Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C@@H:4]([C:6]1[C:11]([F:12])=[CH:10][N:9]=[CH:8][C:7]=1[C:13]1[CH:14]=[C:15]2[C:20](=[N:21][CH:22]=1)[N:19]([C:23]([NH2:25])=[O:24])[CH2:18][CH2:17][CH2:16]2)[CH3:5])=[N+]=[N-]>CCOC(C)=O.CO.[Pd]>[NH2:1][C@@H:4]([C:6]1[C:11]([F:12])=[CH:10][N:9]=[CH:8][C:7]=1[C:13]1[CH:14]=[C:15]2[C:20](=[N:21][CH:22]=1)[N:19]([C:23]([NH2:25])=[O:24])[CH2:18][CH2:17][CH2:16]2)[CH3:5]
Reactant: C[C@@H](N=[N+]=[N-])c1c(F)cncc1-c1cnc2c(c1)CCCN2C(N)=O
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: C[C@@H](N)c1c(F)cncc1-c1cnc2c(c1)CCCN2C(N)=O
Reaction time: 18 h
Yield: 34.4 %

Procedure:
6-[4-((R)-1-azido-ethyl)-5-fluoro-pyridin-3-yl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide (90 mg, 0.24 mmol) is dissolved in a mixture of EtOAc (2 mL) and MeOH (3 mL). The flask is flushed with Argon. Pd/C (26 mg, 0.024 mmol, 10%) is added and the flask is flushed with H2. After stirring for 18 hrs, the reaction is diluted with EtOAc and MeOH (10 mL of a 1:1 mixture), filtered and concentrated. The residue is dissolve in 1 mL of MeOH and 2 drops of water is added. The solution is filtered and purified by reverse phase HPLC to give 26 mg of the titled product.
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]#N)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[H-].C([Al+]CC(C)C)C(C)C.C(OCC)(=[O:25])C.C(O)(=O)C(C(C(O)=O)O)O>C1(C)C=CC=CC=1>[F:1][C:2]1[C:10]([CH:11]=[O:25])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2
Reactant: N#Cc1ccc2[nH]ncc2c1F
Reactant: CCOC(C)=O
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C(O)C(O)C(O)C(=O)O
Agent: [H-]
Solvent: Cc1ccccc1
Product: O=Cc1ccc2[nH]ncc2c1F
Temperature: -40 °C
Reaction time: 2 h
Yield: 92.9 %

Procedure:
805 mg (5 mmols) 4-fluoro-1H-indazole-5-carbonitrile (see EP 1510516, Example 85) were suspended in 25 mL toluene and cooled to −40° C. During 15 minutes 8 mL of a 1.5 M solution of diisobutylaluminium hydride in toluene (12 mmols) were added dropwise. The mixture was stirred for 2 hours at −40° C. At this temperature 5 mL ethyl acetate were added and the mixture was stirred for 20 minutes. 5 mL of a 1 M aqueous solution of tartaric acid were added and the mixture was stirred for 30 minutes at −20 to 0° C. The insolubles were removed by filtration. A small amount of dilute aqueous citric acid was added and the mixture was extracted with ethyl acetate. The extracts were washed with saturated sodium chloride and sodium hydrogen carbonate solutions and dried over sodium sulfate. The crude product was purified with column chromatography to yield 4-fluoro-1H-indazole-5-carbaldehyde 762 mg (92.9%). 1H-NMR (DMSO-d6): 13.82 (br s, 1H); 10.32 (s, 1H); 8.44 (s, 1H); 7.74 (dd, 1H); 7.49 (d, 1H) ppm.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([O:15][CH3:16])[CH2:11][CH2:10]2)[C:5](/[CH:17]=[CH:18]/[C:19](OCC)=[O:20])=[C:4]([CH3:24])[N:3]=1.CCCCC=CCCCCC.C(N(CC)CC)C>COC(C)(C)C>[NH2:1][C:2]1[N:3]=[C:4]([CH3:24])[C:5]2[CH:17]=[CH:18][C:19](=[O:20])[N:8]([C@H:9]3[CH2:14][CH2:13][C@H:12]([O:15][CH3:16])[CH2:11][CH2:10]3)[C:6]=2[N:7]=1
Reactant: CCOC(=O)/C=C/c1c(C)nc(N)nc1N[C@H]1CC[C@H](OC)CC1
Agent: CCCCC=CCCCCC
Solvent: CCN(CC)CC
Solvent: COC(C)(C)C
Product: CO[C@H]1CC[C@H](n2c(=O)ccc3c(C)nc(N)nc32)CC1

