Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([O:5][C:6]1[CH:16]=[CH:15][C:9]([O:10][CH:11]([CH3:14])[CH2:12][NH2:13])=[CH:8][CH:7]=1)[CH2:3][CH3:4].Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19].[OH-].[Na+].O>CCOCC>[CH3:1][CH:2]([O:5][C:6]1[CH:16]=[CH:15][C:9]([O:10][CH:11]([CH3:14])[CH2:12][NH:13][C:18](=[O:19])[O:20][CH2:21][CH3:22])=[CH:8][CH:7]=1)[CH2:3][CH3:4]
Reactant: CCC(C)Oc1ccc(OC(C)CN)cc1
Reactant: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)NCC(C)Oc1ccc(OC(C)CC)cc1
Reaction time: 0.25 h

Procedure:
To a solution of 2-[4-(1-methylpropoxy)phenoxy]propylamine (1.13 g, 5.10 mmol) in 25 ml of ether, at 0° and under N2, is added ethyl chloroformate (1.16 g, 10.60 mmol) by syringe, followed by addition of 10% aqueous sodium hydroxide (3.4 ml). After 15 min., the reaction is worked up by addition of water and extraction with ether. The combined organic phases are washed with 1N sulfuric acid, with water and with brine, dried and filtered, the filtrate is concentrated in vacuo and the product is purified by prep. TLC to give ethyl N-{2-[4-(1-methylpropoxy)phenoxy]propyl}carbamate.
Reaction SMILES: Br[CH2:2][C:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2.[CH3:13][C:14]1([CH3:26])[C:18]([CH3:20])([CH3:19])[O:17][B:16]([C:21]2[CH:22]=[N:23][NH:24][CH:25]=2)[O:15]1.[H-].[Na+]>CN(C)C=O>[CH3:13][C:14]1([CH3:26])[C:18]([CH3:19])([CH3:20])[O:17][B:16]([C:21]2[CH:25]=[N:24][N:23]([CH2:2][C:3]34[CH2:12][CH:7]5[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]5)[CH2:4]3)[CH2:10]4)[CH:22]=2)[O:15]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: BrCC12CC3CC(CC(C3)C1)C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)OB(c2cnn(CC34CC5CC(CC(C5)C3)C4)c2)OC1(C)C
Temperature: 0 °C

Procedure:
A mixture of 1-(bromomethyl)adamantane (0.458 g) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.377 g) in N,N-dimethylformamide (5 mL) was cooled to 0° C. To this solution was added 60% sodium hydride (0.096 g). The solution was heated at 70° C. overnight. The reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted with additional ethyl acetate twice. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 25% ethyl acetate in hexanes to provide the title compound.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.[C:11]1(=O)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C(O)(=O)C.CCOC(C)=O>CCO>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][N:10]=[C:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:5][CH:4]=1
Reactant: O=C1CCCCC1
Reactant: NNc1ccc(Br)cc1
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Brc1ccc(NN=C2CCCCC2)cc1
Temperature: 105 °C
Yield: 91.4 %

Procedure:
A 250-mL round-bottomed flask was charged with 1-(4-bromophenyl)hydrazine hydrochloride (10 g, 45.05 mmol, 1.00 equiv) in EtOH (120 mL). To this was added cyclohexanone (8.8 g, 89.80 mmol, 2.00 equiv) and acetic acid (2.7 g, 45.00 mmol, 1.00 equiv). The resulting mixture was heated to 105° C. in an oil bath for about 1 hour. The reaction progress was monitored by TLC (EtOAc:PE=1:1). Upon completion, the reaction mixture was cooled down to room temperature and filtered off to obtain 1-(4-bromophenyl)-2-cyclohexylidenehydrazine as a yellow solid (11 g, 92%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]3[CH2:15][CH2:14][N:13]([C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]3)=[N:7][C:6]=2[CH:22]=1.[CH3:23][NH:24][C:25](=[O:42])[C:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][C:27]=1[CH3:41]>>[CH3:41][C:27]1[CH:28]=[C:29]([C:2]2[CH:3]=[CH:4][C:5]3[O:9][C:8]([CH:10]4[CH2:15][CH2:14][N:13]([C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]4)=[N:7][C:6]=3[CH:22]=2)[CH:30]=[CH:31][C:26]=1[C:25](=[O:42])[NH:24][CH3:23]
Reactant: CC(C)OC(=O)N1CCC(c2nc3cc(Br)ccc3o2)CC1
Reactant: CNC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1C
Product: CNC(=O)c1ccc(-c2ccc3oc(C4CCN(C(=O)OC(C)C)CC4)nc3c2)cc1C
Yield: 10.1 %

