Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][C:3]=1[S:16]([NH2:19])(=[O:18])=[O:17].CS[C:22](SC)=[C:23]1[C:32](=[O:33])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]([NH:34][CH2:35][CH:36]2[CH2:38][CH2:37]2)[C:24]1=[O:39]>O1CCOCC1>[CH:36]1([CH2:35][NH:34][N:25]2[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:32]([OH:33])=[C:23]([C:22]3[NH:1][C:2]4[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:13])([CH3:14])[CH3:12])=[CH:4][C:3]=4[S:16](=[O:17])(=[O:18])[N:19]=3)[C:24]2=[O:39])[CH2:37][CH2:38]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)c(S(N)(=O)=O)c1
Reactant: CSC(SC)=C1C(=O)c2ccccc2N(NCC2CC2)C1=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3ccccc3n(NCC3CC3)c1=O)N2
Temperature: 25 °C
Yield: 50.7 %

Procedure:
A mixture of the product of Example 414A (78.1 mg, 0.272 mmol) and the product of Example 353B (91.0 mg, 0.272 mmol) in anhydrous dioxane (2.7 mL) was heated under reflux for 3 h. The reaction mixture was then cooled to 25° C. and concentrated under reduced pressure to yield an oily solid. The solid was triturated with methanol to yield the title compound (72.5 mg, 51%). 1H NMR (300 MHz, DMSO-d6) δ 0.14 (d, J=4.04 Hz, 2 H) 0.42 (m, 2 H) 1.00 (m, 1 H) 1.51 (s, 9 H) 2.85 (bd, J=4.78 Hz, 2 H) 6.45 (bs, 1 H) 7.44 (t, J=7.54 Hz, 1 H) 7.62 (d, J=8.82 Hz, 1 H) 7.69 (dd, J=8.82, 2.20 Hz, 1 H) 7.89 (m, J=7.91, 7.91 Hz, 1 H) 8.10 (d, J=8.46 Hz, 1 H) 8.17 (m, 2 H) 9.93 (s, 1 H) 14.08 (s, 1 H) 15.15 (d, J=4.78 Hz, 1 H). MS (ESI−) m/z 524.0 (M−H)−. The sodium salt of the compound was prepared by reacting example 414B (3.9 mg, 0.0074 mmol) with 1 N sodium hydroxide solution (0.0074 mL, 0.0074 mmol) in 0.5 mL water and 0.5 mL tetrahydrofuran at room temperature for 1.2 h. The reaction mixture was then evaporated under a stream of nitrogen to provide the sodium salt (4.1 mg, 100% yield). 1H NMR (300 MHz, DMSO-d6) δ 0.20 (m, J=5.52 Hz, 2 H) 0.46 (d, J=8.82 Hz, 2 H) 1.00 (m, 1 H) 1.50 (s, 9 H) 3.30 (m, 2 H) 5.96 (t, J=6.25 Hz, 1 H) 7.06 (t, J=7.17 Hz, 1 H) 7.20 (d, J=9.19 Hz, 1 H) 7.52 (m, 2 H) 7.67 (d, J=8.82 Hz, 1 H) 7.90 (s, 1 H) 8.06 (d, J=7.35 Hz, 1 H) 9.60 (s, 1 H) 16.22 (s, 1 H). MS (ESI+) m/z 543.1 (M+H+H2O-Na)+, 526.1 (M−Na)+, (ESI−) m/z 524.1 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:11][S:12][CH2:13][CH2:14][NH2:15])=[N:5][CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[N+](N[C:20]1[NH:25][C:24](=[O:26])[C:23]([CH2:27][C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)=[CH:22][N:21]=1)([O-])=O>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]([CH2:11][S:12][CH2:13][CH2:14][NH:15][C:20]2[NH:25][C:24](=[O:26])[C:23]([CH2:27][C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)=[CH:22][N:21]=2)=[N:5][CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccnc(CSCCN)c1OC
Reactant: O=c1[nH]c(N[N+](=O)[O-])ncc1Cc1cccnc1
Solvent: c1ccncc1
Product: COc1ccnc(CSCCNc2ncc(Cc3cccnc3)c(=O)[nH]2)c1OC

