Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:22](C(Cl)=O)=[CH:21][CH:20]=1.[NH2:34][C@@H:35]1[CH2:40][CH2:39][CH2:38][CH2:37][C@H:36]1[CH2:41][OH:42]>>[C:28]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:29]=[CH:30][C:31]([C:6]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]2[C:16]([NH:34][C@@H:35]2[CH2:40][CH2:39][CH2:38][CH2:37][C@H:36]2[CH2:41][OH:42])=[O:18])=[O:7])=[CH:32][CH:33]=1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: N[C@@H]1CCCC[C@H]1CO
Product: CON=C1C[C@@H](C(=O)N[C@@H]2CCCC[C@H]2CO)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]-4-carbonyl chloride, and [(1R,2R)-2-aminocyclohexyl]methanol, the title compound was obtained in 65% purity by HPLC. MS(ESI+): m/z=450.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:10]([OH:12])=[O:11])=[N:4][C:5]([CH2:8][OH:9])=[N:6][CH:7]=1.Cl.[CH3:14][CH2:15]O>>[CH2:14]([O:11][C:10]([C:3]1[C:2]([Br:1])=[CH:7][N:6]=[C:5]([CH2:8][OH:9])[N:4]=1)=[O:12])[CH3:15]
Reactant: O=C(O)c1nc(CO)ncc1Br
Reactant: CCO
Agent: Cl
Product: CCOC(=O)c1nc(CO)ncc1Br
Yield: 80 %

Procedure:
A solution of 4.2 g (18.02 mmol) 5-bromo-2-hydroxymethyl-pyrimidine-4-carboxylic acid in 50 ml 5N HCl/EtOH was stirred for 5 hrs. at RT. After evaporation of the solvent the residue was distributed between 50 ml CH2Cl2 and 30 ml H2O. The organic phase was washed with sat. NaHCO3 and brine. The combined organic phases were dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography to give 3.80 g (80%) 5-bromo-2-hydroxymethyl-pyrimidine-4-carboxylic acid ethyl ester as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[C:14]1[N:19]=[C:18]([C:20]#[N:21])[C:17]2[N:22]=[CH:23][N:24](C3CCCCO3)[C:16]=2[CH:15]=1)[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:11])[F:12])=[CH:6][C:5]=1[C:14]1[N:19]=[C:18]([C:20]#[N:21])[C:17]2[N:22]=[CH:23][NH:24][C:16]=2[CH:15]=1)[CH3:2]
Reactant: CCOc1ccc(C(F)(F)F)cc1-c1cc2c(ncn2C2CCCCO2)c(C#N)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: CCOc1ccc(C(F)(F)F)cc1-c1cc2[nH]cnc2c(C#N)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-(2-Ethoxy-5-trifluoromethyl-phenyl)-1-(tetrahydro-pyran-2-yl)-1H-imidazo-[4,5-c]pyridine-4-carbonitrile (67 mg) and para-toluenesulfonic acid hydrate (10 mg) were added in methanol (5 ml) and DCM (5 ml). The mixture was stirred at room temperature overnight before concentration and purification on preparative HPLC to afford 6-(2-Ethoxy-5-trifluoromethyl-phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile. 1H NMR (MeOH) δ 8.55 (s, 1H) 8.48 (s, 1H) 8.15 (s, 1H) 7.70 (d, 1H) 7.29 (d, 1H) 4.26 (q, 2H) 1.46 (t, 3H) MS m/z 333.1 (m+1)
Reaction SMILES: C([O:4][C@H:5]1[C@@H:9]([O:10]C(=O)C)[C@H:8]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([C:29]#[N:30])=[N:18][C:19]=3[NH:23][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[O:7][C@@H:6]1[CH2:31][O:32]C(=O)C)(=O)C>CO.[Ni]>[NH2:30][CH2:29][C:17]1[N:16]=[C:15]2[C:20]([N:21]=[CH:22][N:14]2[C@H:8]2[C@H:9]([OH:10])[C@H:5]([OH:4])[C@@H:6]([CH2:31][OH:32])[O:7]2)=[C:19]([NH:23][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[N:18]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(NC4CCCC4)nc(C#N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Ni]
Solvent: CO
Product: NCc1nc(NC2CCCC2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (2R,3R,4R,5R)-4-acetyloxy-2-(acetyloxy-methyl)-5-[2-cyano-6-(cyclopentylamino)purin-9-yl]oxolan-3-yl acetate (0.3 g) in methanol was added Raney nickel, and the mixture was stirred under hydrogen at 40 psi for 2 hours at room temperature. The catalyst was filtered off through celite, washed with methanol, and solvent removed from the filtrate under reduced pressure. The residue was crystallized from a mixture of methanol and hexane, to provide (4S,2R,3R,5R)-2-[2-(aminomethyl)-6-(cyclopentylamino)purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol. B. Preparation of a Compound of Formula (6) varying R1 and Y
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH:7]2[CH2:8][CH2:9][CH2:10][CH:6]2[CH2:5][N:4]1C(C1C=C(C)C=CC=1N1N=CC=N1)=O.[CH3:25][C:26]1[CH:27]=[CH:28][C:29]([N:35]2[CH:39]=[N:38][C:37]([C:40]([F:43])([F:42])[F:41])=[N:36]2)=[C:30]([CH:34]=1)[C:31]([OH:33])=O>>[NH2:1][CH2:2][CH:3]1[CH:7]2[CH2:8][CH2:9][CH2:10][CH:6]2[CH2:5][N:4]1[C:31]([C:30]1[CH:34]=[C:26]([CH3:25])[CH:27]=[CH:28][C:29]=1[N:35]1[CH:39]=[N:38][C:37]([C:40]([F:43])([F:42])[F:41])=[N:36]1)=[O:33]
Reactant: Cc1ccc(-n2cnc(C(F)(F)F)n2)c(C(=O)O)c1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CC3CCCC3C2CN)c1
Product: Cc1ccc(-n2cnc(C(F)(F)F)n2)c(C(=O)N2CC3CCCC3C2CN)c1

