Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][CH:22]=1)[O:6][C@@H:7]1[CH2:12][CH2:11][N:10](C)[CH2:9][C@H:8]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:30]([O:32][CH2:33][CH3:34])=[O:31]>C1C=CC=CC=1>[CH2:33]([O:32][C:30]([N:10]1[CH2:11][CH2:12][C@@H:7]([O:6][C:5]2[CH:20]=[CH:21][CH:22]=[C:3]([O:2][CH3:1])[CH:4]=2)[C@H:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9]1)=[O:31])[CH3:34]
Reactant: COc1cccc(O[C@@H]2CCN(C)C[C@H]2c2ccccc2)c1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: CCOC(=O)N1CC[C@@H](Oc2cccc(OC)c2)[C@H](c2ccccc2)C1
Temperature: 25 °C

Procedure:
A mixture of 0.45 g of trans-4-(3-methoxyphenoxy)-1-methyl-3-phenylpiperidine, 0.31 g of anhydrous potassium carbonate, 0.22 ml of ethyl chloroformate and 4 ml of anhydrous benzene is stirred for a few minutes at room temperature, then refluxed overnight. Another 0.11 ml of ethyl chloroformate is added, the mixture is refluxed for another 4 hours, then cooled and partitioned between 25 ml of ether and 25 ml of water. The aqueous phase is extracted with another 25 ml of ether, and the combined ether extracts are washed with 2 N hydrochloric acid (2×10 ml), saturated sodium chloride solution (25 ml), dried over anhydrous sodium sulfate and concentrated in vacuo to afford 0.37 g of product as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2/[CH:15]=[CH:16]/[C:17]([O:19]CC)=[O:18])=[CH:5][CH:4]=1.[OH-].[Na+].O1CCCC1.CO>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2/[CH:15]=[CH:16]/[C:17]([OH:19])=[O:18])=[CH:7][CH:8]=1
Reactant: CCOC(=O)/C=C/c1cnccc1-c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1ccc(-c2ccncc2/C=C/C(=O)O)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 85.6 %

Procedure:
A mixture of ethyl (2E)-3-[4-(4-methoxyphenyl)pyridin-3-yl]prop-2-enoate (2.75 g), 2M aqueous sodium hydroxide solution (7.3 mL), tetrahydrofuran (15 mL) and methanol (15 mL) was stirred at room temperature for 5 hr. To the reaction mixture was added water. The solvent was evaporated under reduced pressure, and the pH of the residue was adjusted to 5-6 with 10% aqueous citric acid solution. The precipitated solid was collected by filtration, washed with water and dried. The obtained solid was suspended in hot ethanol, and the suspension was stirred, and slowly cooled to room temperature. The suspension was filtered, and the obtained solid was washed with ethanol, and dried to give the title compound (2.12 g).
Reaction SMILES: [OH-].[K+].Cl[CH2:4][CH:5]([O:8][CH3:9])[O:6][CH3:7].O.[CH2:11]([OH:14])[CH2:12][OH:13]>>[CH3:7][O:6][CH:5]([O:8][CH3:9])[CH2:4][O:13][CH2:12][CH2:11][OH:14]
Reactant: OCCO
Reactant: COC(CCl)OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COC(COCCO)OC
Temperature: 115 °C
Yield: 44.9 %

