Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([N:10]2[C:25](=[O:26])[C:14]3[CH:15]=[N:16][C:17]4[C:18]([O:23][CH3:24])=[CH:19][CH:20]=[CH:21][C:22]=4[C:13]=3[N:12]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[C:11]2=[O:33])[CH:7]=[CH:8][CH:9]=1.Cl[C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36]>>[CH:38]([O:37][C:35]([N:30]1[CH2:31][CH2:32][CH:27]([N:12]2[C:13]3[C:22]4[CH:21]=[CH:20][CH:19]=[C:18]([O:23][CH3:24])[C:17]=4[N:16]=[CH:15][C:14]=3[C:25](=[O:26])[N:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([Cl:3])[CH:5]=3)[C:11]2=[O:33])[CH2:28][CH2:29]1)=[O:36])([CH3:40])[CH3:39]
Reactant: CC(C)OC(=O)Cl
Reactant: COc1cccc2c1ncc1c(=O)n(-c3cccc(Cl)c3)c(=O)n(C3CCNCC3)c12
Agent: Cl
Product: COc1cccc2c1ncc1c(=O)n(-c3cccc(Cl)c3)c(=O)n(C3CCN(C(=O)OC(C)C)CC3)c12

Procedure:
4-[3-(3-Chloro-phenyl)-7-methoxy-2,4-dioxo-3,4-dihydro-2H-pyrimido[5,4-c]quinolin-1-yl]-piperidine-1-carboxylic acid isopropyl ester (47 mg) was prepared according to general procedure H from 3-(3-chloro-phenyl)-7-methoxy-1-piperidin-4-yl-1H-pyrimido[5,4-c]quinoline-2,4-dione.dihydrochloride (50 mg, 0.105 mmol) and isopropyl chloroformate. LCMS: m/z 523 [M+1]+.
Reaction SMILES: [CH3:1][C:2]([S:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)([CH3:8])[C:3]([O:5]CC)=[O:4].[OH-].[Na+]>CO>[CH3:8][C:2]([S:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=1)([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(C)(C)Sc1ccccc1-c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(Sc1ccccc1-c1ccncc1)C(=O)O
Temperature: 60 °C
Reaction time: 12 h

Procedure:
A mixture of ethyl 2-methyl-2-(2-(pyridin-4-yl)phenylthio)propanoate and aqueous sodium hydroxide solution (1 M) in methanol is stirred at 60° C. for 12 hours. The reaction mixture is then concentrated, acidified, filtered and the isolated solid purified by to chromatography.
Reaction SMILES: B([O-])([O-])[O-].B([O-])([O-])[O-].B([O-])([O-])[O-].B([O-])([O-])[O-].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[CH2:29]([SH:32])[CH2:30][SH:31].[C:33]([NH2:37])(=[O:36])[CH:34]=[CH2:35]>O>[CH2:29]([S:32][CH2:35][CH2:34][C:33]([NH2:37])=[O:36])[CH2:30][S:31][CH2:35][CH2:34][C:33]([NH2:37])=[O:36]
Reactant: C=CC(N)=O
Reactant: SCCS
Agent: [Na+]
Agent: [O-]B([O-])[O-]
Solvent: O
Product: NC(=O)CCSCCSCCC(N)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.3 %