Procedure:
The title compound was prepared following the same general protocol as described for (1-(aminomethyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone in Example A68 using 5-methyl-2-(3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)benzoic acid. MS (ESI) 394 (M+H).
Reaction SMILES: C(OCC[N:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[C:9]([CH3:16])=[N:8]1)(=O)C.C1C(=O)N([Br:24])C(=O)C1.[CH3:25][CH2:26][O:27][C:28]([CH3:30])=[O:29]>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH2:26]([O:27][C:28](=[O:29])[CH2:30][N:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[C:9]([CH2:16][Br:24])=[N:8]1)[CH3:25]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)OCCn1nc(C)c2cccnc21
Reactant: CCOC(C)=O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)Cn1nc(CBr)c2cccnc21

Procedure:
A mixture of (3-methyl-pyrazolo[3,4-b]pyridine-1-yl)ethyl acetate (2.5 mmol, 1 eq.), NBS (3.0 mmol, 1.2 eq.), and benzoyl peroxide (0.05 mmol, 0.02 eq.) in 10 mL of CCl4 was refluxed for 1.5 h. The resultant mixture was cooled to rt, and diluted with 500 mL of EtOAc. The resultant solution was then washed with 100 mL of sat. sodium bicarbonate aqueous solution, brine solution, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (20% EtOAc in hexane to 35% EtOAc in hexane) to provide 450.2 mg of the desired product: HPLC retention time=2.50 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using 1 ml/min flow rate, a 2.5 minute gradient of 0% to 100% B with a 1.1 minute wash at 100% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile); MS (ES) M+H expect=298.0. found=298.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([CH2:21][CH2:22][CH3:23])[C:9]3[O:16][C:15]([C:17]([OH:19])=[O:18])=[CH:14][C:13](=[O:20])[C:10]=3[CH:11]=2)[N:6]=[C:5]([C:24]([OH:26])=[O:25])[CH:4]=1.C(=O)(O)[O-].[Na+:31]>O>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([CH2:21][CH2:22][CH3:23])[C:9]3[O:16][C:15]([C:17]([O-:19])=[O:18])=[CH:14][C:13](=[O:20])[C:10]=3[CH:11]=2)[N:6]=[C:5]([C:24]([O-:26])=[O:25])[CH:4]=1.[Na+:31].[Na+:31]
Reactant: CCCc1c2nc(C(=O)O)cc(OC)c2cc2c(=O)cc(C(=O)O)oc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCCc1c2nc(C(=O)[O-])cc(OC)c2cc2c(=O)cc(C(=O)[O-])oc12
Yield: 92.8 %

