Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[C:4]#[C:5][CH3:6].Cl[C:9]1[CH:14]=[C:13]([O:15][CH:16]([CH:18]2[CH2:20][CH2:19]2)[CH3:17])[N:12]=[CH:11][N:10]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:3]([O:7][C:9]1[CH:14]=[C:13]([O:15][CH:16]([CH:18]2[CH2:20][CH2:19]2)[CH3:17])[N:12]=[CH:11][N:10]=1)[C:4]#[C:5][CH3:6]
Reactant: CC(Oc1cc(Cl)ncn1)C1CC1
Reactant: CC#CCO
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CCOc1cc(OC(C)C2CC2)ncn1
Reaction time: 0.17 h

Procedure:
In 4 ml of tetrahydrofuran was suspended 0.11 g of sodium hydride (60% in oil), to which 0.5 ml of a solution containing 0.15 g of 2-butyn-1-ol in tetrahydrofuran was added dropwise at room temperature, followed by stirring for 10 minutes. To this was slowly added dropwise 0.5 ml of a solution containing the above 4-chloro-6-(1-cyclopropylethoxy)pyrimidine in tetrahydrofuran, followed by stirring at room temperature for 1 hour. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution, which was extracted three times with t-butyl methyl ether. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 0.22 g of 4-(2-butynyloxy)-6-(1-cyclopropylethoxy)pyrimidine (the present compound (2)).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:17]=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([OH:30])=O)=[CH:24][CH:23]=3)[CH:19]=[CH:20][CH:21]=1)[C:10]([CH3:32])([CH3:31])[CH2:9]2)=[O:5])[CH3:2].C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)[C:46]2N=CC=[CH:50][C:45]=2[N:44]=N1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.C(N)(C)C>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:17]=[C:18]([C:22]3[CH:23]=[CH:24][C:25]([C:28](=[O:30])[NH:44][CH:45]([CH3:50])[CH3:46])=[CH:26][CH:27]=3)[CH:19]=[CH:20][CH:21]=1)[C:10]([CH3:32])([CH3:31])[CH2:9]2)=[O:5])[CH3:2]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(-c3ccc(C(=O)O)cc3)c1)N2
Agent: C[NH3+]
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC(C)N
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(-c3ccc(C(=O)NC(C)C)cc3)c1)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a stirred solution of 2-(4′-carboxy-biphenyl-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (860 mg, 2 mmol), 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (HATU) (1.2 g, 3 mmol) and triethyl amine (0.86 mL, 6 mmol) in dichloromethane was added isopropylamine (0.66 mL, 8 mmol) at room temperature and stirred at room temperature for overnight. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-(4′-isopropylcarbamoyl-biphenyl-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (940 mg, quant.) as a light yellow solid which was used for next step without further purification: LC/MS m/e calcd for C30H34N2O3 (M+H)+: 471.62, observed: 471.2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2Cl.[CH3:16][N:17]([CH3:28])[CH2:18][CH2:19][O:20][C:21]1[N:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:27][C:24]1[CH:25]=[N:26][C:21]([O:20][CH2:19][CH2:18][N:17]([CH3:28])[CH3:16])=[CH:22][CH:23]=1
Reactant: CN(C)CCOc1ccc(N)cn1
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Cl
Product: CC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(OCCN(C)C)nc1
Yield: 73.8 %