Procedure:
A solution of (E)-ethyl 3-(2-amino-4-(trans-4-methoxycyclohexylamino)-6-methylpyrimidin-5-yl)acrylate (674 mg, 2.02 mmol) thiophenol (621 ul, 6.05 mmol), 1,5-diazabicyclo5,4,0)undec-5-ene (1.81 mL, 12.1 mmol) and triethylamine (1.69 mL, 12.1 mmol) in N′,N-dimethylformamide (15 mL) was heated in the microwave for 30 minutes at 100° C. then in an oil bath at 100° C. overnight. The reaction mixture was diluted with methyltertbutylether and washed with saturated sodium carbonate, brine, 0.1 N hydrochloric acid, brine, dried (MgSO4), filtered and concentrated. The combined aqueous layer was extracted with dichloromethane (2×). The organic layer was dried (MgSO4), filtered and concentrated. The crude product was purified by flash chromatography eluting with chloroform/methanol (0-5%) to afford 2-amino-8-(trans-4-methoxycyclohexyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (482 mg, 83%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[C:6]([N:8]=[C:9]=[S:10])[CH:7]=1.[NH3:17]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[C:6]([NH:8][C:9]([NH2:17])=[S:10])[CH:7]=1
Reactant: N
Reactant: S=C=Nc1cc(Cl)ccc1N1CCOCC1
Product: NC(=S)Nc1cc(Cl)ccc1N1CCOCC1

Procedure:
Reaction of 5-chloro-2-morpholinophenyl isothiocyanate (10 g) with 33% alcoholic ammonia solution (60 ml) at room temperature for 14 hours gave 1-(5-chloro-2-morpholinophenyl)thiourea as a yellow solid (m.p. 174°-175° C.).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[C:8]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[N:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH:10]=1)=[O:5].[CH3:27][Mg]I.Cl>C1COCC1.CCOCC>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]([N:9]2[CH:10]=[C:6]([C:4](=[O:5])[CH3:27])[N:7]=[C:8]2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])=[CH:16][CH:15]=1
Reactant: CON(C)C(=O)c1cn(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Reactant: C[Mg]I
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)c1cn(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Yield: 97 %

Procedure:
A solution of 1-(4-chloro-phenyl)-2-(2,4-dichloro-phenyl)-1H-imidazole-4-carboxylic acid methoxy-methyl-amide I-7e (1.64 g, 3.99 mmol) in THF (16 ml) was cooled to 0° C., and methylmagnesium iodide (4.4 ml of a 3.0 M solution in Et2O, 9.9 mmol) was added dropwise via syringe. The resultant solution was stirred at 0° C. for 1 h, and then the reaction mixture was poured into cold 1N HCl (100 ml). The mixture was extracted with ethyl acetate (2 85-ml portions), and the combined extracts were washed with saturated aqueous sodium chloride (100 ml). The organics were dried over anhydrous magnesium sulfate and were concentrated to afford 1-[1-(4-chloro-phenyl)-2-(2,4-dichloro-phenyl)-1H-imidazol-4-yl]-ethanone I-7f (1.41 g, 97%) that was used in the next reaction without any further purification.
Reaction SMILES: [C:1]1([CH2:11][C:12]([OH:14])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([OH:10])=[O:9].[N+:15]([O-])([OH:17])=[O:16]>S(=O)(=O)(O)O>[N+:15]([C:5]1[CH:6]=[C:1]([CH2:11][C:12]([OH:14])=[O:13])[C:2]([CH2:7][C:8]([OH:10])=[O:9])=[CH:3][CH:4]=1)([O-:17])=[O:16]
Reactant: O=C(O)Cc1ccccc1CC(=O)O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C(O)Cc1ccc([N+](=O)[O-])cc1CC(=O)O
Temperature: -10 °C
Reaction time: 4 h
Yield: 65 %

