Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)#[N:3].N=O.CO[CH:15](OC)[CH2:16][NH:17]C.[CH3:21]O>>[CH3:21][N:3]1[CH:15]=[CH:16][N:17]=[C:2]1[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: CO
Reactant: CNCC(OC)OC
Agent: Cl
Agent: N=O
Product: Cn1ccnc1-c1ccc(O)cc1
Reaction time: 8 h
Yield: 66.7 %

Procedure:
Hydrogen chloride gas was bubbled through a chilled solution of p-cyanophenol (30 g, 0.25 mole) in methanol (120 mo) for 70 min. The heavy suspension was stoppered and stirred overnight. After cooling in an ice bath, the solid was collected by filtration and rinsed twice with cold methanol. The solid was dried under nitrogen to give 46.56 g. The solid iminoether was resuspended in methanol (150 ml) and treated with methylamino acetaldehyde dimethyl acetal (42 ml, 0.325 m) and then heated at reflux temperature for 3 hr. The reaction was then concentrated to an oil which was redissolved in 2N hydrochloric acid solution (200 ml). The solution was then concentrated to remove the methanol and the resulting aqueous solution was extracted twice with methylene chloride and then made basic first with 50% sodium hydroxide solution and finishing up with 10% sodium bicarbonate solution. The solid was collected and rinsed with water, 2-propanol and isopropyl ether. The solid was dissolved in methanol, treated with charcoal and filtered. The filtrate was partially concentrated by boiling and replacing the methanol with 2-propanol, from which a white, crystalline solid precipitated out of solution. The solid was filtered and dried (14.4 g, 0.083 mole, 66.7% yield, mp 239°-242° C.).
Reaction SMILES: Cl.Cl.N[C@H]1CCN(CC(C2CCCC[C@H]2O)C2C=CC=C([Cl:17])C=2)C1.[Cl:25][C:26]1[CH:27]=[C:28]([C@@H:32]([C:48]2([OH:54])[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]2)[C:33]([N:35]2[CH2:39][CH2:38][C@H:37]([NH:40]C(=O)OC(C)(C)C)[CH2:36]2)=O)[CH:29]=[CH:30][CH:31]=1>CO>[ClH:17].[ClH:25].[NH2:40][C@H:37]1[CH2:38][CH2:39][N:35]([CH2:33][C@H:32]([C:48]2([OH:54])[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]2)[C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([Cl:25])[CH:27]=2)[CH2:36]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)[C@@H](c2cccc(Cl)c2)C2(O)CCCCC2)C1
Reactant: N[C@H]1CCN(CC(c2cccc(Cl)c2)C2CCCC[C@H]2O)C1
Agent: Cl
Solvent: CO
Product: N[C@H]1CCN(C[C@@H](c2cccc(Cl)c2)C2(O)CCCCC2)C1