Procedure:
Sodium tetraborate (1.20 g, 5.95 mmol) was dissolved in DI water (150 mL). 1,2-Ethane dithiol (5.00 mL, 59.4 mmol) was added, followed by acrylamide (9.31 g, 130 mmol), and stirred at room temperature for two hours to give a white-colored slurry. The solid was filtered off, washed with water and dried under vacuum, giving 13.1 g (93.2%) of Compound 1 as a white solid. 1H NMR (500 MHz, d6-DMSO) δ 7.33 (s, 2H), 6.82 (s, 2H), 3.37 (s, 4H), 2.69 (t, J=7.2 Hz 4H), 2.32 (t, J=7.3 Hz, 4H). 13C NMR (126 MHz, d6-DMSO) δ 172.68, 35.69, 31.35, 26.92.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH2:8][O:9][C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[CH:4][C:3]=1[CH:29]=O.C([O-])(=O)C.[NH4+].[N+:36]([CH3:39])([O-:38])=[O:37]>>[NH2:1][C:2]1[N:6]([CH2:7][CH2:8][O:9][C:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[CH:4][C:3]=1/[CH:29]=[CH:39]/[N+:36]([O-:38])=[O:37]
Reactant: Nc1c(C=O)cnn1CCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: Nc1c(/C=C/[N+](=O)[O-])cnn1CCOC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
A solution of 5-amino-1-(2-triphenylmethyloxyethyl)-1H-pyrazole-4-carbaldehyde (15 g) and ammonium acetate (4.07 g) in nitromethane (300 ml) was refluxed for 6.5 hours. The reaction mixture was evaporated under reduced pressure and extracted with dichloromethane. The extract was dried over anhydrous magnesium sulfate, filtered, and evaporated in vacuo to give 5-amino-4—[(E)-2-nitroethenyl]-1-(2-triphenylmethyloxyethyl)-1H-pyrazole (4.46 g). 1H-NMR(DMSO-d6) δ3.15 (2H, t, J=4.9 Hz), 4.16 (2H, t, J=4.9 Hz), 6.96 (2H, s), 7.1–7.3 (15H, m), 7.75 (1H, d, J=12.9 Hz), 7.83 (1H, s), 8.27 (1H, d, J=12.9 Hz)
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([F:15])=[CH:13][C:12]([C:16]2[O:17][C:18]3[CH:24]=[C:23]([O:25][CH2:26][C@@H:27]([NH:29][C:30](=[O:32])[CH3:31])[CH3:28])[CH:22]=[CH:21][C:19]=3[N:20]=2)=[CH:11][C:10]=1[F:33])[C:2]1C=CC=CC=1.BrCC#[N:37]>>[C:2]([CH2:1][O:8][C:9]1[C:10]([F:33])=[CH:11][C:12]([C:16]2[O:17][C:18]3[CH:24]=[C:23]([O:25][CH2:26][C@@H:27]([NH:29][C:30](=[O:32])[CH3:31])[CH3:28])[CH:22]=[CH:21][C:19]=3[N:20]=2)=[CH:13][C:14]=1[F:15])#[N:37]
Reactant: N#CCBr
Reactant: CC(=O)N[C@@H](C)COc1ccc2nc(-c3cc(F)c(OCc4ccccc4)c(F)c3)oc2c1
Product: CC(=O)N[C@@H](C)COc1ccc2nc(-c3cc(F)c(OCC#N)c(F)c3)oc2c1

Procedure:
Using N-((2S)-1-((2-(4-(benzyloxy)-3,5-difluorophenyl)-1,3-benzoxazol-6-yl)oxy)propan-2-yl)acetamide and bromoacetonitrile, and in the same manner as in Example 5, the title compound was obtained.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[CH:6][C:5]([O:11][CH3:12])=[C:4]([O:13][CH3:14])[CH:3]=1.[CH2:15](Br)[C:16]#[CH:17].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CC(C)=O>[CH2:17]([O:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[CH:6][C:5]([O:11][CH3:12])=[C:4]([O:13][CH3:14])[CH:3]=1)[C:16]#[CH:15]
Reactant: CCCc1cc(OC)c(OC)cc1O
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: C#CCOc1cc(OC)c(OC)cc1CCC

Procedure:
Following the same procedure as in Example 3 b), 3.92 g (0.02 moles) of 1-hydroxy-6-propyl-3,4-dimethoxybenzene were reacted with 3.0 g (0.02 moles) of a solution of propargyl bromide in toluene (80% w/w) and 2.8 g (0.02 moles) of anhydrous potassium carbonate in 20 ml of acetone.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1[C:9]([C:13]2[CH:18]=[CH:17][C:16]([O:19]CC3C=CC(OC)=CC=3)=[CH:15][CH:14]=2)=[N:10][O:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.O.C(Cl)Cl.C(OCC)(=O)C>C(Cl)Cl.O>[C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1[C:9]([C:13]2[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=2)=[N:10][O:11][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(COc2ccc(-c3nocc3NC(=O)OC(C)(C)C)cc2)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1conc1-c1ccc(O)cc1
Reaction time: 60 h
Yield: 101.9 %

