Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[N:16]=[C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)[CH:14]=[CH:13][C:9]=2[C:10](O)=[O:11])=[CH:5][CH:4]=1)#[N:2].F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[C:70]([O:74][C:75](=[O:85])[NH:76][CH2:77][CH2:78][CH:79]1[CH2:84][CH2:83][NH:82][CH2:81][CH2:80]1)([CH3:73])([CH3:72])[CH3:71]>CN(C=O)C>[C:70]([O:74][C:75](=[O:85])[NH:76][CH2:77][CH2:78][CH:79]1[CH2:80][CH2:81][N:82]([C:10]([C:9]2[C:8]([O:7][C:6]3[CH:26]=[CH:27][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)=[N:16][C:15]([O:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]#[N:25])=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[O:11])[CH2:83][CH2:84]1)([CH3:73])([CH3:71])[CH3:72]
Reactant: CC(C)(C)OC(=O)NCCC1CCNCC1
Reactant: N#Cc1ccc(Oc2ccc(C(=O)O)c(Oc3ccc(C#N)cc3)n2)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCC1CCN(C(=O)c2ccc(Oc3ccc(C#N)cc3)nc2Oc2ccc(C#N)cc2)CC1
Reaction time: 0.17 h

Procedure:
A solution of 2,6-Bis-(4-cyano phenoxy)-nicotinic acid, 0.335 g (0.94 mmol), in 5 ml of DMF was added dropwise to the stirred suspension of 0.489 g (0.94 mmol) of benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBop) in 5 ml of DMF and followed by N,N-diisopropylethylamine 0.242 g (1.88 mmol) while the temperature was maintained below 5° C. during the addition. The mixture was stirred for 10 min and a solution of (2-piperidin-4-yl-ethyl)-carbamic acid tert-butyl ester (0.214 g, 0.94 mmol) in 2 ml of DMF was added. The mixture was stirred overnight at RT. The solvent was concentrated under reduced pressure and the residue was dissolved in a mixture of water (150 ml) and ethyl acetate (150 ml). The pH was adjusted to 2-3 with 6 N HCl and the phases were separated. The aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with 10% solution of potassium hydrogen sulphate followed by saturated sodium bicarbonate solutiona and saturated brine solution, and dried over sodium sulphate and concentrated. The crude oily residue was purified by column chromatography using hexane-ethyl acetate (10:2) to afford 0.4 g of the required product. Percentage purity: 36.3%, (M+1)=567.2. 1H NMR (DMSO-d6): δ 1.35 (3H, m), 1.38 (9H, s), 1.65 (2H, m), 2.71 (2H, m), 2.95 (4H, m), 3.75 (2H, m), 6.80 (1H, t), 6.95 (1H, d), 7.32 (4H, d), 7.68 (1H, m), 7.85 (4H, d).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]([NH:23][C:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=2[C:30]([O:32]CC)=[O:31])=[O:22])[CH2:13][CH2:12]1.[OH-].[Na+].Cl>CC(O)C.O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]([NH:23][C:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=2[C:30]([OH:32])=[O:31])=[O:22])[CH2:13][CH2:12]1
Reactant: CCOC(=O)C1=C(NC(=O)CCCCN2CCN(c3ccc4ccccc4n3)CC2)CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: O=C(CCCCN1CCN(c2ccc3ccccc3n2)CC1)NC1=C(C(=O)O)CCCC1
Yield: 83.5 %

