Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](N)[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:11][CH2:12][CH3:13].C[N:15](C=O)C>>[CH2:1]([CH2:13][CH2:12][CH2:11][NH2:15])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccco1
Reactant: CCCBr
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: NCCCCc1ccco1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of furfurylamine (1.0 g) in dry DMF (3 ml) was added to a cooled (0°-5° C.) stirred suspension of sodium hydride (60% dispersion; 0.46 g) in DMF (5 ml). After 15 minutes, a solution of 1-bromopropane (1.3 g) in dry DMF (2 ml) was added over 5 minutes. Stirring was continued for 1 h and the reaction mixture was then allowed to warm to room temperature and stirred overnight. The reaction was quenched by the addition of dilute hydrochloric acid. Aqueous sodium hydrogen carbonate solution (100 ml) was then added and the mixture was extracted with ethyl acetate (3×50 ml). The combined organic extracts were washed with water, brine and then dried (magnesium sulphate) and evaporated in vacuo. The residue was distilled under reduced pressure to furnish the title compound (0.21 g) as a colourless liquid.
Reaction SMILES: [Cl:1][SiH:2]([Cl:4])[Cl:3].[C:5]([O:10][CH2:11][CH:12]=[CH2:13])(=[O:9])[C:6]([CH3:8])=[CH2:7].[SiH4].[H][H]>CC(C)=O>[C:5]([O:10][CH2:11][CH2:12][CH2:13][Si:2]([Cl:4])([Cl:3])[Cl:1])(=[O:9])[C:6]([CH3:8])=[CH2:7]
Reactant: [H][H]
Reactant: Cl[SiH](Cl)Cl
Reactant: C=CCOC(=O)C(=C)C
Agent: [SiH4]
Solvent: CC(C)=O
Product: C=C(C)C(=O)OCCC[Si](Cl)(Cl)Cl
Temperature: 55 °C
Yield: 97 %

Procedure:
2 moles of trichlorosilane were heated in a common laboratory stirring vessel to 55° C. 0.1 ml of an 0.01 molar solution of mesityl oxide-platinum dichloride complex catalyst in acetone was added, and 2 moles of allyl methacrylate was added drop by drop under nitrogen over a period of 10 minutes with intense stirring. The internal temperature was in the meantime kept below 62° C., by external cooling. After another 8 minutes of stirring at about 60° C., no more silane hydrogen could be detected. Distillation of the product yielded 3-methacryloxypropyltrichlorosilane, (BP0.5 = 66° C.) in a yield of about 97%, with a residue of about 2%.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C:3]([C:5]1[O:6][C:7]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:8]=2[C:9]=1[CH2:10][C:11]([OH:13])=O)=[O:4].C1C=CC2N(O)N=NC=2C=1.[CH2:32]([NH:36][CH2:37][CH:38]([CH3:40])[CH3:39])[CH:33]([CH3:35])[CH3:34].CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)CCl>[CH3:1][C:2]([CH3:20])([CH3:21])[C:3]([C:5]1[O:6][C:7]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:8]=2[C:9]=1[CH2:10][C:11]([N:36]([CH2:37][CH:38]([CH3:40])[CH3:39])[CH2:32][CH:33]([CH3:35])[CH3:34])=[O:13])=[O:4]
Reactant: CC(C)CNCC(C)C
Reactant: COc1ccc2oc(C(=O)C(C)(C)C)c(CC(=O)O)c2c1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COc1ccc2oc(C(=O)C(C)(C)C)c(CC(=O)N(CC(C)C)CC(C)C)c2c1
Temperature: 40 °C

