Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]([CH:9]=[O:10])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.Cl[CH2:12][C:13]([N:15]1[CH2:20][C@H:19]([CH3:21])[N:18]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:17][C@H:16]1[CH3:30])=[O:14].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.CCOC(C)=O>[F:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][N:18]2[C@@H:19]([CH3:21])[CH2:20][N:15]([C:13](=[O:14])[CH2:12][O:1][C:2]3[C:3]([CH:9]=[O:10])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=3)[C@H:16]([CH3:30])[CH2:17]2)=[CH:24][CH:25]=1
Reactant: Cc1ccc(O)c(C=O)n1
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(OCC(=O)N2C[C@H](C)N(Cc3ccc(F)cc3)C[C@H]2C)c(C=O)n1
Temperature: 60 °C
Reaction time: 8 h
Yield: 120.2 %

Procedure:
To a solution of 3-hydroxy-6-methyl-pyridine-2-carbaldehyde (0.27 g, 1.95 mmol) in dimethylformamide (4 mL) was added 2-chloro-1-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-ethanone (0.53 g, 1.77 mmol), potassium carbonate (0.49 g, 3.5 mmol) and potassium iodide (0.29 g, 1.8 mmol). The resulting mixture was stirred at 60° C. overnight, then diluted with EtOAc, washed with brine and the organic layer was dried over magnesium sulfate. Filtration followed by concentration in vacuo gave the title compound (0.85 g)
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][CH:4]([CH:10]1[NH:14]C(=O)N[C:11]1=[O:16])[CH2:5][C:6]([F:9])([F:8])[F:7].[OH-:19].[Na+]>>[F:1][C:2]([F:18])([F:17])[CH2:3][CH:4]([CH2:5][C:6]([F:9])([F:8])[F:7])[CH:10]([C:11]([OH:19])=[O:16])[NH2:14]
Reactant: [OH-]
Reactant: O=C1NC(=O)C(C(CC(F)(F)F)CC(F)(F)F)N1
Agent: [Na+]
Product: NC(C(=O)O)C(CC(F)(F)F)CC(F)(F)F

Procedure:
5-(3,3,3-Trifluoro-1-(2,2,2-trifluoroethyl)propyl) imidazolidine-2,4-dione (1.0 g, 3.59 mmol) was dissolved in a 10 mL solution of aqueous NaOH (0.575 g in 10 mL H2O, 14.38 mmol). The solution was divided in 2 special vessels for microwave technology. The solution was heated by microwave in sealed vessels for 1 h. Microwave conditions: 15 min at about 100% power, 150° C., 50 psi, then 5 min at rest, 0% power. The sequence was repeated until the reaction was done. Water and ammonia were removed from the reaction mixture in vacuo and the resulting crude 5,5,5-trifluoro-3-(2,2,2-trifluoroethyl)-dl-norvaline (0.92 g, 100%) and NaOH mixture was used in the next reaction without further purification.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([CH2:30][NH:31][CH2:32][CH2:33][O:34][CH3:35])=[CH:26][CH:25]=5)[S:23][C:16]=34)=[C:10]([F:36])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1.[CH3:37][O:38][CH2:39][CH2:40][O:41][CH2:42][C:43](Cl)=[O:44]>C1COCC1.CCOC(C)=O>[CH:1]1([NH:4][C:5](=[O:6])[NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([CH2:30][N:31]([CH2:32][CH2:33][O:34][CH3:35])[C:43](=[O:44])[CH2:42][O:41][CH2:40][CH2:39][O:38][CH3:37])=[CH:26][CH:25]=5)[S:23][C:16]=34)=[C:10]([F:36])[CH:9]=2)[CH2:2][CH2:3]1
Reactant: COCCOCC(=O)Cl
Reactant: COCCNCc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCCOCC(=O)N(CCOC)Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.6 %

