Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:13](=O)[C:12]2[CH:15]=[CH:16][CH:17]=[N:18][C:11]=2[C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:34]2)=CC=1.C1(C)C=CC=CC=1>[Cl-].[Na+].O>[CH2:1]([N:8]1[C:13](=[S:34])[C:12]2[CH:15]=[CH:16][CH:17]=[N:18][C:11]=2[C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=c1c2cccnc2c(-c2ccccn2)nn1Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: S=c1c2cccnc2c(-c2ccccn2)nn1Cc1ccccc1
Reaction time: 2 h

Procedure:
A mixture of 6-benzyl-8-(pyridin-2-yl)pyrido[2,3-d]pyridazin-5(6H)-one RL-10 (45 mg, 0.143 mmol), 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide (57 mg, 0.143 mmol), and 4 mL of toluene were heated to 115° C. for 2 h. Another 35 mg aliquot of 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide was added and the heating was continued for 2 h. Still another 35 mg aliquot of 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide was added and heating continued for an additional 2 h. After cooling, the reaction mixture was poured into 15 mL of saturated brine and then extracted with 4×20 mL of ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and dried overnight at 60° C. under vacuum to give 6-benzyl-8-(pyridine-2-yl)pyrido[2,3-d]pyridazine-5(6H)-thione RL-11 (31 mg, 0.94 mmol). 1H NMR (400 MHz, Chloroform-d) δ 9.25 (dd, J=8.4, 1.7 Hz, 1H), 9.19-9.12 (m, 1H), 9.03 (s, 1H), 8.13 (bd, J=57.3 Hz, 1H), 7.72 (dd, J=8.4, 4.4 Hz, 1H), 7.64-7.52 (m, 3H), 7.40-7.25 (m, 4H), 6.17 (s, 2H). LCMS: (M+H)+, 331.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:17][C:18]([CH3:25])([C:20]1[O:21][CH:22]=[CH:23][N:24]=1)[NH2:19]>>[CH3:17][C:18]([NH:19][C:14]([C:12]1[CH:11]=[CH:10][CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:13]=1)=[O:16])([C:20]1[O:21][CH:22]=[CH:23][N:24]=1)[CH3:25]
Reactant: O=C(O)c1cccc(-c2cccc(Cl)c2)n1
Reactant: CC(C)(N)c1ncco1
Product: CC(C)(NC(=O)c1cccc(-c2cccc(Cl)c2)n1)c1ncco1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chlorophenyl)-2-pyridinecarboxylic acid (CAN 863704-38-5) and α,α-dimethyl-2-oxazolemethanamine (CAN 1211519-76-4) as starting materials, MS (LC/MS): 341.9 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]([O:23][C:24](=[O:26])[NH2:25])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>O1CCCC1.O>[CH2:33]([O:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]([O:23][C:24](=[O:26])[NH2:25])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: BrCc1ccccc1
Reactant: NC(=O)OC(CCN1CCN(c2ccc(O)cc2)CC1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)OC(CCN1CCN(c2ccc(OCc3ccccc3)cc2)CC1)c1ccccc1
Temperature: 70 °C
Reaction time: 10 h

Procedure:
The compound ‘carbamic acid 3-[4-(4-hydroxy-phenyl)-piperazin-1-yl]-1-phenyl-propyl ester (2 mmol) prepared in Example 84 was dissolved in tetrahydrofuran (25 mL), and potassium carbonate (K2CO3, 2.4 mmol) and benzylbromide (2.4 mmol) were added thereto, and the resulting mixture was stirred at 70° C. for 10 hours. The reaction mixture was diluted with water, and extracted several times with ethyl acetate to obtain an organic phase. The prepared organic phase was dried over magnesium sulfate, and concentrated under a reduced pressure. The resulting pellet was purified with column chromatography (hexane:ethyl acetate=1:1) to obtain a title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([C:14]1[CH:15]=[CH:16][C:17]2[O:21][C:20]([C:22]([OH:24])=O)=[CH:19][C:18]=2[CH:25]=1)=[NH:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C@H:34]([NH:40][S:41]([C:44]([F:47])([F:46])[F:45])(=[O:43])=[O:42])[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:29][CH:28]=1>>[CH2:1]([O:8][C:9]([NH:11][C:12]([C:14]1[CH:15]=[CH:16][C:17]2[O:21][C:20]([C:22]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([CH2:33][C@H:34]([NH:40][S:41]([C:44]([F:47])([F:45])[F:46])(=[O:43])=[O:42])[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:29][CH:28]=3)=[O:24])=[CH:19][C:18]=2[CH:25]=1)=[NH:13])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(N)cc1)NS(=O)(=O)C(F)(F)F
Reactant: N=C(NC(=O)OCc1ccccc1)c1ccc2oc(C(=O)O)cc2c1
Product: CCOC(=O)[C@H](Cc1ccc(NC(=O)c2cc3cc(C(=N)NC(=O)OCc4ccccc4)ccc3o2)cc1)NS(=O)(=O)C(F)(F)F
Yield: 65.9 %