Procedure:
Dissolve a mixture of 17 mg [2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]acetic acid from the Step B Example 1 and 18.5 mg HOBt in 1 mL dry DMF. Add 15.4 μL di-i-butylamine followed by 23.0 mg EDC and 35 μL DIEA. This solution was heated at 40° C. for 2 hours. It was purified directly on RP-HPLC using 65-100% MeCN gradient. The fractions containing pure product were pooled and lyophilized to give the title compound. LC-MS: 4.42 min. (m/Z=318.2, 402.2, 424.2).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[NH:19][C:20]1[C:21]2[C:28]([CH3:29])=[C:27]([C:30]([O:32][CH3:33])=[O:31])[S:26][C:22]=2[N:23]=[CH:24][N:25]=1)=O)(C)(C)C.[Cl:34]CCl>FC(F)(F)C(O)=O>[ClH:34].[NH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[NH:19][C:20]1[C:21]2[C:28]([CH3:29])=[C:27]([C:30]([O:32][CH3:33])=[O:31])[S:26][C:22]=2[N:23]=[CH:24][N:25]=1
Reactant: ClCCl
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OCCNC(=O)OC(C)(C)C)c2c1C
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OCCN)c2c1C
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl 4-(2-(2-(tert-butoxycarbonylamino)ethoxy)-4-fluorophenylamino)-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylate (20 mg) was dissolved in 25% solution of trifluoroacetic acid in dichlormethane (2 ml). The reaction was stirred at room temperature for 2 h. The solvent was concentrated in vacuo and the residue was dissolved in methanol and triturated with HCl in methanol.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH2:3]1.[Br:7][CH2:8][CH2:9][O:10][CH3:11]>CC(C)=O>[Br-:7].[CH3:11][O:10][CH2:9][CH2:8][N+:2]1([CH3:1])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CN1CCCC1
Reactant: COCCBr
Solvent: CC(C)=O
Product: COCC[N+]1(C)CCCC1
Product: [Br-]
Yield: 70 %

Procedure:
A mixture of N-methylpyrrolidine (9.11 g, 0.1 mol), 1-bromo-2-methoxyethane (15.0 g, 0.107 mol) and anhydrous acetone (40 cm3) was refluxed for 24 h. After evaporation under reduced pressure, the yellow solid was washed with diethylether. 1-(2-methoxyethyl)-1-methylpyrrolidinium bromide was obtained as white solid in ca. 70% yield. δH (500.13 MHz, CDCl3) 3.95 (2H, m), 3.85 (6H, m), 3.40 (3H, s), 3.23 (3H, s), 2.29 (4H, m).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[N:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][N:19]=2)[CH:5]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:7]=1.Br[C:29]1[CH:30]=[C:31]([CH:36]=[CH:37][CH:38]=1)[C:32]([O:34][CH3:35])=[O:33].O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[CH3:1][C:2]1[CH:7]=[C:6]([C:29]2[CH:38]=[CH:37][CH:36]=[C:31]([C:32]([O:34][CH3:35])=[O:33])[CH:30]=2)[CH:5]=[C:4]([NH:17][C:18]2[N:23]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:21]=[CH:20][N:19]=2)[CH:3]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: COC(=O)c1cccc(Br)c1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(-c2cc(C)cc(Nc3nccc(C(F)(F)F)n3)c2)c1
Temperature: 160 °C

Procedure:
A suspension of N-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (1.00 g, 2.64 mmol), methyl 3-bromobenzoate (0.581 g, 2.70 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.054 g, 0.066 mmol), 1,4-dioxane (10 mL), and aqueous sodium carbonate (2 M, 2.64 mL, 5.27 mmol) was placed under an argon atmosphere by performing 6 vacuum/argon cycles. The reaction mixture was then heated to 160° C. for 10 minutes in a microwave reactor. The resulting suspension was diluted with ethyl acetate (75 mL) and saturated aqueous sodium bicarbonate solution (25 mL). The layers were separated, and the organic layer was washed with water (10 mL) and then brine (25 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (ethyl acetate/hexanes) to afford methyl 3′-methyl-5′-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}biphenyl-3-carboxylate. MS ESI calc'd. for C20H17F3N3O2 [M+H]+ 388, found 388.
Reaction SMILES: [CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:22](Cl)([O:24]C(=O)OC(Cl)(Cl)Cl)Cl.[NH2:33][CH2:34][CH:35]1[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:36]1.C([O-])(O)=O.[Na+]>O1CCCC1>[CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:22]([NH:33][CH2:34][CH:35]2[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:36]2)=[O:24])[C:5]1=[O:13])([CH3:3])[CH3:2]
Reactant: CC(C)n1c(=O)[nH]c2ccccc21
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)n1c(=O)n(C(=O)NCC2CCN(C(=O)OC(C)(C)C)CC2)c2ccccc21
Temperature: 25 °C
Yield: 62 %

