Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][C:16]1[CH:17]=[C:18]([C:23]2[CH:24]=[C:25]([CH:29]=[C:30]([C:36]3[CH:41]=[C:40]([CH3:42])[CH:39]=[C:38]([CH3:43])[CH:37]=3)[C:31]=2[O:32][CH2:33][O:34][CH3:35])[C:26](O)=[O:27])[CH:19]=[C:20]([CH3:22])[CH:21]=1.C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1>CCOC(C)=O.O.C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:26](=[O:27])[C:25]2[CH:29]=[C:30]([C:36]3[CH:37]=[C:38]([CH3:43])[CH:39]=[C:40]([CH3:42])[CH:41]=3)[C:31]([O:32][CH2:33][O:34][CH3:35])=[C:23]([C:18]3[CH:17]=[C:16]([CH3:15])[CH:21]=[C:20]([CH3:22])[CH:19]=3)[CH:24]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCCCCCCc1ccccc1
Reactant: COCOc1c(-c2cc(C)cc(C)c2)cc(C(=O)O)cc1-c1cc(C)cc(C)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COCOc1c(-c2cc(C)cc(C)c2)cc(C(=O)NCCCCCCCc2ccccc2)cc1-c1cc(C)cc(C)c1
Temperature: 25 °C
Yield: 57.5 %

Procedure:
A flamed dried round bottom flask was charged with 7-phenylheptyl amine (354 mg, 2.78 mmol) and 20 mL anhydrous CH2Cl2. To this solution was added 3,5-bis-(3,5-dimethylphenyl)-4-methoxymethoxybenzoic acid (780 mg, 1.85 mmol), triethyl amine (563 mg, 5.56 mmol, 726 μL), anhydrous 1-hydroxybenzotriazole (275 mg, 2.04 mmol), and DCC (459 mg, 2.22 mmol), all at room temperature. The reaction mixture was stirred at room temperature for one-half hour. Then the reaction was worked up by adding water then extracting with EtOAc (3×). The combined organic extracts were dried over Na2SO4 and the solvent removed in vacuo to give a semisolid to which CH2Cl2 was added. This suspension was subjected to column chromatography (15% EtOAc: 85% Hexanes) to give 600 mg, 54.5% of the amide as a colorless oil. 1H NMR (CDCl3) δ 1.34 (bs, 6H); 1.57 (m, 4H); 2.36 (s, 12H); 2.572 (t, J=8.18 Hz, 2H); 2.681 (s, 3H); 3.414 (quartet, J=8.18 Hz, 2H); 4.39 (s, 2H); 6.04 (t, J=5.73 Hz, 1H); 6.97 (s, 2H); 7.12–7.27 (m, 9H); 7.67 (s, 2H).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C[O:8][C:9]([C:11]1[C:12]2[CH:13]=[CH:14][N:15]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:26][CH:27]4[CH2:32][CH2:31][CH:30]([OH:33])[CH2:29][CH2:28]4)[N:21]=3)[C:16]=2[CH:17]=[CH:18][CH:19]=1)=O.O.[OH-].[Na+]>C1COCC1>[OH:8][CH2:9][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[CH:14][N:15]2[C:20]1[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C@H:27]2[CH2:32][CH2:31][C@H:30]([OH:33])[CH2:29][CH2:28]2)[N:21]=1
Reactant: COC(=O)c1cccc2c1ccn2-c1ccnc(NC2CCC(O)CC2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1cccc2c1ccn2-c1ccnc(N[C@H]2CC[C@H](O)CC2)n1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
A solution of LAH (1 M in THF, 0.57 mL) was slowly added at −10° C. under argon atmosphere to a solution of 1-[2-(4-hydroxycyclohexylamino)-pyrimidin-4-yl]-1H-indole-4-carboxylic acid methyl ester (100 mg) in THF (0.3 mL). The resulting mixture was stirred at −10° C. for 30 min, and at RT overnight. The reaction mixture was then cooled to 0° C. and water (20 μL) was added, followed by aqueous NaOH (15%, 20 μL) and a second aliquot of water (70 μL). The resulting mixture was stirred for 30 min, then filtered through a CELITE™ pad. The inorganic salts were triturated, the supernatant added to the filtrate, and the solution evaporated under reduced pressure to give trans-4-[4-(4-hydroxymethylindol-1-yl)-pyrimidin-2-ylamino]-cyclohexanol (32.5 g, 35% yield) as a white solid. MS=339 [M+H]+; MP=212.0-213.3° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][N:6]1[N:10]=[N:9][C:8]([C:11]2[S:15][C:14]([N:16]3[CH2:25][CH2:24][C:19]4(OCC[O:20]4)[CH2:18][CH2:17]3)=[N:13][CH:12]=2)=[N:7]1)[CH3:2].Cl>C1COCC1>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][N:6]1[N:10]=[N:9][C:8]([C:11]2[S:15][C:14]([N:16]3[CH2:17][CH2:18][C:19](=[O:20])[CH2:24][CH2:25]3)=[N:13][CH:12]=2)=[N:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1nnc(-c2cnc(N3CCC4(CC3)OCCO4)s2)n1
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)Cn1nnc(-c2cnc(N3CCC(=O)CC3)s2)n1
Temperature: 65 °C