Procedure:
To a solution of {3-[4-(4-methoxy-benzyloxy)-phenyl]-isoxazol-4-yl}-carbamic acid tert-butyl ester (3.01 g, 7.6 mmol) in CH2Cl2 (80 mL) and water (8 mL) was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (5.17 g, 23 mmol). After stirring for 60 h, the reaction mixture was suspended between a water/CH2Cl2 bilayer. The organic phase was removed and the aqueous phase was extracted twice with CH2Cl2. The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo to give a deep red oil. [3-(4-Hydroxy-phenyl)-isoxazol-4-yl]-carbamic acid tert-butyl ester (2.14 g, 92%) was isolated by chromatography (1-100% ethyl acetate in hexanes).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([C:17](O)([CH2:20][CH3:21])[CH2:18][CH3:19])=[CH:14][C:13]=2[CH:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]1([CH3:31])[C:29]([OH:30])=[CH:28][CH:27]=[CH:26][CH:25]=1.B(F)(F)F.O(CC)CC>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([C:17]([C:26]3[CH:27]=[CH:28][C:29]([OH:30])=[C:24]([CH3:31])[CH:25]=3)([CH2:20][CH3:21])[CH2:18][CH3:19])=[CH:14][C:13]=2[CH:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccccc1O
Reactant: CCC(O)(CC)c1cc2cc(OCc3ccccc3)ccc2o1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCC(CC)(c1ccc(O)c(C)c1)c1cc2cc(OCc3ccccc3)ccc2o1
Yield: 51.3 %

Procedure:
3-(5-Benzyloxy-benzofuran-2-yl)-pentan-3-ol (6.10 g, 19.7 mmol) and o-cresol (2.55 g, 23.6 mmol) and BF3—OEt2 (1.39 g, 9.83 mmol) in CH2Cl2 are reacted analogous to Example 18-C to give the title compound (4.05 g, 51%).
Reaction SMILES: [NH2:1][CH:2]([CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=[CH2:12]>CCO>[CH2:15]([O:14][C:10](=[O:13])[CH2:11][CH2:12][NH:1][CH:2]([CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:16]
Reactant: CCOC(=O)CC(C)N
Reactant: C=CC(=O)OCC
Solvent: CCO
Product: CCOC(=O)CCNC(C)CC(=O)OCC

Procedure:
A solution of ethyl 3-aminobutanoate (4.2 g) and of ethyl 2-propenoate (3.83 mL) in EtOH (20 mL) was stirred at room temperature for 8 h. The solvent was evaporated under reduced pressure and the residue purified by chromatography on NH column eluting with a gradient from 100% cyclohexane to 90% ethyl acetate/cyclohexane. The title compound was isolated as a colourless oil, 3.9 g (MS (m/z): 232 [MH]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:10])=[CH:4][C:5]([CH2:8][OH:9])=[N:6][CH:7]=1.[Mn]([O-])(=O)(=O)=[O:12].[K+].C(O)(C)C>CC(C)=O.[O-2].[O-2].[Mn+4]>[Br:1][C:2]1[C:3]([Cl:10])=[CH:4][C:5]([C:8]([OH:12])=[O:9])=[N:6][CH:7]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: OCc1cc(Cl)c(Br)cn1
Agent: [Mn+4]
Agent: [K+]
Agent: [O-2]
Solvent: CC(C)O
Solvent: CC(C)=O
Product: O=C(O)c1cc(Cl)c(Br)cn1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
0.50 g (2.3 mmol) (5-bromo-4-chloro-pyridin-2-yl)-methanol in 8 mL acetone were added dropwise at RT to 0.71 g (4.5 mmol) potassium permanganate in 10 mL acetone and then the mixture was stirred for 17 h at RT. Then 10 mL isopropanol were added and the mixture was stirred for a further 5 h at RT. The precipitated manganese dioxide was suction filtered and washed with water. The filtrate was partially evaporated down and the aqueous phase was adjusted to a pH of 3 with 1N aqueous hydrochloric acid solution. The precipitate formed was suction filtered.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH:17]([C:19]1[CH:20]=[C:21]([CH:31]=[CH:32][CH:33]=1)[CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=O.O>C(COC)OC.C(OCC)(=O)C>[C:26]([O:25][C:24]([NH:23][CH2:22][C:21]1[CH:20]=[C:19]([CH:33]=[CH:32][CH:31]=1)[CH:17]=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:30])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)NCc1cccc(C=O)c1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C=Cc1cccc(CNC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
374 mg of 60% sodium hydride was suspended in 20.0 mL of dimethoxyethane, and 1.91 g of ethyl diethylphosphonoacetate was added dropwise thereto at −5° C., followed by stirring at room temperature for 10 minutes. To the reaction liquid was added dropwise a solution of tert-butyl (3-formylbenzyl)carbamate in dimethoxyethane (5.00 mL), followed by stirring at 60° C. for 4 hours. The reaction liquid was cooled to room temperature, followed by addition of water and extraction with ethyl acetate. The organic layer was washed with brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain ethyl 3-{[(tert-butoxycarbonyl)amino]methyl}cinnamate. This was dissolved in 5.00 mL of ethyl acetate, and 8.50 mL of a 4 M hydrogen chloride/ethyl acetate solution was added thereto, followed by stirring at room temperature for 6 hours. The resulting precipitate was collected by filtration, washed with ethyl acetate, and then dried under reduced pressure to obtain 1.71 g of ethyl 3-(aminomethyl)cinnamate hydrochloride.
Reaction SMILES: [OH:1][PH2:2]=[O:3].[OH2:4].[OH2:5].O.O.O.O.[N+]([O-])([O-])=O.[Zn+2:14].[N+]([O-])([O-])=O.[Zn]>O>[P:2]([O-:5])([O-:4])([O-:1])=[O:3].[Zn+2:14].[P:2]([O-:5])([O-:4])([O-:1])=[O:3].[Zn+2:14].[Zn+2:14]
Reactant: O=[PH2]O
Reactant: O
Agent: O=[N+]([O-])[O-]
Agent: [Zn+2]
Agent: [Zn]
Product: O=P([O-])([O-])[O-]