Procedure:
In the same manner as in Example 15 (3), 5-(benzyloxycarbonylamidino)-2-benzofurancarboxylic acid (1.02 g, 3.01 mmol) and ethyl (S)-3-(4-aminophenyl)-2-(trifluoromethylsulfonylamino)propionate (1.03 g, 3.03 mmol) were condensed. The reaction mixture was purified by silica gel column chromatography (n-hexane/ethyl acetate=1/1-1/2) to give 1.31 g of ethyl (S)-3-[4-[(5-(benzyloxycarbonylamidino)-2-benzofuranyl]carbonylamino)phenyl]-2-(trifluoromethylsulfonylamino)propionate as a colorless solid (65%). Ethanol (200 ml), 10% palladium-carbon (450 mg) and 1N hydrochloric acid (2 ml) were added to this solid (1.30 g, 1.97 mmol) and the mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. The reaction mixture was filtrated and low boiling matters were distilled away from the filtrate under reduced pressure to quantitatively give 1.11 g of hydrochloride of compound (54) as a colorless solid.
Reaction SMILES: [CH:1]1([C@@H:7]([C:11]2[C:12]([NH2:28])=[N:13][C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:16][CH:15]=3)[CH2:8][CH:9]=[CH2:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.B1C2CCCC1CCC2.[OH-:38].[Na+].OO>O1CCCC1.O>[NH2:28][C:12]1[C:11]([C@H:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:8][CH2:9][CH2:10][OH:38])=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:18]=2)[N:13]=1
Reactant: [OH-]
Reactant: C=CC[C@H](c1cc2cc(Oc3ccccc3)ccc2nc1N)C1CCCCC1
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Nc1nc2ccc(Oc3ccccc3)cc2cc1[C@@H](CCCO)C1CCCCC1
Reaction time: 8 h

Procedure:
To a solution of 3-((S)-1-cyclohexyl-but-3-enyl)-6-phenoxy-quinolin-2-ylamine (0.82 g, 2.2 mmol) in tetrahydrofuran (5.5 mL) at −20° C. was added 9-BBN (0.5 M in THF, 17.6 mL, 8.8 mol) dropwise over 20 min. The reaction mixture was stirred overnight while it reached room temperature. To the reaction mixture at 0° C. was then added aqueous 1N NaOH solution (8.2 mL) and aqueous 30% H2O2 solution (8.2 mL) and stirring was continued for 2.0 h. Water (15.0 mL) was added to the reaction mixture which was then extracted with EtOAc. The separated organic layer was dried (MgSO4) and concentrated in vacuo to yield crude material. The crude material was purified by silica gel column chromatography using 10% MeOH in CHCl3 to yield 4-(2-amino-6-phenoxy-quinoline-3-yl)-4-(S)-cyclohexyl-butan-1-ol.
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Br:8][C:9]1[C:10]([NH2:29])=[N:11][CH:12]=[C:13]([C@@H:15]2[CH2:20][CH2:19][CH2:18][C@H:17]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH2:16]2)[N:14]=1.CCOC(C)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:8][C:9]1[C:10]([NH:29][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[N:11][CH:12]=[C:13]([CH:15]2[CH2:20][CH2:19][CH2:18][CH:17]([O:21][Si:22]([C:25]([CH3:27])([CH3:26])[CH3:28])([CH3:23])[CH3:24])[CH2:16]2)[N:14]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CCC[C@@H](c2cnc(N)c(Br)n2)C1
Reactant: CC(C)(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1ncc(C2CCCC(O[Si](C)(C)C(C)(C)C)C2)nc1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.3 %