Procedure:
To a stirred solution of 1,2-phenylenediacetic acid (10.2 g, 52.5 mmol) in conc. sulfuric acid (33 mL), cooled to −10° C., is added over 10 min a mixture of nitric acid (3.9 mL) and sulfuric acid (1.3 mL). After stirring at −10° C. for 4 h, the reaction mixture is poured onto ice (250 cc). The resulting mixture is extracted with ethyl acetate (3×300 mL). The combined organic phases are washed with H2O (100 mL), dried (MgSO4), filtered and concentrated to afford a white solid. The solid is recrystallized from methyl-tert-butyl ether in hexane to give 8.2 g (34.3 mmol, 65%) of the desired product. mp 187-188° C.
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[N:9][C:8]2[C:3]1=[N:4][CH:5]=[N:6][C:7]=2[NH2:11].C([O-])(=O)C.[Na+].C(O)(=O)C.[Br:21]Br>O>[Br:21][C:10]1[N:2]([CH3:1])[C:3]2[C:8]([N:9]=1)=[C:7]([NH2:11])[N:6]=[CH:5][N:4]=2
Reactant: Cn1cnc2c(N)ncnc21
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cn1c(Br)nc2c(N)ncnc21
Reaction time: 2 h

Procedure:
Fifteen grams (0.1 mol) of 9-methyladenine of Example 1 was dissolved in 1.5 liters of buffer prepared from 30.8 g of sodium acetate, 1.4 liters of water and sufficient acetic acid to provide a pH of 4.0. To this solution was added dropwise 25 ml of bromine in 2 liters of water over a period of two hours. The reaction was stirred a further two hours and the resulting solid filtered off and rinsed with the water. The solid was air dried and warmed to about 50° in about 80 ml of methanol, stripped to a hazy suspension and filtered. The precipitate after rinsing with water and drying at 40° under vacuum overnight weighed 15.6 g. The filtrate was stripped of methanol and a further 1.6 g was collected. The combined solids were triturated in about 100 ml of acetone for three hours and then allowed to sit overnight. The resulting precipitate was filtered and washed with acetone to yield 13.3 g after drying at 40° on a vacuum pump overnight.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].C(=O)(O)[O-].[Na+].Cl[C:16]([O:18][CH3:19])=[O:17]>ClCCl.O>[CH3:19][O:18][C:16](=[O:17])[NH:6][C:5]1[CH:7]=[CH:8][C:2]([Br:1])=[C:3]([CH3:9])[CH:4]=1
Reactant: Cc1cc(N)ccc1Br
Reactant: COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COC(=O)Nc1ccc(Br)c(C)c1
Temperature: 0 °C
Yield: 98.6 %