Procedure:
In an analogous manner to Example 1, step 2,1-[(1R)-2-[(3S)-3-aminopyrrolidin-1-yl-1-(3-chlorophenyl)ethyl]cyclohexanol dihydrochloride was prepared from tert-butyl {(3S)-1-[(2S)-2-(3-chlorophenyl)-2-(1-hydroxycyclohexyl)acetyl]pyrrolidin-3-yl}carbamate (see Example 387B). MS (ES) m/z 323.1; HRMS: calcd for C18H27ClN2O+H+, 323.18847; found (ESI, [M+H]+), 323.188; [α]D25=+24° (c=0.0105 g/mL, MeOH); CD=−@281 nm.
Reaction SMILES: CS[C:3]1[N:7]=[C:6]([CH2:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[S:5][N:4]=1.Cl[C:16]1C=C(C=CC=1)C(OO)=O.[S:26]([O-:29])(O)=[O:27].[Na+]>C(Cl)(Cl)Cl>[CH3:16][S:26]([C:3]1[N:7]=[C:6]([CH2:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[S:5][N:4]=1)(=[O:29])=[O:27]
Reactant: O=S([O-])O
Reactant: CSc1nsc(CC2CCCCC2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)c1nsc(CC2CCCCC2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.2 g of 3-methylthio-5-(cyclohexyl)methyl-1,2,4-thiadiazole was dissolved in 20 ml of chloroform, 2.78 g of 3-chloroperoxybenzoic acid (content>65%) was added thereto, and the reaction mixture was stirred for 1 hour under ice-cooling and for 16 hours at room temperature. Then, the reaction mixture was added to saturated sodium hydrogensulfite aqueous solution, and separated. The organic layer was washed with sodium hydrogencarbonate aqueous solution, dried over anhydrous sodium sulfate, concentrated to give 1.4 g of 3-methylsulfonyl-5-(cyclohexyl)methyl-1,2,4-thiadiazole.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[C:14]([N:16]([CH3:26])[S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)(=[O:19])=[O:18])[CH:15]=1)[NH:12][C:11]([C:27]([O:29]CC)=[O:28])=[CH:10]2.[OH-].[Na+].C(O)C.Cl>O.O1CCCC1>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[C:14]([N:16]([CH3:26])[S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)(=[O:18])=[O:19])[CH:15]=1)[NH:12][C:11]([C:27]([OH:29])=[O:28])=[CH:10]2
Reactant: CCOC(=O)c1cc2cc(OCCCOC)cc(N(C)S(=O)(=O)c3ccccn3)c2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: COCCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C(=O)O)cc2c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
A mixture of ethyl 5-(3-methoxypropoxy)-7-[methyl(pyridin-2-ylsulfonyl)amino]-1H-indole-2-carboxylate (3.50 g), 1N aqueous sodium hydroxide solution (10 mL), ethanol (10 mL) and tetrahydrofuran (10 mL) was stirred at 50° C. for 1 hr. 1N Hydrochloric acid (10 mL) and water were added to the reaction mixture, and the mixture was extracted with a mixed solvent of tetrahydrofuran-ethyl acetate. The organic layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained crystals were washed with hexane to give the title compound (3.26 g, 100%) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:4]([O:14][C:15]2[CH:19]=[CH:18][N:17]([CH2:20][C:21]3[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:28])[N:16]=2)[N:3]=1.[H-].[Na+].C(CNC[CH:36]=[O:37])=O.[CH3:38]OS(OC)(=O)=O>CN(C)C=O>[CH3:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9](=[CH:38][O:37][CH3:36])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([O:14][C:15]2[CH:19]=[CH:18][N:17]([CH2:20][C:21]3[C:22]([Cl:28])=[CH:23][CH:24]=[CH:25][C:26]=3[Cl:27])[N:16]=2)[N:3]=1
Reactant: COS(=O)(=O)OC
Reactant: COC(=O)Cc1c(C)nc(C)nc1Oc1ccn(Cc2c(Cl)cccc2Cl)n1
Reactant: O=CCNCC=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC=C(C(=O)OC)c1c(C)nc(C)nc1Oc1ccn(Cc2c(Cl)cccc2Cl)n1
Reaction time: 2 h

Procedure:
The intermediate methyl 2-[2,4-dimethyl-6-(1-(2,6-dichlorobenzyl)-1H-pyrazol-3-yloxy)-pyrimidin-5-yl]-acetate (9,6 g, 23 mmol) is dissolved in dimethylformamide (20 ml) and added at +30° C. to a suspension of NaH (1.3 g, of a 80% suspension in oil, 46 mmol) and N,N-diformylmethylamine (10 ml) in dimethylformamide (40 ml). The mixture is stirred for 2 hours at +45° C. Dimethylsulfate (2,4 ml, 25 mmol) is added at room temperature with cooling and stirring is continued for additional two hours. Dilution with ether, washing with brine, drying and chromatography on silicagel (eluant:ethyl acetate/hexane 3:1) gives methyl 2-[2,4-dimethyl-6-(1-(2,6-dichlorobenzyl)-1H-pyrazol-3-yloxy)-pyrimidin-5-yl]-3-methoxyacrylate as a colorless oil (4.8 g).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[N+:17]([O-])=O.[NH2:20][CH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23][CH2:22]1.C(N(CC)CC)C.[H][H]>C(#N)C.[C].[Pd].O>[CH:21]1([NH:20][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:9][C:10]4[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=4[N:12]=3)=[CH:4][C:3]=2[NH2:17])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23][CH2:22]1
Reactant: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)ccc1F
Reactant: NC1CCCc2ccccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Nc1cc(-c2nc3ccccc3o2)ccc1NC1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.2 %