Procedure:
To a solution of ethyl{5-[2-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-1,3-thiazol-5-yl]-2H-tetrazol-2-yl}acetate (377 mg, 0.99 mmol) in THF (4.95 mL) was added 1N HCl (1.09 mL, 1.09 mmol). The reaction mixture was heated to 65° C. for 3 h. The volatiles were evaporated under reduced pressure. The mixture was diluted with water (20 mL) and extracted with EtOAc (3×5 mL). The combined organic fractions were dried over MgSO4, filtered and evaporated under reduced pressure. The residue was purified by Combiflash™ chromatography (SiO2, 12 g, elution with 10-70% EtOAc/hexanes over 40 min) to afford the title compound as solid. 1H NMR (500 MHz, DMSO-d6): δ 7.92 (s, 1 H), 5.85 (s, 2 H), 4.22 (q, 2 H), 3.90 (t, 4 H), 2.57 (t, 4 H), 1.23 (t, 3 H). MS (+ESI): m/z 337.1 (MH+).
Reaction SMILES: CO.[Na].[C:4]1([CH:11]=[CH:10][CH:9]=[C:7]([OH:8])[CH:6]=1)[OH:5].[F:12][C:13]([F:29])([F:28])[C:14]1[CH:15]=[C:16]([CH:25]=[CH:26][CH:27]=1)OC1C=C(Br)C=CC=1>N1C=CC=CC=1>[F:12][C:13]([F:29])([F:28])[C:14]1[CH:27]=[C:26]([CH:25]=[CH:16][CH:15]=1)[O:5][C:4]1[CH:6]=[C:7]([OH:8])[CH:9]=[CH:10][CH:11]=1
Reactant: FC(F)(F)c1cccc(Oc2cccc(Br)c2)c1
Reactant: Oc1cccc(O)c1
Agent: [Na]
Solvent: CO
Solvent: c1ccncc1
Product: Oc1cccc(Oc2cccc(C(F)(F)F)c2)c1
Yield: 67.9 %