Procedure:
Pivaloyl chloride (71.5 μL, 0.569 mmol) was added dropwise to a stirred, cooled (0° C.) mixture of (+/−)-3-bromo-5-((1R,3S)-3-((tert-butyldimethylsilyl)oxy)cyclohexyl)pyrazin-2-amine (110 mg, 0.285 mmol) and TEA (159 μL, 1.139 mmol) in CH2Cl2 (949 μL). The red mixture was stirred at 0° C. for 1 h, then at room temperature for 2 h. EtOAc and Sat NaHCO3 was added and stirred well. Organic layer was separated and the aqueous layer was extracted well with EtOAc. Combined EtOAc layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel eluting with EtOAc/heptane to give (+/−)-N-(3-bromo-5-(3-((tert-butyldimethylsilyl)oxy)cyclohexyl)pyrazin-2-yl)pivalamide 97 mg in 72.4% yield. LCMS (m/z): 472.3 (MH+), 1.19 min.
Reaction SMILES: [CH2:1](Cl)[CH:2]=[CH2:3].[CH3:5][C:6]1[CH2:11][CH2:10][CH:9]([CH:12]=[O:13])[CH2:8][CH:7]=1.[Mg].O1CCCC1>C1(C)C=CC=CC=1>[CH2:3]([CH:12]([CH:9]1[CH2:10][CH2:11][C:6]([CH3:5])=[CH:7][CH2:8]1)[OH:13])[CH:2]=[CH2:1]
Reactant: C=CCCl
Reactant: CC1=CCC(C=O)CC1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C=CCC(O)C1CC=C(C)CC1
Temperature: 71 °C
Yield: 65.2 %

Procedure:
A solution of 251 grams (3.3 moles) of allyl chloride and 372 grams (3 moles) of 4-methyl-3-cyclohexenecarboxaldehyde is added dropwise to a stirred slurry of 77 grams of magnesium (3.2 moles) and 1500 ml of tetrahydrofuran at reflux under nitrogen over a three-hour period. The reaction mixture is heated at reflux (71° C.) for 30 minutes after the feed is complete, whereupon 500 ml of toluene is added. A distillation head is attached to the reaction flask and the tetrahydrofuran is distilled off at atmospheric pressure to a pot temperature of 100° C. The remaining organic solution is cooled to 0° C., whereupon 1000 ml of 18% hydrochloric acid solution is slowly added with external cooling. Two clear layers is formed. The aqueous layer is discarded and the organic layer is quickly distilled. The distillate is fractionally redistilled through a 1.5"×12" Goodloe packed column to afford 325 grams of alpha-allyl-4-methyl-3-cyclohexene methanol (b.p. 92° C., 3.0 mm Hg pressure).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][C:26]([NH:29][CH2:30][C:31]4[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=4)=[CH:25][N:24]=3)=[CH:18][CH:17]=2)=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[C:43]([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[CH:17]=[CH:18][C:19]([O:22][C:23]3[CH:28]=[CH:27][C:26]([N:29]([CH3:43])[CH2:30][C:31]4[CH:32]=[CH:33][C:34]([C:37]([F:39])([F:40])[F:38])=[CH:35][CH:36]=4)=[CH:25][N:24]=3)=[CH:20][CH:21]=2)=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Oc2ccc(NCc3ccc(C(F)(F)F)cc3)cn2)cc1)N1CCN(Cc2ccccc2)CC1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN(Cc1ccc(C(F)(F)F)cc1)c1ccc(Oc2ccc(C(=O)N3CCN(Cc4ccccc4)CC3)cc2)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (4-benzylpiperazin-1-yl){4-[5-(4-trifluoromethylbenzylamino)pyridin-2-yloxy]phenyl}methanone (5.40 g, 9.88 mmol) in methanol (150 mL) were added 37% aqueous formaldehyde (2.8 mL), sodium cyanoborohydride (1.86 g, 29.6 mmol) and acetic acid (1.7 mL) under ice cooling, and the resulting solution was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure. Water was added to the residue, and this solution was neutralized with a saturated sodium bicarbonate solution, and extracted with chloroform. The organic layer was washed with water, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (chloroform:methanol=60:1). To the resulting product was then added a solution of 4 M hydrogen chloride in ethyl acetate until the resulting solution had a pH of 1. The precipitates were collected by filtration and recrystallized from ethanol (80 mL), to thereby yield 2.5 g of the title compound.
Reaction SMILES: [C:1]([O:9][C@H:10]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C@@H:12]([CH2:13][CH2:14][C:15]3[C:16]4[C@:28]([CH3:36])([CH2:29][CH2:30][C:31]=32)[C@@H:19]([C@H:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:18][C:17]=4[O:37][Si](C)(C)C)[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45].[F-].C([N+](C)(C)C)C1C=CC=CC=1>C1COCC1.CCCCCC>[C:1]([O:9][C@H:10]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C@@H:12]([CH2:13][CH2:14][C:15]3[C@@:16]4([CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])[C@:28]([CH3:36])([CH2:29][CH2:30][C:31]=32)[C@@H:19]([C@H:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:18][C:17]4=[O:37])[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC(O[Si](C)(C)C)=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](OC(=O)c2ccccc2)C[C@@H]1CC3
Reactant: CCOC(=O)CI
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [F-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C[C@@]12C(=O)C[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CCC1=C2CC[C@H]2C[C@@H](OC(=O)c3ccccc3)CC[C@]12C
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 31.6 %