Procedure:
Potassium hydroxide (30 g, 0.51 mol) was suspended in ethylene glycol (100 ml) and the mixture was heated to 115° C. with stirring. After the KOH dissolved completely, 2-chloro-1,1-dimethoxy-ethane (30.0 mL, 0.263 mol) was added dropwise (ca. 30 minutes) and the solution was stirred at 115° C. for 72 h. The resulting suspension was cooled to room temperature and 150 mL water was added. The solution was extracted with dichloromethane (3×100 mL) and the organic layers combined was washed with brine (2×100 mL) and dried with MgSO4. After filtration the solvent was removed under reduced pressure to give the product as a yellow oil (Yield, 17.7 g, 44.9%). 1H NMR (400.03 MHz, CDCl3, 298 K) δ=2.20 (s, 1H, OH), 3.40 (s, 6H, OCH3), 3.55 (d, J=5.3 Hz, 2H, CHCH2), 3.63-3.61 (m, J=4.0 Hz, OCH2), 3.74-3.72 (m, J=4.0 Hz, 2H, CH2OH), 4.52 (t, 1H, CH(OCH3)2. 13C{1H} NMR (100.59 MHz, CDCl3, 298 K) δ=54.12 (2C, CH3), 61.82 (1C, CH2OH), 70.78 (1C, CHCH2O), 73.00 (1C, OCH2CH2), 102.73 (1C, CH). Anal. Calcd. for C6H14O4: C, 47.99; H, 9.40. Found C, 45.02; H, 8.74
Reaction SMILES: [CH3:1][C:2]#[N:3].[Li]CCCC.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=1[CH2:18]Br>O1CCCC1>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=1[CH2:18][CH2:1][C:2]#[N:3]
Reactant: COc1ccc(Br)c(CBr)c1
Reactant: CC#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(Br)c(CCC#N)c1
Temperature: -78 °C

Procedure:
Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of MeCN (6.2 g, 151.22 mmol, 10.00 equiv) in tetrahydrofuran (20 mL). This was followed by the addition of n-BuLi (15.1 mL, 2.50 equiv, 2.5 M in hexane) dropwise with stirring at −78° C. The resulting solution was stirred for 1 h at −78° C. in a liquid nitrogen bath. To this was added a solution of 1-bromo-2-(bromomethyl)-4-methoxybenzene (4.2 g, 15.11 mmol, 1.00 equiv) in tetrahydrofuran (10 mL) dropwise with stirring at −78° C. The resulting solution was allowed to react, with stirring, for an additional 1 h while the temperature was maintained at −78° C. in a liquid nitrogen bath. The reaction mixture was then quenched by the addition of aqNH4Cl and extracted by EA (100 ml*3). The organic layers was concentrated and applied onto a silica gel column with PE/EA (10:1). This resulted in 2.29 g (63%) of 3-(2-bromo-5-methoxyphenyl)propanenitrile as a yellow semi-solid.
Reaction SMILES: [H-].[Na+].[CH2:3](Br)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:11]([O:27][C:28]([CH3:55])([CH3:54])[CH:29]([OH:53])[CH2:30][O:31]C(C1C=CC(OC)=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].O>CN(C)C=O>[CH2:11]([O:27][C:28]([CH3:54])([CH3:55])[CH:29]([O:53][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:30][OH:31])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCCCCCCCOC(C)(C)C(O)COC(c1ccccc1)(c1ccccc1)c1ccc(OC)cc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCCCCCCCOC(C)(C)C(CO)OCc1ccccc1
Reaction time: 8 h

Procedure:
To a suspension of 3.28 g of 50% sodium hydride in 40 ml of dimethylformamide containing 13.49 g of benzyl bromide was added dropwise a solution of 31.8 g of 3-(hexadecyloxy)-1-[(4-methoxyphenyl)diphenylmethoxy]-3-methyl-2-butanol in 50 ml of dimethylformamide over 45 minutes. The mixture was stirred overnight, then water was added and the mixture extracted with ether. The ether extract was dried and the solvent removed. The residue was stirred with 125 ml of methanol, 25 ml of tetrahydrofuran and 10 g of a strongly acidic ion exchange resin for 1.5 hours with warming, then filtered and the solvent removed. The residue was purified by HPLC, using hexane:ether (9:1), giving 12.14 g of the desired compound as a light yellow oil.
Reaction SMILES: [F:1][C:2]([F:15])([C:11]([F:14])([F:13])[F:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10].N1C=CC=CC=1.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>O>[S:28]([C:25]1[CH:26]=[CH:27][C:22]([CH3:32])=[CH:23][CH:24]=1)([O:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]([F:15])([F:1])[C:11]([F:12])([F:13])[F:14])(=[O:30])=[O:29]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCCCCCCC(F)(F)C(F)(F)F
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCCCCCCCC(F)(F)C(F)(F)F)cc1
Reaction time: 1.5 h