Procedure:
Following general procedure C, 1-(6-bromo-4-chloroquinolin-3-yl)ethanone (5.0 g, 18.0 mmol) was reacted with 6-(2-(dimethylamino)ethoxy)pyridin-3-amine (3.5 g, 19.0 mmol) to afford the desired product (5.7 g, 82%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 11.90 (s, 1H), 9.12 (s, 1H), 8.08-7.98 (m, 1H), 7.87-7.76 (m, 1H), 7.74-7.63 (m, 2H), 7.33 (dd, J=8.8, 2.8 Hz, 1H), 6.83 (d, J=8.8 Hz, 1H), 4.44 (t, J=5.5 Hz, 2H), 2.78 (s, 3H), 2.74 (t, J=8.8 Hz, 2H), 2.36 (s, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:17]=[C:16]([O:18][CH2:19][CH:20]([CH3:34])[CH2:21][Si:22]([CH3:33])([O:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[O:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:15]=[CH:14][C:3]=1[C:4]([O:6]CC1C=CC=CC=1)=[O:5].C1CCCCC=1>[Pd].C(O)C>[OH:1][C:2]1[CH:17]=[C:16]([O:18][CH2:19][CH:20]([CH3:34])[CH2:21][Si:22]([CH3:33])([O:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[O:23][Si:24]([CH3:26])([CH3:25])[CH3:27])[CH:15]=[CH:14][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CC(COc1ccc(C(=O)OCc2ccccc2)c(O)c1)C[Si](C)(O[Si](C)(C)C)O[Si](C)(C)C
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: CC(COc1ccc(C(=O)O)c(O)c1)C[Si](C)(O[Si](C)(C)C)O[Si](C)(C)C

Procedure:
A mixture of 12 g of benzyl 2-hydroxy-4-(2-methyl-3-[1,3,3,3-tetramethyl-1-[(trimethylsilyl)-oxy]disiloxanyl]propyloxy]benzoate (0.023 mol), ethanol (40 ml), cyclohexene (12 ml) and 10% palladium-on-charcoal (1.2 g) was maintained at reflux for 1 hour. The mixture was cooled and was rinsed with ethanol. The fluids were concentrated and the resulting product was recrystallized from a 50/50 water/ethanol mixture to give the 2-hydroxy-4-[2-methyl-3-[1,3,3,3-tetramethyl-1-[(trimethylsilyl)oxy]disiloxanyl]propyloxy]benzoic acid in the form of a white powder.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].[C:6]([NH:9][C:10]1[S:11][C:12]([S:16](Cl)(=[O:18])=[O:17])=[C:13]([CH3:15])[N:14]=1)(=[O:8])[CH3:7].C(N(CC)CC)C>C1COCC1>[OH:5][CH2:4][CH2:3][N:2]([CH3:1])[S:16]([C:12]1[S:11][C:10]([NH:9][C:6](=[O:8])[CH3:7])=[N:14][C:13]=1[CH3:15])(=[O:17])=[O:18]
Reactant: CNCCO
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)Cl)s1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc(C)c(S(=O)(=O)N(C)CCO)s1
Temperature: 25 °C
Reaction time: 17 h
Yield: 80.9 %

Procedure:
To a stirred solution of 2-(methylamino)-ethanol (0.44 g, 5.86 mmol) in THF (12 ml) was added at 0° C. (ice water bath) commercially available 2-acetamido-4-methylthiazole-5-sulfonyl chloride (1.0 g, 3.92 mmol) and triethylamine (0.6 ml, 4.32 mmol). The light yellow suspension was stirred at room temperature for 17 h, and evaporated. The crude product was further purified by flash chromatography on silica gel (dichloromethane/MeOH) and subsequent crystallization (dichloromethane/MeOH/hexane) to yield 2-acetamido-4-methyl-thiazole-5-sulfonic acid (2-hydroxy-ethyl)-methyl-amide (0.93 g, 81%) as a white solid. MS (ISP) 294.0 [(M+H)+]; mp 189° C.
Reaction SMILES: [CH:1]1[C:10]2[C:11]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][C:2]=1[NH2:18].[C:19](Cl)(=[O:28])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>ClCCl>[CH:1]1[C:10]2[C:11]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][C:2]=1[NH:18][C:19](=[O:28])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Nc1cc2c3c(c1)c1c(n3CCC2)CCCCC1
Reactant: O=C(Cl)CCc1ccccc1
Solvent: ClCCl
Product: O=C(CCc1ccccc1)Nc1cc2c3c(c1)c1c(n3CCC2)CCCCC1
Yield: 69.8 %