Procedure:
3β-benzoyloxy-15-trimethylsiloxy-5α-cholest-8,14-diene (1.93 g, 3.35 mmole) in THF (10 mL) and ethyl iodoacetate (0.79 mL, 6.7 mmole) was added at -10° C. to a mixture of benzyl trimethylammonium fluoride (850 mg, 5 mmole) in THF (15 mL). The mixture was stirred at -10° C. for 15 minutes and at ambient temperature for 30 minutes, diluted with hexane, filtered and the filtrate was concentrated. Using the workup described in Example 1(ii), 625 mg of 3β-benzoyloxy-14α-carbethoxymethyl-5α-cholest-8-en-15-one was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH2:11][C:12]2[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14]([F:20])[C:13]=2[F:21])=[CH:4][C:3]=1[N:22]1[C:30](=[O:31])[NH:29][C:28]2[C:23]1=[N:24][C:25]([CH2:34]Cl)=[N:26][C:27]=2[O:32][CH3:33].[N-:36]=[N+:37]=[N-:38].[Na+].Cl>CN(C)C=O>[N:36]([CH2:34][C:25]1[N:24]=[C:23]2[C:28]([NH:29][C:30](=[O:31])[N:22]2[C:3]2[CH:4]=[C:5]([O:10][CH2:11][C:12]3[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14]([F:20])[C:13]=3[F:21])[C:6]([O:8][CH3:9])=[CH:7][C:2]=2[Cl:1])=[C:27]([O:32][CH3:33])[N:26]=1)=[N+:37]=[N-:38]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1cc(Cl)c(-n2c(=O)[nH]c3c(OC)nc(CCl)nc32)cc1OCc1c(OC)ccc(F)c1F
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(Cl)c(-n2c(=O)[nH]c3c(OC)nc(CN=[N+]=[N-])nc32)cc1OCc1c(OC)ccc(F)c1F
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 73.1 %

Procedure:
A mixture of 9-[2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-2-chloromethyl-6-methoxy-7,9-dihydro-8H-purin-8-one (0.1 g) and sodium azide (15 mg) in N,N-dimethylformamide (2 mL) was stirred at 100° C. for 1.5 hours. The reaction mixture was cooled to room temperature, and poured into 0.5 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1−1/4). The obtained product was suspended in a mixed solvent (n-hexane/ethyl acetate=1/1), and collected by filtration. The collected material was dried under reduced pressure to give 2-azidomethyl-9-[2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-6-methoxy-7,9-dihydro-8H-purin-8-one (74 mg). To this material were added tetrahydrofuran (5 mL), ethanol (1 mL) and 10% platinum-carbon powder (20 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere overnight. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/methanol=9/1−methanol) to give 2-aminomethyl-9-[2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-6-methoxy-7,9-dihydro-8H-purin-8-one (44 mg). To this material were added tetrahydrofuran (3 mL), triethylamine (0.1 mL) and di(tert-butyl)dicarbonate (28 mg), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into a saturated aqueous ammonium chloride solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1−1/4) to give the title compound (36 mg).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].[C:8]1([C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([OH:17])[CH2:15]Cl)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>CN(C)C=O>[C:18]1([C:14]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)([OH:17])[CH2:15][N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: OC(CCl)(c1ccccc1)c1ccccc1
Reactant: c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: OC(Cn1cncn1)(c1ccccc1)c1ccccc1

