Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:13])=[CH:9][C:10]=2[CH3:12])[N:5]([C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)[C:4]=1/[CH:24]=[CH:25]/[C:26]([OH:28])=O)#[N:2].C(Cl)(=O)C(Cl)=O.[NH2:35][C:36]1[CH:43]=[CH:42][C:39]([C:40]#[N:41])=[CH:38][CH:37]=1.N1C=CC=CC=1>O.C1COCC1.CN(C=O)C>[C:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:13])=[CH:9][C:10]=2[CH3:12])[N:5]([C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)[C:4]=1/[CH:24]=[CH:25]/[C:26]([NH:35][C:36]1[CH:43]=[CH:42][C:39]([C:40]#[N:41])=[CH:38][CH:37]=1)=[O:28])#[N:2]
Reactant: Cc1cc(C)c2c(C#N)c(/C=C/C(=O)O)n([C@H]3CCCc4ccccc43)c2n1
Reactant: N#Cc1ccc(N)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: c1ccncc1
Product: Cc1cc(C)c2c(C#N)c(/C=C/C(=O)Nc3ccc(C#N)cc3)n([C@H]3CCCc4ccccc43)c2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2E)-3-{3-cyano-4,6-dimethyl-1-[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]-1H-pyrrolo[2,3-b]pyridin-2-yl}prop-2-enoic acid (300 mg, 0.808 mmol).in THF (3 ml) were added DMF (0.03 ml) and oxalylchloride (0.0846 ml, 0.970 mmol), the mixture was stirred at room temperature for 1 hour and the solvent was distilled off under reduced pressure. The residue was added under ice-cooling to a solution of 4-aminobenzonitrile (119 mg, 0.968 mmol), pyridine (0.262 ml, 3.24 mmol) and THF (3 ml), and the mixture was stirred under ice-cooling for 2 hours and at room temperature for 12 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to give the objective product as a solid material. The resultant material was recrystallized from ethyl acetate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:48][N:49]([CH3:55])[C@H:50]1[CH2:54][CH2:53][NH:52][CH2:51]1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:48][N:49]([CH3:55])[C@H:50]1[CH2:54][CH2:53][N:52]([C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH2:51]1
Reactant: COC(=O)c1cccc(Br)c1
Reactant: CN(C)[C@H]1CCNC1
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(N2CC[C@H](N(C)C)C2)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of methyl 3-bromobenzoate (1.0 g, 4.7 mmol), 2-(dicyclohexylphosphino)-2′-(N,N-dimethylamino)biphenyl (0.037 g, 0.093 mmol), tris(dibenzylidineacetone)dipalladium (0) (0.021 g, 0.023 mmol), anhydrous K3PO4 (1.4 g, 6.5 mmol) in 9.3 mL toluene under argon was added (S)—N,N-dimethylpyrrolidin-3-amine (0.71 mL, 5.6 mmol). The reaction was sealed and heated to 80 deg. C. for 3 days. The reaction was cooled to ambient temperature, was diluted with ethyl acetate, and filtered through celite. The filtrate was concentrated in vacuo to give a brown oil, which was further purified by silica gel chromatography, using 90/10/1 dichloromethane/methanol/sat'd ammonium hydroxide as eluent to give (S)-methyl 3-(3-(dimethylamino)pyrrolidin-1-yl)benzoate as a light brown oil.