Procedure:
To a suspension of 113 (120 mg, 0.237 mmol) in THF (3 mL) was added 2-(2-methoxyethoxy)acetyl chloride (54.2 mg, 0.355 mmol) and TEA (71.9 mg, 0.711 mmol) and the reaction mixture was stirred overnight at RT. The reaction mixture was diluted with EtOAc then washed with saturated ammonium chloride solution. The organic phase was collected, dried over anhydrous Na2SO4, filtered and concentrated. The resultant solid was triturated with Et2O to give title compound 115 (113 mg, 77% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.72 (s, 1H), 8.50 (d, J=5.48, 1H), 8.05 (s, 1H, rotamer), 7.90 (m, 2H, rotamer), 7.75 (m, 1H), 7.20 (m, 3H), 7.19 (m, 1H), 6.59 (m, 2H), 4.61 (s, 1H, rotamer), 4.31 (s, 2H, rotamer), 3.61 (m, 2H), 3.49 (m, 6H), 3.23 (m, 7H), 2.55 (m, 1H), 0.64 (m, 2H), 0.43 (m, 2H). MS (m/z)=623.66 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([NH2:10])[CH:3]=1.[Cl:11][CH2:12][C:13]([CH2:15]Cl)=O.O>C(O)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]2[CH:15]=[C:13]([CH2:12][Cl:11])[N:10]=[C:4]2[CH:3]=1
Reactant: O=C(CCl)CCl
Reactant: CSc1nc(N)cc(Cl)n1
Solvent: O
Solvent: CC(=O)O
Product: CSc1nc(Cl)cc2nc(CCl)cn12
Temperature: 105 °C

Procedure:
8 g (45.5 mmol) of 6-chloro-2-(methylthio)pyrimidine-4-amine and 5.78 g (45.55 mmol) of 1,3-dichloroacetone are dissolved in 53 ml of glacial acetic acid and heated at 105° C. for 16 h. After the reaction is complete, water is added and the precipitate is filtered off with suction. The crude product is further purified by silica gel chromatography. Drying under high vacuum results in 5.53 g (49% of theory) of product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:15](C)([C:21](OCC)=O)[C:16]([O:18]CC)=[O:17])[CH:5]=[CH:6][C:7]=1[C:8](=[O:14])[C:9]1[S:13][CH:12]=[CH:11][CH:10]=1.[OH-].[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[C:8](=[O:14])[C:9]1[S:13][CH:12]=[CH:11][CH:10]=1)[CH:15]([CH3:21])[C:16]([OH:18])=[O:17]
Reactant: CCOC(=O)C(C)(C(=O)OCC)c1ccc(C(=O)c2cccs2)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Product: CC(C(=O)O)c1ccc(C(=O)c2cccs2)c(Cl)c1

Procedure:
A mixture of 29.7 parts of diethyl 2-[3-chloro-4-(2-thenoyl)phenyl]-2-methylmalonate and 200 parts of sodium hydroxide solution 5% is stirred and refluxed for 5 hours. The reaction mixture is cooled and washed twice with 80 parts of benzene. The aqueous phase is acidified with concentrated hydrochloric acid solution and the product is extracted with chloroform. The extract is dried, filtered and evaporated. The oily residue is dissolved in 160 parts of ether. This solution is stirred with activated charcoal, filtered and evaporated. The oily residue is purified by column-chromatography, using a mixture of chloroform and 5% of methanol. The pure fractions are collected and the solvent is evaporated. The oily residue which solidifies on standing, is triturated in a mixture of benzene and petroleumether, yielding 3-chloro-4-(2-thenoyl)hydratropic acid; mp. 82.5° C; also named 3-chloro-4-(2-thenoyl)-α-methyl-phenylacetic acid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:32])[NH:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[N:17]=[CH:16][CH:15]=[C:14]2[O:23][C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[C:26]([F:31])[CH:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1([O:39][C:40](=O)[NH:41][CH:42]2[CH2:44][CH2:43]2)C=CC=CC=1>CS(C)=O>[CH2:1]([O:8][C:9](=[O:32])[NH:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[N:17]=[CH:16][CH:15]=[C:14]2[O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:40]([NH:41][CH:42]2[CH2:44][CH2:43]2)=[O:39])=[C:26]([F:31])[CH:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1NC(=O)OCc1ccccc1
Reactant: O=C(NC1CC1)Oc1ccccc1
Solvent: CS(C)=O
Product: COc1cc2nccc(Oc3ccc(NC(=O)NC4CC4)c(F)c3)c2cc1NC(=O)OCc1ccccc1
Yield: 9.2 %