Procedure:
The product of step (b) (0.408 g) was dissolved in water (80 mls) containing sodium bicarbonate (0.192 g). The solution was filtered, and the filtrate freeze dried to give 0.425 g of the title product.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[O:17])[CH:11]=[CH:12][C:13]=1[OH:14].O[CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:15][C:16]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=2)=[O:17])[CH:11]=[CH:12][C:13]=1[O:14][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1
Reactant: OCCc1ccncc1
Reactant: Cn1ncc(Br)c1-c1cc(NC(=O)Nc2ccc(Cl)cc2)ccc1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cn1ncc(Br)c1-c1cc(NC(=O)Nc2ccc(Cl)cc2)ccc1OCCc1ccncc1
Reaction time: 2 h
Yield: 44 %

Procedure:
To a solution of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-hydroxy-phenyl]-3-(4-chloro-phenyl)-urea (0.1 g, 0.24 mmol), 4-(2-hydroxyethyl)-pyridine (0.0443 g, 0.36 mmol), and triphenylphosphine (0.0944 g, 0.36 mmol) in 10 mL of dry THF was added diisopropylazo-dicarboxylate (0.0728 g, 0.36 mmol) at ambient temperature. The mixture was stirred for 2 hours. Next, additional triphenylphosphine (0.0944 g, 0.36 mmol), 4-(2-hydroxyethyl)-pyridine (0.0443 g, 0.36 mmol), and diisopropylazodicarboxylate were added and the reaction mixture further stirred at room temperature overnight. The solvent from the reaction mixture was evaporated and the crude residue was dissolved in 5.0 mL of DMSO and purified by RP-HPLC. The proper fractions were collected and concentrated to ¼ volume. The aqueous solution was neutralized with 1N NaOH and extracted with ethyl acetate (2×, 59 mL). The organic layer was dried with sodium sulfate, filtered and evaporated to dryness to afford 1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyridin-4-yl-ethoxy)-phenyl]-3-(4-chloro-phenyl)-urea as a brown solid in 44% yield. LCMS m/z (%)=526 (M+H 79Br, 100), 528 (M+H 81Br, 67). 1H NMR (DMSO-d6) δ: 9.33 (bs, 1H), 9.24 (bs, 1H), 8.39 (dd, J=4.44 and 1.48 Hz, 2H), 7.63 (d, J=7.28 Hz, 1H), 7.59 (s, 1H), 7.56 (dd, J=8.94 and 2.71 Hz, 2H), 7.48 (m, 1H), 7.34 (d, J=2.67, 1H), 7.31 (d, J=2.67, 1H), 7.28 (dd, J=6.88 and 4.87 Hz, 2H), 7.14 (d, J=9.05 Hz, 1H), 7.09 (d, J=5.93 Hz, 1H), 4.01-4.2 (m, 2H), 3.48 (s, 3H), 2.96-2.91 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH2:12][CH2:13][CH3:14])[CH:8]=[CH:7][C:5]=2[N:6]=1.Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17]>N1C=CC=CC=1>[CH2:19]([O:18][C:16](=[O:17])[NH:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH2:12][CH2:13][CH3:14])[CH:8]=[CH:7][C:5]=2[N:6]=1)[CH3:20]
Reactant: CCCOc1ccc2nc(N)sc2c1
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Product: CCCOc1ccc2nc(NC(=O)OCC)sc2c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a chilled solution of 10.4 g. 2-amino-6-n-propoxybenzothiazole in 50 ml dry pyridine is dropwise added 6 g. ethyl chloroformate with stirring. The mixture is then allowed to stand at room temperature for 8 hrs. It is poured in 200 g. of ice water and stirred for 30 mins. The white solid product is separated by filtration and dried. Crystallization from ethanol gave 12 g. of the product. m.p. 175°-177° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.ClC1C(Cl)=C(S(N2CCC(O)CC2)(=O)=O)C=CC=1N[C:26](=[O:34])[C@:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29].[CH3:35][O:36][C:37]1[CH:43]=[C:42]([S:44]([N:47]([CH3:49])[CH3:48])(=[O:46])=[O:45])[C:41]([O:50][CH3:51])=[CH:40][C:38]=1[NH2:39].C(C1C=CC=C(C(C)(C)C)N=1)(C)(C)C>C(Cl)Cl.CN(C=O)C>[CH3:35][O:36][C:37]1[CH:43]=[C:42]([S:44]([N:47]([CH3:49])[CH3:48])(=[O:46])=[O:45])[C:41]([O:50][CH3:51])=[CH:40][C:38]=1[NH:39][C:26](=[O:34])[C@:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29]
Reactant: C[C@@](O)(C(=O)Nc1ccc(S(=O)(=O)N2CCC(O)CC2)c(Cl)c1Cl)C(F)(F)F
Reactant: COc1cc(S(=O)(=O)N(C)C)c(OC)cc1N
Agent: CC(C)(C)c1cccc(C(C)(C)C)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(S(=O)(=O)N(C)C)c(OC)cc1NC(=O)[C@@](C)(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.8 %