Procedure:
An aqueous solution of 13.67 g 50 wt % H3PO2 was combined with 5.00 g deionized water to form a clear, colorless solution contained in a 250 ml Pyrex beaker. To this solution was added 46.23 g zinc nitrate hexahydrate salt, Zn(NO3)26H2O (Aldrich Chemical Co., Inc. #22,873-7, CAS #10196-18-6), equivalent to 21.97 wt. % Zn. The molar ratio of [Zn]2+/[PO4]−3 in this mixture was 3/2 and the equivalent solids level [as Zn3(PO4)2] was 27.5 wt. %.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([S:11]([NH:14][C:15]2[CH:16]=[C:17]([N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[C:18]3[O:22][CH:21]=[CH:20][C:19]=3[CH:23]=2)(=[O:13])=[O:12])[CH:6]=[CH:7][C:8]=1OC.N1(C2C3OC=CC=3C=C(N)C=2)CCCC1>>[N:24]1([C:17]2[C:18]3[O:22][CH:21]=[CH:20][C:19]=3[CH:23]=[C:15]([NH:14][S:11]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:3][CH:4]=3)(=[O:13])=[O:12])[CH:16]=2)[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: COc1ccc(S(=O)(=O)Nc2cc(N3CCCC3)c3occc3c2)cc1OC
Agent: Nc1cc(N2CCCC2)c2occc2c1
Product: O=S(=O)(Nc1cc(N2CCCC2)c2occc2c1)c1ccccc1

Procedure:
The title compound was prepared according to the procedure of Intermediate 3 starting from 7-pyrrolidin-1-yl-1-benzofuran-5-amine (Intermediate 9). Yield: 30 mg (22%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.86-1.93 (m, 4H), 3.36-3.43 (m, 4H), 6.13 (br s, 1H), 6.59 (br s, 1H), 6.73 (d, 1H), 7.45-7.60 (m, 3H), 7.73 (d, 2H), 7.79 (d, 1H), 9.92 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ ppm 24.73, 48.79, 100.68, 101.51, 106.97, 126.74, 128.33, 129.05, 132.58, 133.70, 134.62, 139.67, 140.68, 145.40; MS (ESI+) for C18H18N2O3S m/z 343 (M+H)+; HPLC 95% (System A).
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][CH:11]=[CH:10]3)[CH:2]=1.[H-].[Na+].Br[C:20]1[CH:21]=[C:22]2[C:26](=CC=1)N(CCCCCCCC)C=[C:23]2CC(O)=O>O>[CH3:23][C:22]([CH3:26])=[CH:21][CH2:20][N:12]1[C:13]2[C:9](=[CH:8][C:7]([C:3]3[CH:2]=[C:1]([CH3:16])[CH:6]=[CH:5][CH:4]=3)=[CH:15][CH:14]=2)[CH:10]=[CH:11]1
Reactant: Cc1cccc(-c2ccc3[nH]ccc3c2)c1
Reactant: CCCCCCCCn1cc(CC(=O)O)c2cc(Br)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC(C)=CCn1ccc2cc(-c3cccc(C)c3)ccc21
Reaction time: 1 h
Yield: 87.1 %