Procedure:
A mixture of 2-(3,4-dimethoxy-2-pyridylmethylthio)ethylamine (0.95 g, 4.16 mmol), 2-nitroamino-5-(3-pyridylmethyl)-4-pyrimidone (0.925 g, 3.74 mmol) and pyridine (3.5 ml) was heated under reflux for 24 hours and evaporated to dryness. The residue was purified by elution from silica gel with methanolchloroform (1:7) and recrystallisation from ethanol to give 2-[2-(3,4-dimethoxy-2-pyridylmethylthio)ethylamino]-5-(3-pyridylmethyl)-4-pyrimidone 121°-1.5°.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([O:14][CH:15]2[CH2:32][CH:31]3[N:17]([C:18](=[O:38])[N:19]([CH3:37])[CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH:25][CH:26]4[C:28]([C:34]([OH:36])=O)([NH:29][C:30]3=[O:33])[CH2:27]4)[CH2:16]2)=[N:4][CH:3]=1.ClC1N=C(OC2CC3N(C(=O)N(C)CCCCC=CC4C(C([NH:74][S:75]([CH:78]5[CH2:80][CH2:79]5)(=[O:77])=[O:76])=O)(NC3=O)C4)C2)C2C(C=1)=CC(OC)=CC=2>>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([O:14][CH:15]2[CH2:32][CH:31]3[N:17]([C:18](=[O:38])[N:19]([CH3:37])[CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH:25][CH:26]4[C:28]([C:34]([NH:74][S:75]([CH:78]5[CH2:80][CH2:79]5)(=[O:77])=[O:76])=[O:36])([NH:29][C:30]3=[O:33])[CH2:27]4)[CH2:16]2)=[N:4][CH:3]=1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)N4C3)nc(Cl)cc2c1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)N4C3)ncc(Br)c2c1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)N4C3)ncc(Br)c2c1

Procedure:
The title product 66 was prepared from 17-(4-bromo-6-methoxyisoquinolin-1-yloxy)-13-methyl-2,14-dioxo-3,13,15-triaza-tricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (65) following the same procedures described for the preparation of N-[17-(3-chloro-6-methoxyisoquinolin-1-yloxy)-13-methyl-2,14-dioxo-3,13,15-triaza-tricyclo-[13.3.0.04,6]octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamide (43, Example 11): m/z=691 (M+H)+; 1H-NMR (CDCl3): 10.7 (br s, 1H), 8.09 (d, J=9.1 Hz, 1H), 7.3 (d, J=2.4 Hz, 1H), 7.25 (s, 1H), 7.15 (dd, J=9.1 Hz, 2.4, 1H), 7 (br s, 1H), 5.8 (br s, 1H), 5.74 (dd, J=18.2 Hz, 8, 1H), 5.16 (t, J=10.3 Hz, 1H), 4.74 (dd, J=9.3 Hz, 7, 1H), 4.05 (dd, J=11.1 Hz, 4, 1H), 3.95 (s, 3H), 3.6 (d, J=11.1 Hz, 1H), 3.1-3.2 (m, 1H), 2.9-3 (m, 1H), 2.83 (s, 3H), 2.4-2.5 (m, 3H), 2.19-2 (m, 2H), 2.5-2.7 (m, 4H), 1.4-1 (m, 3H), 1.2-1.35 (m, 2H), 1.05-1.15 (m, 1H), 0.95-1 (m, 1H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([O:37][CH3:38])=[C:31]([S:33](Cl)(=[O:35])=[O:34])[CH:32]=1>>[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([O:37][CH3:38])=[C:31]([S:33]([N:20]2[CH2:21][CH2:22][CH:17]([N:15]3[C:14](=[O:23])[C:13]([CH3:25])([CH3:24])[C:12]([C:6]4[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:2])[CH:5]=4)=[N:16]3)[CH2:18][CH2:19]2)(=[O:34])=[O:35])[CH:32]=1
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Cl
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(S(=O)(=O)c4cc(Cl)ccc4OC)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 5-chloro-2-methoxybenzenesulfonyl chloride as starting compounds. The crude product is purified by crystallization from EA and diethyl ether to yield the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=2[F:15])[N:5]=[CH:4][N:3]=1.[CH3:16][CH:17]([OH:20])[C:18]#[CH:19].[H-].[Na+].O>CN(C)C=O>[F:15][C:9]1[C:10]([F:14])=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[CH:7]=[C:2]([O:20][CH:17]([CH3:16])[C:18]#[CH:19])[N:3]=[CH:4][N:5]=1
Reactant: C#CC(C)O
Reactant: Fc1cccc(-c2cc(Cl)ncn2)c1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CC(C)Oc1cc(-c2cccc(F)c2F)ncn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 69.7 %