Procedure:
To a stirred solution of 1-isopropyl-1,3-dihydro-2H-benzimidazol-2one (J. Med. Chem. 1999, 42, 2870-2880) (3.00 g, 17.02 mmol) and triethylamine (7.12 ml, 51.06 mmol) in 70 ml tetrahydrofuran was added triphosgen (5.15 g, 17.02 mmol) in 14 ml tetrahydrofuran at room temperature. The reaction mixture was refluxed for 19 hours. The mixture was then cooled to room temperature, tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (J. Prugh, L. A. Birchenough and M. S. Egbertson, Synth. Commun., 1992, 22, 2357-60) (3.28 g, 15.32 mmol) in 10 ml tetrahydrofuran was added. The reaction mixture was refluxed for another 24 hours. Then cooled and basified with aqueous saturated NaHCO3 50 ml, and extracted with ethyl acetate 100 ml for three times. The combined extract was washed with brine, dried over MgSO4 and concentrated. Flash chromatography of the residue (elutent: hexane/ethyl acetate=5/1 to 1/2) afforded a colorless oil 3.99 g (62%) as the titled compound.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=[O:8])=CC=1.[CH2:12]([C:19]1([C:25]([N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:26])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:32]([N:40]1[CH2:45][CH2:44][CH2:43][C:42]([C:54]2[CH:59]=[CH:58][C:57]([Cl:60])=[C:56]([Cl:61])[CH:55]=2)([CH2:46][CH2:47][CH2:48]OS(C)(=O)=O)[CH2:41]1)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C([O-])([O-])=O.[K+].[K+].[ClH:68]>CN(C=O)C.O>[OH2:8].[ClH:60].[C:32]([N:40]1[CH2:45][CH2:44][CH2:43][C:42]([CH2:46][CH2:47][CH2:48][N:22]2[CH2:23][CH2:24][C:19]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)([C:25]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:26])[CH2:20][CH2:21]2)([C:54]2[CH:59]=[CH:58][C:57]([Cl:60])=[C:56]([Cl:61])[CH:55]=2)[CH2:41]1)(=[O:39])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1.[C:32]([N:40]1[CH2:45][CH2:44][CH2:43][C:42]([C:54]2[CH:59]=[CH:58][C:57]([Cl:60])=[C:56]([Cl:61])[CH:55]=2)([CH2:46][CH2:47][CH2:48][N:22]2[CH2:23][CH2:24][C:19]([C:25]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:26])([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:20][CH2:21]2)[CH2:41]1)(=[O:39])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1.[ClH:68]
Reactant: O=C(N1CCCC1)C1(Cc2ccccc2)CCNCC1
Reactant: CS(=O)(=O)OCCCC1(c2ccc(Cl)c(Cl)c2)CCCN(C(=O)c2ccccc2)C1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1ccccc1)N1CCCC(CCCN2CCC(Cc3ccccc3)(C(=O)N3CCCC3)CC2)(c2ccc(Cl)c(Cl)c2)C1
Temperature: 80 °C

Procedure:
A mixture of 4-benzyl-4-(pyrrolidin-1-ylcarbonyl)piperidine p-toluenesulfonate, 0.65 g of the compound obtained in step B of EXAMPLE 1 and 0.7 g of K2CO3 in 6 ml of DMF is heated at 80° C. for 3 hours. The reaction mixture is poured into iced water and the precipitate formed is filtered off and washed with water. The precipitate is dissolved in AcOEt, the organic phase is dried over MgSO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica H using DCM and then a DCM/MeOH mixture (95/5; v/v) as the eluent. The product obtained is taken up with ethereal hydrogen chloride and the precipitate formed is filtered off to give 0.56 g of the expected product.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:35]=[CH:34][C:17]3[C:18]4[N:19]=[C:20]([C:26]5[N:27]([CH:31]([CH3:33])[CH3:32])[N:28]=[CH:29][N:30]=5)[S:21][C:22]=4[CH2:23][CH2:24][O:25][C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.CCOCC>CO>[CH:31]([N:27]1[C:26]([C:20]2[S:21][C:22]3[CH2:23][CH2:24][O:25][C:16]4[CH:15]=[C:14]([CH:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)[CH:35]=[CH:34][C:17]=4[C:18]=3[N:19]=2)=[N:30][CH:29]=[N:28]1)([CH3:33])[CH3:32]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CCN(C(=O)OC(C)(C)C)CC3)ccc1-2
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CCNCC3)ccc1-2
Reaction time: 18 h
Yield: 27.7 %

