])C.[OH-].[K+].Cl>C(O)C.O>[C:18]12([C:16]([NH:15][C:7]3[S:8][C:9]4[CH2:10][O:11][CH2:12][CH2:13][C:14]=4[C:6]=3[C:4]([OH:5])=[O:3])=[O:17])[CH2:27][CH:22]3[CH2:21][CH:20]([CH2:26][CH:24]([CH2:23]3)[CH2:25]1)[CH2:19]2
Reactant: CCOC(=O)c1c(NC(=O)C23CC4CC(CC(C4)C2)C3)sc2c1CCOC2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1c(NC(=O)C23CC4CC(CC(C4)C2)C3)sc2c1CCOC2
Temperature: 25 °C

Procedure:
A mixture of Example 166A (779 mg, 2.00 mmol) and solid potassium hydroxide (841 mg. 15.0 mmol) in ethanol (10 mL) and water (2 mL) was heated to reflux for 1 hour. After cooling to room temperature, 1N HCl was added to adjust the pH to 1. The mixture was extracted with ethyl acetate (4×20 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated by rotary evaporator to afford a crude powder. The product was recrystallized from ethyl acetate/hexanes to afford the title compound. MS (ESI+) m/z 362.1 (M+H)+.
Reaction SMILES: C(O[K])(C)(C)C.F[C:8]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:9]=1[CH:10]=[O:11].[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH2:27][C@H:26]([OH:30])[CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>O1CCOCC1.O>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH2:27][C@H:26]([O:30][C:8]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:9]=2[CH:10]=[O:11])[CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: O=Cc1ccc(F)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](O)C1
Agent: CC(C)(C)O[K]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC[C@H](Oc2cc(F)ccc2C=O)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 18.3 %

Procedure:
tBuOK (434 mg; 3.87 mmol; 1.1 eq.) was added to a solution of 2,4-difluoro-benzaldehyde (500 mg; 3.52 mmol; 1 eq.) and (S)-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (779 mg; 3.87 mmol; 1.1 eq.) in 1,4-dioxane (3 mL) and reaction mixture was stirred at room temperature for 15 minutes. The solution was diluted with water and extracted with DCM. The organic layer was dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography (heptanes/EA) afforded the title compound (208 mg, 18%) as white solid. HPLC (max plot) 92.8%; Rt 4.46 min.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[C@@H:6]([CH3:29])[C:7]([S:15][C@@H:16]1[CH2:20][NH:19][C@H:18]([CH2:21][O:22][CH2:23][CH2:24][NH:25][C:26]([NH2:28])=[O:27])[CH2:17]1)=[C:8]2[C:12]([OH:14])=[O:13])[CH3:3].Cl.[C:31](=[NH:36])(OCC)[CH3:32].C(=O)([O-])[O-].[K+].[K+].Cl>O>[C:31]([N:19]1[CH2:20][C@@H:16]([S:15][C:7]2[C@H:6]([CH3:29])[C@H:5]3[N:9]([C:10](=[O:11])[C@@H:4]3[C@H:2]([OH:1])[CH3:3])[C:8]=2[C:12]([OH:14])=[O:13])[CH2:17][C@H:18]1[CH2:21][O:22][CH2:23][CH2:24][NH:25][C:26]([NH2:28])=[O:27])(=[NH:36])[CH3:32]
Reactant: CCOC(C)=N
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](COCCNC(N)=O)C3)[C@H](C)[C@H]12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(=N)N1C[C@@H](SC2=C(C(=O)O)N3C(=O)[C@H]([C@@H](C)O)[C@H]3[C@H]2C)C[C@H]1COCCNC(N)=O
Yield: 66.9 %