Procedure:
In 6 ml of N,N-dimethylformamide were dissolved 150 mg of 4-chloro-6-(2,3-difluorophenyl)pyrimidine and 56 mg of 3-butyn-2-ol, to which 32 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature for 12 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was 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 120 mg of 4-(2,3-difluorophenyl)-6-(1-methyl-2-propynyloxy)pyrimidine (the present compound (134)).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[CH2:4]Cl.[CH:11]1([CH2:14][CH2:15][NH:16][C:17]([C:19]2[N:20]=[N:21][C:22]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[CH:23][CH:24]=2)=[O:18])[CH2:13][CH2:12]1>>[CH:11]1([CH2:14][CH2:15][NH:16][C:17]([C:19]2[N:20]=[N:21][C:22]([N:25]3[CH2:30][CH2:29][N:28]([CH2:4][C:3]4[CH:6]=[C:7]([Cl:10])[CH:8]=[CH:9][C:2]=4[Cl:1])[CH2:27][CH2:26]3)=[CH:23][CH:24]=2)=[O:18])[CH2:13][CH2:12]1
Reactant: ClCc1cc(Cl)ccc1Cl
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Product: O=C(NCCC1CC1)c1ccc(N2CCN(Cc3cc(Cl)ccc3Cl)CC2)nn1