Procedure:
To a suspension of 2-(4-fluoro-3-nitrophenyl)benzoxazole (see Working Example 15-2) (0.50 g, 1.9 mmol) in acetonitrile (10 mL) was added 1-amino-1,2,3,4-tetrahydronaphthalene (0.31 g, 2.1 mmol) and triethylamine (0.29 g, 3.2 mmol), and this was heated to reflux for 6 hours. After the reaction was complete, this was cooled to room temperature, water was added, and the precipitated crystals were filtered, washed with water and then dried. To a solution of the residue obtained in a solvent mixture of methanol/tetrahydrofuran (1:1, 50 mL) was added 10% palladium-carbon (50 mg). A hydrogen atmosphere was substituted in the flask, and this was stirred at room temperature for 3 hours. After the reaction was complete, this was filtered through Celite and the filtrate was concentrated. The residue obtained was purified by silica gel column chromatography to yield the title compound (0.40 g, 84% yield) as a colorless amorphous mass.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:9][C@H:10]([CH3:13])[CH2:11][OH:12])=[N:4][C:5](Cl)=[N:6][CH:7]=1.[NH2:14][C:15]1[CH:16]=[C:17]([S:20]([F:23])(=[O:22])=[O:21])[S:18][CH:19]=1.NC1SC(S(F)(=O)=O)=CC=1.Cl>C(#N)C.O.O1CCOCC1>[Br:1][C:2]1[C:3]([NH:9][CH:10]([CH3:13])[CH2:11][OH:12])=[N:4][C:5]([NH:14][C:15]2[CH:16]=[C:17]([S:20]([F:23])(=[O:22])=[O:21])[S:18][CH:19]=2)=[N:6][CH:7]=1
Reactant: Nc1csc(S(=O)(=O)F)c1
Reactant: C[C@H](CO)Nc1nc(Cl)ncc1Br
Agent: Cl
Agent: Nc1ccc(S(=O)(=O)F)s1
Solvent: C1COCCO1
Solvent: CC#N
Solvent: O
Product: CC(CO)Nc1nc(Nc2csc(S(=O)(=O)F)c2)ncc1Br

Procedure:
324 mg (1.2 mmol) of (R)-2-(5-bromo-2-chloro-pyrimidin-4-ylamino)-propan-1-ol is added to a suspension of 330 mg of a mixture that consists of 4-amino-thiophene-2-sulfonyl fluoride and 5-amino-thiophene-2-sulfonyl fluoride (ratio: 3:1) in 5 ml of acetonitrile, 0.5 ml of water and 0.5 ml of a 4 molar solution of hydrochloric acid in 1,4-dioxane. The reaction mixture is stirred under reflux for 26 hours. After cooling, the batch is concentrated by evaporation, and the residue is stirred with ethanol. The precipitate that is formed is suctioned off and stirred with warm water. In turn, the solid is suctioned off and dried. 152 mg (0.37 mmol, 31% of theory) of the product 4-[5-bromo-4-(2-hydroxy-1-methyl-ethylamino)-pyrimidin-2-ylamino]-thiophene-2-sulfonyl fluoride is obtained.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[N+:9]([O-:12])([OH:11])=[O:10].[N+:13]([O-])([O:15]C(=O)C)=[O:14].C(OC(C)C)(C)C.[N+]([O-])([O-])=O>C(#N)C>[N+:9]([O-:12])([OH:11])=[O:10].[O:1]([CH2:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[N+:13]([O-:15])=[O:14]
Reactant: CC(=O)O[N+](=O)[O-]
Reactant: OCC1CCNCC1
Agent: O=[N+]([O-])[O-]
Solvent: CC#N
Solvent: CC(C)OC(C)C
Solvent: O=[N+]([O-])O
Product: O=[N+]([O-])OCC1CCNCC1
Reaction time: 3 h

Procedure:
5.8 g. 4-Hydroxymethylpiperidine are dissolved in 100 ml. acetonitrile and cooled to -25° C. By the addition of 3.1 ml. 100% nitric acid, the base is converted into the nitric acid salt. To this solution is added a freshly prepared acetyl nitrate solution (prepared from 9.5 ml. acetic anhydride and 4.2 ml. 100% nitric acid in 40 ml. acetonitrile at -25° C.) and the reaction mixture then stirred for 3 hours at this temperature. The reaction solution is diluted with 300 ml. diisopropyl ether. The crystals obtained are filtered off with suction and washed with diethyl ether. There are obtained 9.5 g. (82% of theory) of the nitrate of the title compound; m.p. 64°-65° C.
Reaction SMILES: Br[C:2](=[CH2:22])[CH2:3][C:4]1([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([Zn][CH2:72][CH3:73])C>C1COCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:22]=[C:2]([CH2:72][CH3:73])[CH2:3][C:4]1([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH2:6][CH2:5]1
Reactant: CC[Zn]CC
Reactant: C=C(Br)CC1(C(=O)OCC)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: C1CCOC1
Product: C=C(CC)CC1(C(=O)OCC)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 100 °C