Reaction SMILES: [Si:1]([O:8][C@H:9]([C@H:34]1[CH2:38][C@@H:37]([O:39][CH2:40][CH2:41][CH3:42])[CH2:36][N:35]1[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[C@@H:10]([NH:20]C(=O)C1C=C(C)C=C(C(OC)=O)C=1)[CH2:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH:50][C:51]1[CH:52]=[C:53]([CH:57]=[C:58]([N:60]2[CH2:64][CH2:63][CH2:62][C:61]2=[O:65])[CH:59]=1)[C:54]([OH:56])=O.BrC1C=C(C=C(C(OC)=O)C=1)C(N[C@@H](CC1C=C(F)C=C(F)C=1)[C@@H]([C@H]1C[C@@H](OCCC)CN1C(OC(C)(C)C)=O)O[Si](C(C)(C)C)(C)C)=O.N([O-])=O.[Na+]>Cl.O.CO>[Si:1]([O:8][C@H:9]([C@H:34]1[CH2:38][C@@H:37]([O:39][CH2:40][CH2:41][CH3:42])[CH2:36][N:35]1[C:43]([O:45][C:46]([CH3:47])([CH3:49])[CH3:48])=[O:44])[C@@H:10]([NH:20][C:54](=[O:56])[C:53]1[CH:57]=[C:58]([N:60]2[CH2:64][CH2:63][CH2:62][C:61]2=[O:65])[CH:59]=[C:51]([OH:50])[CH:52]=1)[CH2:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: O=C(O)c1cc(O)cc(N2CCCC2=O)c1
Reactant: CCCO[C@@H]1C[C@H]([C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(C)cc(C(=O)OC)c2)N(C(=O)OC(C)(C)C)C1
Agent: CCCO[C@@H]1C[C@H]([C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(Br)cc(C(=O)OC)c2)N(C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: O=N[O-]
Solvent: CO
Solvent: O
Product: CCCO[C@@H]1C[C@H]([C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(O)cc(N3CCCC3=O)c2)N(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Step I (4): 3-Hydroxy-5-(2-oxopyrrolidin-1-yl)benzoic acid. To a solution of 3-amino-5-(2-oxopyrrolidin-1-yl)benzoic acid (Step I (3), 140 mg, 0.63 mmol) in 2N HCl (2 mL) were added MeOH (2 mL) followed by NaNO2 (88 mg, 1.26 mmol) in portions at −10° C. After the mixture was warmed up to 0° C., H2O (3 mL) was added to the above mixture and the mixture was stirred at 95° C. for 1 h. 0.1N HCl (30 mL) was added and the mixture was extracted with ethyl acetate (50 mL) three times. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give 130 mg of the title compound: 1H NMR (CD3OD, 500 MHz) δ ppm 2.19 (2H, m), 2.62 (2H, m), 3.94 (2H, m), 7.27 (1H, m), 7.47 (1H, m), 7.66 (1H, m). MS (ESI) (M−H)− 220.12.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][C:19]([C:22](=[NH:25])[NH:23][OH:24])=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[C:32](OC(=O)C)(=O)[CH3:33]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:26][CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][C:19]([C:22]3[N:25]=[C:32]([CH3:33])[O:24][N:23]=3)=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2cnc(C(=N)NO)cn2)cc1Cl
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: Cc1nc(-c2cnc(NC(=O)C(CC3CCCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)cn2)no1
Temperature: 120 °C
Reaction time: 3.5 h
Yield: 21.1 %

Procedure:
A mixture of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(N-hydroxycarbamimidoyl)-pyrazin-2-yl]-propionamide (197.0 mg, 0.423 mmol) and acetic anhydride (970 μL, 10.281 mmol) was placed into a one-dram glass vial. The vial was tightly sealed, and the reaction was stirred at 120° C. for 3.5 h. The reaction was diluted with ethyl acetate (75 mL) and washed with a saturated aqueous sodium bicarbonate solution (50 mL) and a saturated aqueous sodium chloride solution (50 mL). The combined aqueous layers were back-extracted with ethyl acetate (50 mL). The resulting combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40L, Silica, 1/1 ethyl acetate/hexanes) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(5-methyl-[1,2,4]oxadiazol-3-yl)-pyrazin-2-yl]-propionamide (43.8 mg, 21%) as a white foam; mp 101.9–104.8° C. (foam to gel); (ES)+-HRMS m/e calcd for C22H24ClN5O4S (M+H)+ 490.1311, found 490.1315.
Reaction SMILES: C([O-])(O)=[O:2].[Na+].Cl[CH2:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([CH2:15][P:16]([O:21][CH2:22][CH3:23])([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][C:9]=1[CH3:24].O>CS(C)=O.C(Cl)(Cl)Cl>[CH3:24][C:9]1[CH:10]=[C:11]([CH2:15][P:16]([O:21][CH2:22][CH3:23])([O:18][CH2:19][CH3:20])=[O:17])[C:12]([CH3:14])=[CH:13][C:8]=1[CH:7]=[O:2]
Reactant: CCOP(=O)(Cc1cc(C)c(CCl)cc1C)OCC
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOP(=O)(Cc1cc(C)c(C=O)cc1C)OCC
Temperature: 25 °C
Reaction time: 0.12 h

Procedure:
DMSO (32 mL) was heated to 100° C. and then NaHCO3 (4.5 gm) was added all at once. The mixture was stirred vigorously as α-chloro-α'-diethylphosphono-2,5-dimethyl-p-xylene (7 mmol) in DMSO (45 mL) and chloroform (5 mL) was rapidly added. The mixture was stirred for 7 min. and then quickly cooled to room temperature. The reaction mixture was combined with H2O (350 mL) and extracted with 3×125 mL ethyl ether. The combined organic layers were washed with 5×150 mL H2O, dried over MgSO4, and concentrated on a rotatory evaporator to an oil. The crude material was chromatographed on silica gel (175 gm) using ethyl acetate as the eluting solvent. The appropriate fractions were pooled and concentrated to give the product as a clear oil.