Procedure:
In 725 ml of 2-propanol and 365 ml of distilled water, 168.0 g of ethyl 2-[5-(4-quinolin-2-ylpiperazin-1-yl)pentanoylamino]cyclohex-1-enecarboxylate as synthesized in above Step 7-1-D was suspended. To the suspension 580 ml of 1N-aqueous sodium hydroxide was added and heated under reflux for 1.5 hours. After cooling, the reaction mixture was neutralized with 2N-hydrochloric acid. Whereupon precipitated crystals were recovered by filtration and dried to provide 131.8 g (83.4%) of 2-[5-(4-quinolin-2-ylpiperazin-1-yl)pentanoylamino]cyclohex-1-enecarboxylic acid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH3:27])=[C:13]([CH:17]=1)[C:14](O)=[O:15].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH3:27])=[C:13]([CH:17]=1)[C:14]([NH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)=[O:15]
Reactant: COc1ccccc1COc1ccc(Br)cc1C(=O)O
Reactant: Nc1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COc1ccccc1COc1ccc(Br)cc1C(=O)Nc1cccnc1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
Solid pyridin-3-amine (156 mg, 1.66 mmol) was added in one charge to a stirred solution of 5-bromo-2-({[2-(methyloxy)phenyl]methyl}oxy)benzoic acid (may be prepared as described in Description 32; 280 mg, 0.83 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (191 mg, 1.00 mmol) and 1-Hydroxybenzotriazole (135 mg, 1.00 mmol) in DMF (20 ml) under nitrogen at 20° C. The reaction mixture was stirred at 20° C. for 16 h. The organic phase was washed with water (25 ml), extracted with ethyl acetate (3×30 ml), dried over sodium sulphate, evaporated in vacuo and purified by column chromatography (petroleum ether:ethyl acetate=2:1) to yield the title compound as a white solid. 270 mg.
Reaction SMILES: [O:1]1[C:5](=[O:6])[CH2:4][CH2:3][C:2]1=[O:7].[Al+3].[Cl-].[Cl-].[Cl-].[NH:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17]([O:19][CH2:20][CH3:21])=[O:18]>ClCCCl>[CH2:20]([O:19][C:17]([C:13]1[NH:12][CH:16]=[C:15]([C:2](=[O:7])[CH2:3][CH2:4][C:5]([OH:1])=[O:6])[CH:14]=1)=[O:18])[CH3:21]
Reactant: O=C1CCC(=O)O1
Reactant: CCOC(=O)c1ccc[nH]1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCOC(=O)c1cc(C(=O)CCC(=O)O)c[nH]1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 88.5 %

Procedure:
Into a 3000-mL 4-necked round-bottom flask was placed a solution of oxolane-2,5-dione (100 g, 999.27 mmol, 2.00 equiv) in 1,2-dichloroethane (690 mL) and AlCl3 (400.5 g, 3.00 mol, 6.00 equiv), followed by the addition of a solution of ethyl 1H-pyrrole-2-carboxylate (69 g, 495.86 mmol, 1.00 equiv) in 1,2-dichloroethane (660 mL) dropwise with stirring at room temperature over 20 min (FIG. 14). The resulting solution was stirred at room temperature for 3 h and quenched by the addition of 3 kg of water/ice. The solids were collected by filtration, washed with 1×1000 mL of water and dried in a vacuum oven to afford 105 g (89%) of 113g as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:22][S:23](O)(=[O:25])=[O:24]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]([S:23]([CH3:22])(=[O:25])=[O:24])[CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)O
Reactant: CNC1CCN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C1CCN(C(=O)OC(C)(C)C)C1)S(C)(=O)=O
Reaction time: 24 h

Procedure:
To a solution of 3-methylamino-pyrrolidine-1-carboxylic acid tert-butyl ester (0.50 g) in dichloromethane (10 ml) was added triethylamine (0.38 ml) followed by methanesulfonic acid (0.21 ml). After stirring for 24 hours, the reaction mixture was diluted with dichloromethane, washed with sodium bicarbonate solution, dried (MgSO4) and the solvent removed in vacuo. The residue was purified by flash chromatography to yield 3-(methanesulfonyl-methyl-amino)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.52 g). Treatment of this compound with HCl in dichloromethane/methanol yielded N-Methyl-N-pyrrolidin-3-yl-methanesulfonamide hydrochloride salt (0.41 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10](=[O:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].[CH2:18]([O:20][CH:21](OCC)OCC)[CH3:19].C(OC(=O)C)(=O)C>>[CH2:18]([O:20][CH:21]=[C:11]([C:10](=[O:17])[C:3]1[CH:4]=[C:5]([F:9])[C:6]([F:8])=[CH:7][C:2]=1[F:1])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH3:19]
Reactant: CCOC(OCC)OCC
Reactant: CCOC(=O)CC(=O)c1cc(F)c(F)cc1F
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)cc1F
Temperature: 115 °C