Procedure:
Following the General Procedure-3, the titled compound (30 mg) was prepared from Intermediate 13 (250 mg, 0.68 mmol) and N,2-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (187 mg, 0.68 mmol) as an off-white solid. M.P.: 151-154° C. MS (m/z): 436.5 [M+H]+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1/[CH:10]=[CH:11]/[S:12]([NH2:15])(=[O:14])=[O:13].[Br:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[C:19]([Cl:26])[CH:18]=1.O>O1CCOCC1>[Br:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH:15][S:12](/[CH:11]=[CH:10]/[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[Cl:3])(=[O:13])=[O:14])=[O:22])=[C:19]([Cl:26])[CH:18]=1
Reactant: NS(=O)(=O)/C=C/c1ccccc1Cl
Reactant: O=C(Cl)c1ccc(Br)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(NS(=O)(=O)/C=C/c1ccccc1Cl)c1ccc(Br)cc1Cl
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% dispersion in mineral oil) (36 mg, 0.9 mmol) was added to a solution of (E)-2-(2-chloro-phenyl)-ethenesulfonic acid amide (65 mg, 0.3 mmol) in 1,4-dioxane (1.5 mL) and the reaction mixture was shaken for 30 minutes. Crude 4-bromo-2-chloro-benzoyl chloride (114 mg, 0.45 mmol) in dioxane (0.5 mL) was added and the reaction mixture was shaken at room temperature for 18 hours. Water (0.1 mL) was added to the reaction mixture and the whole was concentrated in vacuo. The resultant residue was purified by preparative HPLC under neutral conditions to give (E)-2-(2-chloro-phenyl)-ethenesulfonic acid 4-bromo-2-chloro-benzoylamide; sodium salt (38 mg, 29% yield).
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[C:8]1(CCO)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(Cl)Cl.O=[V].Cl.Cl.Cl>[CH3:6][C:5]([O:4][CH2:1][CH2:2][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7]
Reactant: OCCc1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: O=[V]
Agent: Cl
Solvent: ClCCl
Product: CC(=O)OCCc1ccccc1
Reaction time: 0.17 h
Yield: 93.9 %

Procedure:
In a dry 50-mL, two-necked, round-bottomed flask, vanadyl chloride (1.9 mg, 0.01 mmol) in 3 mL of anhydrous CH2Cl2 was placed. To the above solution, acetic anhydride (153.1 mg, 141.5 μL, 1.5 mmol) was slowly added at ambient temperature. After about 10 min, a solution of 2-phenylethanol (122 mg, 119.3 μL, 1.0 mmol) in CH2Cl2 (2 mL) was slowly added to the above brownish solution, and the reaction mixture was stirred for 7.5 hours. After completion of the reaction as monitored by TLC, the reaction mixture was quenched with cold, saturated aqueous NaHCO3 solution (5 mL). The resulting separated organic layer was washed with brine, dried (MgSO4), filtered, and evaporated. The crude product was purified by column chromatography on silica gel to yield 154.2 mg of 2-phenethyl acetate (94%) as colorless oil. The substrate, reaction time, and yield of this test are summarized in Entry 2 of the following Table 1.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15](C3C=CC(B4OC(C)(C)C(C)(C)O4)=C(C)C=3)=[O:16])[CH2:6][C:5]=12.FC(F)(F)S(O[C:39]1[CH:44]([CH3:45])[CH2:43][CH2:42][CH2:41][CH:40]=1)(=O)=O>>[CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:42]3[CH:41]=[CH:40][C:39]([C:8]4[CH:9]([CH3:10])[CH2:11][CH2:12][CH2:13][CH:14]=4)=[C:44]([CH3:45])[CH:43]=3)=[O:16])[CH2:6][C:5]=12
Reactant: Cc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: CC1CCCC=C1OS(=O)(=O)C(F)(F)F
Product: Cc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1C1=CCCCC1C
Yield: 176.5 %