Procedure:
3.0 g of 8,8,9,9,9-pentafluorononan-1-ol are dissolved in 26 ml of abs. pyridine, 3.1 g of p-toluenesulphonyl chloride are added at 0° C. and the mixture is stirred in the cold for 1.5 hours. The reaction mixture is then added to water, extracted 3 times with ether, dried over magnesium sulphate and concentrated in vacuo. Preparative column chromatography on silica gel using a hexane-ethyl acetate gradient leads to 4.1 g of 8,8,9,9,9-pentafluorononyl tosylate as a clear oil.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[N+:22]([C:25]1[CH:34]=[CH:33][C:28]([CH:29]=[CH:30][CH2:31]O)=[CH:27][CH:26]=1)([O-:24])=[O:23].CCOCC>C(#N)C>[N+:22]([C:25]1[CH:34]=[CH:33][C:28](/[CH:29]=[CH:30]/[CH2:31][Br:20])=[CH:27][CH:26]=1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1ccc(C=CCO)cc1
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCOCC
Product: O=[N+]([O-])c1ccc(/C=C/CBr)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
In 35 mL of dry acetonitrile under nitrogen atmosphere was added 7.3 g (27.9 mmole) of triphenylphosphine. To the solution was added dropwise over 15 minutes 4.31 g of bromine (27.0 mmole) while cooling the reaction mixture to maintain the temperature between 0°-10° C. The solution was allowed to warm to room temperature (about 22°-25° C.) and 5.0 g (27.9 mmole) of p-nitrocinnamyl alcohol (Pfaultz & Bauer Chemical Co.) was added as a slurry in 50 mL of acetonitrile which caused an exothermic reaction, temperature about 45° C. The resulting dark red solution was heated for one hour at 60° C. with stirring and then poured into 500 mL of ether. Triphenylphosphine oxide precipitated from the solution after standing overnight (about 16 hours). The solution was filtered and 15 g of flash silica gel was added to the solution, followed by solvent removal. The resulting powder matrix was applied to a 3 in.×8 in. (7.6 cm×20.3 cm) flash column and the desired product was eluted with hexane, followed by 20% ethyl acetate in hexane to yield 5.8 g (23.9 mmole) of the desired pure trans product in 86% yield (MP=75°-76° C., Rf =0.81, 60:40 ethyl acetate:n-hexane) and was further characterized by:
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6](Br)[CH:7]=[C:8]2[C:12]=1[NH:11][N:10]=[C:9]2[CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)=[O:3].[CH3:27][S:28]([NH:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)(=[O:30])=[O:29].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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>[NH2:1][C:2]([C:4]1[CH:5]=[C:6]([C:36]2[CH:35]=[CH:34][CH:33]=[C:32]([NH:31][S:28]([CH3:27])(=[O:29])=[O:30])[CH:37]=2)[CH:7]=[C:8]2[C:12]=1[NH:11][N:10]=[C:9]2[CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reactant: CS(=O)(=O)Nc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(-c4cccc(NS(C)(=O)=O)c4)cc23)CC1
Temperature: 160 °C