Procedure:
All apparatus is rigorously dried and flushed with nitrogen before use. The reaction is performed in a 500 mL 3-necked flask equipped with a mechanical stirrer, a reflux condenser topped with a nitrogen inlet tube and a stopper. The flask is charged with methanol (100 mL) and sodium (10.0 g, 0.43 mol). After all of the sodium has been consumed the methanol is distilled from the flask, and the last traces are removed by azeotropic distillation with benzene. Pyridine (250 mL) and resorcinol (35.0 g, 0.32 mol) are added to the reaction mixture, followed by 3-(3-trifluoromethyl phenoxy)bromobenzene (50.0 g, 0.22 mol) and cuprous chloride (20.0 g, 0.20 mol), and the mixture is left to stir at reflux for 24 hours. Capillary GC analysis shows that ca. 87% of the mixture is the desired monoalkylation product, the rest being dialkylation product. The mixture is cooled and filtered with the aid of ether (200 mL). The ethereal phase is washed successively with water (250 mL), 5% HCl (2×250 mL), saturated NaHCO3 (200 mL) and brine (200 mL). Then it is dried with MgSO4, and the solvents are removed on the rotary evaporator to leave 38 g of a dark oily residue. Purification is accomplished by fractional distillation in vacuo. The second fraction (distilling at 132° C. @ 1.5 mm) consisted of pure monoalkylation product (colorless oil, 25.20 g, 44.6% yield). The dialkylation product is not isolated.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]=[O:22])=[CH:17][N:16]=1.CO.[BH4-].[Na+].O>O1CCCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][OH:22])=[CH:17][N:16]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(C=O)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO)cn1
Reaction time: 0.5 h

Procedure:
To a solution of 2-(5-methyl-2-phenyl-4-oxazolylmethoxy)pyridine-5-carbaldehyde (13.0 g) in tetrahydrofuran (150 ml)-methanol (10 ml) was gradually added sodium borohydride (835 mg) at 0° C. After stirring for 30 min., water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated to give 2-(5-methyl-2-phenyl-4-oxazolylmethoxy)pyridine-5-methanol as crystals. The crystals were recrystallized from acetone-isopropyl ether to give colorless prism crystals (12.4 g, yield 95%). melting point: 121–122° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([N:9]([CH3:12])[C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1)[CH3:2].[ClH:13].[Br:14][C:15]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:16]=1[NH2:17]>ClC1C=CC=CC=1>[ClH:13].[CH2:1]([C:3]1[CH:4]=[C:5]([N:9]([CH3:12])[C:10]([NH:17][C:16]2[CH:18]=[C:19]([Br:22])[CH:20]=[CH:21][C:15]=2[Br:14])=[NH:11])[CH:6]=[CH:7][CH:8]=1)[CH3:2]
Reactant: Nc1cc(Br)ccc1Br
Reactant: CCc1cccc(N(C)C#N)c1
Agent: Cl
Solvent: Clc1ccccc1
Product: CCc1cccc(N(C)C(=N)Nc2cc(Br)ccc2Br)c1

Procedure:
A mixture of N-(3-ethylphenyl)-N-methylcyanamide (520 mg, 3.3 mmol), 2,5-dibromoaniline hydrochloride (861 mg, 3 mmol), and chlorobenzene (2 mL) were combined in a dry round bottom flask equipped with water cooled condenser under nitrogen and placed in a preheated oil bath (150-160° C.). The reaction mixture was heated for 3 hours. After cooling, the crude reaction product was purified by crystallization from chlorobenzene/diethylether. The resulting crystals were collected by filtration, washed with diethylether, and dried in a vacuum oven (40° C., 15 hours) to yield the title compound, N-(3-ethylphenyl)-N-methyl-N'-(2,5-dibromophenyl)guanidine hydrochloride, as a white solid (780 mg, 59% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[CH2:5][CH:6]([C:9]#[N:10])[C:7]#[N:8].[H-].[Na+].Br[CH2:17][CH2:18][F:19]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[CH2:5][C:6]([CH2:17][CH2:18][F:19])([C:7]#[N:8])[C:9]#[N:10]
Reactant: N#CC(C#N)Cc1cccc(Br)c1
Reactant: FCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCF)Cc1cccc(Br)c1
Yield: 38.3 %

