Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([C:11]2[C@@H:12]([O:20][CH2:21][CH2:22][O:23][CH3:24])[C@@H:13]3[CH2:18][C@@H:17]([OH:19])[CH2:16][N:14]3[N:15]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]>C(Cl)Cl.C(OCC)(=O)C.O>[Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([C:11]2[C@@H:12]([O:20][CH2:21][CH2:22][O:23][CH3:24])[C@@H:13]3[CH2:18][C:17](=[O:19])[CH2:16][N:14]3[N:15]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: COCCO[C@@H]1C(c2ccc(C#N)c(Cl)c2C)=NN2C[C@H](O)C[C@@H]12
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: COCCO[C@@H]1C(c2ccc(C#N)c(Cl)c2C)=NN2CC(=O)C[C@@H]12
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.4 %

Procedure:
To a solution of 2-chloro-4-((3S,3aS,5R)-5-hydroxy-3-(2-methoxyethoxy)-3a,4,5,6-tetrahydro-3H-pyrrolo[1,2-b]pyrazol-2-yl)-3-methylbenzonitrile (50 mg, 0.143 mmol) in DCM (5 mL) at 0° C. was added Dessmartin reagent (121 mg, 0.286 mmol) and reaction mixture was stirred at room temperature for 16 h. Once the starting material had disappeared (monitored by TLC), reaction mixture was diluted with ethyl acetate, water and extracted. Organic layer was washed with saturated NaHCO3 solution, water, and brine then dried over Na2SO4 and concentrated. Purification by column chromatography (silica gel, 1% MeOH in DCM) provided the title compound (36 mg, 73%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([O:13]C)=[O:12])[NH:6]2.[OH-].[K+]>>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([OH:13])=[O:12])[NH:6]2
Reactant: COC(=O)c1cc2c(C)cccc2[nH]1
Agent: [K+]
Agent: [OH-]
Product: Cc1cccc2[nH]c(C(=O)O)cc12

Procedure:
Following the general procedure of PREPARATION 63 and making non-critical variations but starting with methyl 4-methylindole-2-carboxylate (PREPARATION 85, 4.94 g), potassium hydroxide (1.75 g), the title compound is obtained, NMR (300 MHz, CD3OD) 7.24, 7.19, 7.12, 6.85 and 2.51 δ.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([O:47][CH3:48])=[C:7]2[CH2:12][N:13]1[C:19](=[O:20])[C@@H:18]([NH:21][C:22](=[O:34])[C@@H:23]([N:25](C)[C:26](=O)OC(C)(C)C)[CH3:24])[C@H:17]([CH3:35])[N:16]([C:36](=[O:42])[CH2:37][S:38]([CH3:41])(=[O:40])=[O:39])[C:15]2[CH:43]=[CH:44][CH:45]=[CH:46][C:14]1=2.[ClH:49]>CO.CCOCC>[ClH:49].[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([O:47][CH3:48])=[C:7]2[CH2:12][N:13]1[C:19](=[O:20])[C@@H:18]([NH:21][C:22](=[O:34])[C@@H:23]([NH:25][CH3:26])[CH3:24])[C@H:17]([CH3:35])[N:16]([C:36](=[O:42])[CH2:37][S:38]([CH3:41])(=[O:40])=[O:39])[C:15]2[CH:43]=[CH:44][CH:45]=[CH:46][C:14]1=2
Reactant: COc1ccc2c(Br)cccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@H](C)N(C(=O)CS(C)(=O)=O)c2ccccc21
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CN[C@@H](C)C(=O)N[C@@H]1C(=O)N(Cc2c(OC)ccc3c(Br)cccc23)c2ccccc2N(C(=O)CS(C)(=O)=O)[C@H]1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
To a rt solution of tert-butyl(S)-1-((3S,4S)-1-((5-bromo-2-methoxynaphthalen-1-yl)methyl)-4-methyl-5-(2-(methylsulfonyl)acetyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (33.8 mg, 45.3 μmol) in MeOH (45.3 μl) was added 2 M HCl in Et2O (181 μl). The reaction was stirred at rt for 3 h, then concentrated, taken up in H2O, and lyophilized to provide (S)-N-((3S,4S)-1-((5-bromo-2-methoxynaphthalen-1-yl)methyl)-4-methyl-5-(2-(methylsulfonyl)acetyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-2-(methylamino)propanamide hydrochloride (29.0 mg, 94%) as a white solid. MS m/z 645/647 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH:13]=[O:14].[Br:15]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:15][C:11]1[CH:10]=[C:9]([CH:13]=[O:14])[N:8]([C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[Cl:1])[CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=Cc1cccn1-c1ccncc1Cl
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cc(Br)cn1-c1ccncc1Cl
Temperature: 25 °C
Reaction time: 10 h
Yield: 29.4 %