Procedure:
[4-(4-Amino-3-fluorophenoxy)-7-methoxyquinolin-6-yl]carbamic acid benzyl ester (100 mg) and cyclopropylcarbamic acid phenyl ester (64 mg) were heated and stirred in dimethylsulfoxide (0.7 ml) at 85° C. for 5 hours and 40 minutes, in the same manner as Example 224, to obtain the title compound (11 mg) as a solid.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]12[CH2:17][N:16]([C:18]3[CH:27]=[C:26]4[C:21]([C:22](=[O:34])[C:23]([C:31]([OH:33])=[O:32])=[CH:24][N:25]4[CH:28]4[CH2:30][CH2:29]4)=[CH:20][C:19]=3[F:35])[CH2:15][CH:14]1[CH2:13][CH2:12][O:11]2)=O)(C)(C)C.[ClH:36]>>[ClH:36].[NH2:8][CH2:9][C:10]12[CH2:17][N:16]([C:18]3[CH:27]=[C:26]4[C:21]([C:22](=[O:34])[C:23]([C:31]([OH:33])=[O:32])=[CH:24][N:25]4[CH:28]4[CH2:29][CH2:30]4)=[CH:20][C:19]=3[F:35])[CH2:15][CH:14]1[CH2:13][CH2:12][O:11]2
Reactant: CC(C)(C)OC(=O)NCC12CN(c3cc4c(cc3F)c(=O)c(C(=O)O)cn4C3CC3)CC1CCO2
Agent: Cl
Product: NCC12CN(c3cc4c(cc3F)c(=O)c(C(=O)O)cn4C3CC3)CC1CCO2

Procedure:
In an analogous manner to Example 1B, the product from step A is reacted with half-concentrated hydrochloric acid to give 7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]-oct-7-yl)-1-cyclopropyl-6-fluoro-1,4 -dihydro-4 -oxo-3-quinolinecarboxylic acid hydrochloride with a melting point of 223°-226° C. (with decomposition).
Reaction SMILES: N(C1C=C(C=CC=1C)C(O)=O)=[N+]=[N-].C(C1C=CC(OC)=C(N)C=1)(C)(C)C.[N:27]([C:30]1[CH:31]=[C:32]([CH:53]=[CH:54][C:55]=1[CH3:56])[C:33]([NH:35][C:36]1[CH:41]=[C:40]([C:42]([CH3:45])([CH3:44])[CH3:43])[CH:39]=[C:38](NS(C)(=O)=O)[C:37]=1[O:51][CH3:52])=[O:34])=[N+:28]=[N-:29]>>[N:27]([C:30]1[CH:31]=[C:32]([CH:53]=[CH:54][C:55]=1[CH3:56])[C:33]([NH:35][C:36]1[CH:41]=[C:40]([C:42]([CH3:45])([CH3:44])[CH3:43])[CH:39]=[CH:38][C:37]=1[O:51][CH3:52])=[O:34])=[N+:28]=[N-:29]
Reactant: COc1c(NC(=O)c2ccc(C)c(N=[N+]=[N-])c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Agent: COc1ccc(C(C)(C)C)cc1N
Agent: Cc1ccc(C(=O)O)cc1N=[N+]=[N-]
Product: COc1ccc(C(C)(C)C)cc1NC(=O)c1ccc(C)c(N=[N+]=[N-])c1

Procedure:
3-Azido-N-(5-tert-butyl-2-methoxy-phenyl)-4-methyl-benzamide was prepared from 3-azido-4-methyl benzoic acid (U.S. Ser. No. 04/102,492) and 5-tert-butyl-2-methoxy-phenylamine in the same manner as 3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide (Example 15).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Cl[C:9]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10]>>[N:5]1[CH:6]=[CH:7][C:2]([NH:1][C:9](=[O:10])[O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:3][CH:4]=1
Reactant: Nc1ccncc1
Reactant: O=C(Cl)Oc1ccccc1
Product: O=C(Nc1ccncc1)Oc1ccccc1
Yield: 534 %

Procedure:
The title compound was prepared by following the procedure of example 462 step 6 using 4-aminopyridine and phenyl chloroformate. Yield 6 g, 534% yield.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[B:9]([OH:11])[OH:10])=O.[C-:12]#[N:13].[Na+].Cl>O>[C:12]([CH:1]1[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[B:9]([OH:10])[O:11]1)#[N:13]
Reactant: [C-]#N
Reactant: O=Cc1ccccc1B(O)O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: N#CC1OB(O)c2ccccc21
Temperature: 5 °C