Procedure:
Following the procedure of Example 1, Step 4, 5,6,9,10,11,12-hexahydro-4H,8H-cyclohepta[4,5]pyrrolo[3,2,1-ij]quinolin-2-amine (0.12 g, 0.50 mmol), hydrocinnamoyl chloride (0.078 mL, 0.52 mmol) and poly-(4-vinylpyridine) (700 mg) in dichloromethane (10 mL) provided 0.13 g of N-5,6,9,10,11,12-hexahydro-4H,8H-cyclohepta[4,5]pyrrolo[3,2,1-ij]quinolin-2-yl-3-phenylpropanamide. MS (ESI) m/z 373; HPLC purity major: no impurities detected at 210-370 nm window; 99.5% at 252 nm (max. abs), RT=11.0 (Xterra RP18, 3.5 u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN and MeOH) for 10 min, hold 4 min); HRMS: calcd for C25H28N2O+H+, 373.22744; found (ESI, [M+H]+), 373.2287.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C@@H:7]([N:12]([CH3:26])[C:13]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]3[CH2:25][CH2:24]3)=[CH:17][N:16]=1)=[O:14])[CH2:6][CH2:5]2.[CH2:27](C([Sn])=C(CCCC)CCCC)[CH2:28]CC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(C(C)C)CC)(C)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C>[CH3:26][N:12]([C@H:7]1[CH2:6][CH2:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH:27]=[CH2:28])[CH:3]=2)[CH2:8]1)[C:13]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)=[CH:17][N:16]=1)=[O:14]
Reactant: CN(C(=O)c1ccc(OCC2CC2)cn1)[C@H]1CCc2cc(Br)ccc2C1
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=Cc1ccc2c(c1)CC[C@H](N(C)C(=O)c1ccc(OCC3CC3)cn1)C2
Temperature: 100 °C

Procedure:
A mixture of N—((S)-6-bromo-1,2,3,4-tetrahydronaphthalen-2-yl)-N-methyl-5-cyclopropylmethoxypyridine-2-carboxamide (1.50 g), tributylvinyltin (1.37 g), palladium(II) acetate (16 mg), triphenylphosphine (76 mg), diisopropylethylamine (8.5 ml) and DMF (20 ml) was heated to 100° C. for 12 hours. The cooled reaction mixture was partitioned between ethyl acetate and sodium carbonate solution. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel. The product was thus obtained with the molecular weight of 362.48 (C23H26N2O2); MS (ESI): 363 (M+H+).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C:13]3[O:14][C:15](=[O:29])[CH:16]4[C@:21]([C:23]=3[CH2:24][CH2:25]2)([CH3:22])[CH2:20][CH2:19][C:18](=O)[CH2:17]4)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].Cl.[CH3:31][O:32][NH2:33].N1C=CC=CC=1.[Cl-].[NH4+]>C(O)C>[CH3:31][O:32][N:33]=[C:18]1[CH2:19][CH2:20][C@@:21]2([CH3:22])[CH:16]([C:15](=[O:29])[O:14][C:13]3[C@H:12]4[C@:26]([CH3:27])([CH2:25][CH2:24][C:23]=32)[C@@H:9]([C@@H:7]([CH3:8])[CH2:6][CH2:5][CH2:4][CH:2]([CH3:3])[CH3:1])[CH2:10][CH2:11]4)[CH2:17]1
Reactant: CC(C)CCC[C@H](C)[C@H]1CC[C@H]2C3=C(CC[C@]12C)[C@@]1(C)CCC(=O)CC1C(=O)O3
Reactant: CON
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: c1ccncc1
Product: CON=C1CC[C@]2(C)C3=C(OC(=O)C2C1)[C@@H]1CC[C@H]([C@@H](C)CCCC(C)C)[C@@]1(C)CC3
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.8 %