Procedure:
To a solution of 2.95 g of 1-(3-chloro-4-pyridinyl)-1H-pyrrole-2-carbaldehyde in 20 ml of N,N-dimethylformamide was added 2.66 g of N-bromosuccinimide. The resulting mixture was stirred at room temperature for 10 hours. Water was poured into the reaction mixture, and a deposited precipitate was collected by filtration to obtain 1.2 g of 4-bromo-1-(3-chloro-4-pyridinyl)-1H-pyrrole-2-carbaldehyde of the formula:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[NH:11][CH2:10]2.[H-].[Na+].Br[CH2:23][C:24]([NH2:26])=[O:25]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[N:11]([CH2:23][C:24]([NH2:26])=[O:25])[CH2:10]2
Reactant: O=C1NCc2cc(OCc3cccc(F)c3)ccc21
Reactant: NC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: NC(=O)CN1Cc2cc(OCc3cccc(F)c3)ccc2C1=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 67 %

Procedure:
A mixture of 5-(3-fluoro-benzyloxy)-2,3-dihydro-isoindol-1-one (400 mg, 1.6 mmol), sodium hydride (55% in mineral oil, 75 mg, 1.7 mmol) in THF (20 mL) was stirred at RT for 45 min, and then 2-bromoacetamide (75 mg, 1.9 mmol) was added and the resulting mixture heated at 50° C. for 16 h. After cooling to RT the mixture was half-evaporated and diluted with water. The mixture was extracted with ethyl acetate and the combined organic layers were washed with brine and dried over sodium sulfate. After filtration and evaporation the residue was purified by chromatography (SiO2, CH2Cl2:2N NH3-MeOH 98:2 to 85:15) to afford the title product (337 mg, 67%) as a white solid. MS m/e=315.3 (M+H+).
Reaction SMILES: C([O:5][C:6](=[O:38])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([C:26]([C:28]2[NH:29][C:30]3[C:35]([CH:36]=2)=[CH:34][C:33]([Cl:37])=[CH:32][CH:31]=3)=[O:27])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.Cl.C(OCC)(=O)C>C(O)=O>[Cl:37][C:33]1[CH:34]=[C:35]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28]([C:26]([N:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:17][CH2:16][C:14]1[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:38])=[O:5])[S:12][CH:13]=1)=[O:27])=[CH:36]2
Reactant: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1)C(=O)c1cc2cc(Cl)ccc2[nH]1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O=CO
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)C(=O)c1cc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.8 %

Procedure:
2-[(4-{2-[[(5-Chloro-1H-indol-2-yl)carbonyl](heptyl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (270 mg) obtained in Example 312-1 was dissolved in formic acid (5 mL), 4N hydrochloric acid/ethyl acetate solution (5 mL) was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, and ether was added to the residue to give the title compound (192 mg) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([S:9](Cl)(=[O:11])=[O:10])=[C:4]([Cl:13])[CH:3]=1.[CH3:14][C:15]1[C:20]([NH2:21])=[CH:19][CH:18]=[CH:17][N:16]=1>N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([S:9]([NH:21][C:20]2[C:15]([CH3:14])=[N:16][CH:17]=[CH:18][CH:19]=2)(=[O:11])=[O:10])=[C:4]([Cl:13])[CH:3]=1
Reactant: Cc1ncccc1N
Reactant: O=S(=O)(Cl)c1c(Cl)cc(Br)cc1Cl
Solvent: c1ccncc1
Product: Cc1ncccc1NS(=O)(=O)c1c(Cl)cc(Br)cc1Cl
Yield: 64.5 %

