Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[CH2:13]([SH:17])[CH2:14][CH2:15][SH:16].B(F)(F)F.CCOCC>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]1[S:17][CH2:13][CH2:14][CH2:15][S:16]1
Reactant: COc1cccc(C=O)c1OC
Reactant: SCCCS
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: COc1cccc(C2SCCCS2)c1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.2 %

Procedure:
A solution of 49.5 g (298 mmol) of 2,3-dimethoxybenzaldehyde and 48.4 g (447 mmol) of propane-1,3-dithiol in 800 mL of methylene chloride was cooled to 0° C. Boron trifluoride etherate (7.5 mL, 61 mmol) was added dropwise to the cooled solution and the reaction mixture was stirred at 0° C. for 0.5 h, then at ambient temperature for 18 h. The methylene chloride solution was washed with 2×200 mL of 10% aqueous sodium hydroxide solution, 200 mL of water and 100 mL of brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give 75 g (98% yield) of 2-(2',3'-dimethoxyphenyl)-1,3-dithiane, m.p. 119°-120° C.; 1H NMR (CDCl3) δ: 1.8-2.0 (m, 1H), 2.1-2.25 (m, 1H), 2.86 (t, 1H), 2.91 (t, 1H), 3.05-3.2 (m, 2H), 3.83 (s, 3H), 3.91 (s, 3H), 5.68 (s, 1H), 6.86 (dd, 1H), 7.07 (t, 1H), 7.19 (dd, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)[CH3:2].[H-].[Na+].[CH2:22]([O:24][C:25](=[O:33])[C:26]1[CH:31]=[CH:30][C:29](Cl)=[N:28][CH:27]=1)[CH3:23]>CN(C=O)C>[CH2:22]([O:24][C:25](=[O:33])[C:26]1[CH:31]=[CH:30][C:29]([NH:14][CH:11]2[CH2:10][CH2:9][N:8]([CH2:7][C:6]3[CH:15]=[CH:16][C:17]([O:18][CH3:19])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=3)[CH2:13][CH2:12]2)=[N:28][CH:27]=1)[CH3:23]
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1OC
Reactant: CCOC(=O)c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(NC2CCN(Cc3ccc(OC)c(OCC)c3)CC2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 18 %

Procedure:
To a solution of 1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamine (39.7 mg, 0.15 mmol, 1.0 equiv; intermediate A1) in dry DMF (1.5 mL) under Ar was added sodium hydride (6.6 mg, 0.15 mmol, 1.0 equiv; 55% free-flowing powder moistened with oil) and the reaction mixture stirred at rt. After 2 h, 6-chloro-nicotinic acid ethyl ester (46.4 mg, 0.25 mmol, 1.67 equiv; commercially available) was added and the mixture heated by microwave irradiation to 220° C. for 15 min. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 10.9 mg (18%) of the title compound. MS (ISP): 414.4 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12])=O.C(N=CC)(C)(C)C.ClP(=O)(OCC)[O:26][CH2:27][CH3:28].C(O)(=O)C(O)=O>CCCCCC.O1CCCC1>[F:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12])=[CH:28][CH:27]=[O:26]
Reactant: O=C(c1ccccc1F)c1ccccc1F
Reactant: CCOP(=O)(Cl)OCC
Agent: CC=NC(C)(C)C
Agent: O=C(O)C(=O)O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=CC=C(c1ccccc1F)c1ccccc1F
Temperature: 85 °C