Procedure:
1,2,4-Triazole (0.03 mol, 2.07 g) was added portionwise to a suspension of sodium hydride (0.03 mol, 0.72 g) in DMF (30 ml) and the solution stirred until effervescence ceased. 1,1-Diphenyl-2-chloro-ethan-1-ol (0.015 mol, 2.94 g) in dimethylformamide (DMF; 10 ml) was added dropwise and the solution warmed at 100° for six hours. The reaction mixture was poured into water and a white solid crystallised out. This was filtered off, washed with water, dried, and recrystallised from ethanol to give the title compound as a white crystalline solid, m.p. 128°-129°.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[CH:14][C:13]=3[OH:23])[CH:11]=2)=[O:6])[CH2:3][CH2:2]1.Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][F:30].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[CH:14][C:13]=3[O:23][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][F:30])[CH:11]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: CCNC(=O)c1ccc(-n2cc(C(=O)NC3CC3)nn2)c(O)c1
Reactant: FCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCNC(=O)c1ccc(-n2cc(C(=O)NC3CC3)nn2)c(OCCCCCF)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 58.6 %

Procedure:
To a solution of N-cyclopropyl-1-{4-[(ethylamino)carbonyl]-2-hydroxyphenyl}-1H-1,2,3-triazole-4-carboxamide (0.16 g) obtained in Example 139 in DMF (5 ml) were added 1-bromo-5-fluoropentane (0.11 g) and potassium carbonate (0.07 g), and the mixture was stirred at 50° C. overnight. The reaction mixture was allowed to cool to room temperature, and water was added to the reaction mixture. The deposited precipitate was collected by filtration, washed with water, and recrystallized from ethanol-water to give the title compound as a pale-brown powder (0.12 g, 60%).
Reaction SMILES: [CH3:1][C:2]1(O)[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][CH2:3]1.CCN(S(F)(F)[F:33])CC>ClCCl>[F:33][C:2]1([CH3:1])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][CH2:3]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(C)(O)CC3)c(F)c2)C(=O)O1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(C)(F)CC3)c(F)c2)C(=O)O1
Yield: 66 %

Procedure:
The title compound was prepared by stirring (S)—N-{3-[4-(4-methyl-4-hydroxy piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (1.36 mmol) with DAST (1.64 mmol) in dichloromethane (10 ml) at a temperature 0° C. for half hour and by purifying the compound by silica gel column chromatography in 66% yield.
Reaction SMILES: Cl.Cl.[OH:3][CH2:4][CH2:5][NH:6][C:7](=[O:21])[C:8]1[C:13]([O:14][CH2:15][C@H:16]2[CH2:20][CH2:19][CH2:18][NH:17]2)=[CH:12][CH:11]=[CH:10][N:9]=1.[F:22][C:23]([F:34])([F:33])[C@H:24]1[CH2:29][CH2:28][C@H:27]([C:30](O)=[O:31])[CH2:26][CH2:25]1.COC1C=C(OC[C@H]2CCCN2C([C@H]2CC[C@H](C(F)(F)F)CC2)=O)C(C(O)=O)=NC=1>>[OH:3][CH2:4][CH2:5][NH:6][C:7](=[O:21])[C:8]1[C:13]([O:14][CH2:15][C@H:16]2[CH2:20][CH2:19][CH2:18][N:17]2[C:30]([C@H:27]2[CH2:26][CH2:25][C@H:24]([C:23]([F:22])([F:33])[F:34])[CH2:29][CH2:28]2)=[O:31])=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: O=C(NCCO)c1ncccc1OC[C@H]1CCCN1
Reactant: O=C(O)[C@H]1CC[C@H](C(F)(F)F)CC1
Agent: COc1cnc(C(=O)O)c(OC[C@H]2CCCN2C(=O)[C@H]2CC[C@H](C(F)(F)F)CC2)c1
Agent: Cl
Product: O=C(NCCO)c1ncccc1OC[C@H]1CCCN1C(=O)[C@H]1CC[C@H](C(F)(F)F)CC1