Reaction SMILES: [CH2:1]([CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][NH:21][C:22]([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[OH:36])=[CH:26][CH:25]=2)=[O:23])=[CH:14][CH:13]=1)[C:6]([O:8]CC)=[O:7])[CH2:2][CH2:3][CH3:4].[OH-].[Na+:38].[Na]>ClCCl.CO>[CH2:1]([CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][NH:21][C:22]([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[OH:36])=[CH:26][CH:25]=2)=[O:23])=[CH:14][CH:13]=1)[C:6]([O-:8])=[O:7])[CH2:2][CH2:3][CH3:4].[Na+:38]
Reactant: CCCCC(Cc1ccc(OCCNC(=O)c2ccc(-c3ccccc3O)cc2)cc1)C(=O)OCC
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CCCCC(Cc1ccc(OCCNC(=O)c2ccc(-c3ccccc3O)cc2)cc1)C(=O)[O-]

Procedure:
In a similar manner to that described in Example 2, ethyl 2-butyl-3-[4-[2-(2′-hydroxybiphenyl-4-carbonylamino)ethoxy]phenyl]propionate (345 mg), which is the product of Example 44, was reacted with aqueous sodium hydroxide solution (1N, 2.82 ml) and the reaction mixture was treated to afford the crude free acid which was subjected to chromatography on a silica gel thin layer plate using dichloromethane/methanol=10/1 as the eluant. The product was converted to the sodium salt to give the title compound (200 mg) as colorless crystals.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Cl.[NH:9]1[CH2:12][CH:11]([C:13]2[NH:17][C:16]3[CH:18]=[CH:19][C:20]([CH3:22])=[CH:21][C:15]=3[N:14]=2)[CH2:10]1.[Cl:23][C:24]1[C:25](F)=[N:26][CH:27]=[CH:28][CH:29]=1>CN1C(=O)CCC1>[Cl:23][C:24]1[C:25]([N:9]2[CH2:12][CH:11]([C:13]3[NH:17][C:16]4[CH:18]=[CH:19][C:20]([CH3:22])=[CH:21][C:15]=4[N:14]=3)[CH2:10]2)=[N:26][CH:27]=[CH:28][CH:29]=1
Reactant: Fc1ncccc1Cl
Reactant: Cc1ccc2[nH]c(C3CNC3)nc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: Cc1ccc2[nH]c(C3CN(c4ncccc4Cl)C3)nc2c1
Temperature: 100 °C
Yield: 9.6 %

Procedure:
To a mixture of cesium carbonate (435 mg, 1.34 mmol) and 2-(azetidin-3-yl)-5-methyl-1H-benzo[d]imidazole dihydrochloride (0.100 g, 0.384 mmol) was added NMP (1 mL) and 3-chloro-2-fluoropyridine (0.105 g, 0.798 mmol). The reaction mixture was degassed and heated to 100° C. for 1 h, then heated to 130° C. for 2 h. The reaction was diluted with EtOAc. The organic phase was washed with water (2×), brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (30% to 90% EtOAc in hexanes) followed by purification by reverse phase HPLC (10% to 50% water/MeCN followed by neutralization of the TFA salt with saturated NaHCO3) gave 2-(1-(3-chloropyridin-2-yl)azetidin-3-yl)-5-methyl-1H-benzo[d]imidazole (0.011 g, 0.037 mmol, 10% yield) as a dark yellow foam.