Procedure:
Prepared from 4-bromo-2,6-dichlorobenzenesulfonyl chloride (1.00 g, 3.1 mmol) and 2-methyl-3-aminopyridine (0.33 g, 3.1 mmol) in pyridine (6 ml) according to the method of intermediate 1, to give the title compound as a yellow solid (0.80 g, 2.0 mmol, 65%). 5H (CDCl3, 300K) 8.31 (1H, dd J 4.8 Hz 1.4 Hz), 7.65 (1H, d J 1.4 Hz), 7.64 (2H, s), 7.10 (2H, m), 2.52 (3H, s). m/z (ES+, 70V) 396.9 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[NH:11][C:12]1[S:13][CH:14]=[C:15]([C:17]2[CH:18]=[C:19]([C:25]([NH2:27])=[NH:26])[S:20][C:21]=2[S:22][CH2:23]C)[N:16]=1.Br.COC1C=CC(OC)=CC=1NC1SC=C(C2C=C(C(OC)=S)SC=2C)N=1.N>CO.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[NH:11][C:12]1[S:13][CH:14]=[C:15]([C:17]2[CH:18]=[C:19]([C:25]([NH2:27])=[NH:26])[S:20][C:21]=2[S:22][CH3:23])[N:16]=1
Reactant: CCSc1sc(C(=N)N)cc1-c1csc(Nc2cc(OC)ccc2OC)n1
Agent: Br
Agent: COC(=S)c1cc(-c2csc(Nc3cc(OC)ccc3OC)n2)c(C)s1
Agent: N
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(OC)c(Nc2nc(-c3cc(C(=N)N)sc3SC)cs2)c1
Yield: 27 %

Procedure:
4-{2-[(2,5-Dimethoxyphenyl)amino](1,3-thiazol-4-yl)}-5-ethylthiothiophene-2-carboxamidine: Methyl 4-{2-[(2,5-dimethoxyphenyl)amino]-(1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxylate hydrobromide (45.5 mg, 0.09 mmol) was treated as described in Example 154, step (b), followed by preparative thin layer chromatography (500 μm silica gel plate, J. T. Baker, Phillipsburg, N.J., 10%-methanol-CH2Cl2-sat'd. NH3 eluent) to give 9.9 mg (27% yield of 4-{2-[(2,5-dimethoxyphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxamidine. 1H NMR (DMSO-d6, 300 MHz) δ 2.60 (s, 3H), 3.73 (s, 3H), 3.81 (s, 3H), 6.48 (dd, 1H, J=3.1, 8.8 Hz), 6.92 (d, 1H, J=7.9 Hz), 7.05 (s, 1H), 7.5 (bs, 2H), 8.04 (s, 1H), 8.34 (d, 1H, J=1.0 Hz), 9.6 (bs, 1H); Mass Spectrum (ESI) m/z calcd. for C17H18N4O2S3, 406.55 (M+H), found 407.1.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[N:10]([CH:21]([CH:25]([CH3:27])[CH3:26])[C:22]([OH:24])=O)[C:9]1=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.Cl.[CH2:39]([O:46][NH2:47])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[N:10]([CH:21]([CH:25]([CH3:27])[CH3:26])[C:22]([NH:47][O:46][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:24])[C:9]1=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C2CN(Cc3ccccc3)C(=O)N2C(C(=O)O)C(C)C)cc1
Reactant: NOCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(C2CN(Cc3ccccc3)C(=O)N2C(C(=O)NOCc2ccccc2)C(C)C)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 61.5 %

Procedure:
2-(3-Benzyl-5-(4-methoxyphenyl)-2-oxoimidazolidin-1-yl)-3-methylbutyric acid (150 mg; 0.39 mmol) was introduced into DMF (10 ml) and cooled to 0° C. Then N,N-diisopropylethylamine (202 mg; 1.56 mmol), O-benzylhydroxylamine hydrochloride (125 mg, 0.78 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU; 223 mg; 0.58 mmol) were added, and the mixture was stirred at 0° C. for 2 h. The reaction solution was then concentrated and partitioned between dilute HCl solution/EtOAc and extracted with EtOAc (2×). The combined organic phases were dried over MgSO4, and the solvent was removed in a rotary evaporator. Purification by chromatography resulted in 2-(3-benzyl-5-(4-methoxyphenyl)-2-oxoimidazolidin-1-yl)-N-benzyloxy-3-methylbutyramide (116 mg; 0.24 mmol). MS: 488.25 (M+H); Rt: 3.50 min (method: gradient 95% H2O (0.05% TFA) to 95% acetonitrile over 3.5 min, 95% acetonitrile for 1.0 min, 5% acetonitrile 1.0 min; flow rate 0.5 ml/min; column 1 μL (Merck Purospher 5μ 2×55 mm); 30° C.)
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[C:11]([OH:13])=[O:12].CN(C=O)C.[CH2:25](O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)Cl.N1C=CC=CC=1>[F:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[C:11]([O:13][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:12]
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Reactant: OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(OCc1ccccc1)c1ccc([N+](=O)[O-])c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.2 %