Procedure:
To a solution of 10.00 g 4-bromo-3-methylaniline in 50 ml dichloromethane was added 80 ml of a 10% solution of sodium bicarbonate in water. The mixture was cooled to 0° C. and 6.2 ml (7.62 g) methyl chloroformate was added during 10 min. with stirring. The reaction mixture was stirred at room temperature for 1 h. The phases were separated. The organic phase was washed with a 10% solution of citric acid in water, 10% solution of sodium bicarbonate in water and brine, dried with magnesium sulfate and evaporated to yield 12.94 g of (4-bromo-3-methyl-phenyl)-carbamic acid methyl ester as light brown solid melting at 71–72° C.
Reaction SMILES: [I-:1].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[N:14]=[C:13]([CH2:24]OS(C)(=O)=O)[CH:12]=2)[CH:7]=[CH:8][C:9]=1[Cl:10]>C1COCC1.C1(C)C=CC=CC=1>[Cl:3][C:4]1[CH:5]=[C:6]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[N:14]=[C:13]([CH2:24][I:1])[CH:12]=2)[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: COc1ccc(-n2nc(COS(C)(=O)=O)cc2-c2ccc(Cl)c(Cl)c2)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(-n2nc(CI)cc2-c2ccc(Cl)c(Cl)c2)cc1
Temperature: 40 °C

Procedure:
Sodium iodide (4.06 kg, 27.1 mol) was added to the THF/toluene solution of methanesulfonic acid 5-(3,4-dichlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-ylmethyl ester (Example 517, 6.32 kg, 14.8 mol). The resulting reaction mixture was heated at 40° C. for 6 h and then allowed to cool to rt overnight. When HPLC analysis indicated the disappearance of the starting material, the reaction was quenched with 28% aq. sodium thiosulfate (6.3 L). The organic layer was washed with sat. aq. NaHCO3 (6.3 L), brine (6.3 L), then dried (MgSO4). After filtration to remove the drying agent, the desired product was obtained in a solution, which was used in the next synthetic step without isolation. Chemical characterization data obtained herein for the title compound is not duplicated in this Example in light of the same data given in Example 1, Step E.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]1.C(OCC)(=O)C.Cl>CO>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCCc2cccs2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: c1csc(CCCN2CCNCC2)c1
Yield: 93.6 %

Procedure:
1.94 g (6.25 mmol) of tert-butyl 4-[3-(2-thienyl) propyl]-1-piperazinecarboxylate was dissolved in 20 ml of methanol, and 15 ml of a 4N hydrogen chloride-ethyl acetate solution was added. After completion of the reaction, the mixture was evaporated. The residue was adjusted to pH 11 with a 2N aqueous sodium hydroxide, then the objective product was extracted with chloroform and dried over anhydrous magnesium sulfate. The solvent was evaporated, to give 1.23 g (5.85 mmol, 93.6%) of the title compound as ayellow oil, as acrude product. 1H-NMR (400 MHz, CDCl3) δ 1.84-1.92 (m, 2H), 2.35-2.48 (m, 6H), 2.83-2.93 (m, 6H), 6.77-6.80 (m, 1H), 6.91 (dd, J 3.2 Hz, 5.2 Hz, 1H), 7.11 (dd, J=1.2 Hz, 5.2 Hz, 1H)
Reaction SMILES: [I:1][CH:2]1[CH:8]2[CH2:9][C:5]([CH3:18])([C:6](=[O:17])[N:7]2[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:4][CH2:3]1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[I:1][C:2]1[CH:8]2[CH2:9][C:5]([CH3:18])([C:6](=[O:17])[N:7]2[C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])[CH2:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)C2(C)CCC(I)C1C2
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N1C(=O)C2(C)CC=C(I)C1C2
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 4-iodo-1-methyl-7-oxo-6-azabicyclo[3.2.1]octane-6-carboxylate, 52d, (7.6 g, 20.8 mmol) in 100 mL of toluene was added 1,8-diazabicyclo[5.4.0]undec-7-ene (6.2 mL, 41.6 mmol). The reaction was warmed to reflux and stirred overnight. The reaction was concentrated in vacuo and the resulting residue was purified by silica gel chromatography (4:1 Hexanes:EtOAc), yielding 4.9 g of the desired product, 52e.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[N+:7]([CH2:10][CH2:11][CH3:12])([O-:9])=[O:8].[CH:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=1>C1COCC1>[N+:7]([CH:10]([CH2:11][CH3:12])[CH:13]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[OH:20])([O-:9])=[O:8]
Reactant: O=Cc1cccnc1
Reactant: CCC[N+](=O)[O-]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC(C(O)c1cccnc1)[N+](=O)[O-]
Reaction time: 1 h
Yield: 70.9 %