Procedure:
(10,11-Dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanone of Example 2, Step B (0.428 g, 1.00 mmol) and 6-methyl-cyclohex-1-en-1-yl trifluoromethanesulfonate (0.269 g, 1.10 mmol) were reacted in the manner of Example 2, Step C. Purification by flash column chromatography on silica gel, eluting with 20% ethyl acetate in hexane, followed by recrystallization from petroleum ether afforded the title compound (0.350 g) as white crystals, m.p. 132–133° C.
Reaction SMILES: [C:1](=[O:19])([O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH:7]=1)[O:2][CH2:3][CH3:4].[H-].[Na+].Cl.Cl[CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>CN(C=O)C.C(Cl)Cl>[C:1](=[O:19])([O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([N:14]([CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[S:15]([CH3:18])(=[O:16])=[O:17])[CH:7]=1)[O:2][CH2:3][CH3:4]
Reactant: ClCCN1CCOCC1
Reactant: CCOC(=O)Oc1ccc(OC)c(NS(C)(=O)=O)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)Oc1ccc(OC)c(N(CCN2CCOCC2)S(C)(=O)=O)c1
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 21.1 %

Procedure:
A solution of ethyl 4-methoxy-3-(methylsulfonamido)phenyl carbonate (0.850 g, 2.94 mmol) in dry DMF (15 ml) was cooled to 0° C. under nitrogen atmosphere, and sodium hydride (60% w/w, 0.300 g, 7.50 mmol) was added portion-wise. After 10 minutes, the cold bath was removed, 4-(2-chloroethyl)morpholine hydrochloride (0.680 mg, 3.65 mmol) was added, and the mixture was heated to 90° C. for 2 hours. After cooling to RT, the reaction mixture was diluted with DCM and washed with water. The organic layer was washed with brine and dried over Na2SO4; the solvent was evaporated and the crude was purified by flash chromatography on silica gel column (DCM:MeOH=10:0.1) affording ethyl 4-methoxy-3-(N-(2-morpholinoethyl)methylsulfonamido)-phenyl carbonate (0.250 g, 0.621 mmol, 21.14% yield, UPLC-MS purity: 97%, MS/ESI+ 403.1 [MH]+).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][C@H:13]([NH:27][C:28]([C@H:30]1[CH2:32][C@@H:31]1[C:33]1[S:34][CH:35]=[CH:36][CH:37]=1)=[O:29])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C@@H:22]([CH3:25])[CH2:23][CH3:24])=[CH:16][C:15]=1[CH3:26].NN>CCO>[NH2:3][CH2:12][C@H:13]([NH:27][C:28]([C@H:30]1[CH2:32][C@@H:31]1[C:33]1[S:34][CH:35]=[CH:36][CH:37]=1)=[O:29])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C@@H:22]([CH3:25])[CH2:23][CH3:24])=[CH:16][C:15]=1[CH3:26]
Reactant: CC[C@H](C)COc1ccc([C@H](CN2C(=O)c3ccccc3C2=O)NC(=O)[C@H]2C[C@@H]2c2cccs2)c(C)c1
Agent: NN
Solvent: CCO
Product: CC[C@H](C)COc1ccc([C@H](CN)NC(=O)[C@H]2C[C@@H]2c2cccs2)c(C)c1
Temperature: 55 °C
Yield: 50.7 %

Procedure:
To a solution of (1S,2S)-2-Thiophen-2-yl-cyclopropanecarboxylic acid {(R)-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-1-[2-methyl-4-((S)-2-methyl-butoxy)-phenyl]-ethyl}-amide (50 mg, 0.097 mmol) dissolved in 5 mL EtOH was added anhydrous hydrazine (31 mg, 0.97 mmol), and heated to 55° C. for 1 hr with stirring. The reaction mixture was concentrated on the rotavap, and the residue redissolved in EtOAc, and washed with aq. NaHCO3, brine and dried over MgSO4. It was concentrated and purified on the neutral PREP HPLC to obtain 19 mg (51%) of the product. 1H NMR (400 MHz, MeOD) δ ppm 8.73-8.68 (d, J=5.2 Hz, 1H), 7.23-7.31 (m, 1H), 7.16 (dd, J=5.1, 1.3 Hz, 1H), 6.89 (dd, J=5.2, 3.4 Hz, 1H), 6.82 (dd, J=4.7, 2.1 Hz, 3H), 5.36-5.48 (m, 1H), 3.68-3.89 (m, 2H), 3.33-3.29 (m, 2H), 2.51-2.60 (m, 1H), 2.40 (s, 3H), 1.98 (d, J=3.7 Hz, 1H), 1.77-1.87 (m, 1H), 1.54-1.66 (m, 2H), 1.23-1.33 (m, 2H), 1.02 (d, 3H), 0.97 (d, J=6.8 Hz, 3H); m/e LCMS calcd 387.3 [(M+1)+, for C22H31N2O2S 387.3].
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[O:7][CH2:6][C:5](CO)([N+:8]([O-:10])=[O:9])[CH2:4][O:3]1.[OH-].[Na+]>C(O)(=O)C>[CH3:1][C:2]1([CH3:13])[O:3][CH2:4][CH:5]([N+:8]([O-:10])=[O:9])[CH2:6][O:7]1
Reactant: CC1(C)OCC(CO)([N+](=O)[O-])CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC1(C)OCC([N+](=O)[O-])CO1
Temperature: 60 °C
Yield: 92 %