Procedure:
To the solution of 5-m-tolyl-1H-indole (3, 4 mmol, 1 equiv.) in anhydrous dimethylsulfoxide(DMSO) was added NaH (60% in mineral oil dispersion, 4.8 mmol, 1.2 equiv.) at room temperature. The mixture was stirred for about 1 h at the same temperature, then 1-chloro-3-methylbut-2-ene (4, 4.8 mmol, 1.2 equiv.) was added and the mixture was stirred for 4 h. Water was added to stop the reaction. The mixture was extracted by dichloromethane and the organic layer was washed with brine, dried (Na2SO4), filtered, and evaporated. The residue was purified by column chromatography of silica gel to get off-yellow oil. Yield: 87.1%. 1H NMR (300 MHz, CDCl3): δ 1.82 (s, 3 H), 1.88 (s, 3 H), 2.48 (s, 3 H), 4.74 (d, J=6.6 Hz, 2 H), 5.45 (t, J=6.9 Hz, 1 H), 6.57 (d, J=2.4 Hz, 1 H), 7.17 (t, J=3.3 Hz, 2 H), 7.34-7.43 (m, 2H), 7.49-7.52 (m, 3H), 7.89 (s, 1H). 13C NMR (75 MHz, CDCl3) δ 18.0, 21.6, 25.6, 44.2, 101.3, 109.6, 119.4, 119.9, 121.2, 124.4, 126.9, 128.0, 128.2, 128.5, 129.2, 132.9, 135.5, 136.3, 138.1, 142.6.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].[CH2:8](O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1.O>[Br:1][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6]
Reactant: OCc1ccccc1
Reactant: O=C(O)CCCBr
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: O=C(CCCBr)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 44.8 %

Procedure:
To a mixture of 4-bromobutyric acid (1 g), benzyl alcohol (0.65 g) and triphenyl phosphine (1.57 g) in tetrahydrofuran (12 mL) was added diethylazodicarboxylate (40% toluene solution, 2.88 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with diethylether. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=20/1) to give the title compound (0.69 g).
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]([NH:13][C:14]([C:16]2[CH:32]=[CH:31][C:19]([O:20][CH:21]3[CH2:26][CH2:25][CH:24]([C:27]([O:29]C)=[O:28])[CH2:23][CH2:22]3)=[CH:18][CH:17]=2)=[O:15])=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.O.[OH-].[Li+]>O>[CH2:1]([C:8]1[S:12][C:11]([NH:13][C:14]([C:16]2[CH:32]=[CH:31][C:19]([O:20][CH:21]3[CH2:22][CH2:23][CH:24]([C:27]([OH:29])=[O:28])[CH2:25][CH2:26]3)=[CH:18][CH:17]=2)=[O:15])=[N:10][N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C1CCC(Oc2ccc(C(=O)Nc3nnc(Cc4ccccc4)s3)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1nnc(Cc2ccccc2)s1)c1ccc(OC2CCC(C(=O)O)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.3 %