Procedure:
A mixture of 1,1-dimethylethyl 4-[7-(aminocarbonyl)-5-bromo-1H-indazol-3-yl]-1-piperidinecarboxylate (Intermediate 5) (30 mg, 0.07 mmols), {3-[(methylsulfonyl)amino]phenyl}boronic acid (46 mg, 0.21 mmols), cesium carbonate (150 mg), and Pd(PPh3)4 (10 mg) in dioxane/water (3/1, 4 mL) was heated at 160° C. for 2700 secs. (microwave irradiation). The resulting mixture was concentrated, redissolved in methylene chloride and filtered. The filtrate was concentrated and used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][CH:5]=[C:6](Cl)[C:7]=1[Cl:8].CCN(C(C)C)C(C)C.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>CN1C(=O)CCC1>[Cl:1][C:2]1[N:3]=[N:4][CH:5]=[C:6]([N:23]2[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]2)[C:7]=1[Cl:8]
Reactant: CN1CCNCC1
Reactant: Clc1cnnc(Cl)c1Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2cnnc(Cl)c2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.4 %

Procedure:
3,4,5-Trichloropyridazine (3 g, 16.36 mmol) was dissolved in dry NMP (18 mL) and cooled in an ice-bath. DIPEA (2.326 g, 3.135 mL, 18 mmol) was added, followed, dropwise, by 1-methylpiperazine (1.721 g, 1.906 mL, 17.18 mmol). The resulting mixture was stirred at RT overnight. The reaction mixture was concentrated under reduced pressure to give an brown solid which was partitioned between 10% MeOH in DCM and saturated NaHCO3. The aqueous layer was extracted with further 10% MeOH in DCM (5×20 mL) and the combined organics were dried over Na2SO4, filtered and concentrated under reduced pressure to give a brown oil which was purified by column chromatography (7.5% MeOH in DCM, ˜300 mL silica, loaded in DCM) to provide 3,4-dichloro-5-(4-methylpiperazin-1-yl)pyridazine as a light yellow solid (2.36 g, 58% Yield).
Reaction SMILES: [CH3:1][N:2]1[C:10](=[O:11])[NH:9][C:8]2[C:3]1=[N:4][C:5](/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[N:6][CH:7]=2.CN(C)C=O>[Pd].C(O)C>[CH3:1][N:2]1[C:10](=[O:11])[NH:9][C:8]2[C:3]1=[N:4][C:5]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[N:6][CH:7]=2
Reactant: Cn1c(=O)[nH]c2cnc(/C=C/c3ccccc3)nc21
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCO
Product: Cn1c(=O)[nH]c2cnc(CCc3ccccc3)nc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 9-methyl-2-[(E)-2-phenylethenyl]-7,9-dihydro-8H-purine-8-one <the compound of Reference Example 3> (80 mg), N,N-dimethylformamide (2 ml) and ethanol (3 ml) was added 10% palladium on carbon (2 mg) and the mixture was stirred at room temperature under hydrogen atmosphere for 1 hour. The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=100/0˜0/100) to give the title compound 47 mg.
Reaction SMILES: [CH:1](=O)[CH:2]([CH3:4])[CH3:3].[NH2:6][CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.O>C1C=CC=CC=1>[CH:1](=[C:12]1[CH:13]=[C:8]([CH2:7][NH2:6])[CH:9]=[CH:10][NH:11]1)[CH:2]([CH3:4])[CH3:3]
Reactant: NCc1ccncc1
Reactant: CC(C)C=O
Solvent: c1ccccc1
Solvent: O
Product: CC(C)C=C1C=C(CN)C=CN1
Yield: 91.7 %