Procedure:
Into a 250 ml round bottom flask equipped with a stir bar, thermometer and reflux condenser topped with a nitrogen inlet was added 5.73 (0.03) mole) of 2,2-dimethyl-5-hydroxymethyl-5-nitro-1,3-dioxane and 70 ml 10% sodium hydroxide which was heated to 60° C. for one hour. The solution was cooled to 5° C. and at this temperature acidified to pH 5 with concentrated acetic acid. The precipitated solid was filtered off and dried to give 5.2 g (92%) of 2,2-dimethyl-5-nitro-1,3-dioxane m.p. 60°-61° C. 1H NMR in CD3OD also confirmed the structure.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=1[NH:18][C:19]1[C:24]([F:25])=[CH:23][N:22]=[C:21]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][O:36][CH3:37])=[CH:29][CH:28]=2)[N:20]=1)C1C=CC=CC=1>CO.C1COCC1.[Pd]>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([NH:18][C:19]2[C:24]([F:25])=[CH:23][N:22]=[C:21]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][O:36][CH3:37])=[CH:29][CH:28]=3)[N:20]=2)[CH:11]=1
Reactant: COCCOc1ccc(Nc2ncc(F)c(Nc3cc([N+](=O)[O-])ccc3OCc3ccccc3)n2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COCCOc1ccc(Nc2ncc(F)c(Nc3cc(N)ccc3O)n2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 104.9 %