Reaction SMILES: Cl.[F:2][C:3]([F:18])([F:17])[C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[NH2:16])=[N:8][CH:9]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:50][C:51]1[CH:52]=[CH:53][C:54]([N:60]2[N:64]=[CH:63][CH:62]=[N:61]2)=[C:55]([CH:59]=1)[C:56](O)=[O:57]>CN(C=O)C>[CH3:50][C:51]1[CH:52]=[CH:53][C:54]([N:60]2[N:64]=[CH:63][CH:62]=[N:61]2)=[C:55]([CH:59]=1)[C:56]([NH:16][CH:12]1[CH2:13][CH2:14][CH2:15][CH:11]1[CH2:10][C:7]1[CH:6]=[CH:5][C:4]([C:3]([F:17])([F:2])[F:18])=[CH:9][N:8]=1)=[O:57]
Reactant: NC1CCCC1Cc1ccc(C(F)(F)F)cn1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-n2nccn2)c(C(=O)NC2CCCC2Cc2ccc(C(F)(F)F)cn2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-{[5-(trifluoromethyl)pyridin-2-yl]methyl}cyclopentan-1-amine hydrochloride (Intermediate 36; 0.60 g, 2.44 mmol) in DMF (5 ml) was added DIPEA (0.63 g, 4.80 mmol), TBTU (0.94 g, 2.93 mmol) and added 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid (Intermediate 6; 0.49 g, 2.44 mmol). The reaction was stirred at room temperature for 1 hour and then partitioned between ethyl acetate (50 ml) and water (10.0 ml). The aqueous layer was further extracted with ethyl acetate (50 ml) and the combined organics were concentrated in vacuo. The resulting residue was purified by column chromatography (silica, 0-2% methanol/DCM) to afford the title compound.
Reaction SMILES: Br[C:2]1[C:10]2[S:9][C:8]([NH:11][C:12](=[O:16])[NH:13][CH2:14][CH3:15])=[N:7][C:6]=2[CH:5]=[C:4]([C:17]2[CH:18]=[N:19][C:20]([N:23]3[CH2:28][CH2:27][C:26]([CH3:34])([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][CH2:24]3)=[N:21][CH:22]=2)[CH:3]=1.C([Sn](CCCC)(CCCC)[C:40]([O:42][CH2:43][CH3:44])=[CH2:41])CCC.C(OC=C)=C>CN(C=O)C.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>[CH2:43]([O:42][C:40]([C:2]1[C:10]2[S:9][C:8]([NH:11][C:12](=[O:16])[NH:13][CH2:14][CH3:15])=[N:7][C:6]=2[CH:5]=[C:4]([C:17]2[CH:22]=[N:21][C:20]([N:23]3[CH2:28][CH2:27][C:26]([CH3:34])([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][CH2:24]3)=[N:19][CH:18]=2)[CH:3]=1)=[CH2:41])[CH3:44]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(Br)c2s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C=COC=C
Solvent: CN(C)C=O
Product: C=C(OCC)c1cc(-c2cnc(N3CCC(C)(C(=O)OCC)CC3)nc2)cc2nc(NC(=O)NCC)sc12
Temperature: 100 °C

Procedure:
The ethyl 1-[5-[7-bromo-2-(ethylcarbamoylamino)-1,3-benzothiazol-5-yl]pyrimidin-2-yl]-4-methyl-piperidine-4-carboxylate (1 g, 1.82 mmol) and tributyl-(1-ethoxy-vinyl)-stannane (1.31 g, 3.64 mmol) were dissolved in DMF (20 mL) and the mixture deoxygenated by bubbling N2 through the solution for 20 min. Pd(PPh3)4, (210 mg, 0.18 mmol) was added and the reaction heated to 100° C. for 4 h under a N2 atmosphere, at the end of which time LCMS indicated clean formation of the vinyl ether. The reaction was concentrated under reduced pressure then diluted with EtOAc, washed with water then brine, the organic layer dried (MgSO4), filtered and the solvent removed in vacuo to give the desired compound.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17])[C:5]([CH3:18])=[C:4]([CH3:19])[N:3]=1.O.O.O.O.O.O.O.[Cl-].[Ce+3].[Cl-].[Cl-].[N-:31]=[N+:32]=[N-:33].[Na+].C(#N)C>O>[CH3:19][C:4]1[N:3]2[N:31]=[N:32][N:33]=[C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17])[C:5]=1[CH3:18]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(NCCCCCO)c1C
Agent: [Ce+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Cc1c(NCCCCCO)c([N+](=O)[O-])c2nnnn2c1C
Temperature: 25 °C

Procedure:
The preparation of 5-(2-chloro-5,6-dimethyl-3-nitropyridin-4-ylamino)pentan-1-ol was described in Part A of Example 85. Under a nitrogen atmosphere, cerium (III) chloride heptahydrate (8.08 g, 21.7 mmol) and sodium azide (5.64 g, 86.8 mmol) were added to a solution of 5-(2-chloro-5,6-dimethyl-3-nitropyridin-4-ylamino)pentan-1-ol (12.48 g, 43.38 mmol) in a 9:1 mixture of acetonitrile and water (145 mL). The reaction was stirred and heated at reflux for two days then allowed to cool to room temperature. A precipitate was removed by filtration and washed with acetonitrile. The filtrate was concentrated under reduced pressure to provide 12.13 g of 5-[(5,6-dimethyl-8-nitrotetrazolo[1,5-a]pyridin-7-yl)amino]pentan-1-ol as a yellow solid.