Procedure:
227 g (3.15 mols) of isobutyraldehyde is added dropwise, within 1.5 hours, to a solution of 324 g (3.0 mols) of 4-aminomethylpyridine in 300 ml of benzene, the addition being made in a manner ensuring that the temperature in the solution does not exceed 35° C. The water which has formed (about 39 g) is separated, and the benzene (with residual water) is distilled off under a slight water-jet vacuum. The residue is distilled in an oil-pump vacuum. After a small preliminary fraction of 5 g, there is obtained 445 g (2.75 mols) of isobutylidene-4-aminomethylpyridine as a slightly yellowish main fraction, corresponding to a yield of 91.5% of theory; b.p. 81.5°-82° C./133 Pa; nD° =1.5105.
Reaction SMILES: [CH3:1][C:2]1[S:7](=[O:9])(=[O:8])[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[O:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.O[CH2:22][CH2:23][CH2:24][N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH3:1][C:2]1[S:7](=[O:9])(=[O:8])[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[O:4][C:3]=1[C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:22][CH2:23][CH2:24][N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:18][CH:19]=1
Reactant: OCCCN1CCCC1
Reactant: CC1=C(c2ccc(O)cc2)Oc2ccccc2S1(=O)=O
Product: CC1=C(c2ccc(OCCCN3CCCC3)cc2)Oc2ccccc2S1(=O)=O

Procedure:
The entitled compound was obtained according to the method of Example 3 but using the compound synthesized in the above (1) and 1-(3-hydroxypropyl)pyrrolidine as the starting material.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[CH3:27][S:28]([C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=1)(=[O:30])=[O:29]>ClC1C=CC=CC=1Cl.Cl.COC(C)(C)C>[Cl:1][C:2]1[C:3]([NH:35][C:34]2[CH:33]=[CH:32][C:31]([S:28]([CH3:27])(=[O:30])=[O:29])=[CH:37][CH:36]=2)=[C:4]2[NH:10][C:9]([C:11]3[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)=[CH:15][CH:16]=3)=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(N)cc1
Reactant: Clc1cnc2[nH]c(-c3ccc(OCCN4CCOCC4)cc3)nc2c1Cl
Agent: Cl
Solvent: Clc1ccccc1Cl
Solvent: COC(C)(C)C
Product: CS(=O)(=O)c1ccc(Nc2c(Cl)cnc3nc(-c4ccc(OCCN5CCOCC5)cc4)[nH]c23)cc1
Temperature: 180 °C
Yield: 26.5 %

Procedure:
6,7-Dichloro-2-[4-(2-morpholin-4-ylethoxy)phenyl]-3H-imidazo[4,5-b]pyridine (Example 206) (0.02 g, 0.05 mmol) and 4-(methylsulfonyl)aniline (0.1 g) were dissolved in o-dichlorobenzene (0.7 ml) and 4 drops of concentrated HCl were added and the reaction mixture was heated in a microwave oven at 180° C. for 10 min. The reaction mixture was diluted with tert-butyl methyl ether (5 ml) and extracted with 2M HCl (10 ml). The aqueous phase was basified with 10M NaOH and extracted with EtOAc. The organic phase was evaporated in vacuo and the residue was dissolved in CH3CN (2 ml) and purified by HPLC-C is, giving the title product (7 mg, 26%).
Reaction SMILES: Cl[CH:2]([C:6]1[CH:21]=[CH:20][C:9]2[O:10][CH2:11][C:12]3[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=3[C:14](=[O:15])[C:8]=2[CH:7]=1)[C:3]([OH:5])=[O:4].[H][H]>[C].[Pd].C(OCC)(=O)C>[O:15]=[C:14]1[C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[CH2:11][O:10][C:9]2[CH:20]=[CH:21][C:6]([CH2:2][C:3]([OH:5])=[O:4])=[CH:7][C:8]1=2
Reactant: O=C1c2ccccc2COc2ccc(C(Cl)C(=O)O)cc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(O)Cc1ccc2c(c1)C(=O)c1ccccc1CO2
Reaction time: 4 h