Procedure:
Into a 50 mL autoclave was charged Pd—C (0.025 g). MeOH was added under nitrogen. A solution of N4-(2-(benzyloxy)-5-nitrophenyl)-5-fluoro-N2-(4-(2-methoxyethoxy)phenyl)pyrimidine-2,4-diamine (0.10 g) in methanol and THF was added to the suspension. The autoclave was flushed with nitrogen and 8 kg/cm2 Hydrogen pressure was applied. The reaction mixture was stirred at room temperature for 18 h at same pressure. After completion, the reaction mixture was filtered using Celite and the filter cake was washed with methanol. The filtrate was concentrated under reduced pressure at 40° C. to give 0.08 g of 4-amino-2-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenol. Crude material was taken in next step without further purification.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[C:21]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][O:37][Si](C(C)(C)C)(C)C)=[CH:30][CH:29]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:45][O:46][C:47](=[O:49])[CH3:48])(=[O:3])[CH3:2].C(O)(=O)C.O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[C:21]([CH2:27][C:28]3[CH:29]=[CH:30][C:31]([O:34][CH2:35][CH2:36][OH:37])=[CH:32][CH:33]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:45][O:46][C:47](=[O:49])[CH3:48])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(C#N)c(Cc3ccc(OCCO[Si](C)(C)C(C)(C)C)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(C#N)c(Cc3ccc(OCCO)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To a solution of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(3-(4-(2-((tert-butyl dimethyl silyl)oxy)ethoxy)benzyl)-4-cyanophenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (180.0 mg, 0.25 mmol), was added acetic acid (1.5 mL) and water (0.5 mL) and the reaction mixture was stirred overnight at r.t. After the completion of the reaction as confirmed by TLC, the reaction mixture was diluted with ethyl acetate (50 mL) followed by neutralization with sodium bicarbonate solution till effervescence ceased. The organic layer was separated, washed with water (2×20 mL), dried over Na2SO4 and concentrated in vacuo to afford crude product which was purified by column chromatography (silica gel, 3:2 EtOAc:Pet Ether) to afford title compound (140.0 mg, 95%) as a solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C[Al](C)C.[C:16]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)=[CH:20][CH:19]=1)#[N:17]>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl.CO>[CH3:1][S:2]([C:5]1[CH:11]=[CH:10][C:8]([NH:9][C:16]([C:18]2[CH:19]=[CH:20][C:21]([C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)=[CH:22][CH:23]=2)=[NH:17])=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(N)cc1
Reactant: N#Cc1ccc(-c2cccs2)cc1
Agent: C[Al](C)C
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(NC(=N)c2ccc(-c3cccs3)cc2)cc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a suspension of 4-(methylsulfonyl)aniline (0.428 g, 2.5 mmol) in toluene (15 mL) at 0° C. was added over 5 minutes trimethylaluminum (3.83 mL, 0.98 M solution in hexane, 3.75 mmol). The reaction mixture was warmed to room temperature and stirred for 3.5 hours. A solution of 2-(4-cyanophenyl)thiophene (0.926 g, 5 mmol, prepared according to the method of Heterocycles, 1990, 31, 1951) in toluene (10 mL) was added over 5 minutes and the reaction mixture heated to 70° C. After 18.5 hours, the reaction mixture was cooled to room temperature and poured over a slurry of silicagel in chloroform-methanol (2:1, 150 mL). After filtration, the residue was washed with a mixture of CH2Cl2—methanol (2:1, 75 mL). The combined filtrates were concentrated in vacuo ,and the resulting yellowish solid was washed with hexane-ether (2:1, 100 mL) to give the subtitle compound (0.711 g).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[O:8][CH:9]=[C:10]([CH2:12][O:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][N:23]4[CH:27]=[CH:26][N:25]=[CH:24]4)=[CH:16][CH:15]=3)[N:11]=2)=[CH:4][C:3]=1[CH3:28].C(O)(=O)C>[Zn].O>[N:23]1([CH2:22][CH2:21][CH2:20][C:17]2[CH:16]=[CH:15][C:14]([O:13][CH2:12][C:10]3[N:11]=[C:7]([C:5]4[S:6][CH:2]=[C:3]([CH3:28])[CH:4]=4)[O:8][CH:9]=3)=[CH:19][CH:18]=2)[CH:27]=[CH:26][N:25]=[CH:24]1
Reactant: Cc1cc(-c2nc(COc3ccc(CCCn4ccnc4)cc3)co2)sc1Br
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: Cc1csc(-c2nc(COc3ccc(CCCn4ccnc4)cc3)co2)c1
Yield: 81.1 %

Procedure:
A mixture of 2-(5-bromo-4-methyl-2-thienyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole (700 mg), zinc powder (200 mg), acetic acid (5 ml) and water (5 ml) was heated for 4 hours under reflux. The residue was filtered off, the filtrate was concentrated. To the residue was added ethyl acetate, washed with saturated aqueous sodium bicarbonate and water, dried (MgSO4), and concentrated under reduced pressure to give crystals of 4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-(4-methyl-2-thienyl)oxazole (470 mg, 81%). Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 077-178° C.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.Cl.[C:12]1([NH:18]N)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CCO>[CH2:7]1[C:2]2[NH:18][C:12]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:3]=2[CH2:4][CH:5]([C:8]([OH:10])=[O:9])[CH2:6]1
Reactant: NNc1ccccc1
Reactant: O=C1CCC(C(=O)O)CC1
Agent: Cl
Solvent: CCO
Product: O=C(O)C1CCc2[nH]c3ccccc3c2C1
Temperature: 25 °C
Yield: 84.1 %