Procedure:
To a solution of (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[(2S,4S)-2-{(2-ureidoethyl)oxymethyl}-pyrrolidin-4-yl]thio-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (0.15 g) in water (30 ml) was added ethyl acetimidate hydrochloride (1.65 g) by portions at 0°-5° C., keeping the pH between 8.4-8.6 with 10% aqueous potassium carbonate. After adjusting to pH 6.5 with lN aqueous hydrochloric acid, the solution was washed with 10% solution of tetrahydrofuran in ethyl acetate (50 ml) by four portions and the organic solvent was removed by evaporation. The residual solution was subjected to a column chromatography on nonionic adsorption resin, "HP-20" (30 ml), washed with water, eluted with 5% aqueous isopropyl alcohol and lyophilized to give (4R,5S,6S)-3-[(2S,4S)-1-acetimidoyl-2-{(2-ureidoethyl)oxymethyl}pyrrolidin-4-yl]thio-6-[ (1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (0.11 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:22]2[C:27](=[O:28])[NH:26][C:25](=[O:29])[CH:24]=[N:23]2)[CH:5]=[C:6]([Cl:21])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([S:17](Cl)(=[O:19])=[O:18])[CH:10]=1.[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>CN(C)C=O.C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:22]2[C:27](=[O:28])[NH:26][C:25](=[O:29])[CH:24]=[N:23]2)[CH:5]=[C:6]([Cl:21])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([S:17]([N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)(=[O:19])=[O:18])[CH:10]=1
Reactant: COc1ccc(Oc2c(Cl)cc(-n3ncc(=O)[nH]c3=O)cc2Cl)cc1S(=O)(=O)Cl
Reactant: C1CCNCC1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1ccc(Oc2c(Cl)cc(-n3ncc(=O)[nH]c3=O)cc2Cl)cc1S(=O)(=O)N1CCCCC1
Reaction time: 1 h

Procedure:
To a stirred solution of 2-[3,5-dichloro-4-(3-chlorosulfonyl-4-methoxy-phenoxy)-phenyl]-2H-[1,2,4]triazine-3,5-dione (0.7 g) in dimethylformamide (8 mL) was added piperidine (0.4 mL). After 1 h, the reaction was diluted in diethyl ether, washed with 1N hydrochloric acid, brine, dried (Na2SO4) and concentrated in vacuo to a solid. Recrystallization from diethyl ether/petroleum ether afforded the title compound of Step B, 0.5 g. MS Calc.:527.4 Found:527.0.
Reaction SMILES: [OH-].[Na+].[CH:3]1[CH2:7][CH:6]=[CH:5][CH:4]=1.[CH:8]1(Br)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].O>[CH:8]1([C:4]2[C:3]([CH:8]3[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)=[C:7]([CH:8]3[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)[CH2:6][CH:5]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: BrC1CCCCC1
Reactant: C1=CCC=C1
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: C1=C(C2CCCCC2)C(C2CCCCC2)=C(C2CCCCC2)C1
Temperature: 8 °C
Reaction time: 2 h

Procedure:
A double-walled reactor having a volume of 1 L, provided with baffles, condenser, top stirrer, thermometer and dropping funnel was charged with 600 g of clear 50% strength NaOH (7.5 mol), followed by cooling to 8° C. Then 20 g of Aliquat 336 (49 mmol) and 33 g (0.5 mol) of freshly cracked cyclopentadiene were added. The reaction mixture was stirred turbulently for a few minutes. Then 256 g of cyclohexyl bromide (1.57 mol) were added, cooling with water taking place at the same time. After 1 hour's stirring at room temperature the reaction mixture was warmed to 70° C., followed by a further 2 hours' stirring. After 2 hours, stirring was stopped and phase separation was awaited. The water layer was drawn off and 600 g (7.5 mol) of fresh 50% strength NaOH were added, followed by a further 4 hours' stirring at 70° C. GC was used to show that at that instant 10% of di- and 90% of tri(cyclohexyl)cyclopentadiene were present in the mixture. The product was distilled at 0.04 mbar and 130° C. After distillation, 87.4 g of tri(cyclohexyl)cyclopentadiene were obtained. Characterization took place with the aid of GC, GC-MS, 13C- and 1H-NMR.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[N:12]([C@@H:15]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C@H:16]([OH:19])[CH2:17][OH:18])=[N+:13]=[N-:14]>CN(C)C1C=CN=CC=1.ClCCl.N1C=CC=CC=1>[N:12]([C@@H:15]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C@H:16]([OH:19])[CH2:17][O:18][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8])=[N+:13]=[N-:14]
Reactant: [N-]=[N+]=N[C@@H](Cc1ccccc1)[C@H](O)CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@@H](O)[C@H](Cc2ccccc2)N=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 82.4 %