Procedure:
To a solution of LiAlH4 (2M in THF) (0.93 mL, 1.87 mmol) in dry THF (80 mL) at 0° C., was slowly added 1-nitropropane (8.30 mL, 93 mmol) under argon. After 60 min, nicotinaldehyde (2.00 g, 18.7 mmol) was added in one portion. The mixture was stirred for 16 hours, while allowing the temperature to rise from 0° C. to room temperature. The reaction mixture was quenched by addition of 1 mL of 2M aqueous HCl, followed by addition of 4 grams of Na2SO4. The resulting suspension was stirred for 15 minutes and then filtered. The filtrate was concentrated. The residue was purified by column chromatography (40 g SiO2) using EtOAc in hexane from 0% to 100% in order to give the title compound as a white solid (2.6 g, 71%) as a mixture of diastereoisomers A and B. LC-MS: [M+H] 197.1; Rt 0.52 min; (LCMS method 1). A) 1H NMR (400 MHz, CHCl3-d): 8.70-8.60 (m, 2H), 7.80-7.74 (m, 1H), 7.42-7.32 (m, 1H), 5.28 (dd, 1H), 4.70-4.58 (m, 1H), 2.97 (d, 1H), 2.29-2.12 (m, 1H), 1.65-1.42 (m, 1H), 0.99 (t, 3H). B) 1H NMR (400 MHz, CHCl3-d): 8.70-8.60 (m, 2H), 7.80-7.74 (m, 1H), 7.42-7.32 (m, 1H), 5.15 (dd, 1H), 4.70-4.58 (m, 1H), 2.81 (d, 1H), 1.99-1.85 (m, 1H), 1.65-1.42 (m, 1H), 0.94 (t, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)O)=[CH:4][S:5][CH:6]=1.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[C:3]([CH2:7][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)=[CH:4][S:5][CH:6]=1
Reactant: OC(c1cccc(Cl)c1)c1cscc1Br
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1cccc(Cc2cscc2Br)c1
Reaction time: 0.5 h