Procedure:
The compound was prepared according to the procedure described in Example 84. The following reagents were used: 2,2'-difluorobenzophenone (6.0 g) diisopropylamine (28.8 mL) 1.6M n-butyl lithium in hexane (129 mL). acetaldehyde N-tert-butylimine (13.2 mL), diethyl chlorophosphonate (14.85 mL) and tetrahydrofurane (100 mL). The reaction was worked up in the usual manner, with the exception that the oxalic acid catalyzed hydrolysis was slow and it was necessary to heat the mixture to 85° C. for one hour to complete the conversion. The crude product (5.8 g), obtained as an orange oil, was crystallized from hexane to give 4.6 g of 3,3-bis(2-fluorophenyl)-2-propenal mp 75°-77° C.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[Cl:7][C:8]1[N:13]=[C:12]([N:14]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[N:11]=[C:10]2[N:29]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=3)[N:30]=[C:31]([CH2:32][CH:33]([OH:36])CO)[C:9]=12.O1CCCC1.CO>O>[Cl:7][C:8]1[N:13]=[C:12]([N:14]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[N:11]=[C:10]2[N:29]([CH2:37][C:38]3[CH:39]=[CH:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=3)[N:30]=[C:31]([CH2:32][CH2:33][OH:36])[C:9]=12
Reactant: COc1ccc(Cn2nc(CC(O)CO)c3c(Cl)nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc32)cc1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1ccc(Cn2nc(CCO)c3c(Cl)nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
Sodium periodate (19 g) was added to a mixture composed of the above di-tert-butyl {4-chloro-3-(2,3-dihydroxypropyl)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl}imidodicarbonate (10 g), tetrahydrofuran (100 ml), methanol (100 ml) and water (100 ml) under cooling in an ice bath, and the mixture was stirred at room temperature for one hour. The reaction mixture was separated with water (600 mL) and ethyl acetate (400 mL). The organic layer was washed with brine, and then dried over anhydrous sodium sulfate and filtered. Then, the filtrate was concentrated under reduced pressure. Methanol (200 mL) was added to the resulting residue. Sodium borohydride (1000 mg) was added under cooling in an ice bath, and the mixture was stirred for one hour. Water (400 ml) was added to the reaction mixture, followed by extraction with ethyl acetate (300 ml) twice. Then, the organic layers were washed with brine. The organic layers were dried over anhydrous sodium sulfate and filtered. Then, the filtrate was concentrated under reduced pressure and the solvent was evaporated to obtain the title compound (8.5 g, 90%) as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]([C:17]#[N:18])=[CH:12][N:7]3[C@@H:8]([CH3:11])[CH2:9][O:10][C:5]([C:6]=23)=[C:4](F)[C:3]=1[F:20].[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C@@H:27]1[CH2:31][CH2:30][C@H:29]([NH2:32])[CH2:28]1.C(N(CC)CC)C>CS(C)=O>[NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]([C:17]#[N:18])=[CH:12][N:7]3[C@@H:8]([CH3:11])[CH2:9][O:10][C:5]([C:6]=23)=[C:4]([NH:32][C@H:29]2[CH2:30][CH2:31][C@@H:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=3)[CH2:28]2)[C:3]=1[F:20]
Reactant: N[C@H]1CC[C@@H](c2ccccn2)C1
Reactant: C[C@H]1COc2c(F)c(F)c(N)c3c(=O)c(C#N)cn1c23
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: C[C@H]1COc2c(N[C@H]3CC[C@@H](c4ccccn4)C3)c(F)c(N)c3c(=O)c(C#N)cn1c23
Temperature: 80 °C
Reaction time: 8 h
Yield: 20.4 %