Procedure:
A solution of 7.88 g of 2,4,5-trifluoro-β-oxobenzenepropanoic acid, ethyl ester, 8.15 ml of 98% triethoxymethane and 7.5 ml of acetic anhydride in a 50 ml of flask was connected through a short distillation head to a 160 mm vacuum source and heated at 115° C. for 3 hours. The solution was then evaporated in vacuo at 45° C. giving 9.67 g of α-(ethoxymethylene)-2,4,5-trifluoro-β-oxobenzenepropanoic acid, ethyl ester as a yellow oil.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH2:6][NH:7][CH:8]([C:11](=[O:13])[NH2:12])[CH2:9][CH3:10].C(N(CC)CC)C.OC1C=CC=CN=1>O1CCCC1.C1(C)C=CC=CC=1>[CH3:10][CH2:9][C@H:8]([N:7]1[C:3](=[O:2])[CH2:4][CH2:5][CH2:6]1)[C:11]([NH2:12])=[O:13]
Reactant: CCC(NCCCC(=O)OC)C(N)=O
Agent: Oc1ccccn1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC[C@@H](C(N)=O)N1CCCC1=O
Temperature: 80 °C

Procedure:
Hydrochloride salt of methyl-4-(1-carbamoylpropylamino)butyrate (VId) (0.7 g, 2.9 mmol) is dissolved in a mixture of tetrahydrofuran (10 ml) and triethylamine (0.6 g, 2 equiv.). The suspension is filtered and filtrates are concentrated to dryness to afford an oil. The resulting residue is dissolved in toluene (15 ml) and 2-hydroxypyridine (53 mg, 0.56 mmol, 20 mol %) is added. The mixture is heated to 80° C. until complete conversion. After 3 days (GC: 100% conversion) the mixture is concentrated to dryness under reduced pressure.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[Li]CCCC.[C:20](=[O:22])=[O:21].O>C1COCC1.CCCCCC>[F:12][C:11]([F:14])([F:13])[C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([C:20]([OH:22])=[O:21])[CH:3]=1)[NH:9][CH:8]=[CH:7]2
Reactant: O=C=O
Reactant: FC(F)(F)c1cc(Br)c2[nH]ccc2c1
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(O)c1cc(C(F)(F)F)cc2cc[nH]c12
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 31 %

Procedure:
584 mg of 7-bromo-5-trifluoromethyl-indole (2.2 mmol) were dissolved in 15 ml THF and 4.1 ml of a 1.6 molar solution of n-BuLi in hexane were added at −78° C. The reaction mixture was then allowed to warm to 0-5° C. and was stirred at this temperature for 30 min. Then it was cooled again to −78° C., dry ice was added and the mixture was allowed to warm to rt. After 15 min at rt it was poured into water and extracted twice with ether. The aqueous phase was then acidified with 1 N HCl solution and extracted several times with DCM. The combined DCM extracts were then washed with brine, dried with magnesium sulfate, filtered and the solvent was evaporated. The remaining residue was triturated with n-hexane. Final filtration yielded 157 mg (31%) of 5-trifluoromethyl-1H-indole-7-carboxylic acid as an off-white solid. 1H NMR (DMSO-d6, 300 MHz): δ 6.66 (m, 1H), 7.48 (m, 1H), 7.89 (s, 1H), 8.18 (s, 1H), 11.46 (br s, 1H), 13.48 (br s, 1H).
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12].[Br:21][CH2:22][CH2:23][C:24](Cl)=[O:25].O>C(Cl)Cl>[Br:21][CH2:22][CH2:23][C:24]([NH:9][CH:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:25]
Reactant: CCOC(=O)C(N)C(=O)OCC
Reactant: O=C(Cl)CCBr
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C(NC(=O)CCBr)C(=O)OCC
Reaction time: 0.5 h
Yield: 80.9 %