Procedure:
Compound 1 (40 mg, 0.10 mmol) obtained in Example 1 was dissolved in ethanol (5 mL), and O-methylhydroxyamine hydrochloride (25 mg, 0.30 mmol) and pyridine (0.024 mL, 0.03 mmol) were added thereto, followed by stirring at room temperature for 3 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate twice. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield a residue. The residue was purified by preparative thin layer chromatography to obtain the title compound (39 mg, 93%) as an E/Z mixture.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[O:9]1[CH2:18][CH:10]1[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CO>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH2:18][CH:10]([OH:9])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: c1ccc(CC2CO2)cc1
Reactant: Nc1ccc(Br)cc1
Solvent: CO
Product: OC(CNc1ccc(Br)cc1)Cc1ccccc1
Temperature: 25 °C
Yield: 70.5 %

Procedure:
A mixture of 4-bromoaniline (1.75 g, 0.0102 mol) and 2,3-epoxy-propylbenzene (1.77 g, 0.0132 mol) in methanol (40 mL) was heated at reflux for 16 hours. The mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was purified by flash chromatography on silica using ethyl acetate/n-heptane (1:5) as mobile phase to yield 1-(4-bromoanilino)-3-phenyl-2-propanol (2.2 g, 0.00719 mol) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:8])=[N:6][CH:7]=1.[CH3:9][C:10]1[CH:14]=[C:13]([Sn](CCCC)(CCCC)CCCC)[O:12][N:11]=1.C1CCC(P(C2C(C3C=CC=CC=3)=CC=CC=2)C2CCCCC2)CC1.CN(C=O)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:8][C:5]1[CH:4]=[CH:3][C:2]([C:13]2[O:12][N:11]=[C:10]([CH3:9])[CH:14]=2)=[CH:7][N:6]=1
Reactant: Fc1ccc(Br)cn1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C)no1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Solvent: CN(C)C=O
Product: Cc1cc(-c2ccc(F)nc2)on1
Temperature: 90 °C
Yield: 54.3 %

Procedure:
A 48 mL tube was charged with 5-bromo-2-fluoropyridine (1.17 ml, 11.4 mmol), 3-methyl-5-(tributylstannyl)isoxazole (5.29 g, 14.2 mmol), cyclohexyl JohnPhos (0.398 g, 1.14 mmol), Pd2dba3 (0.312 g, 0.341 mmol), and DMF (12.4 ml, 159 mmol), flushed with argon, sealed, then heated at 90° C. for 16 hours. Additional 3-methyl-5-(tributylstannyl)isoxazole (5.29 g, 14.2 mmol) (2 g), Pd2 dba3 (0.312 g, 0.341 mmol), and cyclohexyl JohnPhos (0.398 g, 1.14 mmol) were added and the mixture was stirred at 90° C. for 10 more hours. This was concentrated and the brown residue was purified by MPLC, eluting with 15% ethyl acetate in hexanes isocratic. 2-fluoro-5-(3-methylisoxazol-5-yl)pyridine (1.1029 g, 54.5% yield) isolated as a light yellow solid.
Reaction SMILES: [Mg].[CH:2](Br)=[CH2:3].[CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[CH:15]=[O:16].[Cl-].[NH4+]>O1CCCC1>[CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[CH:15]([OH:16])[CH:2]=[CH2:3]
Reactant: C=CBr
Reactant: O=Cc1ccc2ccccc2c1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CC(O)c1ccc2ccccc2c1
Reaction time: 1 h