Procedure:
A mixture of (3S)-8-amino-9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carbonitrile (180 mg, 0.649 mmol), cis-3-(2-pyridyl)cyclopentylamine (158 mg, 0.973 mmol) and triethylamine (0.200 mL, 0.976 mmol) in anhydrous DMSO (3 mL) was stirred at 80° C. for 8 h. After cooling, the reaction mixture was poured into ice-water and then extracted with CH2Cl2-MeOH. The organic layer was washed with water and brine, and dried over anhyd Na2SO4 followed by the removal of solvent. The crude product was purified by column chromatography (Hexane/EtOAc=1/3) to yield (3S)-8-amino-9-fluoro-2,3-dihydro-3-methyl-7-oxo-10-[cis-3-(2-pyridyl)cyclopentylamino]-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carbonitrile (diastereomer mixture, 55.6 mg, 20%) as a yellow powder.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:19])([F:18])[C:5]1[CH:10]=[C:9]([NH:11][C:12]2[CH2:16][CH2:15][C:14](=[O:17])[CH:13]=2)[CH:8]=[CH:7][N:6]=1.CC1CCCO1.[C:26]([C:28]1[CH:33]=[CH:32][C:31]([N:34]([CH2:42]S(C2C=CC=CC=2)(=O)=O)[C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[C:30]([S:52]([CH3:55])(=[O:54])=[O:53])[CH:29]=1)#[N:27]>C(OCC)(=O)C.O>[C:26]([C:28]1[CH:33]=[CH:32][C:31]([N:34]([CH2:42][C:13]2[C:14](=[O:17])[CH2:15][CH2:16][C:12]=2[NH:11][C:9]2[CH:8]=[CH:7][N:6]=[C:5]([C:4]([F:3])([F:18])[F:19])[CH:10]=2)[C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[C:30]([S:52]([CH3:55])(=[O:53])=[O:54])[CH:29]=1)#[N:27]
Reactant: O=C1C=C(Nc2ccnc(C(F)(F)F)c2)CC1
Reactant: CC(C)(C)OC(=O)N(CS(=O)(=O)c1ccccc1)c1ccc(C#N)cc1S(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC1CCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(CC1=C(Nc2ccnc(C(F)(F)F)c2)CCC1=O)c1ccc(C#N)cc1S(C)(=O)=O

Procedure:
Sodium hydride (60% in mineral oil, 515 mg, 12.9 mmol) is added in portions to a mixture of 3-(2-(trifluoromethyl)pyridin-4-ylamino)cyclopent-2-enone (intermediate 17, 2.60 g, 10.7 mmol) and 2-methyltetrahydrofuran (40 mL). After 10 min tert-butyl (4-cyano-2-(methylsulfonyl)phenyl)(phenylsulfonyl)methylcarbamate (intermediate 15, 4.83 g, 10.7 mmol) is added, and the mixture is stirred at room temperature for 30 min Water and ethyl acetate are added, and the phases are separated. The organic phases is washed twice with water and concentrated under reduced pressure. Yield: 6.20 g; ESI mass spectrum [M+H]+=551; Retention time HPLC: 1.12 min (Z018_S04).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH2:42]([O:49][C:50]1[CH:77]=[CH:76][C:75](O)=[CH:74][C:51]=1[C:52]([NH:54][C:55]1[CH:67]=[C:66]([C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)[CH:65]=[CH:64][C:56]=1[C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])=[O:53])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>O1CCCC1>[CH2:42]([O:49][C:50]1[CH:77]=[CH:76][C:75]([O:1][CH:2]2[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]2)=[CH:74][C:51]=1[C:52]([NH:54][C:55]1[CH:67]=[C:66]([C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)[CH:65]=[CH:64][C:56]=1[C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])=[O:53])[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(O)ccc1OCc1ccccc1
Reactant: CN1CCC(O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN1CCC(Oc2ccc(OCc3ccccc3)c(C(=O)Nc3cc(-c4ccccc4)ccc3C(=O)OC(C)(C)C)c2)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
4-Hydroxy-1-methylpiperidine (0.17 g), triphenylphosphine (0.39 g), and diisopropyl azodicarboxylate (0.30 mL) were added to a tetrahydrofuran (3.0 mL) solution of tert-butyl 2-(2-(benzyloxy)-5-hydroxybenzamido)-4-phenylbenzoate (0.15 g), followed by stirring at room temperature for 3 hours and 20 minutes. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography [eluent: 60-50% hexane/ethyl acetate to 100-90% chloroform/methanol] to obtain tert-butyl 2-(2-(benzyloxy)-5-((1-methylpiperidin-4-yl)oxy)benzamido)-4-phenylbenzoate.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][O:5][C:6]1[CH:7]=[N:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[CH:10][CH:11]=1.[BH4-].[Li+].O>C1COCC1>[F:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:9]1[N:8]=[CH:7][C:6]([O:5][CH2:4][CH2:3][OH:2])=[CH:11][CH:10]=1
Reactant: COC(=O)COc1ccc(-c2ccccc2F)nc1
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCCOc1ccc(-c2ccccc2F)nc1