Procedure:
Using 0.24 g of (3-bromobenzyl)malononitrile, 3 ml of N,N-dimethylformamide, 0.10 g of sodium hydride (60% in oil), and 0.13 g of 1-bromo-2-fluoroethane, and according to the process described in the Production Example 1, there was obtained 0.11 g of 2-(3-bromobenzyl)-2-(2-fluoroethyl)malononitrile (the present compound (65)).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].ClC(Cl)(Cl)[C:13]([NH:15][C:16]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:17]=1[CH:18]=[C:19]([CH3:26])[N:20]=[N:21]2)=[O:14].C1CCN2C(=NCCC2)CC1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH:6][C:13]([NH:15][C:16]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:17]=1[CH:18]=[C:19]([CH3:26])[N:20]=[N:21]2)=[O:14]
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: Cc1cc2c(NC(=O)C(Cl)(Cl)Cl)cccc2nn1
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cc2c(NC(=O)NCc3ccc(Cl)c(Cl)c3)cccc2nn1

Procedure:
The title compound was prepared using 3,4-dichlorobenzylamine, the product from Example 16A, DBU and the procedure described in Example 1B. MS (ESI+) m/z 362 (M+H)+; 1H NMR (DMSO-d6) δ 2.88 (s, 3H), 4.36 (d, 2H), 7.10 (t, 1H), 7.34 (dd, 1H), 7.59 (m, 2H), 7.76 (t, 1H), 8.04 (d, 2H), 8.19 (d, 1H), 8.93 (s, 1H).
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:9][C@@H:8]([C:10]([O:12][CH3:13])=[O:11])[C@H:7]([CH2:14][N:15]=[N+]=[N-])[C@@H:6]1[NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:4].S1C=CC=C1[CH2:31][C:32](O)=[O:33]>>[C:22]([O:21][C:19]([NH:18][C@H:6]1[C@@H:7]([CH2:14][NH:15][C:32](=[O:33])[CH3:31])[C@H:8]([C:10]([O:12][CH3:13])=[O:11])[CH2:9][C@@H:5]1[C:3]([OH:2])=[O:4])=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: COC(=O)[C@H]1C[C@@H](C(=O)OC)[C@H](CN=[N+]=[N-])[C@@H]1NC(=O)OC(C)(C)C
Reactant: O=C(O)Cc1cccs1
Product: COC(=O)[C@@H]1C[C@H](C(=O)O)[C@@H](NC(=O)OC(C)(C)C)[C@H]1CNC(C)=O
Yield: 48 %

Procedure:
(±)-(1S,2S,3R,4R)-2-(t-Butyloxycarbonylamino)-3-(azidomethyl)-cyclopentane-1,4-dicarboxylic acid dimethyl ester (506 mg, 1.42 mmole) and thiolacetic acid (0.4 mL) were reacted at room temperature for 6 hours. The reaction mixture was concentrated in vacuo and the crude product was purified by silica gel chromatography using 3% methanol in chloroform to provide the title compound (yield: 255 mg, 48%). MS: (M+H)+=373.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:14]=[C:13]([O:15][CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:22])[CH:11]=2)[CH:6]=1.[C:24](Cl)(=[O:26])[CH3:25]>O1CCCC1.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:14]=[C:13]([O:15][CH:16]2[CH2:17][CH2:18][N:19]([C:24](=[O:26])[CH3:25])[CH2:20][CH2:21]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:22])[CH:11]=2)[CH:6]=1
Reactant: CC(=O)Cl
Reactant: COC(=O)Cc1cc(OC2CCNCC2)c2cc(F)ccc2c1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COC(=O)Cc1cc(OC2CCN(C(C)=O)CC2)c2cc(F)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
To a solution of [6-fluoro-4-(piperidin-4-yloxy)-naphthalen-2-yl]-acetic acid methyl ester (the intermediate for example 4-1, 1st step, 80 mg, 0.25 mmol) and acetyl chloride (39 mg, 0.5 mmol) in tetrahydrofuran (2 mL) was added a solution of 4-dimethylaminopyridine (76 mg, 0.63 mmol) in tetrahydrofuran (1 mL) dropwise. After being stirred at room temperature overnight, the mixture was concentrated in vacuo. The residue was purified by column chromatography (gradient elution with 10-50% ethyl acetate in petroleum ether) to afford [4-(1-acetyl-piperidin-4-yloxy)-6-fluoro-naphthalen-2-yl]-acetic acid methyl ester (72 mg, 79%) as a white solid.
Reaction SMILES: [CH2:1]([N:4]([CH2:19][CH2:20][CH3:21])[C:5]([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[NH:10][CH:9]=1)=[O:6])[CH2:2][CH3:3].[H-].[Na+].[CH3:24]I>CN(C)C=O.C(OCC)C>[CH2:19]([N:4]([CH2:1][CH2:2][CH3:3])[C:5]([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[N:10]([CH3:24])[CH:9]=1)=[O:6])[CH2:20][CH3:21]
Reactant: CI
Reactant: CCCN(CCC)C(=O)Cc1c[nH]c2ccc(OC)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCCN(CCC)C(=O)Cc1cn(C)c2ccc(OC)cc12
Reaction time: 0.5 h
Yield: 67.2 %