Procedure:
Alternatively, to a suspension of 4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-piperidine-1-carboxylic acid tert-butyl ester (470 mg, 0.95 mmol) in MeOH (10 mL) was added 1M HCl in ether (1.9 mL, 1.90 mmol). The reaction mixture was stirred for 18 hours then the volatiles were removed in vacuo. The resultant residue was stirred in diethyl ether (20 mL) for 20 minutes then the solid was filtered off and further triturated with a mixture of MeOH and ether to give 375 as a white solid (104 mg, 28%). LCMS: RT=7.82 min, [M+H]+=396. 1H NMR δ (ppm) (DMSO-d6): 8.86 (2H, s), 8.26 (1H, d, J=8.20 Hz), 8.05 (1H, s), 7.03 (1H, dd, J=8.26, 1.83 Hz), 6.87 (1H, d, J=1.78 Hz), 5.81-5.71 (1H, m), 4.31 (2H, t, J=5.01 Hz), 3.37 (2H, t, J=5.01 Hz), 3.30 (2H, d, J=12.46 Hz), 2.93 (2H, d, J=11.52 Hz), 2.84-2.75 (1H, m), 1.92-1.75 (4H, m), 1.49 (6H, d, J=6.59 Hz)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.[F:9][C:10]([F:16])([F:15])[S:11]([OH:14])(=[O:13])=[O:12]>>[F:9][C:10]([F:16])([F:15])[S:11]([O-:14])(=[O:13])=[O:12].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N+:3]=1[CH3:10]
Reactant: Fc1cccc(F)n1
Reactant: O=S(=O)(O)C(F)(F)F
Product: C[n+]1c(F)cccc1F
Product: O=S(=O)([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10 mmol of 2,6-difluoropyridine and 10 mmol of trifluoromethanesulphonic acid are mixed in a 50 ml round-bottomed flask and the mixture is stirred for 1 hour at ambient temperature under a nitrogen atmosphere. The white solid obtained is used directly in the following reaction without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:12]([NH2:14])=O)[NH:9]2)=[CH:5][C:4]=1[CH3:15].P(Cl)(Cl)(Cl)=O.C(Cl)(Cl)Cl>O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:12]#[N:14])[NH:9]2)=[CH:5][C:4]=1[CH3:15]
Reactant: COc1cc2[nH]c(C(N)=O)cc2cc1C
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc2[nH]c(C#N)cc2cc1C
Reaction time: 1 h
Yield: 62.3 %

Procedure:
A mixture of 202 mg of 6-methoxy-5-methyl-1H-indole-2-carboxamide (1 mmol), 0.47 mL of phosphorus oxychloride (5 mmol) and 3 mL of chloroform was refluxed for 2 hs. Then cooled solution was poured into 10 mL of water and stirred for 1 hr. After separation the organic layer was dried over sodium sulfate and concentrated. The residue was purified on silica gel column using hexane-ethyl acetate 5:1 to afford 116 mg of 6-methoxy-5-methyl-1H-indole-2-carbonitrile. 1H NMR (600 MHz, CDCl3): δ 8.26 (br, 1H), 7.37 (s, 1H), 7.06 (s, 1H), 6.76 (s, 1H), 3.88 (s, 1H), 2.28 (s, 3H).
Reaction SMILES: Cl.[NH2:2][N:3]=[CH:4][C:5]1[CH:32]=[CH:31][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:30]=[CH:29][C:19]([C:20]([N:22]([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])=[O:21])=[CH:18][CH:17]=2)=[CH:7][CH:6]=1.Cl.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1.C(N(CC)CC)C>C(Cl)Cl>[C:34]([N:2]=[N:3][CH2:4][C:5]1[CH:32]=[CH:31][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([C:20]([N:22]([CH:23]([CH3:24])[CH3:25])[CH:26]([CH3:27])[CH3:28])=[O:21])=[CH:29][CH:30]=2)=[CH:7][CH:6]=1)(=[O:41])[C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1
Reactant: CC(C)N(C(=O)c1ccc(OCCCCCOc2ccc(C=NN)cc2)cc1)C(C)C
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)N(C(=O)c1ccc(OCCCCCOc2ccc(CN=NC(=O)c3ccncc3)cc2)cc1)C(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a mixture of 5.0 g (9.2 mmol) of 4-[5-[4-(aminoiminomethyl)phenoxy]pentyloxy]-N,N-bis(1-methylethyl)benzamide monohydrochloride in 10 ml of methylene chloride is added 3.3 g (18.4 mmol) of isonicotinoyl chloride hydrochloride and 5.0 ml of triethylamine. The mixture is stirred at room temperature for 24 hours and purified by chromatography on silica gel with 80% ethyl acetate/hexane as the eluent to obtain 4-[5-[4-[(isonicotinoylimino)aminomethyl]phenoxy]pentyloxy]-N,N-bis(1 -methylethyl)benzamide:
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:14]([CH3:16])[CH3:15])=[C:9]([C:17]([F:20])([F:19])[F:18])[CH:8]=2)=[N:5][N:6]=1.[F:21][C:22]1[CH:23]=[C:24](/[CH:39]=[CH:40]/[O:41][CH3:42])[C:25]([O:37][CH3:38])=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:27]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:21][C:22]1[CH:23]=[C:24](/[CH:39]=[CH:40]/[O:41][CH3:42])[C:25]([O:37][CH3:38])=[C:26]([C:2]2[S:3][C:4]([C:7]3[CH:12]=[CH:11][C:10]([O:13][CH:14]([CH3:16])[CH3:15])=[C:9]([C:17]([F:20])([F:19])[F:18])[CH:8]=3)=[N:5][N:6]=2)[CH:27]=1
Reactant: CC(C)Oc1ccc(-c2nnc(Br)s2)cc1C(F)(F)F
Reactant: CO/C=C/c1cc(F)cc(B2OC(C)(C)C(C)(C)O2)c1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CO/C=C/c1cc(F)cc(-c2nnc(-c3ccc(OC(C)C)c(C(F)(F)F)c3)s2)c1OC
Temperature: 120 °C
Yield: 33.9 %