Procedure:
1.8 g of magnesium are covered with 10 ml of absolute tetrahydrofuran. About 1 ml of a solution of 8 g of vinyl bromide in 8 ml of absolute tetrahydrofuran is added dropwise and the reaction is initiated by slight warming. Then, the remainder of the vinyl bromide solution is added dropwise. The mixture is left to react until it reaches room temperature. A solution of 7 g of 2-naphthaldehyde in 50 ml of absolute tetrahydrofuran is then added slowly dropwise, as the temperature rises to 40° C. The reaction is completed within 1 hour. The mixture is then hydrolyzed by the addition with stirring of 20 ml of saturated ammonium chloride solution at 0° C. The residue is filtered and rinsed with ether. The filtrate is diluted with water and extracted twice with ether. The ether extracts are washed with semi-saturated and saturated sodium chloride solution, dried over sodium sulfate and evaporated to yield 1-(2-naphthyl)-2-propen-1-ol which, without further purification, is esterified with cyclopropane carboxylic acid chloride in the process of Example 2. The resulting product is cyclopropane carboxylic acid 1-(2-naphthyl)allyl ester of melting point 30°-32° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:16]2[N:21]=[N:20][C:19]([C:22]([OH:24])=O)=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.[NH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[N:26]1([NH:25][C:22]([C:19]2[N:20]=[N:21][C:16]([O:15][CH2:14][C:9]3[N:10]([CH3:13])[N:11]=[N:12][C:8]=3[C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:17][CH:18]=2)=[O:24])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: NN1CCOCC1
Reactant: Cn1nnc(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)nn1
Product: Cn1nnc(-c2ccc(F)cc2)c1COc1ccc(C(=O)NN2CCOCC2)nn1
Yield: 29 %

Procedure:
As described for example 42b, 6-[5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-pyridazine-3-carboxylic acid (67 mg, 0.20 mmol) was converted, using 4-aminomorpholine instead of 4-aminotetrahydropyran, to the title compound (25 mg, 29%) which was obtained as a white solid. MS: m/e=414.3 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([CH:9]1[C:13]2([CH3:30])[CH:14]([OH:29])[CH2:15][CH:16]3[C:21]4([CH3:27])[CH2:22][CH2:23][CH:24]([OH:26])[CH2:25][CH:20]4[CH2:19][CH:18]([OH:28])[CH:17]3[CH:12]2[CH2:11][CH2:10]1)[CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].[CH3:31][S:32](Cl)(=[O:34])=[O:33].CCOC(C)=O>N1C=CC=CC=1>[OH:28][C@@H:18]1[CH2:19][C@H:20]2[C@:21]([CH3:27])([CH2:22][CH2:23][C@@H:24]([O:26][S:32]([CH3:31])(=[O:34])=[O:33])[CH2:25]2)[C@@H:16]2[C@@H:17]1[C@H:12]1[C@:13]([CH3:30])([C@@H:14]([OH:29])[CH2:15]2)[C@@H:9]([C@H:2]([CH3:1])[CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6])[CH2:10][CH2:11]1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)CCC(C)C1CCC2C3C(O)CC4CC(O)CCC4(C)C3CC(O)C12C
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](OS(C)(=O)=O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Temperature: 25 °C
Reaction time: 6 h
Yield: 82.7 %

Procedure:
To a solution of cholic acid methyl ester (25 g, 59.2 mmol) in pyridine (75 mL), stirring at 0° C., was added methanesulfonyl chloride (5.04 mL, 65.1 mmol) dropwise over 30 minutes. The reaction was allowed to warm to room temperature and stir for 6 hours. The reaction mixture was poured into a mixture of EtOAc (200 mL), 1 N HCI (200 mL), and ice. The layers were separated, and the organic layer was washed with 1N HCI (2×50 mL), dried (Na2SO4) and concentrated to provide a light yellow oil. The crude material was passed through a plug of silica eluting with 50% EtOAc/hexanes to provide 24.5 g (83%) of the title compound as a light yellow oil that foamed into a white, sticky foam when placed on the high vacuum pump.
Reaction SMILES: [CH2:1]([N:4]([CH2:16][CH2:17][CH3:18])[C:5]1[C:10]2[N:11]([CH3:15])[C:12](=O)[NH:13][C:9]=2[CH:8]=[CH:7][N:6]=1)[CH2:2][CH3:3].P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:12]1[N:11]([CH3:15])[C:10]2[C:5]([N:4]([CH2:16][CH2:17][CH3:18])[CH2:1][CH2:2][CH3:3])=[N:6][CH:7]=[CH:8][C:9]=2[N:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCN(CCC)c1nccc2[nH]c(=O)n(C)c12
Product: CCCN(CCC)c1nccc2nc(Cl)n(C)c12