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:7][CH2:6][NH:5][C:4]1=[O:8].Br[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1[F:20].O>C1COCC1.CN(C=O)C>[F:20][C:12]1[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:11]=1[CH2:10][N:5]1[CH2:6][CH2:7][O:3][C:4]1=[O:8]
Reactant: O=C1NCCO1
Reactant: O=[N+]([O-])c1ccc(CBr)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C1OCCN1Cc1ccc([N+](=O)[O-])cc1F
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride 60% in oil (4.48 mmoles) in a mixture of THF/DMF (2.7 ml/0.45 ml) at 0° C. under an inert atmosphere there is added, dropwise, a solution of 1,3-oxazolidin-2-one (24.1 mmoles) in a mixture of THF/DMF (71 ml/5.6 ml) over 30 minutes. After stiffing for 1 hour, a solution of the compound obtained in Step A (26.5 mmoles) in a mixture of THF/DMF (56 ml/11.2 ml) is added over 1.5 hours, maintaining the temperature below 10° C. Stirring is maintained for 1.5 hours. Water (12 ml) is slowly added to the reaction mixture and then the THF is removed under reduced pressure. The reaction mixture is diluted with saturated aqueous NaCl solution and then extracted 3 times with 100 ml of AcOEt. The organic phases are combined, washed with saturated aqueous NaCl solution and then dried with MgSO4. After filtration, the organic phase is evaporated to dryness. The residue is purified on silica gel (SiO2, eluant CH2Cl2) to yield the title product which is used directly in the next Step.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([O:15][CH3:16])[C:9]=2[F:17])[N:5]=[C:4]([C:18]([O:20][CH3:21])=[O:19])[C:3]=1[Cl:22].[CH2:23](O)C>CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([O:15][CH3:16])[C:9]=2[F:17])[N:5]=[C:4]([C:18]([O:20][CH2:21][CH3:23])=[O:19])[C:3]=1[Cl:22]
Reactant: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)cc(N)c1Cl
Reactant: CCO
Agent: [Ti+4]
Agent: CC(C)[O-]
Product: CCOC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)cc(N)c1Cl

Procedure:
To a solution of 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylic acid, methyl ester (200 mg, 0.9 mmol) in ethanol (5 mL) was added a catalytic amount of titanium tetraisopropoxide and the solution heated under reflux for 2 hours. The solution was cooled and partitioned between ethyl acetate (10 mL) and water (10 mL) and the organic phase was dried (sodium sulfate) and concentrated. The residue was passed over a plug of silica gel (1:1 ethyl acetate: hexanes) to give 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylic acid, ethyl ester (150 mg. 0.6 mmol): mp 74-75° C.
Reaction SMILES: C(C1C=CC(C2N(C(NC)=O)C(=O)N(C3C=CC=C(C(F)(F)F)C=3)C3CCC(=O)C2=3)=C(F)C=1)#N.[C:35]([C:37]1[CH:42]=[CH:41][C:40]([CH:43]2[N:48]([C:49](OC3C=CC([N+]([O-])=O)=CC=3)=[O:50])[C:47](=[O:61])[N:46]([C:62]3[CH:67]=[CH:66][N:65]=[C:64]([C:68]([F:71])([F:70])[F:69])[CH:63]=3)[C:45]3[CH2:72][CH2:73][C:74](=[O:75])[C:44]2=3)=[CH:39][CH:38]=1)#[N:36].[NH2:76][CH2:77][C:78]([CH3:81])([OH:80])[CH3:79]>>[C:35]([C:37]1[CH:38]=[CH:39][C:40]([CH:43]2[N:48]([C:49]([NH:76][CH2:77][C:78]([OH:80])([CH3:81])[CH3:79])=[O:50])[C:47](=[O:61])[N:46]([C:62]3[CH:67]=[CH:66][N:65]=[C:64]([C:68]([F:71])([F:70])[F:69])[CH:63]=3)[C:45]3[CH2:72][CH2:73][C:74](=[O:75])[C:44]2=3)=[CH:41][CH:42]=1)#[N:36]
Reactant: CC(C)(O)CN
Reactant: N#Cc1ccc(C2C3=C(CCC3=O)N(c3ccnc(C(F)(F)F)c3)C(=O)N2C(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Agent: CNC(=O)N1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CC2)C1c1ccc(C#N)cc1F
Product: CC(C)(O)CNC(=O)N1C(=O)N(c2ccnc(C(F)(F)F)c2)C2=C(C(=O)CC2)C1c1ccc(C#N)cc1

Procedure:
The title compound is prepared in analogy to 4-(4-cyano-2-fluorophenyl)-N-methyl-2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-1H-cyclopenta[d]pyrimidine-3(2H)-carboxamide (example 49), using 4-nitrophenyl 4-(4-cyanophenyl)-2,5-dioxo-1-(2-(tri-fluoromethyl)pyridin-4-yl)-4,5,6,7-tetrahydro-1H-cyclopenta[d]pyrimidine-3(2H)-carboxylate (intermediate 30.3, 100 mg, 0.25 mmol) as starting material and employing 1-amino-2-methylpropan-2-ol as reagent. Yield: 60 mg; ESI mass spectrum [M+H]+=514; Retention time HPLC: 0.97 min (Z018_S04).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH:10]([NH:12][C:13](=[O:17])OCC)[CH3:11])[CH:5]=[CH:6][C:7]=1[OH:8].O.[NH2:20][NH2:21].O>C(O)CCC>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]([CH3:11])[NH:12][C:13](=[O:17])[NH:20][N:21]=2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: CCOC(=O)NC(C)C(=O)c1ccc(O)c(Cl)c1
Reactant: NN
Solvent: CCCCO
Solvent: O
Product: CC1NC(=O)NN=C1c1ccc(O)c(Cl)c1
Yield: 51.1 %

Procedure:
32.64 g of ethyl N-[2-(3-chloro-4-hydroxyphenyl)-1-methyl-2-oxoethyl]carbamate [prepared as described in Example 1(b)] and 75.20 g of 80% hydrazine hydrate (i.e. a grade of hydrazine hydrate containing 20% w/w water) were added to 240 ml of butanol, and the mixture was heated under reflux for 18 hours. The butanol used as the solvent was distilled off under reduced pressure, and then 10% w/v aqueous hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried and concentrated by evaporation under reduced pressure. The residue was collected by filtration, washed with ethyl acetate and dried, to give 14.71 g of the title compound as a yellow powder melting at 218°-222° C. (with decomposition). The filtrate was purified by column chromatography through silica gel eluted with a 10:1 by volume mixture of chloroform and methanol, to give a further 5.64 g of the title compound as a pale yellow powder.
Reaction SMILES: [C:1]1([CH2:7][O:8][CH2:9][CH:10]2[O:14][CH:13]([CH2:15][OH:16])[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:18][C:19]([N:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])=[O:20].[H-].[Na+].O>CS(C)=O>[CH2:22]([N:21]([CH2:25][CH2:26][CH3:27])[C:19](=[O:20])[CH2:18][O:16][CH2:15][CH:13]1[CH2:12][CH2:11][CH:10]([CH2:9][O:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:14]1)[CH2:23][CH3:24]
Reactant: OCC1CCC(COCc2ccccc2)O1
Reactant: CCCN(CCC)C(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCCN(CCC)C(=O)COCC1CCC(COCc2ccccc2)O1
Temperature: 25 °C
Yield: 71.5 %

Procedure:
A mixture of 4.44 g of tetrahydro-5-[(phenylmethoxy)methyl]-2-furanmethanol (0.02 mole) and 3.55 g of 2-chloro-N,N-dipropylacetamide (0.02 mole) is dissolved in 125 ml of dry dimethyl sulfoxide and the mixture stirred at room temperature under nitrogen. Slowly, 0.50 g of sodium hydride (0.02 mole) is added to the dimethyl sulfoxide mixture and the reaction allowed to stir at ambient temperature (23°). After stirring for 10 minutes an exothermic reaction begins to take place and an ice-bath is used to maintain the reaction temperature below 30°. After stirring for 1 hour, the ice-bath is removed and the reaction allowed to stir at room temperature for 18 hours. The excess NaH is destroyed by adding 5 ml of methanol and the entire reaction mixture is then poured into 400 ml of water. The product is extracted with 3×125 ml portions of chloroform. The CHCl3 extracts are combined and washed with 4×300 ml portions of water. The CHCl 3 is then removed in vacuo yielding a pale yellow oil which is vacuum distilled and the fraction distilling at 210°-225° @0.5 mm is collected yielding 5.2 g (72%) of the above compound.