Procedure:
To a suspension of 2-bromo-5-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,3,4-thiadiazole (D4) (393 mg), 2-{5-fluoro-2-(methyloxy)-3-[(E)-2-(methyloxy)ethenyl]phenyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (495 mg) and tripotassium phosphate (568 mg) in N,N-dimethylformamide (DMF) (8 mL) and water (2 mL) under nitrogen was added Pd(Ph3P)4 (61.8 mg). The reaction vessel was sealed and heated under microwave at 120° C. for 10 min. Water was added. The reaction mixture was extracted with EA for 3 times, the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, the dried solution was concentrated, and purified by column chromatography to afford 2-{5-fluoro-2-(methyloxy)-3-[(E)-2-(methyloxy)ethenyl]phenyl}-5-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,3,4-thiadiazole (D34) (170 mg) as a yellow solid. MS (ES): C22H20F4N2O3S requires 468. found 469.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.F[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=1[F:19].C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C>O>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=2[F:19])[CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccnc(Cl)c1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Nc2ccnc(Cl)c2)c(F)c1
Temperature: 25 °C
Yield: 26.8 %

Procedure:
Add 2-chloropyridin-4-amine (500 mg, 3.9 mmol), 1,2-difluoro-4-nitrobenzene (620 mg, 3.9 mmol), Cs2CO3 (3.2 g, 9.8 mmol) to DMF (15 mL). Stir the reaction at 110° C. for 16 hrs. Cool to room temperature, add water (100 mL), extract with EtOAc (15 mL×3). Combine the organic layers and wash with brine, dry over anhydrous Na2SO4. Concentrate under reduced pressure to give the crude product. Purification by chromatography (silica gel, EtOAc:PE=1:4) affords the title compound (280 mg, 27%). MS: (M+1): 268.1.
Reaction SMILES: [C:1]([OH:10])(=[O:9])/[CH:2]=[CH:3]\[CH:4]=[CH:5]\[C:6]([OH:8])=[O:7].II>C1COCC1>[C:1]([OH:10])(=[O:9])/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[C:6]([OH:8])=[O:7]
Reactant: O=C(O)/C=C\C=C\C(=O)O
Agent: II
Solvent: C1CCOC1
Product: O=C(O)/C=C/C=C/C(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 84 %

Procedure:
Cis,trans-muconic acid (19 g, 133.8 mmol) is dissolved in THF (250 mL) at room temperature and a crystal of iodine (160 mg, 0.63 mmol, 0.5 mole percent) is added. The reaction is performed in the presence of ambient light in the laboratory. The reaction mixture is allowed to stir at room temperature for 5 hours and the precipitant is filtered, washed with acetonitrile and dried under reduced pressure to yield 16 g of trans, trans-muconic acid, an 84 percent yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:15]4=[C:16]([CH2:18][S:19][CH2:20][CH2:21][N:14]4[C@H:13]4[CH2:22][CH2:23][N:24](C(OC(C)(C)C)=O)[CH2:25][C@@H:12]34)[CH:17]=2)=[C:5]([CH3:33])[CH:4]=1.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:15]4=[C:16]([CH2:18][S:19][CH2:20][CH2:21][N:14]4[C@H:13]4[CH2:22][CH2:23][NH:24][CH2:25][C@@H:12]34)[CH:17]=2)=[C:5]([CH3:33])[CH:4]=1
Reactant: COc1ccc(-c2cc3c4c(c2)[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2N4CCSC3)c(C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(-c2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCSC3)c(C)c1