Procedure:
0.128 g of methyl 4-[4-(5-benzyl[1.3.4]thiadiazol-2-ylcarbamoyl)phenoxy]cyclohexanecarboxylate (0.28 mmol, 1 eq.) is placed in 2 mL of a mixture of tetrahydrofuran and water at room temperature. 0.024 g of lithium hydroxide monohydrate (0.57 mmol, 2 eq.) in 1 mL of water is added. After stirring for 2 hours at room temperature, the tetrahydrofuran is evaporated off and water is added. The aqueous phase is washed with dichloromethane. The aqueous phase is cooled to a temperature of 4° C. in an ice bath and acidified with 1N hydrochloric acid solution. The solid is filtered off and washed successively with water, with ethanol and then with diethyl ether to give 0.069 g of 4-[4-(5-benzyl[1.3.4]thiadiazol-2-ylcarbamoyl)phenoxy]cyclohexanecarboxylic acid.
Reaction SMILES: [CH2:1]([S:3][C:4]1[C:5]2[N:6]([CH:13]=[C:14]([C:16]3[N:17]=[N:18][N:19]([CH3:21])[N:20]=3)[CH:15]=2)[N:7]=[CH:8][C:9]=1[C:10]([NH2:12])=[O:11])[CH3:2].[OH:22]OS([O-])=O.[K+]>CC(C)=O.O>[CH2:1]([S:3]([C:4]1[C:5]2[N:6]([CH:13]=[C:14]([C:16]3[N:17]=[N:18][N:19]([CH3:21])[N:20]=3)[CH:15]=2)[N:7]=[CH:8][C:9]=1[C:10]([NH2:12])=[O:11])=[O:22])[CH3:2]
Reactant: O=S([O-])OO
Reactant: CCSc1c(C(N)=O)cnn2cc(-c3nnn(C)n3)cc12
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCS(=O)c1c(C(N)=O)cnn2cc(-c3nnn(C)n3)cc12
Temperature: 23 °C
Reaction time: 1 h
Yield: 85.2 %

Procedure:
To a solution of 4-(ethylthio)-6-(2-methyl-2H-tetrazol-5-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide (64 mg, 0.211 mmol) in acetone (1.0 mL) was added oxone (285 mg, 0.464 mmol) in water (1.0 mL). The reaction mixture was stirred at 23° C. for 1 hr. The reaction mixture was added 5 ml of water and stirred for 10 minutes. The solid was collected as the desired product (57.4 mg, 85% yield). 1H NMR (400 MHz, methanol-d4) δ 8.59 (d, J=1.8 Hz, 1H), 8.52 (s, 1H), 8.27 (d, J=1.5 Hz, 1H), 4.46 (s, 3H), 3.55-3.42 (m, 2H), 1.53 (s, 3H). MS (ES+) m/z: 320.10 (M+H); HPLC retention time: 2.007 min (analytical HPLC Method F).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH:12]=[C:13]([CH3:15])[CH3:14].CCOC(C)=O>[Pd]>[OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][CH:13]([CH3:15])[CH3:14]
Reactant: COC(=O)c1ccc(O)c(C=C(C)C)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(O)c(CC(C)C)c1
Reaction time: 16 h
Yield: 76.8 %

Procedure:
To a stirred solution of methyl 4-hydroxy-3-(2-methylprop-1-enyl)benzoate T23.2 (0.320 g, 1.6 mmol) in EtOAc (2.00 mL, 20 mmol) at 23° C. was added palladium on carbon (0.017 g, 0.16 mmol). The reaction was stirred under an atmosphere of hydrogen (0.0031 g, 1.6 mmol) for 16 hours. The reaction mixture was then filtered and concentrated in vacuo to give a clear oil. The residue was purified on silica gel (0-20% EtOAc in hexanes) to yield T23.3 as a colorless oil (0.256 g, 79% yield)
Reaction SMILES: [CH2:1]([NH:3][S:4](C1C=CC=CC=1O)(=[O:6])=[O:5])[CH3:2].[Cl:14][C:15]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:16]=1[C:17]([NH:19][CH2:20][C:21]1([C:27]2[C:32]([F:33])=[CH:31][CH:30]=[CH:29][N:28]=2)[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=[O:18].Cl>O1CCOCC1>[Cl:14][C:15]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:16]=1[C:17]([NH:19][CH2:20][C:21]1([C:27]2[C:32]([F:33])=[CH:31][CH:30]=[CH:29][N:28]=2)[CH2:22][CH2:23][N:24]([S:4]([NH:3][CH2:1][CH3:2])(=[O:6])=[O:5])[CH2:25][CH2:26]1)=[O:18]
Reactant: CCNS(=O)(=O)c1ccccc1O
Reactant: O=C(NCC1(c2ncccc2F)CCNCC1)c1ccc(Cl)cc1Cl
Agent: Cl
Solvent: C1COCCO1
Product: CCNS(=O)(=O)N1CCC(CNC(=O)c2ccc(Cl)cc2Cl)(c2ncccc2F)CC1