Procedure:
Following the procedure of Example 11, making variations only as required to use 2,5-dichlorobenzyl chloride in place of 2-trifluoromethylbenzyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white solid (43% yield). 1H NMR (300 MHz, CDCl3) δ 7.96-8.04, 7.53, 7.16-7.33, 6.96, 3.75-3.84, 3.64, 3.56, 2.62-2.70, 1.53, 1.51, 0.70-0.83, 0.43-0.51, 0.06-0.13. MS (ES+) m/z 434 (M).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:20]=[C:19](/[CH:21]=[CH:22]/[CH:23]([C:28]2[CH:33]=[C:32]([Cl:34])[C:31]([Cl:35])=[C:30]([Cl:36])[CH:29]=2)[C:24]([F:27])([F:26])[F:25])[CH:18]=[CH:17][C:4]=1[C:5]([NH:7][N:8](C)[C:9](OC(C)(C)C)=O)=[O:6]>O1CCOCC1>[Br:2][C:3]1[CH:20]=[C:19](/[CH:21]=[CH:22]/[CH:23]([C:28]2[CH:29]=[C:30]([Cl:36])[C:31]([Cl:35])=[C:32]([Cl:34])[CH:33]=2)[C:24]([F:26])([F:27])[F:25])[CH:18]=[CH:17][C:4]=1[C:5]([NH:7][NH:8][CH3:9])=[O:6]
Reactant: CN(NC(=O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CNNC(=O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Temperature: 25 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
HCl (4M in dioxane) was added to a stirred solution of (E)-tert-butyl 2-(2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzoyl)-1-methylhydrazinecarboxylate (1.0 g 1.6 mmol) in 1,4-dioxane (100 mL). The reaction mixture was stirred at ambient temperature for 4 h. The volatiles were evaporated and the residue was triturated with ether to afford the title compound as a light yellow solid (660, 99%): 1H NMR (300 MHz, DMSO-d6) δ11.8 (s, 1H), 8.02 (s, 1H), 7.91 (s, 2H), 7.68 (d, J=9.3 Hz, 2H), 7.52 (d, J=8.1 Hz, 1H), 7.07 (dd, J=15.6, 9.3 Hz, 1H), 6.78 (d, J=15.3 Hz, 1H), 4.89-4.83 (m, 1H), 2.81 (s, 3H); ESIMS m/z 517.0 ([M+H]+).
Reaction SMILES: [CH3:1][CH2:2][NH:3][CH2:4][CH2:5][N:6]1[C:14]2[C:13](=[O:15])[N:12]([CH2:16][CH2:17][CH3:18])[C:11](=[O:19])[N:10]([CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[CH:24][CH:23]=3)[C:9]=2[N:8]=[C:7]1[CH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1.O.NN.[H][H]>[Pd]>[NH2:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][CH2:20][N:10]2[C:9]3[N:8]=[C:7]([CH2:31][C:32]4[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=4)[N:6]([CH2:5][CH2:4][NH:3][CH2:2][CH3:1])[C:14]=3[C:13](=[O:15])[N:12]([CH2:16][CH2:17][CH3:18])[C:11]2=[O:19])=[CH:27][CH:26]=1
Reactant: [H][H]
Reactant: CCCn1c(=O)c2c(nc(Cc3cccnc3)n2CCNCC)n(CCc2ccc([N+](=O)[O-])cc2)c1=O
Agent: [Pd]
Agent: NN
Solvent: O
Product: CCCn1c(=O)c2c(nc(Cc3cccnc3)n2CCNCC)n(CCc2ccc(N)cc2)c1=O

Procedure:
By the method of Example 2, 3-pyridylacetic acid is reacted with 5,6-diamino-1-[2-(4-nitrophenyl)ethyl]-3-propyluracil (6) to yield 3-[2-(4-nitrophenyl)ethyl]-1-propyl-8-[(3-pyridyl)methyl]xanthine. By the method of Example 3, this substance is reacted with sodium carbonate, 1,2-dichloroethane and ethylamine to yield 4,7-(2-ethylamino)ethyl-3-[2-(4-nitrophenyl)ethyl]-1-propyl-8-[(3-pyridyl)methyl]xanthine. By the method of Example 4, 7-(2-ethylamino)ethyl-3-[2-(4-nitrophenyl)ethyl]-1-propyl-8-[(3-pyridyl)methyl]xanthine is reduced with hydrazine hydrate or hydrogen gas in the presence of a palladium catalyst to yield 3-[2-(4-aminophenyl)ethyl]-7-(2-ethylamino)ethyl-1-propyl-8-[(3-pyridyl)methyl]xanthine free base. The corresponding hydrochloride salt is then made on exposure to an excess of hydrogen chloride in solution.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:14][C:15]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:16]=2[C:17]([O:19]C(C)(C)C)=[O:18])[CH:5]=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:14][C:15]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:16]=2[C:17]([OH:19])=[O:18])[CH:5]=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cc1ccc(Nc2cnc(-c3ccccc3)c(Cl)c2)c(C(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(Nc2cnc(-c3ccccc3)c(Cl)c2)c(C(=O)O)c1