Procedure:
2-formyl phenyl boronic acid (1.0 parts, 0.007M) was added to an aqueous solution of sodium cyanide (0.35 parts) in water (20 ml) at 20° C. with stirring. After 15 mins the reactants were cooled to 5° C. and carefully neutralised to pH 5 with concentrated hydrochloric acid. The resultant white precipitate was filtered and recrystallised from water (25,ml). The product was dried over calcium chloride. Yield=0.29 parts (26% theory) mp=114°-5° C.
Reaction SMILES: [N:1]([CH:4]1[CH2:10][CH2:9][N:8]([C:11]2[N:15]([CH3:16])[N:14]=[CH:13][C:12]=2[N+:17]([O-:19])=[O:18])[CH2:7][CH2:6][CH:5]1[OH:20])=[N+:2]=[N-:3].[H-].[Na+].I[CH3:24].O>CN(C=O)C>[N:1]([CH:4]1[CH:5]([O:20][CH3:24])[CH2:6][CH2:7][N:8]([C:11]2[N:15]([CH3:16])[N:14]=[CH:13][C:12]=2[N+:17]([O-:19])=[O:18])[CH2:9][CH2:10]1)=[N+:2]=[N-:3]
Reactant: CI
Reactant: Cn1ncc([N+](=O)[O-])c1N1CCC(O)C(N=[N+]=[N-])CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC1CCN(c2c([N+](=O)[O-])cnn2C)CCC1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 79.5 %

Procedure:
To a solution of 5-azido-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-ol (420 mg, 1.49 mmol) in dry DMF (15 mL) cooled to 0° C. was added sodium hydride (60% in mineral oil, 90 mg, 2.24 mmol). After stirring for 15 min, iodomethane (0.14 mL, 2.24 mmol) was added and the reaction mixture was allowed to warm to room temperature and stirred for 1 hr. Water (20 mL) was added and the mixture was extracted with EtOAc (150 mL). The organic layer was washed with water (6×30 mL) and brine (20 mL), separated, dried over MgSO4, and concentrated under reduced pressure. Purification via silica gel column chromatography gave 4-azido-5-methoxy-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepane as a yellow oil (350 mg). A solution of this oil (350 mg, 1.19 mmol) in THF/water (15 mL/3 mL) was treated with triphenylphosphine (311 mg, 1.19 mmol) and the reaction mixture was heated at 60° C. behind a blast screen for 18 hr. Water (2 mL) was added and the mixture was extracted with EtOAc (2×50 mL) The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The resulting oil was triturated in Et2O, the resulting solid was filtered off and the filtrate concentrated under reduced pressure to give a yellow oil. To a solution of this oil (319 mg, 1.19 mmol) in dry DCM (10 mL) at 0° C. was added a solution of di-tert-butyl-dicarbonate (310 mg, 1.42 mmol) in DCM (10 mL) and DIPEA (1.0 mL, 5.93 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 72 hr. Water (20 mL) was added and the mixture extracted with DCM (100 mL). The organic layer was separated, dried over MgSO4 and concentrated under reduced pressure. Purification via silica gel column chromatography (40-50% EtOAc/isohexane) gave tert-butyl 5-methoxy-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-ylcarbamate as a yellow oil (355 mg, 64% over three steps). 1H NMR (400 MHz, CDCl3) δ 8.02 (s, 1H), 5.14 (d, J=8.9 Hz, 1H), 4.00-3.90 (m, 1H), 3.78 (s, 3H), 3.68-3.60 (m, 1H), 3.48 (t, J=12.6 Hz, 1H), 3.39 (s, 3H), 3.33-3.23 (m, 1H), 3.19-3.11 (m, 1H), 3.04-2.95 (m, 1H), 2.25-2.06 (m, 2H), 1.88-1.76 (m, 2H), 1.45 (s, 9H).
Reaction SMILES: [CH:1]([C:4]1[C:13]2[CH:12]3[CH2:14][CH2:15][CH:9]([CH2:10][CH2:11]3)[C:8]=2[C:7](=[O:16])[NH:6][N:5]=1)([CH3:3])[CH3:2].CC([O-])(C)C.[K+].C1(P(O[NH2:38])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1.CN(C=O)C.CCOC(C)=O>[NH2:38][N:6]1[N:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:13]2[CH:12]3[CH2:14][CH2:15][CH:9]([CH2:10][CH2:11]3)[C:8]=2[C:7]1=[O:16]
Reactant: NOP(=O)(c1ccccc1)c1ccccc1
Reactant: CC(C)c1n[nH]c(=O)c2c1C1CCC2CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)c1nn(N)c(=O)c2c1C1CCC2CC1
Reaction time: 4 h
Yield: 54.5 %