Procedure:
To a solution of 1-tert-butyl 4-ethyl 4-(2-bromoallyl)piperidine-1,4-dicarboxylate (5.0 g, 13.3 mmol) in THF (80 mL) in a sealed tube was added BINAP (3.31 g, 5.32 mmol), diethylzinc (15.95 mL, 15.95 mmol) and Pd(OAc)2 (0.597 g, 2.66 mmol) and the resulting mixture was degassed and heated for 16 hours at 100° C. The reaction mixture was evaporated to remove solvent under reduced pressure and the crude product was purified by silica gel column chromatography (RediSep 220 g Gold column) using (0-30) % EtOAc/Hexanes as mobile phase and the title compound was isolated.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4]([CH3:12])[N:3]=1.[Br:13][C:14]1[CH:20]=[C:19]([CH:21]([CH3:23])[CH3:22])[CH:18]=[CH:17][C:15]=1[NH2:16].C(OCC)(=O)C>O1CCOCC1>[Br:13][C:14]1[CH:20]=[C:19]([CH:21]([CH3:22])[CH3:23])[CH:18]=[CH:17][C:15]=1[NH:16][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4]([CH3:12])[N:3]=1
Reactant: CC(C)c1ccc(N)c(Br)c1
Reactant: COC(=O)c1cc(C)nc(Cl)n1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1cc(C)nc(Nc2ccc(C(C)C)cc2Br)n1
Temperature: 25 °C

Procedure:
A mixture of 2-chloro-4-carbomethoxy-6-methylpyrimidine (47.0 g, 252 mmol) and 2-bromo-4-(2-propyl)aniline (54.0 g, 252 mmol) in dioxane (400 mL) was stirred at reflux temperature for 20 h under a nitrogen atmosphere. The reaction mixture was cooled to ambient temperature and concentrated on a rotary evaporator. The residue was treated with a saturated sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and filtered. Solvent was removed in vacuo to provide a red oil. Column chromatography (ethyl acetate:hexanes::1:1) gave the title product as a crude oil. Recrystallization from ether-hexanes, collection by filtration and drying in vacuo afforded the title compound as a solid (42.8 g, 17% yield): mp 75-76° C.; NMR (CDCl3, 300 MHz): 8.4 (d, 1H, J=8); 7.65 (br s, 1H), 7.4 (d, 1H, J=1), 7.3 (s, 1H), 7.2 (dd, 1H, J=8,1), 4.0 (s, 3H), 2.85 (septet, 1H, J=7), 2.5 (br s, 3H), 1.25 (d, 6H, J=7); Anal. (C16H18BrN3O2): C, 52.76, H, 4.98; N, 11.54; Br, 21.94; Found: C, 52.71; H, 4.99; N, 11.38; Br, 21.83.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6](P(OCC)(OCC)=O)[F:7])=[O:5].C([Li])CCC.[O:21]1[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1.O>O1CCCC1.CCCCCC>[CH2:2]([O:3][C:4](=[O:5])[C:6]([F:7])=[C:24]1[CH2:25][CH2:26][O:21][CH2:22][CH2:23]1)[CH3:1]
Reactant: O=C1CCOCC1
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(F)=C1CCOCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 88.8 %

Procedure:
Into a cooled (−10° C.) solution of 5.25 g (21.68 mmol) of 2-fluoro-2-phosphonoacetic acid triethyl ester in tetrahydrofuran (30 mL) under an atmosphere of argon was dropped 13.2 mL (19.87 mmol) of 1.5 mol/L n-butyllithium in hexane (available from KANTO KAGAKU). After stirring for 20 minutes at room temperature, 2.0 g (19.87 mmol) of tetrahydropyran-4-one was dropped thereto and stirred for 2 hours at about 55° C. The obtained mixture was left to cool to room temperature and then poured into water, followed by extraction with ether. The ether extract was washed with water (three times) and saturated brine and dried over anhydrous magnesium sulfate, and the solvent was removed. The obtained residue was purified by medium pressure liquid column chromatography on silica gel (developing solvent: hexane-ethyl acetate) to obtain 3.32 g (yield 88.8%) of fluoro-(tetrahydropyran-4-ylidene)acetic acid ethyl ester (IX-16) as colorless liquid. Its physical property is shown blow.
Reaction SMILES: C(C1C(OC)=CC([CH2:11][C:12]([OH:14])=[O:13])=C(F)C=1)#N.C(OC(C)(C)C)(=O)CC(OC(C)(C)C)=O.[F:31][C:32]1[CH:39]=[C:38](F)[C:37]([O:41][CH3:42])=[CH:36][C:33]=1[C:34]#[N:35]>>[C:34]([C:33]1[C:32]([F:31])=[CH:39][C:38]([CH2:11][C:12]([OH:14])=[O:13])=[C:37]([O:41][CH3:42])[CH:36]=1)#[N:35]
Reactant: COc1cc(CC(=O)O)c(F)cc1C#N
Reactant: COc1cc(C#N)c(F)cc1F
Agent: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Product: COc1cc(C#N)c(F)cc1CC(=O)O