Procedure:
Obtained (0.005 g, 87% of yield) following the procedure described in Example 8 (step B) starting with 0.006 g (0.02 mmol) of tert-Butyl 2-(5-chloro-6-phenylpyridin-3-ylamino)-5-methylbenzoate in 1 ml of TFA.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.Cl[CH2:9][CH2:10][C:11]1[N:20]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]3[O:27][CH2:28][O:29][C:23]=3[CH:22]=2)[C:18]2[C:13](=[CH:14][C:15]3[O:32][CH2:31][O:30][C:16]=3[CH:17]=2)[N:12]=1.[Na+].[I-]>CN(C=O)C.CCCCCC>[N:3]1([CH2:9][CH2:10][C:11]2[N:20]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]4[O:27][CH2:28][O:29][C:23]=4[CH:22]=3)[C:18]3[C:13](=[CH:14][C:15]4[O:32][CH2:31][O:30][C:16]=4[CH:17]=3)[N:12]=2)[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: ClCCc1nc(-c2ccc3c(c2)OCO3)c2cc3c(cc2n1)OCO3
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: c1cn(CCc2nc(-c3ccc4c(c3)OCO4)c3cc4c(cc3n2)OCO4)cn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 37.2 %

Procedure:
To a suspension of hexane washed NaH (60% in oil, 84 mg, 2.1 mmol) in dry DMF (5 mL) was added imidazole (142 mg, 2.1 mmol). The mixture was stirred at rt for 15 min and was treated with 2-chloroethyl-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazoline (232 mg, 0.7 mmol), and then with NaI (105 mg, 0.7 mmol). The mixture was stirred at rt for 15 h and it was poured into ice-water. The precipitated solid was collected by filtration, washed with water, and air dried. The yellow solid was then crystallized from EtOAc to give the title compound as pale yellow needles (101 mg); mp 160-163° C.; 1H NMR (CDCl3) 7.5 (s, 1H) 7.33 (s, 1H), 7.27 (s, 1H), 7.15-7.20 (m, 2H), 6.91-7.05 (m, 3H), 6.15 (s, 2H), 6.08 (s, 2H), 4.60 (m, 211), 3,53 (m, 2H). Anal. calcd. for C21H16N4O4: C, 64.94; H, 4.15; N, 14.43. Found: C, 64.52; H, 4.11; N, 14.12.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH:12]3[CH2:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH2:14][NH:13]3)[NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:22]([O:26][C:27]([NH:29][CH:30]([CH2:34][C:35]1[C:40]([CH3:41])=[CH:39][C:38]([C:42](=[O:44])[NH2:43])=[CH:37][C:36]=1[CH3:45])[C:31](O)=[O:32])=[O:28])([CH3:25])([CH3:24])[CH3:23].O.OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[C:22]([O:26][C:27](=[O:28])[NH:29][CH:30]([CH2:34][C:35]1[C:36]([CH3:45])=[CH:37][C:38]([C:42](=[O:44])[NH2:43])=[CH:39][C:40]=1[CH3:41])[C:31](=[O:32])[N:13]1[CH:12]([C:9]2[NH:10][CH:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14]1)([CH3:25])([CH3:24])[CH3:23]
Reactant: c1ccc(-c2c[nH]c(C3Cc4ccccc4CN3)n2)cc1
Reactant: Cc1cc(C(N)=O)cc(C)c1CC(NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C(N)=O)cc(C)c1CC(NC(=O)OC(C)(C)C)C(=O)N1Cc2ccccc2CC1c1nc(-c2ccccc2)c[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 220 mg (0.8 mmol) of 3-(4-phenyl-1H-imidazol-2-yl)-1,2,3,4-tetrahydro-isoquinoline, 269 mg (0.8 mmol) of 2-tert-butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionic acid, 216 mg (1.6 mmol) of of hydroxybenzotriazole hydrate and 184 mg (0.96 mmol) of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride was added 3 mL of dimethylformamide. The resulting mixture was allowed to stir overnight at room temperature under argon. The mixture was then partitioned between ethyl acetate and water. The organic layer was separated, dried over magnesium sulfate and concentrated. The product {1-(4-carbamoyl-2,6-dimethyl-benzyl)-2-oxo-2-[3-(4-phenyl-1H-imidazol-2-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-carbamic acid tert-butyl ester was taken to the next step without further purification.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:9]([O:11][CH2:12][CH3:13])=[O:10].[CH2:14]([O:21][C:22]([NH:24][C@H:25]([C:27](O)=[O:28])[CH3:26])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(OCC)(=O)C>[CH2:14]([O:21][C:22]([NH:24][C@H:25]([C:27]([N:1]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:28])[CH3:26])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)C1CCCCCCN1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCCCCCN1C(=O)[C@H](C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 9.4 g of ethyl azacyclooctane-2-carboxylate in 400 ml of ethyl acetate add 17.0 g of N-benzyloxycarbonyl- (S) -alanine, N-hydroxysuccinimide ester. Stir the reaction mixture at room temperature for 20 hours and concentrate it in vacuo to give 1-[N-benzyloxycarbonyl-(S)-alanyl]azacyclooctane-2(R,S)-carboxylic acid, ethyl ester, as a colorless oil.
Reaction SMILES: [Na].Cl.[C:3]([NH2:9])(=[NH:8])[CH2:4][CH2:5][CH2:6][CH3:7].[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]=[C:25]=[O:26])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CC(C)=O>[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH:24][C:25]([NH:8][C:3](=[NH:9])[CH2:4][CH2:5][CH2:6][CH3:7])=[O:26])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCCCC(=N)N
Reactant: O=C=Nc1ccccc1OCc1ccccc1
Agent: Cl
Agent: [Na]
Solvent: CC(C)=O
Product: CCCCC(=N)NC(=O)Nc1ccccc1OCc1ccccc1