Procedure:
Under argon, 675 mg (2.58 mmol) of (6-(2-fluorophenyl)pyridin-3-yloxy)acetic acid methyl ester and 112.5 mg (5.17 mmol) of lithium borohydride were stirred in 20 ml of THF at 60° C. for 2 h. After cooling, the mixture was cautiously hydrolyzed with water and concentrated, and water and ethyl acetate were added. The organic phase was separated, washed with water and concentrated. Yield: 350 mg (58%).
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(=O)([O-])[O-].[K+].[K+].F[C:29]1[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=1.O>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:9][C:10]1[CH:11]=[CH:12][C:13]([N:16]2[CH2:21][CH2:20][N:19]([C:29]3[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=3)[CH2:18][CH2:17]2)=[CH:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: N#Cc1ccc(F)cc1
Reactant: CCCCCCCCOc1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCCCCCOc1ccc(N2CCN(c3ccc(C#N)cc3)CC2)cc1
Temperature: 160 °C
Reaction time: 5 h
Yield: 82.9 %

Procedure:
To a suspension of 1-(4-n-Octyloxyphenyl)piperazine (1 g) and potassium carbonate (0.476 g) in N,N-dimethyl-formamide (1 ml) was added p-fluorobenzonitrile (0.347 g), and stirred for 5 hours at 160° C. The reaction mixture was added to a mixture of water and ethyl acetate. The organic layer was taken, and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give 4-[4-(4-n-Octyloxyphenyl)piperazin-1-yl]benzonitrile (0.93 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][N:3]=1.C1N2CCN(CC2)C1.[Cl:16][C:17]1[CH:18]=[C:19]([S:24](Cl)(=[O:26])=[O:25])[CH:20]=[CH:21][C:22]=1[F:23]>C(#N)C>[Cl:16][C:17]1[CH:18]=[C:19]([S:24]([NH:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][N:3]=2)(=[O:25])=[O:26])[CH:20]=[CH:21][C:22]=1[F:23]
Reactant: O=S(=O)(Cl)c1ccc(F)c(Cl)c1
Reactant: Nc1ccncn1
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: O=S(=O)(Nc1ccncn1)c1ccc(F)c(Cl)c1
Reaction time: 16 h
Yield: 27 %

Procedure:
4-Aminopyrimidine (1.0 g, 10.5 mmol) and DABCO™ (1.18 g, 10.5 mmol) were added concurrently to a solution of 3-chloro-4-fluorobenzenesulfonyl chloride (1.25 mL, 10.0 mmol) in anhydrous acetonitrile (49 mL). The reaction mixture immediately turned yellow and a precipitate was formed. After stirring for 16 hours, the mixture was concentrated in vacuo. The crude material was suspended in ethyl acetate (75 mL) and water (75 mL) and stirred for 15 minutes. The resulting solid was filtered and dried in vacuo to afford the title compound, 0.83 g, 27% yield.
Reaction SMILES: C1C2C(COC([NH:18][CH2:19][C:20]([NH:22][CH2:23][CH:24]3[CH2:29][CH2:28][N:27]([CH2:30][C:31]4[CH:36]=[CH:35][C:34]([S:37][CH3:38])=[CH:33][CH:32]=4)[CH2:26][CH2:25]3)=[O:21])=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>CN(C=O)C>[NH2:18][CH2:19][C:20]([NH:22][CH2:23][CH:24]1[CH2:29][CH2:28][N:27]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([S:37][CH3:38])=[CH:33][CH:32]=2)[CH2:26][CH2:25]1)=[O:21]
Reactant: CSc1ccc(CN2CCC(CNC(=O)CNC(=O)OCC3c4ccccc4-c4ccccc43)CC2)cc1
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: CSc1ccc(CN2CCC(CNC(=O)CN)CC2)cc1