Procedure:
(4-Cyano-5-fluoro-2-methoxyphenyl)acetic acid was prepared in a similar fashion to the previously described synthesis of (4-cyano-2-fluoro-5-methoxyphenyl)acetic acid starting from di-tert-butyl malonate and 2,4-difluoro-5-methoxybenzonitrile. LC-MS (IE, m/z): 208 [M−1]+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@H:5]([CH:7]([CH3:9])[CH3:8])[NH2:6].CCN(C(C)C)C(C)C.[Br:20][C:21]1[N:26]=[C:25]([CH:27]=O)[CH:24]=[CH:23][CH:22]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1(C)C=CC=CC=1.CC(O)=O>[Br:20][C:21]1[N:26]=[C:25]([CH2:27][NH:6][CH:5]([CH:7]([CH3:9])[CH3:8])[C:4]([O:3][CH3:2])=[O:10])[CH:24]=[CH:23][CH:22]=1
Reactant: O=Cc1cccc(Br)n1
Reactant: COC(=O)[C@@H](N)C(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COC(=O)C(NCc1cccc(Br)n1)C(C)C
Temperature: 80 °C
Reaction time: 15 h

Procedure:
To a stirred solution of L-valine methyl ester hydrochloride (0.54 g, 3.24 mmol) in dry toluene (15 mL) at 80° C. was added DIEA (2.0 mL 11 mmol) followed by (6-bromo-2-pyridyl)formaldehyde (0.50 g, 2.70 mmol). The resulting mixture was heated at 80° C. for 3 h. The reaction was brought to RT and a solution of NaBH(OAc)3 (1.4 g, 6.75 mmol) in glacial AcOH (4 mL) was added. The resulting mixture was stirred for 15 h and concentrated by rotary evaporation. The resulting yellow oil was dissolved in CH2Cl2 (100 mL), washed with a saturated solution of NaHCO3 (aq) (50 mL), brine (50 mL), dried over Na2SO4, filtered, concentrated by rotary evaporation and purified by flash chromatography (2:1 hexanes/EtOAc) to afford the title compound as a pale-yellow oil. EI-MS m/z 301 (M+H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CCN(C(C)C)C(C)C.[CH3:22][C:23]1[S:24][C:25]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH:34]([OH:42])[CH2:35][N:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)=[CH:28][C:26]=2[N:27]=1>CCO>[CH3:22][C:23]1[S:24][C:25]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][C@H:34]([OH:42])[CH2:35][N:36]3[CH2:37][CH2:38][N:39]([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)[CH2:40][CH2:41]3)=[CH:28][C:26]=2[N:27]=1
Reactant: Cc1nc2cc(OCC(O)CN3CCNCC3)ccc2s1
Reactant: ClCCCCOc1ccccc1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2cc(OC[C@H](O)CN3CCN(CCCCOc4ccccc4)CC3)ccc2s1
Temperature: 88 °C
Reaction time: 14 h