Procedure:
Oxalyl chloride (4.60 mL), 53.6 mmol) is added to a stirred suspension of 3-fluoro-4-nitrobenzoic acid (5.11 g, 26.8 mmol) in CH2Cl2 (100 mL). DMF (0.1 mL) is added, and the solution stirred for 2 h at room temperature. The solvent is evaporated, and the residue is dissolved in CH2Cl2 (100 mL). Benzyl alcohol (5.54 mL, 53.6 mmol) and pyridine (2 mL) are added and the solution stirred for 16 h. The solvent is removed and the residue purified by filtration through a pad of silica gel, eluting with EtOAc/heptanes (1:9) to afford the title compound (6.8 g, 24.7 mmol).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[C:5]([C:17]#[N:18])=[C:4]([SH:19])[N:3]=1.[CH2:20]([N:22]([CH2:27][CH3:28])[C:23](=[O:26])[CH2:24]Br)[CH3:21].C([O-])(O)=O.[Na+].C(Cl)Cl.CO>CN(C=O)C.O.C(OCC)(=O)C>[NH2:1][C:2]1[N:3]=[C:4]([S:19][CH2:24][C:23]([N:22]([CH2:27][CH3:28])[CH2:20][CH3:21])=[O:26])[C:5]([C:17]#[N:18])=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=2)[C:7]=1[C:8]#[N:9]
Reactant: N#Cc1c(N)nc(S)c(C#N)c1-c1ccc(O)cc1
Reactant: CCN(CC)C(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCN(CC)C(=O)CSc1nc(N)c(C#N)c(-c2ccc(O)cc2)c1C#N

Procedure:
At RT, 53.6 mg (0.2 mmol) of 2-amino-4-(4-hydroxyphenyl)-6-sulfanyl-3,5-pyridinedicarbonitrile and 58.2 mg (0.3 mmol) of N,N-diethylbromoacetamide are stirred in 0.5 ml of DMF together with 33.6 mg (0.4 mmol) of NaHCO3 for 4 hours. TLC (CH2Cl2/CH3OH 10:1) shows complete conversion. The entire mixture is diluted with water and ethyl acetate and the EA phase is dried with MgSO4 and concentrated under reduced pressure. The residue crystallizes from methanol.
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][C:5]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]([CH:18]=[O:19])[CH:3]=1.[CH2:20]([O:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31](OB(O)O)=[CH:30][CH:29]=1)[CH2:21][CH2:22][CH3:23].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O>[CH2:20]([O:24][CH2:25][CH2:26][O:27][C:28]1[CH:29]=[CH:30][C:31]([C:2]2[CH:17]=[CH:16][C:5]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]([CH:18]=[O:19])[CH:3]=2)=[CH:32][CH:33]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CCOC(=O)CCCCOc1ccc(Br)cc1C=O
Reactant: CCCCOCCOc1ccc(OB(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CCCCOCCOc1ccc(-c2ccc(OCCCCC(=O)OCC)c(C=O)c2)cc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 99.2 %