Procedure:
The title compound was prepared according to the procedure described in Step 5 of EXAMPLE 31 using (R)—N-(2-hydroxyethyl)-3-(pyrrolidin-2-ylmethoxy)picolinamide dihydrochloride (EXAMPLE 33 Step 4) and trans-4-(trifluoromethyl)cyclohexanecarboxylic acid instead of ammonium chloride and 5-methoxy-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)m ethoxy)picolinic acid.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH:10]([CH3:14])[C:11]([OH:13])=O)=[O:8])=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[C:23]([N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:24])[NH2:19].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[Cl:15][C:16]1[CH:17]=[C:18]([NH:19][C:11]([CH:10]([NH:9][C:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:8])[CH3:14])=[O:13])[CH:20]=[CH:21][C:22]=1[C:23]([N:25]1[CH2:26][CH2:27][CH2:28][CH2:29]1)=[O:24]
Reactant: Nc1ccc(C(=O)N2CCCC2)c(Cl)c1
Reactant: CC(NC(=O)c1ccc(Cl)s1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(NC(=O)c1ccc(Cl)s1)C(=O)Nc1ccc(C(=O)N2CCCC2)c(Cl)c1

Procedure:
Prepared analogously to Example 1a from 2-[(5-chloro-thiophene-2-carbonyl)-amino]-propionic acid and 3-chloro-4-(pyrrolidin-1-yl-carbonyl)-aniline with TBTU and NMM in DMF.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]2[N:15]=[CH:14][N:13]=[C:12]3[C:8]=2[N:9]=[CH:10][N:11]3[C@@H:16]2[O:20][C@H:19]([CH2:21][NH:22][C:23]([NH:25][CH3:26])=[O:24])[C@@H:18]([OH:27])[C@H:17]2[OH:28])[CH2:2]1.[CH2:29](N=C=O)[CH2:30]C.CN=C=O>>[O:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]2[N:15]=[CH:14][N:13]=[C:12]3[C:8]=2[N:9]=[CH:10][N:11]3[C@@H:16]2[O:20][C@H:19]([CH2:21][NH:22][C:23]([NH:25][CH2:26][CH2:29][CH3:30])=[O:24])[C@@H:18]([OH:27])[C@H:17]2[OH:28])[CH2:2]1
Reactant: CCCN=C=O
Reactant: CNC(=O)NC[C@H]1O[C@@H](n2cnc3c(N[C@@H]4CCOC4)ncnc32)[C@H](O)[C@@H]1O
Agent: CN=C=O
Product: CCCNC(=O)NC[C@H]1O[C@@H](n2cnc3c(N[C@@H]4CCOC4)ncnc32)[C@H](O)[C@@H]1O

Procedure:
Compound 93 was prepared in the manner of compound 24 substituting propyl isocyanate for methyl isocyanate and refluxing for 16 h [MS 422.3 (M+1)].
Reaction SMILES: [CH2:1]([C:3]1[CH:7]=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[O:5][N:4]=1)[CH3:2].ClCl.[Cl:14]C(Cl)(Cl)Cl.O>C(O)(=O)C>[CH2:1]([C:3]1[C:7]([Cl:14])=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[O:5][N:4]=1)[CH3:2]
Reactant: CCc1cc(NC(C)=O)on1
Reactant: ClC(Cl)(Cl)Cl
Agent: ClCl
Solvent: CC(=O)O
Solvent: O
Product: CCc1noc(NC(C)=O)c1Cl
Temperature: 25 °C
Yield: 203.3 %

Procedure:
3-Ethyl-5-acetylaminoisoxazole (1) (1.98 g) was dissolved in acetic acid (15 ml), chlorine-tetrachloromethane (18 ml, containing 1.09 g of chlorine) was added thereto under stirring at room temperature and after addition of water the mixture was extracted with chloroform after 5 minutes. The extract was washed with water, dried over sodium sulfate and evaporated. The resulting crystalline residue was recrystallized from ether/hexane to give 3-ethyl-4-chloro-5-acetylaminoisoxazole (2) (1.86 g), mp. 113°-114° C.