Procedure:
Following a procedure similar to that described in Example 1 but using 2.9 g. sodium in 300 ml. dry acetone, 17.7 g. valeramidine hydrochloride, and 29.3 g. 2-(benzyloxy)phenyl isocyanate in 200 ml. dry acetone, there was obtained after recrystallization from isopropyl alcohol 33.9 g. of the hydrochloride of 1-[2-(benzyloxy)phenyl]-3-(pentanimidoyl)urea; m.p. 145°-147°C.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[N:3]=1.[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>CN(C)C=O.C(=O)(O)[O-].[Na+]>[CH3:13][O:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)[CH:11]=[CH:10]2
Reactant: COc1ccc2nc(Cl)ccc2c1
Reactant: C1CNCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2nc(N3CCNCC3)ccc2c1
Temperature: 110 °C
Yield: 50.9 %

Procedure:
To a solution of 2-chloro-6-methoxy-quinoline of Step C, (2.5 g, 12.91 mmol) in N,N-dimethylformamide (50 mL) is added piperazine (12 g) and the mixture is heated at 110° C. under nitrogen for 6 hours. The solution is diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The extracts are dried over anhydrous magnesium sulfate and evaporated to dryness. The residue is flash chromatographed on silica gel Merck-60 using a gradient of methanol (4–10%) in dichloromethane containing 0.2% ammonium hydroxide to provide the title compound (1.6 g) as an off-white solid, m.p. 95–97° C.
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[O:7][C:5](=O)[C:4]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:3]12.[NH:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1C(O)=O>C(O)C>[CH3:1][N:2]1[C:3]2[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=2[C:5](=[O:7])[N:14]2[CH2:21][CH2:20][CH2:19][CH:15]2[C:8]1=[O:9]
Reactant: Cn1c(=O)oc(=O)c2ccccc21
Reactant: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Product: CN1C(=O)C2CCCN2C(=O)c2ccccc21