Procedure:
A DMF (4 mL) solution of 4-[[N-(9-fluorenylmethyloxycarbonyl)glycyl]aminomethyl]-1-(4-methylthiobenzyl)piperidine (590 mg) and piperidine (1 mL) was stirred at 60° C. for 2 hours. After concentrating, the obtained crude product was purified by column chromatography (SiO2,triethylamine/methanol/dichloromethane=1:1:9) to thereby afford 4-[(glycylamino)methyl]-1-(4-methylthiobenzyl)piperidine (365 mg) as a white solid. 1H NMR (CDCl3, 270 MHz) δ 1.25 (dd, J=12 Hz, 4.1 Hz, 2H), 1.34 (dd, J=12 Hz, 4.1 Hz, 2H), 1.51 (br-s, 2H), 1.66 (d, J=12 Hz, 2H), 1.77 (d, J=7.3 Hz, 1H), 1.94 (t, J=9.5 Hz, 2H), 2.48 (s, 3H), 2.80 (d, J=12 Hz, 2H), 3.18 (t, J=6.2 Hz, 2H), 3.35 (s, 2H), 3.45 (s, 2H), 7.18-7.29 (m, 4H), 7.35 (br-s, 1H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6](=[O:8])[CH3:7].Br[CH2:10][CH2:11][CH2:12][C:13](=[O:16])[CH2:14][CH3:15]>>[CH3:10][C:11]([CH2:12][CH3:13])=[CH:2][CH2:3][CH2:4][CH2:5][C:6](=[O:8])[CH3:7].[CH3:2][C:3]([CH2:4][CH3:5])=[CH:10][CH2:11][CH2:12][C:13](=[O:16])[CH2:14][CH3:15]
Reactant: CC(=O)CCCCBr
Reactant: CCC(=O)CCCBr
Product: CCC(=O)CCC=C(C)CC
Product: CCC(C)=CCCCC(C)=O

Procedure:
By repeating the above process using the ethylene ketal of each of 1-bromo-5-hexanone and 1-bromo-4-hexanone, there is obtained 7-methyl-6-nonen-2-one and 7-methyl-6-nonen-3-one.
Reaction SMILES: [NH2:1][N:2]1[C:6]([CH3:7])=[N:5][NH:4][C:3]1=[O:8].[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=O)[CH:10]=1>Cl>[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[N:1][N:2]2[C:6]([CH3:7])=[N:5][NH:4][C:3]2=[O:8])[CH:10]=1
Reactant: Cc1n[nH]c(=O)n1N
Reactant: O=Cc1cccnc1
Agent: Cl
Product: Cc1n[nH]c(=O)n1N=Cc1cccnc1

Procedure:
A mixture of 5.7 g of 4-amino-5-methyl-1,2,4-triazol-3-one and 100 ml of alcohol is heated to the reflux temperature and 5.4 g of pyridine-3-carbaldehyde and 2 drops of 6N hydrochloric acid are added thereto. After 14 hours under reflux the reaction mixture is cooled to 20°. The product that has precipitated is then filtered off with suction and dried under a high vacuum. 3.4 g of the title compound having a melting point of 208°-210° are obtained.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[O:8]=[C:9]1[CH:15]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:14][S:13][CH2:12][CH2:11][NH:10]1.[F:24][C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([F:33])[CH:32]=1)[CH2:28]Br>O.CCOC(C)=O>[F:24][C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([F:33])[CH:32]=1)[CH2:28][N:10]1[C:9](=[O:8])[CH:15]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21])[CH2:14][S:13][CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)NC1CSCCNC1=O
Reactant: Fc1cc(F)cc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CSCCN(Cc2cc(F)cc(F)c2)C1=O
Yield: 79 %