Procedure:
(4-Chlorobutoxy) benzene (320 mg, 1.39 mmol) in EtOH (17 Ml) was treated with DIEA (0.48 Ml, 2.78 mmol) and 1-(2-methylbenzothiazol-5-yloxy)-3-piperazin-1-ylpropan-2-ol as prepared in Example 3A (427 mg, 1.39 mmol), then stirred 14 hours at 88° C. Upon cooling, concentrated in vacuo and purified on the Isco™ (10 g Redisep™ columns, 100% EtOAc hold 2 min., 8 min. gradient to 20% MeOH/EtOAc, hold 10 min) to provide (2R)-3-(2-methylbenzothiazol-5-yloxy)-1-[4-(4-phenoxybutyl)piperazinyl]propan-2-ol.
Reaction SMILES: [NH2:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13](=[O:30])[C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])=[CH:16][CH:15]=2)[CH2:5][CH2:4][CH2:3]1.[C:31]1([N:37]=[C:38]=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>ClCCl>[NH:37]([C:38]([NH:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13](=[O:30])[C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])=[CH:16][CH:15]=2)[CH2:5][CH2:4][CH2:3]1)=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(N)c3ccccc32)cc1
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(NC(=O)Nc3ccccc3)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.4 %

Procedure:
To a solution of 5-amino-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.6 g) in dichloromethane (10 ml) is added phenyl isocyanate (0.2 g) under ice-cooling. The mixture is stirred at the same temperature for 30 minutes, and the temperature thereof is raised to room temperature and then the mixture is stirred overnight. The reaction solution is distilled off and the resulting residue is recrystallized from dioxane to give 5-anilinocarbonylamino-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.65 g) as colorless prisms, m.p. 269°-271° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]([O:25][CH2:26][C:27](Cl)=[O:28])(=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>C1(C)C=CC=CC=1.C(N(CC)CC)C>[C:18]1([CH2:17][O:25][CH2:26][C:27]([N:14]2[CH2:13][CH2:12][N:11]([C:9](=[O:10])[CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:16][CH2:15]2)=[O:28])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(CCc1ccccc1)N1CCNCC1
Reactant: O=C(Cl)COC(=O)c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(CCc1ccccc1)N1CCN(C(=O)COCc2ccccc2)CC1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1-(3-phenylpropionyl)piperazine (115 g) in toluene (557 ml) and triethylamine (76 ml) was added benzoyloxyacetyl chloride (87 ml) at such a rate to keep the temperature below 30° C. After 30 min water (577 ml) was added and the reaction was stirred for a further 30 min. The layers were separated and the organic layer was washed with sodium carbonate and sodium chloride solution. The dried solution was evaporated in vacuo to give 193 g of 1-[(phenylmethoxy)acetyl]-4-(3-phenylpropionyl)piperazine.
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[C:13]([F:14])=[CH:12][C:11]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Cl)=[CH:10][C:9]=2[F:22])[C:6](=[O:23])[CH:5]=[CH:4][C:3]=1[C:24](=[O:33])[C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32].Cl.[NH2:35][C@H:36]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH:38]([CH3:40])[CH3:39].[I-].[Na+].C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[N:7]([C:8]2[C:13]([F:14])=[CH:12][C:11]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:35][C@H:36]([C:41]([O:43][C:44]([CH3:46])([CH3:45])[CH3:47])=[O:42])[CH2:37][CH:38]([CH3:40])[CH3:39])=[CH:10][C:9]=2[F:22])[C:6](=[O:23])[CH:5]=[CH:4][C:3]=1[C:24](=[O:33])[C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32]
Reactant: CC(C)C[C@H](N)C(=O)OC(C)(C)C
Reactant: Nc1c(C(=O)c2ccc(F)cc2F)ccc(=O)n1-c1c(F)cc(OCCCCCCl)cc1F
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](NCCCCCOc1cc(F)c(-n2c(N)c(C(=O)c3ccc(F)cc3F)ccc2=O)c(F)c1)C(=O)OC(C)(C)C
Temperature: 90 °C
Yield: 18 %

Procedure:
From Intermediate 4G. To a solution of 6-Amino-1-{4-[(5-chloropentyl)oxy]-2,6-difluorophenyl}-5-(2,4-difluorobenzoyl)pyridin-2(1H)-one (96 mg, 0.20 mmol) in anhydrous DMF (3 ml) under an atmosphere of nitrogen was added tert-butyl L-leucinate hydrochloride (198 mg, 0.99 mmol, 5 eq), sodium iodide (60 mg, 0.40 mmol, 2 eq) and N,N-diisopropylethylamine (0.072 ml, 0.40 mmol, 2 eq). The mixture was heated at 90° C. for 20 hours, before being allowed to cool to room temperature and diluted with EtOAc (20 ml). The solution was washed with water (2×20 ml) and brine (20 ml). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. Purification by column chromatography (1-3% MeOH in DCM) followed by preparative HPLC afforded the title compound as a white solid (23 mg, 18% yield).