Procedure:
Oxalyl chloride (0.15 ml, 1.8 mmol) was added to a stirred suspension of (R)-(+)-2-hydroxy-2-methyl-3,3,3-trifluoropropanoic acid (0.18 g, 1.15 mmol) (Method 3) in DCM (10 ml) containing DMF (1 drop). The mixture was stirred at ambient temperature overnight, then 2,5-dimethoxy-4-[dimethylaminosulphonyl]aniline (200 mg, 0.77 mmol)‡ and 2,6-di-t-butylpyridine (0.19 ml, 0.9 mmol) was added and the resulting mixture stirred a further 2 hours at room temperature. Dichloromethane (25 ml) was added and the mixture was washed with water (2×50 ml) and brine then dried. Volatile material was removed by evaporation and the residue was purified by chromatography on a silica gel Mega Bond Elut column eluting with 50% EtOAc/iso-hexane to give the title compound as a foam (212 mg, 0.53 mmol); NMR: 1.74 (s, 3H), 2.83 (s, 6H), 3.91 (s, 6H), 7.40 (s, 1H), 8.27 (s, 1H), 9.17 (s, 1H); m/z 399.
Reaction SMILES: ClCCC[O:5][P:6]1[CH2:10][CH:9]=[C:8]([CH3:11])[CH2:7]1.[CH2:12](O)[C:13]#[C:14][CH2:15][OH:16].P1CCCC=1>ClCCCl>[OH:16][CH2:15][C:14]([P:6]1(=[O:5])[CH2:10][CH:9]=[C:8]([CH3:11])[CH2:7]1)=[C:13]=[CH2:12]
Reactant: CC1=CCP(OCCCCl)C1
Reactant: OCC#CCO
Agent: C1=PCCC1
Solvent: ClCCCl
Product: C=C=C(CO)P1(=O)CC=C(C)C1
Reaction time: 0.5 h