Procedure:
A mixture of Example 8B (31.5 mg, 0.144 mmol) and KOtBu (1 M in THF, 0.16 mL, 0.16 mmol) in THF (0.3 mL) and DMF (0.2 mL) was stirred for 30 minutes, and O-(diphenylphosphoryl)hydroxylamine (37.0 mg, 0.159 mmol) was added and stirred 4 h. The mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3 and brine, dried (Na2SO4), and filtered. The residue was chromatographed on SiO2 (2.5% MeOH/CH2Cl2) to give the title compound as a white solid (18.3 mg) which was used without further purification. LC/MS (APCI) M/Z 234.2 (M+H)+.
Reaction SMILES: COC1C=CC(C([O:22][CH2:23][C@H:24]2[O:28][C@@H:27]([N:29]3[CH:37]=[N:36][C:35]4[C:30]3=[N:31][CH:32]=[N:33][C:34]=4[NH:38][C:39](=[O:46])[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C@@H:26]([F:47])[C@@H:25]2[OH:48])(C2C=CC=CC=2)C2C=CC(OC)=CC=2)=CC=1.[Si:51](O[C@@H]1[C@@H](CO)O[C@@H](N2C3N=CN=C(NC(=O)C4C=CC=CC=4)C=3N=C2)C1)([C:54]([CH3:57])([CH3:56])[CH3:55])([CH3:53])[CH3:52]>>[Si:51]([O:48][C@@H:25]1[C@@H:24]([CH2:23][OH:22])[O:28][C@@H:27]([N:29]2[CH:37]=[N:36][C:35]3[C:30]2=[N:31][CH:32]=[N:33][C:34]=3[NH:38][C:39](=[O:46])[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C@H:26]1[F:47])([C:54]([CH3:57])([CH3:56])[CH3:55])([CH3:53])[CH3:52]
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(NC(=O)c5ccccc5)ncnc43)[C@@H](F)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1CO
Product: CC(C)(C)[Si](C)(C)O[C@H]1[C@H](F)[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1CO

Procedure:
This compound is prepared from 9-[2-deoxy-5-O-(4,4'-dimethoxytrityl)-2-fluoro-β-D-arabinofuranosyl]-N6 -benzoyladenine by the same procedure used for the preparation of 3'-O-t-butyldimethylsilyl-N6 -benzoyl-2'-deoxyadenosine.
Reaction SMILES: [NH:1]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH:27]1[C:36]2[N:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH2:30][CH2:29][CH2:28]1)[CH2:12][CH2:13][CH2:14][CH2:15][N:16]1C(=O)C2C(=CC=CC=2)C1=O.O.NN>C(O)C>[NH:1]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH:27]1[C:36]2[N:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH2:30][CH2:29][CH2:28]1)[CH2:12][CH2:13][CH2:14][CH2:15][NH2:16]
Reactant: O=C1c2ccccc2C(=O)N1CCCCN(Cc1nc2c([nH]1)CCCC2)C1CCCc2cccnc21
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCCCN(Cc1nc2c([nH]1)CCCC2)C1CCCc2cccnc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.2 %