Procedure:
1.05 g (5.5 mmol) of p-toluenesulphonyl chloride were added to a solution of 0.95 g (4.6 mmol) of 3(S)-azido-4-phenyl-1,2(S)-butanediol and 30 mg of 4-dimethylaminopyridine in a mixture of 30 ml of dichloromethane and 5 ml of pyridine. The resulting solution was stirred at room temperature for 48 hours. The solvents were removed under reduced pressure and the oily residue was partitioned between water and ethyl acetate. The aqueous phase was back-extracted twice with ethyl acetate. The organic phases were combined, washed with 10% aqueous sulphuric acid and with sodium chloride solution, dried over anhydrous magnesium sulphate and evaporated to dryness. Purification of the crude product by flash chromatography on silica gel using n-hexane/ethyl acetate (3:1) for the elution gave 1.37 g of 3(S)-azido-4-phenyl-1-(p-toluenesulphonyloxy)-2(S)-butanol in the form of a viscous oil: MS: m/e 362 [M+H]+.
Reaction SMILES: C(Cl)(=O)C.[CH2:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15]([N:17]3[CH2:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18]3)=[O:16])=[CH:11][CH:12]=2)[CH2:7][NH:6]1.NC1C=C2C(=CC=1)CN(C(NC1C=[CH:43][C:42]([C:45](=[O:50])NCCC)=[CH:41]C=1)=O)C2>>[C:45]([N:6]1[CH2:7][C:8]2[C:13](=[CH:12][CH:11]=[C:10]([NH:14][C:15]([N:17]3[CH2:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18]3)=[O:16])[CH:9]=2)[CH2:5]1)(=[O:50])[CH:42]([CH3:43])[CH3:41]
Reactant: O=C(Nc1ccc2c(c1)CNC2)N1Cc2ccccc2C1
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(N)cc3C2)cc1
Solvent: CC(=O)Cl
Product: CC(C)C(=O)N1Cc2ccc(NC(=O)N3Cc4ccccc4C3)cc2C1

Procedure:
The title compound was prepared as described in Example 278, substituting isobutyryl chloride for acetyl chloride and N-(isoindolin-5-yl)isoindoline-2-carboxamide for 5-amino-N-(4-(propylcarbamoyl)phenyl)isoindoline-2-carboxamide. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.40 (s, 1H), 7.59-7.61 (bs, 1H), 7.46 (ddd, J=10.8, 8.5, 2.1 Hz, 1H), 7.30-7.38 (m, 4H), 7.20-7.24 (m, 1H), 4.82-4.87 (m, 2H), 4.76-4.77 (bs, 4H), 4.55-4.60 (m, 2H), 2.78 (h, J=6.9 Hz, 1H), 1.07 (d, J=6.7 Hz, 6H); MS (ESI(+)) m/e 350 (M+H)+.
Reaction SMILES: FC(F)(F)[C:3]1[CH:4]=[C:5]([C:9]2[C:10]3[N:11]([N:15]=[C:16]([NH2:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1.[CH3:21][O:22]C1C=CC(B(O)O)=CC=1>>[CH3:21][O:22][C:8]1[CH:7]=[CH:6][C:5]([C:9]2[C:10]3[N:11]([N:15]=[C:16]([NH2:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: Nc1nc2c(-c3cccc(C(F)(F)F)c3)cccn2n1
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2cccn3nc(N)nc23)cc1

Procedure:
Made by following the procedure described for the preparation of 8-(3-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine with 4-methoxyphenyl boronic acid and making non-critical variations.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]([O:10]CC)=[O:9])[N:6]=1.[OH-].[Na+].CO>O1CCCC1>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: CCOC(=O)C(=NOC1CCCCC1)c1csc(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1nc(C(=NOC2CCCCC2)C(=O)O)cs1
Yield: 66.2 %

Procedure:
Ethyl 2-(2-aminothiazol-4-yl)-2-cyclohexyloxyiminoacetate (syn isomer, 3.5 g.), 2N aqueous solution of sodium hydroxide (11.8 ml.), methanol (11.8 ml.) and tetrahydrofuran (11.8 ml.) were treated in a similar manner to that of Example F-(4) to give 2-(2-aminothiazol-4-yl)-2-cyclohexyloxyiminoacetic acid (syn isomer, 2.1 g.), mp. 148° C. (dec.).