Procedure:
121 mg of sodium hydride as a 60% suspension in oil (3.05 mmol) are introduced at room temperature into a 50 ml round-bottomed flask, with stirring and under an argon atmosphere, containing 20 ml of DMF and 500 mg of 26 (2.03 mmol). The medium is stirred for 1 hour and 454 mg (2.03 mmol) of 3,5-difluorobenzyl bromide are then added. The medium is stirred for 3 hours, 50 ml of EtOAc and 50 ml of water are added to the reaction medium and, after separation of the phases by settling, the organic phase is washed with 50 ml of water. The organic phase is dried, filtered and then evaporated to dryness. 1.5 g of crude product are recovered, which product is chromatographed on a silica cartridge (20 g, eluent: 80/20 heptane/EtOAc). 600 mg of product 33 are recovered (yield=79%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[O:7][CH:8]([C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[CH:12][CH:11]=1)[CH3:9].O.[OH-].[Li+].O.CO>O1CCCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[O:7][CH:8]([C:10]1[CH:19]=[CH:18][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1)[CH3:9]
Reactant: COC(=O)c1ccc(C(C)Oc2ncccn2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(Oc1ncccn1)c1ccc(C(=O)O)cc1
Temperature: 20 °C
Reaction time: 5 h
Yield: 76.8 %

Procedure:
A mixture of methyl 4-(1-(pyrimidin-2-yloxy)ethyl)benzoate (400 mg, 1.6 mmol), lithium hydroxide monohydrate (326 mg, 7.8 mmol), water (4 mL) and methanol (4 mL) in tetrahydrofuran (12 mL) was stirred at 20° C. for 5 hours. The reaction mixture was concentrated. The residue was acidified to pH=2 with concentrated hydrochloride solution. The mixture was extracted with ethyl acetate (20 mL×2). The organic phase was dried over sodium sulfate and filtered. The filtrate was concentrated. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=2:1) to give 4-(1-(pyrimidin-2-yloxy)ethyl)benzoic acid as a white solid (300 mg, 88%). LRMS (M+H+) m/z: 244.08. found 244.
Reaction SMILES: ON=[CH:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][CH:11]=[CH:10]2)=[O:5].S(=O)(=O)(O)[OH:18].O.C(=O)([O-])[O-].[Na+].[Na+].Cl>O>[C:3]1(=[O:18])[C:8]2=[C:9]3[C:14](=[CH:15][CH:16]=[C:7]2[NH:6][C:4]1=[O:5])[N:13]=[CH:12][CH:11]=[CH:10]3
Reactant: O=C(C=NO)Nc1ccc2ncccc2c1
Reactant: O=S(=O)(O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C1Nc2ccc3ncccc3c2C1=O
Temperature: 120 °C
Yield: 60 %

Procedure:
2-Hydroxyimino-N-(6-quinolinyl)acetamide (7.00 g, 32.5 mmol) was combined with 70 mL of concentrated sulfuric acid with stirring and heated to a reaction temperature of 120° C. for 20 min, followed by an hour at 95° C. The reaction was allowed to cool to room temperature and was added dropwise to a mixture of 155 g (1.25 mole) of sodium carbonate monohydrate and 200 g of ice. After the addition was complete, water (600 mL) was added gradually to the mixture with stirring until all inorganic white solid was dissolved. The aqueous mixture was neutralized to pH 7 with 1 M hydrochloric acid and the product was collected by filtration. The collected solid was added to 200 mL of water and dissolved by dropwise addition of 1 M hydrochloric acid to free entrapped salts. The product was then precipitated by addition of saturated aqueous sodium bicarbonate to pH 7. The product was collected by filtration and dried under vacuum at 55° C. to give 3.89 g (60%) of 3-H-pyrrolo[3,2-f]quinoline-1,2-dione as a red-brown solid. Mass spectrum (negative ion chemical ionization): m/z=197 (30%). NMR (DMSO-d6): δ7.43 (d, 1H, J=8.8 Hz), 7.66 (dd, 1H, J=4.1, 8.4 Hz); 8.29 (d, 1H, J=8.8 Hz); 8.72 (d, 1H, J=8.4 Hz); 8.82 (d, 1H, J=3.3 Hz); 11.2 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:16])[CH3:15])=[CH:9][CH:8]=2)[N:6]=1.[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[CH:20][C:19]=1[S:26](Cl)(=[O:28])=[O:27]>>[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[CH:20][C:19]=1[S:26]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14](=[O:16])[CH3:15])=[CH:11][CH:12]=2)[N:6]=1)(=[O:28])=[O:27]
Reactant: CC(=O)Nc1ccc(-c2csc(N)n2)cc1
Reactant: O=S(=O)(Cl)c1cc(Cl)c(Cl)cc1Cl
Product: CC(=O)Nc1ccc(-c2csc(NS(=O)(=O)c3cc(Cl)c(Cl)cc3Cl)n2)cc1