Procedure:
2(a) 2.8 ml of triethylamine were added to a suspension of 2.11 g of diethyl 2-aminomalonate hydrochloride in 50 ml of methylene chloride. 1.71 g of 3-bromopropionyl chloride were then added to the mixture, whilst ice-cooling, and then the mixture was stirred for 30 minutes. At the end of this time, the reaction mixture was poured into water and extracted with diethyl ether. The extract was washed with a 5% w/v aqueous solution of sodium bicarbonate and with water, in that order, after which it was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, to give 2.5 g of diethyl 2-(3-bromopropionamido)malonate.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].[NH2:7][CH2:8][C:9]([OH:11])=[O:10]>>[NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].[NH2:7][C@H:8]([C:9]([OH:11])=[O:10])[CH2:4][OH:5]
Reactant: NCC(=O)O
Agent: C[C@H](N)C(=O)O
Product: N[C@@H](CO)C(=O)O

Procedure:
The formation of Z--Ala--SerOH is obtained by the same process as that described in Example 1.a, but using 1.1 mmol of lyophilised hydrated serine in place of cysteine and 1 mmol of alanine protected by Z and activated in place of glycine.
Reaction SMILES: [CH:1]1([C@H:7]2[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C@H:9]([CH:19]=[O:20])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1CCN2C(=NCCC2)CC1>C1COCC1>[CH:1]1([C@H:7]2[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[C@@H:9]([CH:19]=[O:20])[CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](C2CCCCC2)C[C@H]1C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](C2CCCCC2)C[C@@H]1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.9 %

Procedure:
(2S,4S)-tert-butyl 4-cyclohexyl-2-formylpyrrolidine-1-carboxylate (943 mg, 3.35 mmol) was treated with THF (20 mL) and DBU (1.0 mL, 6.70 mmol) and allowed to stir at room temperature overnight. The reaction mixture was concentrated to dryness on the rotovap, treated with DCM and a saturated solution of NH4Cl and extracted, washed with brine, dried over MgSO4, filtered and concentrated affording a mixture of crude (2S,4S)-tert-butyl 4-cyclohexyl-2-formylpyrrolidine-1-carboxylate and (2R,4S)-tert-butyl 4-cyclohexyl-2-formylpyrrolidine-1-carboxylate (470 mg, 1.67 mmol, 99% yield) as a clear, colorless viscous oil. MS (ESI) 304.1 [M+Na]+.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[C:18]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[O:9])=[N:4][CH:3]=1.[CH3:25][N:26]1[CH:30]=[N:29][N:28]=[C:27]1[SH:31]>>[CH:20]1([C:18]([C:12]2[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:11]=2[NH:10][C:8]([NH:7][C:5]2[S:6][C:2]([S:31][C:27]3[N:26]([CH3:25])[CH:30]=[N:29][N:28]=3)=[CH:3][N:4]=2)=[O:9])=[O:19])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: Cn1cnnc1S
Reactant: Cc1ccc(NC(=O)Nc2ncc(Br)s2)c(C(=O)C2CCCC2)c1
Product: Cc1ccc(NC(=O)Nc2ncc(Sc3nncn3C)s2)c(C(=O)C2CCCC2)c1
Yield: 28.2 %