Procedure:
A mixture containing 6,11-dihydro-α-chloro-11-oxodibenz[b,e]oxepin-2-acetic acid in the amount of 0.2 grams, 0.2 grams of 5% palladium-carbon reduction catalyst, 30 ml ethyl acetate and commercially available 4Å molecular sieve (Davidson Grade 514, Type 4A, 8-12 mesh beads, alumina silicate base with sodium cation, available from W. R. Grace) was treated with hydrogen (10 psi). The reduction reaction was run for 4 hours and then worked up by filtration and concentration in vacuo to yield 0.18 grams of crude product. 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetic acid (V) was obtained after purification by chromatography on silica gel using ethyl acetate. Its structure was confirmed by comparison of its infra-red, proton-NMR and thin layer chromatography with that of an authentic sample.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH3:15])[CH2:10][CH2:9][CH2:8][CH:7]([N:11]=[N+]=[N-])[CH:6]1[OH:14])=[O:4]>CO.CC(O)=O.[Pd]>[CH3:1][O:2][C:3]([C:5]1([CH3:15])[CH2:10][CH2:9][CH2:8][CH:7]([NH2:11])[CH:6]1[OH:14])=[O:4]
Reactant: COC(=O)C1(C)CCCC(N=[N+]=[N-])C1O
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)C1(C)CCCC(N)C1O

Procedure:
A solution of racemic methyl-3-azido-2-hydroxy-1-methyl-cyclohexane-carboxylate, 66c, (0.90 g, 4.22 mmol) in a mixture of MeOH (50 mL) and AcOH (10 mL) was stirred under a hydrogen atmosphere (balloon) with the presence of palladium (0.50 g, 0.47 mmol) overnight at room temperature. The mixture was filtered through a celite bed and washed with MeOH. The combined filtrates were evaporated to provide methyl-3-amino-2-hydroxy-1-methyl-cyclohexanecarboxylate as a oil. Et2O was added and the resulted acetic acid salt was stirred for 0.5 hour and was then filtered to give 1.0 g of racemic methyl-3-amino-2-hydroxy-1-methyl-cyclohexanecarboxylate acetic acid salt as a white solid.
Reaction SMILES: O1CC1CO[C:6]1[CH:23]=[CH:22][CH:21]=[CH:20][C:7]=1[C:8]([NH:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[CH:14][NH:15]2)=[O:9].C(N)(CC)(C)C>C(O)C>[NH:15]1[C:16]2[C:12](=[C:11]([NH:10][C:8](=[O:9])[C:7]3[CH:6]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:19]=[CH:18][CH:17]=2)[CH:13]=[CH:14]1
Reactant: O=C(Nc1cccc2[nH]ccc12)c1ccccc1OCC1CO1
Agent: CCC(C)(C)N
Solvent: CCO
Product: O=C(Nc1cccc2[nH]ccc12)c1ccccc1

Procedure:
3.5 g of the product of Step B dissolved in 35 ml of ethanol was refluxed with stirring and under an inert atmosphere for 5 hours with 3 ml of tert-pentyl-amine and the solvent was evaporated off. The residue was purified by chromatography over silica (eluant: methylene chloride/methanol 9:1) to obtain 3.5 g of 2-[3-[1,1-dimethylpropyl)amino]-2-hydroxypropoxy]-N-(1H-indol-4-yl)benzamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:20]=[C:19]([CH3:21])[C:13]2[N:14]=[C:15]([NH2:18])[N:16]=[N:17][C:12]=2[CH:11]=1.Br[C:23]1[CH:28]=[CH:27][C:26]([S:29]([CH2:32][CH2:33][CH2:34][N:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)(=[O:31])=[O:30])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:20]=[C:19]([CH3:21])[C:13]2[N:14]=[C:15]([NH:18][C:23]3[CH:28]=[CH:27][C:26]([S:29]([CH2:32][CH2:33][CH2:34][N:35]4[CH2:36][CH2:37][CH2:38][CH2:39]4)(=[O:31])=[O:30])=[CH:25][CH:24]=3)[N:16]=[N:17][C:12]=2[CH:11]=1
Reactant: O=S(=O)(CCCN1CCCC1)c1ccc(Br)cc1
Reactant: COc1ccc(Cl)c(-c2cc(C)c3nc(N)nnc3c2)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClCCl
Product: COc1ccc(Cl)c(-c2cc(C)c3nc(Nc4ccc(S(=O)(=O)CCCN5CCCC5)cc4)nnc3c2)c1
Yield: 89.1 %