Procedure:
The title compound was prepared from N-[4-(2-amino-1,3-thiazol-4-yl)phenyl]acetamide (63 mg) and 2,4,5-trichlorobenzenesulfonyl chloride (76 mg) as described in the synthetic METHOD B to give a white-yellow solid (5,0 mg) with purity >90%: MS (pos) m/z 476.3. 478.3.
Reaction SMILES: CC1NC(C)=CC=1C1C=[CH:11][CH:10]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][N:21]3[CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:15][CH:14]=2)[N:8]=1.Cl.[NH2:35]O.[CH2:37](O)[CH3:38].Cl>O>[CH2:26]([N:21]1[CH2:22][CH2:23][CH2:24][CH2:25][CH:20]1[CH2:19][C:16]1[CH:15]=[CH:14][C:13]([C:9]2[N:8]=[C:38]([NH2:35])[CH:37]=[CH:11][CH:10]=2)=[CH:18][CH:17]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: Cc1cc(-c2cccc(-c3ccc(CC4CCCCN4Cc4ccccc4)cc3)n2)c(C)[nH]1
Reactant: CCO
Reactant: NO
Agent: Cl
Solvent: O
Product: Nc1cccc(-c2ccc(CC3CCCCN3Cc3ccccc3)cc2)n1

Procedure:
To a 100 mL round-bottomed flask equipped with condenser and N2 inlet were added 36 mg (0.0827 mmol) 2-(2,5-dimethylpyrrolyl)-6-[4-(1-benzyl-piperidin-2-ylmethyl)-phenyl]-pyridine, 29 mg (0.414 mmol) hydroxylamine hydrochloride, 4 mL ethanol and 1 mL water. The reaction was refluxed 84 h (additional hydroxylamine hydrochloride was used to complete the reaction), cooled, poured into dilute hydrochloric acid, and washed with ethyl acetate. The aqueous layer was adjusted to pH 10 with 6 N sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and evaporated. The resulting oil was converted to the hydrochloride salt using 1 N HCl in ether to afford a solid, 17 mg (48%), mp 70-85° C.
Reaction SMILES: [O:1]1[C:5]([CH:6]=O)=[CH:4][C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:19][C:20](=[O:22])[CH3:21])C=CC=CC=1.O>CS(C)=O>[O:1]1[C:5]([CH:6]=[CH:19][C:20](=[O:22])[CH3:21])=[CH:4][C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2
Reactant: O=Cc1cc2ccccc2o1
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)C=Cc1cc2ccccc2o1

Procedure:
A solution of benzo[b]furan-2-carboxaldehyde (3.3 g) and 1-triphenylphosphoranylidene-2-propanone (1.2 equivalents) in dimethyl sulfoxide (180 ml) was stirred at a temperature of 35° C. for a period of 30 minutes. The cooled mixture was poured into water and the aqueous mixture was extracted with diethyl ether. The solvent was evaporated from the dried (MgSO4) fraction and the residue was purified by column chromatography over silica gel (dichloromethane elution) to give 1-(benzo[b]furan-2-yl)but-1-en-3-one (3.0 g) as an orange solid, mp 100°-101° C.