Procedure:
1-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-3-[5-(4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl)-thiazol-2-yl]-urea (125 mg, 25%) was prepared from 1-(5-bromo-thiazol-2-yl)-3-(2-cyclo pentanecarbonyl-4-methyl-phenyl)-urea (408 mg, 1 mmol) and 4-methyl-4H-[1,2,4]triazole-3-thiol (230 mg, 2 mmol) following the general procedure Y
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5]Cl)[CH3:2].[C:10]([OH:18])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O.CN(C=O)C>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][O:18][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:2]
Reactant: O=C(O)c1ccccc1
Reactant: CCOC(CCl)OCC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(COC(=O)c1ccccc1)OCC
Temperature: 25 °C
Yield: 55.7 %

Procedure:
Chloroacetaldehyde diethyl acetal (2.00 g), benzoic acid (2.16 g), potassium iodide (0.27 g), potassium carbonate (1.11 g) and DMF (20 mL) were placed in a three-neck flask, followed by refluxing. Twenty hours later, the reaction mixture was cooled to room temperature, and water (30 mL) and ethyl acetate (80 mL) were added thereto, followed by stirring. After filtration, the organic layer was separated, was subjected to vacuum concentration and thereby yielded the target compound (1.74 g) in a yield of 56%.
Reaction SMILES: Cl.[O-:2][C:3]#[N:4].[Na+].[CH2:6]([NH:9][C@H:10]([CH:36]1[CH2:45][CH2:44][C:43]2[C:38](=[CH:39][CH:40]=[C:41]([O:54][CH2:55][C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)[C:42]=2[O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH2:37]1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]([C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1)[CH2:7][CH3:8]>ClC1C=CC=CC=1>[CH2:6]([NH:9][C@H:10]([CH:36]1[CH2:45][CH2:44][C:43]2[C:38](=[CH:39][CH:40]=[C:41]([O:54][CH2:55][C:56]3[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=3)[C:42]=2[O:46][CH2:47][C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH2:37]1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]([C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])[CH2:17][CH2:18][C:19]1[CH:20]=[CH:21][C:22]([NH:25][C:3]([NH2:4])=[O:2])=[CH:23][CH:24]=1)[CH2:7][CH3:8]
Reactant: N#C[O-]
Reactant: CCCN[C@@H](CCCCCN(CCc1ccc(N)cc1)C(=O)OCc1ccccc1)C1CCc2c(ccc(OCc3ccccc3)c2OCc2ccccc2)C1
Agent: Cl
Agent: [Na+]
Solvent: Clc1ccccc1
Product: CCCN[C@@H](CCCCCN(CCc1ccc(NC(N)=O)cc1)C(=O)OCc1ccccc1)C1CCc2c(ccc(OCc3ccccc3)c2OCc2ccccc2)C1

Procedure:
Concentrated HCl (0.7 g; 7.1 mmoles) and sodium cyanate (0.38 g; 5.8 mmoles) were added at room temperature to a stirred solution of Intermediate 64 (2.2 g; 2.9 mmoles), prepared as described in example 32, in chlorobenzene (20 ml) under nitrogen.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].C(N(CC)CC)C.[C:13]12[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=1)[NH:18]C(=O)[O:16][C:14]2=O.C(=O)(O)[O-].[Na+]>C(O)C>[CH3:5][O:4][N:3]([CH3:2])[C:14](=[O:16])[C:13]1[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=1)[NH2:18]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: CNOC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CON(C)C(=O)c1ccccc1N
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of N,O-dimethylhydroxylamine hydrochloride (51.2 g, 0.53 mmol) in 90-95% aqueous ethanol (200 ml) is added triethylamine (53 g, 0.53 mmol) and, after 10 minutes stirring at 25° C., isatoic anhydride (37.0 g, 0.35 mmol) in portions. The reaction is then heated at reflux for 1.5 hrs and poured onto an equal volume of ice and saturated sodium bicarbonate. The ethanol is then removed by rotary evaporation, the resulting aqueous mixture extracted with ethyl acetate (3×150 ml), the combined extracts washed with water, brine, dried over magnesium sulfate and activated charcoal, and concentrated to an orange oil. The oil is chromatographed on silica gel (1:1 diethyl ether:hexanes, then acetone) and distilled to give N-methoxy-N-methyl anthranilic acid amide as a pale yellow oil; yield 47.4 g (75%); b.p. 148°-151° C./0.35 mm.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([C:5]1[CH:10]=[C:9]([CH:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[OH:12])[CH:8]=[CH:7][C:6]=1[F:20])=[O:4].CC1(C)N([O])C(C)(C)CCC1.[K+].[Br-].C([O-])(O)=O.[Na+].[O-]Cl.[Na+]>C(Cl)Cl>[F:22][C:2]([F:1])([F:21])[C:3]([C:5]1[CH:10]=[C:9]([C:11](=[O:12])[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:8]=[CH:7][C:6]=1[F:20])=[O:4]
Reactant: O=C(c1cc(C(O)c2ccc(F)cc2)ccc1F)C(F)(F)F
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=C([O-])O
Agent: [Br-]
Solvent: ClCCl
Product: O=C(c1ccc(F)cc1)c1ccc(F)c(C(=O)C(F)(F)F)c1
Temperature: 0 °C