Procedure:
A suspension of ethyl 5-(4-bromo-2-formylphenoxy)pentanoate (9.0 g) and 4-(2-butoxyethoxy)phenylboric acid (7.8 g) and potassium carbonate (9.1 g) in toluene (100 ml), ethanol (10 ml) and water (10 ml) was stirred under an argon atmosphere for 30 minutes. After addition of tetrakis(triphenyl)phosphine palladium (1.6 g), the solution was heated at 100° C. for 12 hours under an argon atmosphere. The solution was allowed to cool. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain brown amorphous ethyl 5-[[4′-(2-butoxyethoxy)-3-formyl [1,1′-biphenyl]-4-yl]oxy]pentanoate (12.0 g).
Reaction SMILES: [CH:1]1[C:15](=[NH:16])[N:14]=[C:13]2[N:3]([C@@H:4]3[O:8][C@H:7]([CH2:9][OH:10])[C@@H:6]([OH:11])[C@@H:5]3[O:12]2)[CH:2]=1.Cl.C[OH:19]>>[C@@H:4]1([N:3]2[CH:2]=[CH:1][C:15]([NH2:16])=[N:14][C:13]2=[O:12])[O:8][C@H:7]([CH2:9][OH:10])[C@@H:6]([OH:11])[C@@H:5]1[OH:19]
Reactant: N=c1ccn2c(n1)O[C@H]1[C@H](O)[C@@H](CO)O[C@H]12
Reactant: CO
Agent: Cl
Product: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)c(=O)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of the diacetyl derivative (30 mg.) of the carbocyclic analog of cyclocytidine, described immediately above, in methanol (15 ml.) saturated with hydrogen chloride was stirred at room temperature overnight. Evaporation of volatile components with a stream of nitrogen, then under reduced pressure, and in a high vacuum left the hydrochloride of the carbocyclic analog of cyclocytidine (30 mg.); the mass spectrum included the expected peaks (m/e 223, 206, 192). A solution of this material in 1 N aqueous ammonia (2 ml.) was heated at 80°-85° for 5 min. Volatile components were evaporated under reduced pressure and, then, in a high vacuum. Crystallization of the residue from ethanol gave the carbocyclic analog of 1-β-arabinofuranosylcytosine. This compound may also be isolated by ion-exchange chromatography, by preparative thin-layer chromatography, or by the sequential use of these techniques after impure preparations containing the carbocyclic analog of cyclocytidine are treated with aqueous ammonia. The properties of the pure compound prepared by the procedure of either Part A or Part B are summarized in Part A.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].C[CH:17](C)[CH2:18][C:19](=[O:21])C.BrCCCO>O>[OH:21][CH2:19][CH2:18][CH2:17][O:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: CC(=O)CC(C)C
Agent: O=C([O-])[O-]
Agent: OCCCBr
Agent: [K+]
Solvent: O
Product: N#Cc1ccc(OCCCO)cc1

Procedure:
To a flask was added 4-hydroxybenzonitrile (50 g, 0.41 mol, 1 eq.) and potassium carbonate (0.51 mol, 1.25 eq.). To this mixture was added 4-methyl-2-pentanone (400 mL). Stirring was started and 3-bromo-1-propanol (61.50 g, 0.4 mol, 1.05 eq.) was added in one portion. The reaction mixture was heated to between 85 and 90° C. for 5 hours. Water (250 mL) was then added and the resultant mixture heated to 30° C. until all solids had gone into solution. The aqueous layer was separated from the organic layer. The organic layer was diluted with 4-methyl-2-pentanone (400 mL) to provide a solution of the sub-title compound that was employed directly in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([O:13][CH:14]([CH3:16])[CH3:15])=[CH:11][C:10]([C:17]([O:19]C)=[O:18])=[N:9]1>[OH-].[Na+]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([O:13][CH:14]([CH3:16])[CH3:15])=[CH:11][C:10]([C:17]([OH:19])=[O:18])=[N:9]1
Reactant: COC(=O)c1cc(OC(C)C)n(-c2ccccc2F)n1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)Oc1cc(C(=O)O)nn1-c1ccccc1F
Temperature: 40 °C
Reaction time: 5 h
Yield: 70 %