Procedure:
A mixture of 17.7 g. of N-methyl isatoic anhydride, 11.5 g. of L-proline and 250 ml. of ethanol is heated on a steam bath for three hours and then concentrated to remove the ethanol. The residue is mixed with benzene and a small portion of water and the layers are separated. The benzene layer is washed twice with water and concentrated to remove the solvent. The residue is triturated with ether. The crystals which form are collected by filtration and recrystallized from ethyl acetate yielding the pure dextrorotatory isomer, melting point 120°-122° C., [α]D25 + 486° (1%, methanol).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[CH2:10][C:11]1([OH:18])[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:1]([O:8][C:9](=[O:19])[CH2:10][C:11]1([OH:18])[CH2:16][CH2:15][CH:14]([NH:27][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(O)(CC(=O)OCc2ccccc2)CC1
Reactant: NCc1ccccc1
Product: O=C(CC1(O)CCC(NCc2ccccc2)CC1)OCc1ccccc1

Procedure:
Prepared from (1-Hydroxy-4-oxo-cyclohexyl)-acetic acid benzyl ester and benzylamine following the procedure described in Step 2 of Example 43. The crude product was purified by flash chromatography on silica gel (0-10% CH3OH:CH2Cl2). ESI-MS m/z 354 (MH)+.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:6]=[CH:5][C:4]=1[OH:13].O.Cl.FC(F)(F)[C:20](O)=[O:21]>>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:8]=[C:7]([C:9]([CH3:11])([CH3:12])[CH3:10])[CH:6]=[C:5]([CH:20]=[O:21])[C:4]=1[OH:13]
Reactant: CC(C)(C)c1ccc(O)c(C(F)(F)F)c1
Reactant: O=C(O)C(F)(F)F
Agent: Cl
Solvent: O
Product: CC(C)(C)c1cc(C=O)c(O)c(C(F)(F)F)c1

Procedure:
0.1 mole of 2-trifluoromethyl-4-tert-butylphenol and 0.1 mole of hexamethylenetretramine is dissolved in trifluoroacetic acid (150 ml.) and the mixture refluxed for 8 hours. After this time, 150 ml. of water and 50 ml. of concentrated hydrochloric acid is added. This mixture is then refluxed for 1/2 hour. The reaction mixture is cooled and extracted with ether (5 × 50 ml.) and the ether extract is dried over magnesium sulfate. The ether is evaporated and the residue is crystallized from ethanol to yield 3-trifluoromethyl-5-t-butyl salicylaldehyde.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C@:11]([OH:15])([CH3:14])[CH2:12][OH:13])[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[CH3:16][S:17](Cl)(=[O:19])=[O:18].Cl>N1C=CC=CC=1>[Cl:1][C:2]1[N:3]([CH2:10][C@:11]([OH:15])([CH3:14])[CH2:12][O:13][S:17]([CH3:16])(=[O:19])=[O:18])[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: C[C@](O)(CO)Cn1cc([N+](=O)[O-])nc1Cl
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: C[C@](O)(COS(C)(=O)=O)Cn1cc([N+](=O)[O-])nc1Cl
Temperature: 5 °C
Reaction time: 1 h
Yield: 80.6 %

Procedure:
(R)-2-Chloro-1-(2,3-dihydroxy-2-methylpropyl)-4-nitroimidazole prepared in Example 10 (879 g, 3.73 mol) was dissolved in pyridine (1778 ml) and cooled to 5° C. To this solution, methanesulfonyl chloride (432.7 ml, 5.59 mol) was added dropwise below 15° C., and the resulting mixture was stirred at the same temperature for 1 hour. To the mixture, 6N hydrochloric acid (5500 ml) was added below 30° C., and the resulting mixture was stirred for 40 minutes with cooling on ice-bath. The precipitates were filtered off and washed with water and toluene in this order to afford primary crystals. In addition, the filtrate was extracted with ethyl acetate (5 liters) twice. The organic phase was washed with water, dried over magnesium sulfate, and filtered to afford a solid. The filtrate was concentrated under reduced pressure. To the residue, toluene was added and the precipitates were filtered off to afford a solid. The solids were combined and dried at 60° C. to afford (R)-2-chloro-1-(2-hydroxy-3-methanesulfonyloxy-2-methylpropyl)-4-nitroimidazole (942.6 g, yield 81%) as a white powder.