Procedure:
To a solution of 3-(di-n-propylaminocarbonylmethyl)-5-methoxyindole (180 mg, 0.62 mmol) in 1.8 mL of N,N-dimethylformamide was added sodium hydride (55%, 40 mg, 0.93 mmol) at 0° C. After the reaction mixture was stirred at the same temperature for 30 min, methyl iodide (0.10 mL, 1.2 mmol) was added with additional stirring at room temperature for 12 h. After the reaction mixture was diluted with diethyl ether, and washed with water and brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=95/5 to 80/20) to obtain the title compound (126 mg, 67%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14](C(=O)COC[C@@H](C)[C@H](N(C(OC(C)(C)C)=O)C)C2OC=CC=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](COCC(=O)N1CCN(C(=O)OCc2ccccc2)CC1)[C@@H](c1ccco1)N(C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(OCc1ccccc1)N1CCNCC1
Reaction time: 1 h
Yield: 160.3 %

Procedure:
To a solution of 4-{2-[(2S,3S)-3-(tert-butoxycarbonyl-methylamino)-3-furan-2-yl-2-methyl-propoxy]-acetyl}-piperazine-1-carboxylic acid benzyl ester (250.0 mg, 0.47 mmol) in DCM (4 mL) at 0° C. was added TFA (4 mL). After stirring for 1 hour, the reaction mixture was diluted with DCM (30 mL) and washed with saturated aqueous NaHCO3, brine, dried over Na2SO4, filtered, and concentrated in vacuo to give 4-[2-(2S,3S)-3-furan-2-yl-2-methyl-3-methylamino-propoxy)-acetyl]-piperazine-1-carboxylic acid benzyl ester as a solid (166.0 mg) which was used for the next step without further purification. MS m/z (M+1) 430.3
Reaction SMILES: [OH-].[Na+].C1(C)C=CC=CC=1.Br[CH2:11][CH2:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[F:22])[CH:17]=[O:18].O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[F:22][C:21]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][C:14]=1[O:13][CH:12]=[CH2:11]
Reactant: O=Cc1ccc(F)c(OCCBr)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: C=COc1cc(C=O)ccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.1 %