Procedure:
A solution of N-ethyl-2-hydroxyl-benzenesulfonamide (30 mg, 0.137 mmol) and 2,4-dichloro-N-{[4-(3-fluoropyridin-2-yl)piperidin-4-yl]methyl}benzamide (57.5 mg, 0.150 mmol) (prepared by the method in Example 1) in dioxane (2 ml) was refluxed under nitrogen for 4.5 hours. The mixture was allowed to cool then poured into 1 M HCl solution and extracted with diethyl ether (2×20 ml). The organic phase was washed with water (20 ml) and brine (20 ml), dried over MgSO4, filtered, and evaporated. The crude product was purified by preparatory TLC eluted with 50% ethyl acetate in isohexane to give the title product as a white foamy solid. 1H NMR δ (ppm)(CDCl3): 8.39-8.35 (1 H, m), 7.55 (1 H, d, J=8.4 Hz), 7.43-7.35 (2 H, m), 7.30-7.01 (2 H, m), 6.76-6.69 (1 H, m), 4.00-3.94 (3 H, m), 3.54-3.45 (2 H, m), 3.26-3.20 (2 H, m), 3.17-3.09 (2 H, m), 2.74-2.63 (2 H, m), 1.88-1.80 (2 H, m), 1.19 (3 H, t, J=7.2 Hz). m/e=489/491 (3:2).
Reaction SMILES: Cl.C(OC(=O)[NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[O:15][CH2:16][CH3:17])(C)(C)C>>[CH2:16]([O:15][C@H:10]1[CH2:11][CH2:12][CH2:13][CH2:14][C@H:9]1[NH2:8])[CH3:17]
Reactant: CCO[C@H]1CCCC[C@H]1NC(=O)OC(C)(C)C
Agent: Cl
Product: CCO[C@H]1CCCC[C@H]1N

Procedure:
This compound was prepared as HCl salt by using procedures analogous to those described for the synthesis of Example 55, Step 2 starting from tert-butyl(cis-2-ethoxycyclohexyl)carbamate. Analytic LCMS (M+H)+: m/z=144.1.
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:26])/[CH:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)[CH2:10][C@H:9]1[CH2:27][C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[NH:30][CH:29]=1)=[O:7].[OH-].[Na+].Cl.[CH3:49][N:50]([CH3:54])[CH2:51][CH2:52][Cl:53]>[Br-].C([N+](C)(C)C)CCCCCCCCCCCCCCC.ClCCl>[ClH:53].[F:45][C:2]([F:44])([F:1])[C:3]1[CH:4]=[C:5]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:26])/[CH:15]=[CH:16]/[C:17]2[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][CH:22]=2)[CH2:10][C@H:9]1[CH2:27][C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:30]([CH2:52][CH2:51][N:50]([CH3:54])[CH3:49])[CH:29]=1)=[O:7]
Reactant: CN(C)CCCl
Reactant: O=C(/C=C/c1ccc([N+](=O)[O-])cc1)N1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)C1
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: Cl
Agent: [Br-]
Solvent: ClCCl
Product: CN(C)CCn1cc(C[C@@H]2CN(C(=O)/C=C/c3ccc([N+](=O)[O-])cc3)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccccc21
Reaction time: 14 h
Yield: 29 %

Procedure:
To a mixture of (2R)-1-[3,5-bis(trifluoromethyl)-benzoyl]-2-(1H-indol-3-yl-methyl)-4-(4-nitro-trans-cinnamoyl)piperazine (100 mg), powdered sodium hydroxide (30 mg) and cetyltrimethylammonium bromide (10 mg) in dichloromethane (2 ml) was added 2-dimethylaminoethyl chloride hydrochloride (50 mg) at room temperature. The resulting mixture was stirred at the same temperature for 14 hours. After adding dichloromethane (10 ml), the reaction mixture was filtered through Celite pad and the filtrate was concentrated in vacuo. The resulting residue was purified by column chromatography on a silica gel eluting with a mixture of dichloromethane and methanol (30:1) and then treated with 4N hydrogen chloride in ethyl acetate solution to give (2R)-1-[3,5-bis(-trifluoromethyl)benzoyl]-2-[1-(2-dimethylaminoethyl)-1H-indol-3-yl-methyl]-4-(4-nitro-trans-cinnamoyl)piperazine hydrochloride (34 mg).