Procedure:
In a dry 25 mL round bottom flask, 7-(2-chloro-5-methoxy-phenyl)-5-methyl-benzo[1,2,4]triazin-3-ylamine (0.0361 g, 0.122 mmol, 1 equiv), 1-[3-(4-bromo-benzenesulfonyl)-propyl]-pyrrolidine (0.061 g, 0.184 mmol, 1.5 equiv), cesium carbonate (0.120 g, 0.367 mmol, 3 equiv), 4,5-bis(diphenylphosphino)-9,9-dimethyl xanthene (0.014 g, 0.0244 mmol, 0.2 equiv) and tris(dibenzylideneacetone)dipalladium (0.012 g, 0.0122 mmol, 0.1 equiv) were combined. The reactants were flushed with argon, diluted with dioxane (6 mL) and outfitted with reflux condenser. The reaction was heated to reflux for 18 hours, filtered hot, diluted with ethyl acetate and washed with brine. The brine layer was back extracted once with fresh ethyl acetate. The organic phases were combined and dried over sodium sulfate (Na2SO4). Filtration followed by evaporation provided crude product, which was dissolved in minimum amount of DCM and precipitated out with excess hexanes. Solids were filtered off and dried to yield a yellow powder (0.06 g, 91% yield).
Reaction SMILES: [F:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][C:11]=2[O:19][CH3:20])[CH2:3]1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[S:32][C:31]([C:33](OC)=[O:34])=[C:30](/[N:37]=[CH:38]/N(C)C)[CH:29]=2)=[CH:24][CH:23]=1.C1(O)C=CC=CC=1>C(Cl)Cl>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[S:32][C:31]3[C:33](=[O:34])[N:16]([C:13]4[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][N:4]5[CH2:5][CH2:6][CH:2]([F:1])[CH2:3]5)=[C:11]([O:19][CH3:20])[CH:12]=4)[CH:38]=[N:37][C:30]=3[CH:29]=2)=[CH:26][CH:27]=1
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1/N=C/N(C)C
Reactant: COc1cc([N+](=O)[O-])ccc1OCCN1CCC(F)C1
Solvent: Oc1ccccc1
Solvent: ClCCl
Product: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OCCN1CCC(F)C1
Temperature: 200 °C
Reaction time: 0.75 h
Yield: 11.5 %

Procedure:
3-Fluoro-1-[2-(2-methoxy-4-nitrophenoxy)ethyl]pyrrolidine (0.0442 g, 0.1740 mmol) and methyl 5-(4-chlorophenyl)-3-{[(1E)-(dimethylamino)methylidene]amino}thiophene-2-carboxylate (0.056 g, 0.1740 mmol) were charged to a flask. Phenol (1 g) was added and the reaction heated to 200° C. The reaction was stirred for 45 min until all starting material was gone. The mix was then cooled to RT, diluted with CH2Cl2 (30 mL) and washed with 1N NaOH (2×30 mL), water (1×30 mL), brine (1×30 mL), dried over MgSO4, filtered, and concentrated. The residue was purified on a chromatatron (98:2 CH2Cl2:MeOH) to give 0.010 g (0.020 mmol, 11%) of the product as a tan solid. 1H NMR (CDCl3) δ 8.13 (s, 1H), 7.65 (d, 2H, J=8.3 Hz), 7.52 (s, 1H), 7.43 (d, 2H, J=8.4 Hz), 7.00 (d, 1H, J=8.4 Hz), 6.93 (m, 2H), 5.29-5.13 (m,1H), 4.23 (t, 2H, J=5.7 Hz), 3.88 (s, 3H), 3.12-2.93 (m, 5H), 2.68 (bs, 1H), 2.25-2.06 (m, 2H).