Procedure:
The crude methyl 1-(2-fluoro-phenyl)-5-isopropoxy-1H-pyrazole-3-carboxylate obtained in step 1 was dissolved in 6 ml of MOH, 2 ml of an aqueous 1 M solution of sodium hydroxide were added, and the mixture was stirred for 5 h at 40° C. The solvent was removed and the residue subjected to acidic aqueous work-up to give 70% of the title compound.
Reaction SMILES: [C:1]1([Li])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]([N:12]=[N:13][C:14](Cl)([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])([CH3:11])([CH3:10])[CH3:9]>CCOCC>[C:8]([N:12]=[N:13][C:14]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])([CH3:11])([CH3:10])[CH3:9]
Reactant: [Li]c1ccccc1
Reactant: CC(C)CC(C)(Cl)N=NC(C)(C)C
Solvent: CCOCC
Product: CC(C)CC(C)(N=NC(C)(C)C)c1ccccc1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
To a clean, dry 250 ml. round bottom 4 neck flask equipped with a magnetic stirrer, thermometer, condenser and addition funnel, which was being purged with nitrogen was added an ether solution containing .06 moles of phenyllithium. The solution was cooled to 5° C. and a solution of 10.25 g. (.05 moles) of 2-t-butylazo-2-chloro-4-methylpentane in 50 ml. ether was added dropwise over 1/2 hour. After the addition was complete, the reaction was warmed to 20° C. and stirred for 1/2 hour. The excess phenyllithium was destroyed with wet ether and the reaction mixture poured into 200 ml. water. The ether layer was separated, dried over anhydrous sodium sulfate, filtered and the ether removed on a rotating evaporator leaving 11.9 g. (96%) of a liquid. The infrared spectrum was in agreement with the structure of the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.O1CCOC[CH2:14]1.CB1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C>[CH3:12][O:11][C:4]1[N:3]=[C:2]([CH3:14])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Reactant: C1COCCO1
Agent: [Pd]
Agent: CB1OB(C)OB(C)O1
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Product: COc1ccc([N+](=O)[O-])c(C)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred suspension of 2-chloro-6-methoxy-3-nitropyridine (2.44 g, 12.9 mmol) in 10% v/v aqueous dioxane (25 mL) was added tetrakis(triphenyl phosphine) palladium (1.50 g, 1.3 mmol) and the mixture stirred for 15 min prior to the addition of trimethylboroxine (1.81 mL, 12.9 mmol) and potassium carbonate (5.36 g, 38.8 mmol). The reaction mixture was heated under reflux for 6 h then allowed to cool to rt over 16 h. Ethyl acetate (100 mL) was added and the mixture stirred vigorously for 1 h. The mixture was filtered through celite, washing through with ethyl acetate. The aqueous phase was separated and extracted with ethyl acetate (3×30 mL) and the combined organics were washed with brine (50 mL), dried (MgSO4), filtered and adsorbed onto silica gel. Purification via flash column chromatography (SiO2, ethyl acetate/isohexane, 1:20) gave the title compound as a pale yellow solid. δH (CDCl3): 2.81 (3H, s), 4.01 (3H, s), 6.65 (1H, d), 8.26 (1H, d).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[CH2:9]([N:16]1[C:25]2[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=2)[C:19]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[C:18]([C:33]#[N:34])[C:17]1=[O:35])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>N1C=CC=CC=1>[CH2:9]([N:16]1[C:25]2[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=2)[C:19]([N:27]2[CH2:32][CH2:31][N:30]([C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[O:7])[CH2:29][CH2:28]2)=[C:18]([C:33]#[N:34])[C:17]1=[O:35])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: N#Cc1c(N2CCNCC2)c2cc(F)ccc2n(Cc2ccccc2)c1=O
Reactant: O=C(Cl)c1cccs1
Solvent: c1ccncc1
Product: N#Cc1c(N2CCN(C(=O)c3cccs3)CC2)c2cc(F)ccc2n(Cc2ccccc2)c1=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
2-Thiophene carbonyl chloride (160 μL, 1.5 mmol) was added to a stirred solution of Compound 48 (362 mg, 1.0 mmol) in pyridine (5 mL) under argon at 0° C. The solution was allowed to come to room temperature and further stirred overnight. The solution was poured into ice water and the solids formed were filtered. The solids were washed by excess water, dried, and recrystallized by ethyl acetate to yield 359 mg (76%) of white solids. M.P. 246° C. 1H NMR (DMSO-d6): δ 3.67 (m, 4H), 3.94 (m, 4H), 5.49 (s, 2H), 7.16 (m, 1H), 7.20–7.26 (m, 3H), 7.45 (dd, J=4.6, 9.4 Hz, 1H), 7.50 (d, J=3.9 Hz, 1H), 7.55 (td, J=2.7, 9.2 Hz, 1H), 7.66 (dd, J=2.8, 9.7 Hz, 1H), 7.80 (d, J=5.1 Hz, 1H). EIMS m/z 473 (M+1). Anal. (C26H21FN4O2S) C, H, N.