Procedure:
A homogeneous yellow solution of crude 2,2,2-trifluoro-1-(2-fluoro-5-((4-fluorophenyl)(hydroxy)methyl)phenyl)ethanone (1.15 g, 3.64 mmol, Intermediate 35: step b) and TEMPO (18.4 mg, 0.118 mmol) in DCM (7.3 mL) was stirred on an ice bath while a solution of aqueous KBr (43 mg, 0.36 mmol) in 1 M aqueous NaHCO3 (1.27 mL, 1.27 mmol) was added in one portion. NaOCl [4.6 mL, 0.89 M (6.15% w/w Clorox bleach), 4.1 mmol] was then added dropwise over 5 minutes to the homogeneous bilayer. After 20 minutes stirring on the ice bath, the clear yellow organic layer was collected, and the aqueous layer extracted with DCM (1×6 mL). The combined organic layers were washed with 5 M aqueous NaCl (1×3 mL), dried (Na2SO4), filtered, and concentrated to provide the crude title compound as a clear yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[N:14]=[CH:15][N:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][N:19]=3)[CH:17]=2)=[C:11]([CH3:27])[N:10]=[N:9]1.[CH:28]1([NH2:31])[CH2:30][CH2:29]1>>[CH:28]1([NH:31][C:22](=[O:24])[C:21]2[CH:25]=[CH:26][C:18]([N:16]3[CH:17]=[C:13]([C:12]4[N:8]([C:3]5[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=5[F:1])[N:9]=[N:10][C:11]=4[CH3:27])[N:14]=[CH:15]3)=[N:19][CH:20]=2)[CH2:30][CH2:29]1
Reactant: Cc1nnn(-c2ccccc2F)c1-c1cn(-c2ccc(C(=O)O)cn2)cn1
Reactant: NC1CC1
Product: Cc1nnn(-c2ccccc2F)c1-c1cn(-c2ccc(C(=O)NC3CC3)cn2)cn1
Yield: 51 %

Procedure:
As described for example 43c, 6-(4-(1-(2-fluorophenyl)-4-methyl-1H-1,2,3-triazol-5-yl)-1H-imidazol-1-yl)nicotinic acid (74 mg, 0.203 mmol) was converted, using cyclopropylamine instead of isopropylamine, to the title compound (42 mg, 51%) which was obtained as a white foam after purification by chromatography (reverse phase HPLC then silica, ethyl acetate). MS: m/e=404.4 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14]2[N:15]([CH3:33])[C:16](=[O:32])[C:17]([CH3:31])=[C:18]([NH:19][C:20]3[CH:21]=[C:22]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:23]=[CH:24][CH:25]=3)[C:13]=2[C:12](=[O:34])[N:11]([CH3:35])[C:10]1=[O:36].CC(C)([O-])C.[K+].CO.C(O)(=O)C>O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:14]1[N:15]([CH3:33])[C:16](=[O:32])[C:17]([CH3:31])=[C:18]2[C:13]=1[C:12](=[O:34])[N:11]([CH3:35])[C:10](=[O:36])[N:19]2[C:20]1[CH:21]=[C:22]([NH:26][S:27]([CH3:30])(=[O:28])=[O:29])[CH:23]=[CH:24][CH:25]=1
Reactant: Cc1c(Nc2cccc(NS(C)(=O)=O)c2)c2c(=O)n(C)c(=O)n(-c3ccc(I)cc3F)c2n(C)c1=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: Cc1c(=O)n(C)c(Nc2ccc(I)cc2F)c2c(=O)n(C)c(=O)n(-c3cccc(NS(C)(=O)=O)c3)c12
Temperature: 25 °C
Yield: 97.1 %