Procedure:
A 50% sodium hydroxide solution (5 mL) and tetrabutylammonium hydrogen sulfate (859 mg) were added to the toluene (8 mL) solution of 3-(2-bromoethoxy)-4-fluorobenzaldehyde derivative (606 mg) obtained above, and the reaction solution was agitated at room temperature for 1 hour. Water and ethyl acetate were added to the reaction solution after the reaction ended, and the organic layer was separated. The obtained organic layer was washed with a saturated sodium chloride solution, and the solvent was evaporated under reduced pressure after dried over anhydrous magnesium sulfate. The obtained residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate 6:1), and 200 mg (49%) of 4-fluoro-3-vinyloxybenzaldehyde was obtained. The physical properties of the compound are as follows.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[N:7]([CH2:10][C:11]1[C:20](Br)=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1)[CH2:8][CH3:9])([CH3:4])([CH3:3])[CH3:2].[CH2:23]([O:25][C:26](=[O:45])[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=1)[CH3:24]>>[CH2:23]([O:25][C:26](=[O:45])[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([C:20]2[C:11]([CH2:10][N:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:22])[CH2:8][CH3:9])=[N:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:29]=1)[CH3:24]
Reactant: CCOC(=O)Cc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CCN(Cc1nc2ccccc2cc1Br)C(=O)OC(C)(C)C
Product: CCOC(=O)Cc1ccc(OC)c(-c2cc3ccccc3nc2CN(CC)C(=O)OC(C)(C)C)c1

Procedure:
Prepared according to the procedure described in Example 5, Step 3, using the following starting materials: (3-bromo-quinolin-2-ylmethyl)-ethyl-carbamic acid tert-butyl ester and [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester.
Reaction SMILES: CS[C:3]([N:7]1[CH2:11][CH:10]([CH2:12][CH3:13])[CH:9]=[N:8]1)=[N:4][CH2:5][CH3:6].[N:14]1([S:20]([NH2:23])(=[O:22])=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>C(#N)C>[CH2:5]([NH:4][C:3]([N:7]1[CH2:11][CH:10]([CH2:12][CH3:13])[CH:9]=[N:8]1)=[N:23][S:20]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)(=[O:22])=[O:21])[CH3:6]
Reactant: CCN=C(SC)N1CC(CC)C=N1
Reactant: NS(=O)(=O)N1CCCCC1
Solvent: CC#N
Product: CCNC(=NS(=O)(=O)N1CCCCC1)N1CC(CC)C=N1
Yield: 0.4 %

Procedure:
0.70 g (1 mol equiv.) 4,N-Diethyl-4,5-dihydro-pyrazole-1-carboximidothioic acid methyl ester and 0.61 g (1.05 mol equiv.) piperidine-1-sulfonic acid amide were added to 7 mL acetonitrile, and the reaction mixture was refluxed overnight. Volatiles were removed under reduced pressure, and the residue was taken up in ethyl acetate and extracted with 2N NaOH. The organic layer was dried over Na2SO4, filtered and evaporated to dryness. Purification by flash chromatography on silica gel (Et2O:PA=2:1) afforded 1.12 g (96%) piperidine-1-sulfonic acid ethylamino-(4-ethyl-4,5-dihydro-pyrazol-1-yl)-methyleneamide. 1H NMR (400 MHz, CDCl3) δ 0.99 (t, J=7.5 Hz, 3H), 1.21 (t, J=7.2 Hz, 3H), 1.45-1.72 (m, 8H), 3.07-3.17 (m, 5H), 3.48-3.57 (m, 2H), 3.73 (dd, J=11.0, 7.7 Hz, 1H), 4.08-4.19 (m, 1H), 6.58 (br.s., 1H), 6.87 (d, J=1.3 Hz, 1H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[C:20](=[CH:24][N:25]([C:27]4[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=4)[N:26]=3)[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.Cl.[CH3:36][S:37]([CH2:40][CH2:41][NH2:42])(=[O:39])=[O:38].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>CN(C)C=O.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[C:20](=[CH:24][N:25]([C:27]4[CH:28]=[CH:29][C:30]([CH2:31][NH:42][CH2:41][CH2:40][S:37]([CH3:36])(=[O:39])=[O:38])=[CH:33][CH:34]=4)[N:26]=3)[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: CS(=O)(=O)CCN
Reactant: O=Cc1ccc(-n2cc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3n2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CS(=O)(=O)CCNCc1ccc(-n2cc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.4 %