Procedure:
To a solution of 2-{4-[(4,5,6,7-tetrahydro-1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-butyl}-isoindole-1,3-dione (0.2466 g, 0.51 mmol) in ethanol (5 mL) was added hydrazine hydrate (0.3 mL, 2.5 mmol), and stirred at room temperature for 18 hours. The reaction mixture was concentrated, and purification of the crude material by column chromatography on silica gel (20:1:1 CH2Cl2—MeOH—NH4OH) provided 0.1031 g (58%) of COMPOUND 89 as a pale yellow solid. 1H NMR (CDCl3) δ 1.32-1.43 (m, 5H), 1.60-1.68 (m, 1H), 1.72-1.81 (m, 5H), 1.96-2.02 (m, 1H), 2.08-2.17 (m, 1H), 2.45-2.60 (m, 9H), 2.69-2.71 (m, 1H), 2.76-2.86 (m, 1H), 3.70-3.84 (m, 2H), 3.95-4.01 (m, 1H), 7.05-7.10 (m, 1H), 7.36 (d, 1H, J=7.5 Hz), 8.44 (d, 1H, J=3 Hz). 13C NMR (CDCL3) δ 20.80, 22.38, 22.71, 23.07, 25.37, 28.77, 30.54, 41.23, 48.53, 49.81, 60.54, 121.36, 133.94, 136.52, 146.20, 146.32, 157.37. ES-MS m/z 354.5 (M+H). Anal. Calcd. for (C21H31N5)0.7(H2O)0.1(CH2Cl2): C, 67.65; H, 8.77; N, 18.69. Found: C, 67.46; H, 8.80; N, 18.43.
Reaction SMILES: [O:1]=[C:2]([CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].S(Cl)([Cl:18])(=O)=O>C(OCC)C>[Cl:18][CH:3]([C:2](=[O:1])[CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)CC(=O)C1CCOCC1
Reactant: O=S(=O)(Cl)Cl
Solvent: CCOCC
Product: CCOC(=O)C(Cl)C(=O)C1CCOCC1
Yield: 85.2 %

Procedure:
Using ethyl 3-oxo-3-(tetrahydro-2H-pyran-4-yl)propanoate (1.0 g, 5.0 mmol), sulfuryl chloride (810 mg, 6.0 mmol) and diethyl ether (50 mL) as starting materials and in the same manner as in Example 20-B(i), the title compound (1.0 g, 85%) was obtained as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([OH:11])[CH:3]=1.[H-].[Na+].Br[CH2:15][C:16]([O:18][CH3:19])=[O:17].CO>CN(C)C=O>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[O:11][CH2:15][C:16]([O:18][CH3:19])=[O:17])(=[O:10])[CH3:9]
Reactant: COC(=O)CBr
Reactant: CC(=O)c1ccc(Br)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)COc1cc(Br)ccc1C(C)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.1 %

Procedure:
A solution of 1-(4-bromo-2-hydroxyphenyl)ethanone (1.06 g, 5 mmol) in dry N,N-dimethylformamide (10 mL) was charged with sodium hydride (240 mg, 10 mmol) and the mixture was stirred at room temperature for 30 minutes, then methyl 2-bromoacetate (0.84 g, 5.5 mmol) was added and the mixture was stirred at room temperature for 12 hours. After completed (40 mL) of methanol was added followed by concentrating under vacuum to give methyl 2-(2-acetyl-5-bromophenoxy)acetate (1.38 g, 90%) as colorless oil. 1H NMR (300 MHz, CD3OD) δ 8.01 (s, 1H), 7.65 (d, J=8.1 Hz, 1H), 7.18 (d, J=8.1 Hz, 1H), 6.97 (s, 1H), 4.73 (s, 2H), 3.81 (s, 3H), 2.69 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:7]=1.[NH2:16][CH2:17][C:18]([CH3:21])([OH:20])[CH3:19]>N1C=CC=CC=1>[CH3:19][C:18]([OH:20])([CH3:21])[CH2:17][NH:16][C:2]1[N:3]=[N:4][C:5]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(C#Cc2ccccc2)nn1
Reactant: CC(C)(O)CN
Solvent: c1ccncc1
Product: CC(C)(O)CNc1ccc(C#Cc2ccccc2)nn1
Yield: 24 %

Procedure:
A solution of 3-chloro-6-(phenylethynyl)pyridazine (CAS 77778-15-5) (300 mg, 1.4 mmol) and 1-amino-2-methylpropan-2-ol (137 mg, 147 μl, 1.54 mmol, 1.1 equiv.) in 3 ml of pyridine was heated 20 hours at 120° C. in a sealed tube. The solvent was removed in vaccuo. The residue was taken up in ethyl acetate/methanol, adsorbed onto 4 g of silica and purified on a 20 g flash chromatography column using a heptane to ethyl acetate gradient to yield 90 mg (24% yield) of the title compound as a crystalline light yellow solid, MS: m/e=268.2 (M+H+).
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]=[C:9]1[CH2:14][CH2:13][CH:12]([NH:15]C(=O)OC(C)(C)C)[CH2:11][CH2:10]1.CN1CCOCC1.[CH2:30]([O:32][C:33]1[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][C:34]=1[CH3:43])[CH3:31]>C(Cl)Cl.CCCCCCC.C(OCC)(=O)C>[CH2:30]([O:32][C:33]1[CH:38]=[CH:37][C:36]([S:39]([NH:15][CH:12]2[CH2:11][CH2:10][C:9](=[O:8])[CH2:14][CH2:13]2)(=[O:41])=[O:40])=[CH:35][C:34]=1[CH3:43])[CH3:31]
Reactant: CCOc1ccc(S(=O)(=O)Cl)cc1C
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOc1ccc(S(=O)(=O)NC2CCC(=O)CC2)cc1C
Reaction time: 3.5 h
Yield: 24.5 %