Procedure:
To a solution of tert-butyl (7bR,11aS)-6-(4-methoxy-2-methylphenyl)-1,2,7b,10,11,11a-hexahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole-9(8H)-carboxylate (34 mg, 0.07 mmol) in CH2Cl2 (5 ml) at 25° C. was added trifluoroacetic acid (1 mL). The mixture was stirred at ambient temperature for 1 hour before saturated NaHCO3 (10 mL) was added and then extracted with EtOAc (2×20 mL). The combined extracts were dried over magnesium sulfate and concentrated to afford the title compound of EXAMPLE 9. 1H NMR(CDCl3, 300 MHz): δ 7.16 (d, 1H, J=8.0 Hz), 6.88 (s, 1H), 6.75 (m, 3H), 3.80 (s, 3H), 3.80 (m, 1H), 3.65 (m, 1H), 3.52 (m, 1H), 3.23-2.85 (m, 6H), 2.61 (m, 1H), 2.24 (s, 3H), 2.90 (m, 4H). LRMS (ES+): 367 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH2:20][CH:21]([C:23]2[O:24][C:25]([CH2:28][N:29]([CH3:31])[CH3:30])=[CH:26][CH:27]=2)[NH2:22])=[CH:11][C:12]([Cl:19])=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32](Cl)(=[O:36])[CH:33]([CH3:35])[CH3:34].C(N(CC)CC)C>O1CCCC1>[CH2:1]([O:8][C:9]1[C:10]([CH2:20][CH:21]([NH:22][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[C:23]2[O:24][C:25]([CH2:28][N:29]([CH3:30])[CH3:31])=[CH:26][CH:27]=2)=[CH:11][C:12]([Cl:19])=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)Cc1ccc(C(N)Cc2cc(Cl)c3cccnc3c2OCc2ccccc2)o1
Reactant: CC(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)C(=O)NC(Cc1cc(Cl)c2cccnc2c1OCc1ccccc1)c1ccc(CN(C)C)o1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 48.5 %

Procedure:
To a round bottom flask containing 2-[8-(benzyloxy)-5-chloroquinolin-7-yl]-1-{5-[(dimethylamino)methyl]-2-furyl}ethanamine (0.710 mmol) at 0° C. was added a solution of isobutyryl chloride (0.852 mmol, 1.2 eq.) and triethylamine (0.852 mmol, 1.2 eq.) in tetrahydrofuran (5 mL) that was pre-mixed and stirred 5 min prior to addition. After warming to room temperature, the resulting solution was stirred 2 h and quenched with saturated aqueous sodium bicarbonate solution (1 mL) and stirred 5 min. The reaction was diluted with 0.1N NaOH (15 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were dried (MgSO4), filtered and concentrated to a yellow syrup that was purified by column chromatography to afford the final product as a white solid (0.344 mmol, 47% for 2 steps). HRMS: calcd for C29H32ClN3O3+H+, 506.22049; found (ESI, [M+H]+ Obs'd), 506.2208.
Reaction SMILES: [CH:1]([C:4]1([CH3:21])[C:19](=[O:20])[N:7]2[C:8](=[O:18])[C:9]3[CH:10]=[C:11]4[CH:17]=[CH:16][O:15][C:12]4=[N:13][C:14]=3[C:6]2=[N:5]1)([CH3:3])[CH3:2].C[O-].[Na+].[C:25](O)(=[O:27])C>CO>[CH:1]([C:4]1([CH3:21])[C:19](=[O:20])[NH:7][C:6]([C:14]2[N:13]=[C:12]3[O:15][CH:16]=[CH:17][C:11]3=[CH:10][C:9]=2[C:8]([O:27][CH3:25])=[O:18])=[N:5]1)([CH3:2])[CH3:3]
Reactant: CC(C)C1(C)N=C2c3nc4occc4cc3C(=O)N2C1=O
Reactant: CC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc2ccoc2nc1C1=NC(C)(C(C)C)C(=O)N1
Temperature: 25 °C
Reaction time: 72 h
Yield: 84 %

Procedure:
The compound prepared in Example 40 (10.5 g, 0.037 mol) is suspended in 150 mL absolute methanol and 4.0 g sodium methoxide is added. After stirring for 72 hours at room temperature the mixture is poured onto ice containing acetic acid to maintain the pH at 3-4. A white solid forms and is filtered yielding 9.8 g (84%) of the title compound with mp 134°-137° C.