Procedure:
To a solution of 4-[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]benzaldehyde (80 mg) and 2-(methylsulfonyl)ethylamine hydrochloride (40 mg) in N,N-dimethylformamide (2 mL) was added acetic acid (0.02 mL), and the mixture was stirred at room temperature for 1 hr. Subsequently, sodium triacetoxyborohydride (54 mg) was added, and the mixture was stirred at the same temperature for 2 hrs. After the completion of the reaction, saturated aqueous sodium hydrogen carbonate was added, and the mixture was concentrated under reduced pressure. The residue was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate/methanol=5/1) to give the title compound (70 mg) as a white solid.
Reaction SMILES: Cl.NCCC(NN[C:9]([N:11]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[O:14][C:13]2[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:12]1=2)=[O:10])=O.S1C=CC=C1S(Cl)(=O)=[O:33]>>[Cl:26][C:24]1[CH:23]=[CH:22][C:13]2[O:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[CH2:17][N:11]([C:9]([OH:10])=[O:33])[C:12]=2[CH:25]=1
Reactant: NCCC(=O)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reactant: O=S(=O)(Cl)c1cccs1
Agent: Cl
Product: O=C(O)N1Cc2ccccc2Oc2ccc(Cl)cc21

Procedure:
8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[1-oxo-3-[(2-thienylsulfonyl)amino]propyl hydrazide (30) was prepared from 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)carboxylic acid, 2-(3-amino-1-oxopropyl)hydrazide, monohydrochloride (9), prepared as described above in Example 9, and 2-thiophenesulfonyl chloride in the same manner as described in Example 10 on a 1.9 mmol scale to yield 0.48 g (50%) of product. Analysis calculated for C21H19N4O5ClS2 (M.W. 506.99): C, 49.26; H, 4.36; N, 12.77; Cl, 6.99; S, 12.65. Found: C, 49.05; H, 4.40: N, 12.66; Cl, 7.13; S, 12.88.
Reaction SMILES: Cl[S:2]([C:5]1[N:13]=[C:12]2[N:7]([C:8]([O:17][CH3:18])=[N:9][C:10]3[S:16][CH:15]=[CH:14][C:11]=32)[N:6]=1)(=[O:4])=[O:3].[Cl:19][C:20]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:21]=1[NH2:22].N1C=CC=CC=1.CS(C)=O>C(#N)C>[Cl:19][C:20]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:21]=1[NH:22][S:2]([C:5]1[N:13]=[C:12]2[N:7]([C:8]([O:17][CH3:18])=[N:9][C:10]3[S:16][CH:15]=[CH:14][C:11]=32)[N:6]=1)(=[O:4])=[O:3]
Reactant: COc1nc2sccc2c2nc(S(=O)(=O)Cl)nn12
Reactant: Nc1c(Cl)cccc1Cl
Solvent: CS(C)=O
Solvent: CC#N
Solvent: c1ccncc1
Product: COc1nc2sccc2c2nc(S(=O)(=O)Nc3c(Cl)cccc3Cl)nn12
Reaction time: 8 h
Yield: 47.4 %

Procedure:
2-Chlorosulfonyl-5-methoxythieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine (1.5 g, 4.9 mmol) and 2,6-dichloroaniline (1.59 g, 9.8 mmol) were dissolved in 20 mL of acetonitrile and to this was added under nitrogen at ambient temperature with stirring 0.40 mL (4.9 mmol) of pyridine and 0.05 mL of dimethyl sulfoxide. The mixture was allowed to stir overnight and was then concentrated by evaporation under reduced pressure. The residue was flash chromatographed on silica gel and fractions containing the major product were recovered. Evaporation of the solvents under reduced pressure gave a white powder. This was extracted with 200 mL of hexane and the insoluble white solid was dried to obtain 1.0 g of the title compound melting at 224°-226° C. The proton NMR spectra of this was consistent with the assigned structure.