Procedure:
Trifluoroacetic acid (13.13 ml, 170 mmol) was added via addition funnel to solution of tert-butyl 4-oxocyclohexylcarbamate (1.817 g, 8.52 mmol) in DCM (34.1 ml) at room temperature. The reaction was stirred 3.5 hours then concentrated and the residue was placed under vacuum for 30 minutes. The residue was suspended in DCM (34.1 ml) and cooled in ice/water bath. N-methylmorpholine (20.61 ml, 187 mmol) was added followed by solid 4-ethoxy-3-methylbenzenesulfonyl chloride (2.0 g, 8.52 mmol) and the ice/water bath was removed. After stirring for 70 hours, LCMS indicated some product mass. The reaction was placed in water bath and pH adjust to 3 using 3N hydrochloric acid (aq). The resulting layers were separated, and the aqueous extracted second time with dichloromethane. The combined organics were dried over sodium sulfate to yield 2.9 g of a crude oil. TLC (50% ethyl acetate in heptane): indicated a major product at Rf=0.40, with minor spots at Rf=0.58 and Rf=0.12. The crude was chromatograph on Biotage 40M by TLC generated gradient to yield 4-ethoxy-3-methyl-N-(4-oxocyclohexyl)benzenesulfonamide (650 mg, 2.087 mmol). LCMS [M+H]=312.3.
Reaction SMILES: I[CH2:2][C@H:3]([CH3:16])[CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:15].[CH2:17]([CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[CH2:18][CH2:19][CH3:20]>CC#N>[CH2:17]([CH:21]1[CH2:26][CH2:25][N:24]([CH2:2][C@H:3]([CH3:16])[CH2:4][N:5]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[O:8][CH2:7][C:6]2=[O:15])[CH2:23][CH2:22]1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCC1CCNCC1
Reactant: C[C@@H](CI)CN1C(=O)COc2ccccc21
Solvent: CC#N
Product: CCCCC1CCN(C[C@H](C)CN2C(=O)COc3ccccc32)CC1
Temperature: 60 °C
Reaction time: 72 h
Yield: 59.5 %

Procedure:
A 4 ml vial was charged with crude (R)-4-(3-iodo-2-methyl-propyl]-4H-benzo[1,4]oxazin-3-one (108LM46-43) (0.312 g) and 4-butyl-piperidine (0.210 g, 1.49 mmol) in dry MeCN (½ ml) and shaken at 60° C. for 3 days. The reaction mixture was quenched with water (1 ml), and the product extracted into EtOAc (2×1 ml). The combined organic layers were added a cation exchange column. The column was washed with MeOH (2 column volumes) then the product was eluded of the column using 8% ammonium hydroxide in MeOH (2 column volumes). The product was purified by flash CC (SiO2; MeOH/DCM 1:20) to give the title compound (108LM53-50) (0.193 g, 17%-3 steps). 1H NMR (CDCl3) δ 7.18 (d, J=7.8 Hz, 1H), 7.03-6.96 (m, 3H), 4.58 (ABq, J=14.3 Hz, J=33.9 Hz, CH2), 4.05-3.90 (m, 2H), 2.88 (bd, J=10.4 Hz, 1H), 2.71 (bd, J=10.4 Hz, 1H), 2.25-2.01 (m, 3H), 2.00-1.92 (m, 1H), 1.83-1.75 (m, 1H), 1.68-1.56 (m, 2H), 1.33-1.12 (m, 9H), 0.95-0.85 (m, 6H); 13C NMR (CDCl3) δ 164.9, 145.7, 128.9, 123.8, 122.7, 117.2, 115.8, 67.8, 64.2, 55.8, 54.4, 45.4, 36.6, 36.1, 33.0, 32.8, 29.3, 23.2, 17.1, 14.4; HPLC-MS (ammonium acetate) [M+H]+=345.3.