Procedure:
A total of 14.3 g. (0.08 mole) of 1-(chloropropoxy)-3-methyl-3-phospholene was added in two halves to a suspension of 6.8 g. (0.08 mole) of 2-butyn-1,4-diol in 25 ml. of 1,2-dichloroethane. The second half of the phospholene was added dropwise after the slow exotherm, generated by the first addition, had subsided. The maximum temperature reached in the first exotherm was 45° C and, in the second exotherm, was 60° C. After the addition of all phospholene was complete, the mixture was stirred for 30 minutes without heating and then was heated under reflux for 30 minutes. At the end of this time the solvent was removed by distillation and the residue was distilled in vacuo. There was thus obtained 1-(1-hydroxymethylallenyl)-3-methyl-3-phospholene-1-oxide in the form of a liquid.
Reaction SMILES: [Cl:1][C:2]1[C:12]2[CH2:11][CH2:10][NH:9][CH2:8][CH:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:5]=[C:4]([O:19][CH3:20])[C:3]=1[O:21][CH3:22].[OH-].[Na+].[CH:25](O)=O>C=O>[Cl:1][C:2]1[C:12]2[CH2:11][CH2:10][N:9]([CH3:25])[CH2:8][CH:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:5]=[C:4]([O:19][CH3:20])[C:3]=1[O:21][CH3:22]
Reactant: COc1cc2c(c(Cl)c1OC)CCNCC2c1ccccc1
Reactant: O=CO
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Product: COc1cc2c(c(Cl)c1OC)CCN(C)CC2c1ccccc1

Procedure:
A solution of 3.7 g of 6-chloro-7,8-dimethoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine in 15 ml of formic acid and 10 ml of formaldehyde is refluxed for 18 hours. The reaction mixture is evaporated to dryness, 20 ml of 6N hydrochloric acid is added and the solution is again evaporated to dryness to give a liquid. The latter is treated with 20 ml of 10% sodium hydroxide solution and the mixture is extracted with ether. The dried extract is evaporated to give 6-chloro-7,8-dimethoxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[N:11]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH:10]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[C:22]([Cl:27])[CH:21]=3)[CH2:9][C:8]([CH2:29][CH3:30])([CH3:28])[C:7]=2[N:6]=1)=[O:4].[OH-].[Na+]>O1CCCC1.CO.O>[Cl:27][C:22]1[CH:21]=[C:20]([CH:10]2[CH2:9][C:8]([CH2:29][CH3:30])([CH3:28])[C:7]3[N:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:14]=[CH:13][C:12]=3[N:11]2[CH2:15][CH2:16][CH:17]([CH3:18])[CH3:19])[CH:25]=[CH:24][C:23]=1[F:26]
Reactant: CCC1(C)CC(c2ccc(F)c(Cl)c2)N(CCC(C)C)c2ccc(C(=O)OC)nc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCC1(C)CC(c2ccc(F)c(Cl)c2)N(CCC(C)C)c2ccc(C(=O)O)nc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 35.8 %