Procedure:
A solution of 0.91 g (3.66 mmol) of 4-dipropylamino-3-methyl-1,3-dihydroimidazo[4,5-c]pyridin-2-one in 30 mL of phosphorous oxychloride was heated at 100° C. overnight and concentrated in vacuo. The thus obtained residue was quenched with water, adjusted with aqueous sodium bicarbonate to pH 5, and extracted with ethyl acetate. The organics were dried over sodium sulfate, filtered and concentrated in vacuo. The thus obtained residue was triturated with acetonitrile, filtered, and the filtrate, which contained the desired product, was concentrated in vacuo. The residue thus obtained (0.18 g, 18%) was used in the next reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH:14]1([N:19]2[C:24]3=[N:25][C:26](S(C)=O)=[N:27][CH:28]=[C:23]3[CH2:22][NH:21][C:20]2=[O:32])[CH2:18][CH2:17][CH2:16][CH2:15]1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.O1CCOCC1>C(Cl)(Cl)Cl.C(OCC)(=O)C>[CH:14]1([N:19]2[C:24]3=[N:25][C:26]([NH:1][C:2]4[CH:3]=[CH:4][C:5]([N:8]5[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]5)=[CH:6][CH:7]=4)=[N:27][CH:28]=[C:23]3[CH2:22][NH:21][C:20]2=[O:32])[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: Nc1ccc(N2CCCCC2)cc1
Reactant: CS(=O)c1ncc2c(n1)N(C1CCCC1)C(=O)NC2
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: O=C1NCc2cnc(Nc3ccc(N4CCCCC4)cc3)nc2N1C1CCCC1
Yield: 24 %

Procedure:
A solution of 377 mg (2.14 mmol) of 1-(4-aminophenyl)piperidine, 300 mg (1.07 mmol) of 1-cyclopentyl-7-methanesulfinyl-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one, 745 mg (3.21 mmol) of camphorsulfonic acid, and 2 mL of p-dioxane is heated at 130° C. for 1 hour in a sealed tube. The mixture is cooled and diluted with chloroform. The solution is washed twice with saturated aqueous sodium bicarbonate and once each with aqueous sodium chloride then brine. The organic phase is dried over magnesium sulfate and concentrated to leave a dark green residue that is dissolved in chloroform and chromatographed on silica gel eluting with 9:1:0.5 ethyl acetate/ethanol/triethylamine. The product fractions are pooled and concentrated to leave a residue that is dissolved in chloroform. The solution is diluted with ethyl acetate while most of the chloroform is being boiled away. Upon cooling, crystals form and are then collected to leave 101 mg (24%) of the title compound:
Reaction SMILES: [Cl:1][CH2:2][CH:3]=O.Cl.[Cl:6][C:7]([Cl:12])=[CH:8][CH2:9][O:10][NH2:11]>>[Cl:6][C:7]([Cl:12])=[CH:8][CH2:9][O:10][N:11]=[CH:3][CH2:2][Cl:1]
Reactant: NOCC=C(Cl)Cl
Reactant: O=CCCl
Agent: Cl
Product: ClCC=NOCC=C(Cl)Cl
Temperature: 25 °C
Yield: 58.2 %

Procedure:
To 2.94 g of 40% aqueous chloroacetaldehyde solution was added 2.94 g of O-(3,3-dichloro-2-propenyl)hydroxylamine hydrochloride with stirring at room temperature. After stirring at room temperature for 2 hours, the reaction mixture was extracted twice with diethyl ether. The diethyl ether layers were combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated, which afforded 1.94 g (yield, 96%) of chloroacetaldehyde O-(3,3-dichloro-2-propenyl)oxime, nD23.2 1.5038.
Reaction SMILES: [C:1]([O:11]C)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[CH3:13][O:14][CH:15]([O:20][CH3:21])[CH2:16][CH2:17][CH2:18][NH2:19]>C[O-].C[O-].C([Sn+2]CCCC)CCC>[CH3:13][O:14][CH:15]([O:20][CH3:21])[CH2:16][CH2:17][CH2:18][NH:19][C:6](=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2][C:1]([NH:19][CH2:18][CH2:17][CH2:16][CH:15]([O:20][CH3:21])[O:14][CH3:13])=[O:11]
Reactant: COC(CCCN)OC
Reactant: COC(=O)CCCCC(=O)OC
Agent: CCCC[Sn+2]CCCC
Agent: C[O-]
Product: COC(CCCNC(=O)CCCCC(=O)NCCCC(OC)OC)OC
Yield: 67.5 %