Procedure:
Under ice-cooling, to a suspension of N-{3-[1-(2-fluoro-4-iodophenyl)-3,6,8-trimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-ylamino]phenyl}methanesulfonamide 71 (3.10 g) obtained in Step 7 in tetrahydrofuran (31.0 ml) was added dropwise a mixture of potassium t-butoxide (1.33 g), methanol (0.482 ml) and tetrahydrofuran (15.5 ml), and the mixture was stirred under ice-cooling for 2 hrs. Acetic acid (1.36 ml) was added, the mixture was allowed to warm to room temperature and stirred for 1 hr. The reaction mixture was concentrated, methanol/water [1:2 (volume ratio), 45.0 ml] was added, and the mixture was further stirred at room temperature for 1 hr. The crystals were collected by filtration and dried to give N-{3-[5-(2-fluoro-4-iodophenylamino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}methanesulfonamide 72 (3.01 g, yield 97%) as a pale-gray solid.
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]([CH:6]1[CH2:9][N:8]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:20][C@@H:19]([CH2:21]CS([O-])(=O)=O)[O:18][C:17]3=[O:27])=[CH:12][C:11]=2[F:28])[CH2:7]1)[CH3:5].[N-:29]=[N+:30]=[N-:31].[Na+].CO.C(Cl)(Cl)Cl.S([O-])(=O)(=O)C>CN(C)C=O>[F:1][CH2:2][CH2:3][N:4]([CH:6]1[CH2:9][N:8]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:20][C@H:19]([CH2:21][N:29]=[N+:30]=[N-:31])[O:18][C:17]3=[O:27])=[CH:12][C:11]=2[F:28])[CH2:7]1)[CH3:5]
Reactant: [N-]=[N+]=[N-]
Reactant: CN(CCF)C1CN(c2ccc(N3C[C@@H](CCS(=O)(=O)[O-])OC3=O)cc2F)C1
Agent: CS(=O)(=O)[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CN(C)C=O
Product: CN(CCF)C1CN(c2ccc(N3C[C@H](CN=[N+]=[N-])OC3=O)cc2F)C1
Temperature: 65 °C
Reaction time: 3 h
Yield: 85.9 %

Procedure:
A solution of (R)-[[3-[4-[3-[N-(2-fluoroethyl)-N-methylamino]-1-azetidinyl]-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]methanesulfonate (1.65 g, 3.94 mmol) in dry N,N-dimethylformamide (15 mL) was treated with solid sodium azide (0.768 g, 11.8 mmol). The reaction mixture was then heated to 65° C. under a nitrogen atmosphere. After 3 h, TLC analysis (5% methanol/chloroform) revealed a small amount of starting mesylate still remained. An additional portion of sodium azide (0.256 g, 3.94 mmol) was added and the reaction mixture heated at 65° C. for 1 h. The reaction mixture was cooled to ambient temperature, filtered and concentrated under reduced pressure. The residue was chromatographed over silica gel (100 g), eluting with a gradient of 1-4% methanol/chloroform, to afford, after concentration of appropriate fractions, 1.24 g (86%) of the title compound as an off-white solid with mp 60°-63° C. and MS(EI) 366 (M+).