Procedure:
To a solution of 6-(3-chloro-4-fluoro-phenyl)-8-ethyl-8-methyl-5-(3-methyl-butyl)-5,6,7,8-tetrahydro-[1,5]naphthyridine-2-carboxylic acid methyl ester (100 mg, 0.2 mmol) in tetrahydrofuran (2 mL) and methanol (2 mL) was added 3 N sodium hydroxide (1 mL). The reaction mixture was stirred at room temperature for 16 hours, and then diluted with water (10 mL), extracted with diethyl ether (20 mL). The organic layer was discarded. The aqueous layer was acidified with concentrated hydrochloric acid to pH 4 and extracted with ethyl acetate (40 mL×3), and the combined organics were dried over anhydrous Na2SO4. The solvent was removed in vacuo and purified by preparative HPLC to afford 6-(3-chloro-4-fluoro-phenyl)-8-ethyl-8-methyl-5-(3-methyl-butyl)-5,6,7,8-tetrahydro-[1,5]naphthyridine-2-carboxylic acid (30 mg, 31.3%) as a yellow oil. MS (ESI+) [(M+H)+] 419.1.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([F:16])([F:15])[F:14])=[CH:10][CH:11]=2)[C:6]([CH3:18])([CH3:17])[C:5]1=[O:19])(=O)C.[OH-].[Na+]>C(O)C>[CH3:17][C:6]1([CH3:18])[C:7]2[C:12](=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:14])[F:15])[CH:8]=2)[NH:4][C:5]1=[O:19]
Reactant: CC(=O)N1C(=O)C(C)(C)c2cc(C(F)(F)F)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)C(=O)Nc2ccc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
464 mg of 1-acetyl-3,3-dimethyl-5-trifluoromethyl-1,3-dihydroindol-2-one were dissolved in 4 ml of ethanol, and 1 ml of 1N sodium hydroxide solution was added. The reaction mixture was then stirred at room temperature for one hour. The reaction solution was extracted with 80 ml of methyl tert-butyl ether. The organic phase was washed with 30 ml of water and with 30 ml of saturated NaCl solution, dried over MgSO4 and concentrated under reduced pressure. This gave 354 mg of 3,3-dimethyl-5-trifluoromethyl-1,3-dihydroindol-2-one as a colorless solid.
Reaction SMILES: [C:1](OCC)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[C:17]([C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCCCCC.C(O)(=O)C.O1CCCC1>[OH:4][C:3]1[CH2:5][C:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)([C:25]2[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=2)[O:24][C:1](=[O:6])[CH:2]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: O=C(c1ccccc1)c1ccncc1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1C=C(O)CC(c2ccccc2)(c2ccncc2)O1

Procedure:
The title compound was prepared as described in General Method 1 using 90 mmol of ethyl acetoacetate, 99 mmol of NaH 60% dispersion in oil, 95 mmol of 1.6M n-butyl lithium in hexane and 90 mmol of 4-benzoylpyridine and 250 mL of tetrahydrofuran. The reaction mixture was acidified with acetic acid and the crude solid was washed with ice water (m.p. 148°-150° C).
Reaction SMILES: [CH:1]([CH:4]1[NH:8][S:7](=[O:10])(=[O:9])[NH:6][C:5]1=[O:11])(C)[CH3:2].[C:12]1([S:18][CH2:19]Cl)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:21]1(C)C=CC=CC=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:12]1([S:18][CH2:19][N:6]2[C:5](=[O:11])[CH:4]([CH2:1][CH2:2][CH3:21])[NH:8][S:7]2(=[O:10])=[O:9])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)C1NS(=O)(=O)NC1=O
Reactant: ClCSc1ccccc1
Reactant: Cc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Product: CCCC1NS(=O)(=O)N(CSc2ccccc2)C1=O

Procedure:
To a mixture of 4-isopropyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (7.0 g, 39.32 mmol) suspended in 150 ml of toluene was added phenylthiomethyl chloride (6.83 g, 43 mmol) and tetrabutylammonium bromide (1.26 g, 3.93 mmol). The resulting mixture was refluxed for 17 hours, cooled, filtered, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography to afford 5.2 g of 2-phenylthiomethyl-4-isopropyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula VI: R1 =H; R2 =isopropyl; R3 =H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:15]([CH3:16])=[C:14]3[N:10]([CH2:11][CH2:12][CH2:13]3)[CH:9]=2)=[CH:4][CH:3]=1.[Br:17]N1C(=O)CCC1=O.C(OC(C)C)(C)C.CCCCCC>C1COCC1>[Br:17][C:9]1[N:10]2[C:14](=[C:15]([CH3:16])[C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH2:13][CH2:12][CH2:11]2
Reactant: Cc1c(-c2ccc(F)cc2)cn2c1CCC2
Reactant: O=C1CCC(=O)N1Br
Solvent: CCCCCC
Solvent: CC(C)OC(C)C
Solvent: C1CCOC1
Product: Cc1c(-c2ccc(F)cc2)c(Br)n2c1CCC2
Yield: 62.2 %