Procedure:
Dimethyl adipate (25.00 g, 0.1435 mol) was aminated with 38.63g (0.290 mol) of 4,4-dimethoxybutylamine and 2.50 g (0.00847 mol) of dibutyl tin dimethoxide in 200 g of mixed xylenes according to the procedure used in Example 1. This procedure afforded 36.47 g (0.0969 mol, 67.5% isolated yield) of the desired N,N'-bis(4,4-dimethoxybutyl)adipamide after recrystallization from mixed xylenes, mp 73°-75° C.; IR (KBr) 1640 (C=O), 1540, 1415, 1195, 1135, 1040 cm-1 ; 1H NMR (CDCl3 ; 300 MHz)δ1.42-1.63 (m, 12H, --CH2 --), 2.06-2.18 (m, 4H, CO--CH2 --), 3.13-3.20 (m, 4H, --NH2CH2 --), 3.23 (s , 12H, --OCH3), 4.27 (t, 2H, J=5.2 Hz, CH2CH--), 6.38 (t, 2 H, J=5.5 Hz, --NH--CH2 --); 13C NMR (CDCl3 ; 75.5 MHz)δ24.4, 25.0, 29.8, 36.0, 39.0, 52.8, 104.2, 172.7; MS (70eV) m/z (rel. intensity) 286 (2.96), 244 (10.19), 228 (14.05), 212 (29.35), 85 (28.09), 84 (38.06), 75 (89.07), 70 (100.00); HRMS (FAB) 377.2652 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][C:4]=1[C:14]([O-:16])=O.C(Cl)(=O)C(Cl)=O.[F:23][C:24]([F:34])([F:33])[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.C(N(CC)C(C)C)(C)C>ClCCl.CN(C)C=O>[F:23][C:24]([F:33])([F:34])[O:25][C:26]1[CH:27]=[CH:28][C:29]([NH:30][C:14](=[O:16])[C:4]2[CH:5]=[C:6]([CH:12]=[CH:13][C:3]=2[O:2][CH3:1])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:31][CH:32]=1
Reactant: CCOC(=O)c1ccc(OC)c(C(=O)[O-])c1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1ccc(OC)c(C(=O)Nc2ccc(OC(F)(F)F)cc2)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 86.9 %

Procedure:
1-Ethyl 4-methoxyisophthalate (150 mg) obtained in step D, and 3 μL of N,N-dimethylformamide were dissolved in 10 mL of dichloromethane, and the solution was cooled to 0° C. To this solution, 88 μL of oxalyl chloride was added little by little, and the mixture was stirred for 20 minutes at 0° C., followed by stirring the mixture for. 16 hours at room temperature. The reaction mixture was distilled under reduced pressure, and dried to obtain a light yellow solid. This solid was dissolved in 9 mL of dichloromethane, and 3 mL of the solution was added to a solution of 42 mg of 4-trifluoromethoxyaniline and 123 μL of N,N-diisopropylethylamine-dissolved in 2 mL of dichloromethane. The mixture was stirred for 6 hours at room temperature, and then dichloromethane was distilled off under reduced pressure. The resulting residue was purified by column chromatography (5 g of silica gel) using a 1:1 mixture of dichloromethane and n-hexane as an elution solvent, thereby obtaining 79 mg (92%) of ethyl N-(4-trifluoromethoxyphenyl)-4-methoxyisophthalamate.