Procedure:
A mixture of 4-oxo-cyclohexanecarboxylic acid (4.05 g, 28.5 mmol) and phenylhydrazine hydrochloride (4.12 g, 28.5 mmol) in EtOH (200 ml) is stirred at reflux for 3 h. Then, the solvent is evaporated and the residue is dissolved in boiling toluene. Precipitating ammonium chloride is filtered off and the clear filtrate is cooled to rt. The resulting precipitate is filtered and tried under high vacuum to give pure subtitle compound as a white solid (5.16 g) in 84% yield. tR (LC-3) 2.21 min; ESI-MS (positive ion): m/z 216.30 [M+H]+(calcd 215.09 for C13H13NO2). 1H-NMR (CDCl3): 2.01 (m, 1H); 2.28 (m, 1H); 2.83 (m, 4H); 3.04 (dd, J=14.8 Hz, 4.7 Hz, 1H); 7.02 (m, 2H); 7.19 (d, J=7.2 Hz, 1H); 7.38 (d, J=7.0 Hz, 1H); 7.63 (s br, 1H).
Reaction SMILES: Cl.[CH3:2][N:3]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:4]1[N:9]=[C:8]([NH2:10])[N:7]=[C:6]([C:11]2[N:15]=[C:14]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[O:13][N:12]=2)[N:5]=1.[H-].[Na+].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C=O)C.C(Cl)Cl>[CH2:30]([N:19]1[CH2:18][CH2:17][CH:16]([C:14]2[O:13][N:12]=[C:11]([C:6]3[N:5]=[C:4]([N:3]([CH3:2])[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:9]=[C:8]([NH2:10])[N:7]=3)[N:15]=2)[CH2:21][CH2:20]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CN(c1ccccc1)c1nc(N)nc(-c2noc(C3CCNCC3)n2)n1
Reactant: BrCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(c1ccccc1)c1nc(N)nc(-c2noc(C3CCN(Cc4ccccc4)CC3)n2)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 1.9 %

Procedure:
To 2-N-methyl-2-N-phenyl-6-[5-(piperidin-4-yl)-1,2,4-oxadiazol-3-yl]-1,3,5-triazine-2,4-diamine hydrochloride (Intermediate 105, 0.100 g, 0.257 mmol) in DMF (2 mL) was added sodium hydride (60% dispersion in mineral oil, 0.012 g, 0.309 mmol) at 0 C and stirred for 5 min. Benzyl bromide (30.6 μL, 0.257 mmol) was added, the reaction mixture was warmed to room temperature and stirred for 18 h. The mixture was then heated at 45 C for 18 h and re-treated with benzyl bromide (30.6 L, 0.257 mmol). The mixture was then heated at 50 C for 18 h and stirred room temperature for 72 h. The reaction mixture was diluted with DCM and then washed with a saturated aqueous solution of sodium bicarbonate and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude compound was purified by preparative HPLC, Method A, to afford the title compound (2.2 mg, 1.9%).
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9](Cl)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CCOCC>[C:9]([NH:8][NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NNc1ccccc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCOCC
Product: O=C(NNc1ccccc1)c1ccccc1
Temperature: 5 °C

Procedure:
A four neck flask (2 liters) equipped with a thermometer and a stirrer was charged with 216 g (2.0 mol) of phenylhydrazine and 1.5 liter of ether and cooled down to 5° C. Dropwise added thereto was 56.2 g (0.4 mol) of benzoyl chloride in 2 hours while stirring, and then the solution was heated to room temperature (20° C.) to continue stirring for 12 hours. Crystal was filtered off and washed sufficiently with deionized water and then dried under reduced pressure to obtain slightly brown crystal.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([CH3:7])=[C:4]([CH2:8][OH:9])[CH:3]=1>O1CCCC1.[O-2].[O-2].[Mn+4]>[Br:1][C:2]1[O:6][C:5]([CH3:7])=[C:4]([CH:8]=[O:9])[CH:3]=1
Reactant: Cc1oc(Br)cc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: Cc1oc(Br)cc1C=O
Temperature: 40 °C
Reaction time: 48 h
Yield: 51.5 %

Procedure:
A solution of methyl 5-bromo-2-methyl-3-furancarboxylate (Example 49 (1)) (7.5 g) in tetrahydrofuran (30 mL) was added dropwise to a suspension of lithium aluminum hydride (1.9 g) in tetrahydrofuran (30 mL) at 0° C. and, after the completion of the dropwise addition, the mixture was stirred at 0° C. for 30 min. The reaction mixture was treated with 1N hydrochloric acid, poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (5% ethyl acetate/hexane to 40% ethyl acetate/hexane) to give (5-bromo-2-methylfuran-3-yl)methanol (5.7 g, 60%) as an oil. A suspension of the obtained (5-bromo-2-methylfuran-3-yl)methanol (5.5 g) and manganese dioxide (15 g) in tetrahydrofuran (100 mL) was stirred at 40° C. for 2 days. Manganese dioxide was filtered off, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 20% ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (2.8 g, 51%) as a white solid.