Procedure:
The solution of 6-(4-fluorophenyl)-7-methyl-2,3-dihydro-1H-pyrrolizine (9.0 g, 42 mmol) in abs. THF (50 ml) is cooled to −15° C. N-Bromosuccinimide (3.46 g, 19.4 mmol) is added in portions; the mixture is stirred until no more starting material is detectable (TLC SiO2, diisopropyl ether-hexane 2:1). The black-purple-coloured reaction mixture is chromatographed on a column (20 cm×3 cm) packed with Al2O3 (ICI, for dry packing). The column is subsequently washed with n-hexane (80 ml), and the filtrates are concentrated. 3.55 g (28.9%) of a black-brown oil are obtained, which rapidly decomposes.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:29])([F:28])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]1[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([CH3:22])[NH:14][N:13]=[C:12]1[C:23]([O:25][CH2:26][CH3:27])=[O:24].[H][H].Cl[CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>CN(C=O)C.C1(C)C=CC=CC=1>[F:29][C:4]([F:3])([F:28])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]1[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([CH3:22])[N:14]([CH2:33][CH2:34][N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[N:13]=[C:12]1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)C1=NNC(C)=C(C(=O)OCC)C1c1ccccc1C(F)(F)F
Reactant: ClCCN1CCOCC1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)C1=NN(CCN2CCOCC2)C(C)=C(C(=O)OCC)C1c1ccccc1C(F)(F)F
Reaction time: 4 h

Procedure:
To a slurry of sodium hydride (2.6 g.; 55 mmole; 50:50 oil dispersion) in dry, distilled DMF (50 ml) under nitrogen atmosphere is added a solution of diethyl 1,4-dihydro-4-(2-trifluoromethylphenyl)-6-methyl-3,5-pyridazine dicarboxylate (19.9 g.; 50 mmole) in DMF (125 ml). After hydrogen bubbling ceases, the reaction mixture is warmed in a water bath for 1/2 hour, and a toluene (200 ml) solution of N-(2-chloroethyl)morpholine (60 mmole) is added dropwise. The reaction mixture is stirred at 110°-115° for 4 hours.
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.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:15][C:14]=1[C@H:26]([OH:29])[CH2:27][OH:28].Cl.C(OCC)C>N1C=CC=CC=1>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:15][C:14]=1[C@H:26]([OH:29])[CH2:27][O:28][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)CCc1ccc(Cl)c([C@H](O)CO)c1
Agent: Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCOC(=O)CCc1ccc(Cl)c([C@H](O)COS(=O)(=O)c2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.2 %

Procedure:
p-Toluenesulfonyl chloride (1.08 g, 5.69 mmol) in pyridine (15 mL) was added drop wise over 30 min to a cooled (0° C.) solution of ethyl 3-{4-chloro-3-[(1S)-1,2-dihydroxyethyl]phenyl}propanoate (1.41 g, 5.17 mmol) in pyridine (20 mL) under N2. The solution slowly warmed to rt overnight. After 16 h, 1N HCl and ethyl ether were added. The organic layer was isolated and the aqueous layer washed with ethyl ether (2×). The combined organic fractions were washed with 1N HCl, 10% aqueous Cu2SO4, brine, dried (Na2SO4), and concentrated. The crude product was purified by Biotage chromatography (0%-10% EtOAc/Hexanes) to afford 1.77 g of product as an oil (80%). 1H NMR (400 MHz, chloroform-d) δ ppm 7.81 (d, J=8.08 Hz, 2 H) 7.43 (d, J=2.27 Hz, 1 H) 7.36 (d, J=8.34 Hz, 2 H) 7.22 (d, J=8.08 Hz, 1 H) 7.10 (dd, J=8.21, 1.89 Hz, 1 H) 5.34 (td, J=5.62, 2.91 Hz, 1 H) 4.28 (dd, J=10.61, 2.53 Hz, 1 H) 4.14 (q, J=7.24 Hz, 2 H) 3.98 (dd, J=10.61, 8.34 Hz, 1 H) 2.93 (t, J=7.71 Hz, 2 H) 2.60 (t, J=7.83 Hz, 2 H) 2.47 (s, 3 H) 1.25 (t, J=7.07 Hz, 3 H).