Procedure:
To (4-bromo-3-thienyl)(3-chlorophenyl)methanol from Example 3, Step 1 (144 mg, 0.474 mmol) in CH2Cl2 (1 mL) at 0° C., were successively added triethylsilane (303 μL, 1.90 mmol), quickly and TFA (364 μL, 4.74 mmol) dropwise. After 30 min., the reaction was concentrated to dryness and the residue was dissovled in CHCl3 and washed with 5% aq. NaHCO3. The aqueous layer was extracted with CHCl3 and the combined organics were washed with water and brine, dried (Na2SO4) and concentrated. The crude product was purified on silica gel (toluene/hexane 5:95) to afford the desired product as a colorless oil.
Reaction SMILES: [CH2:1]([S:4](Cl)(=[O:6])=[O:5])[CH2:2][CH3:3].[Cl:8][C:9]1[C:29]([F:30])=[CH:28][CH:27]=[C:26]([F:31])[C:10]=1[C:11]([NH:13][CH2:14][C:15]1([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][N:20]2[CH3:25])[CH2:18][NH:17][CH2:16]1)=[O:12].C(N(CC)CC)C.CN(C)CCN>ClCCl>[Cl:8][C:9]1[C:29]([F:30])=[CH:28][CH:27]=[C:26]([F:31])[C:10]=1[C:11]([NH:13][CH2:14][C:15]1([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][N:20]2[CH3:25])[CH2:16][N:17]([S:4]([CH2:1][CH2:2][CH3:3])(=[O:6])=[O:5])[CH2:18]1)=[O:12]
Reactant: CCCS(=O)(=O)Cl
Reactant: CN1CCCCC1C1(CNC(=O)c2c(F)ccc(F)c2Cl)CNC1
Agent: CN(C)CCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCS(=O)(=O)N1CC(CNC(=O)c2c(F)ccc(F)c2Cl)(C2CCCCN2C)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
tert-butyl 3-{[(2-chloro-3,6-difluorobenzoyl)amino]methyl}-3-(1-methylpiperidin-2-yl)azetidine-1-carboxylate (0.40 g, 0.9 mmol) was dissolved in dichloromethane (3 ml) and trifluoroacetic acid (2 eq) was added. The reaction was stirred at room temperature overnight. The mixture was evaporated to dryness and the residue treated with saturated aqueous sodium carbonate. The product was extracted into dichloromethane. The organic phase was washed with brine, dried over anhydrous magnesium sulfate and evaporated to give 2-chloro-3,6-difluoro-N-{[3-(1-methylpiperidin-2-yl)azetidin-3-yl]methyl}benzamide (0.20 g, 64%) which was used without further purification. Propane-1-sulfonyl chloride (0.04 ml, 0.34 mmol) was added to 2-chloro-3,6-difluoro-N-{[3-(1-methylpiperidin-2-yl)azetidin-3-yl]methyl}benzamide (0.10 g, 0.28 mmol) and triethylamine (0.08 g, 0.56 mmol) in dichloromethane (2 ml) at 0° C. The reaction was then stirred at room temperature for 30 mins before quenching with N,N-dimethylethylenediamine (0.5 eq). The resulting mixture was partitioned between dichloromethane and water. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated to dryness. Purification by flash column chromatography on a silica cartridge eluting with dichloromethane (containing 1% ammonia) on a gradient of methanol (0-5%) led to 2-chloro-3,6-difluoro-N-{[3-(1-methylpiperidin-2-yl)-1-(propylsulfonyl)azetidin-3-yl]methyl}benzamide as an off-white solid. m/z (M++H) 464, 1H NMR (500 MHz, DMSO): δ 9.34 (s, 1 H); 7.58 (t, J=6.7 Hz, 1 H); 7.43 (s, 1 H); 4.07 (t, J=12.7 Hz, 1H); 3.91 (d, J=7.8 Hz, 1 H); 3.79 (d, J=7.8 Hz, 2 H); 3.65 (d, J=8.1 Hz, 1 H); 3.53 (d, J=10.8 Hz, 1 H); 3.17 (s, 2 H); 3.05 (t, J=7.4 Hz, 2 H); 2.80 (s, 1 H); 2.56 (s, 2 H); 1.75 (s, 1 H); 1.67 (dd, J=7.8, 15.0 Hz, 5 H); 1.39 (s, 2 H); 0.96 (t, J=7.3 Hz, 3 H).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]([CH2:8][NH:9][C:10]([C:12]2[S:16][C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[N:14][C:13]=2[CH3:24])=[O:11])[CH2:2]1.F[C:26]1[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=1[C:28]([O:30][CH3:31])=[O:29]>>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([C:15]2[S:16][C:12]([C:10]([NH:9][CH2:8][CH:3]3[CH2:4][CH2:5][CH2:6][CH2:7][N:1]([C:26]4[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=4[C:28]([O:30][CH3:31])=[O:29])[CH2:2]3)=[O:11])=[C:13]([CH3:24])[N:14]=2)=[CH:18][CH:19]=1
Reactant: COC(=O)c1ccccc1F
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1C(=O)NCC1CCCCNC1
Product: COC(=O)c1ccccc1N1CCCCC(CNC(=O)c2sc(-c3ccc(Cl)cc3)nc2C)C1
Yield: 19.2 %

Procedure:
Using N-(perhydroazepin-3-yl methyl)-2-(4-chlorophenyl)-4-methylthiazole-5-carboxamide (200 mg, 0.550 mmol) and methyl 2-fluorobenzoate (0.140 mL, 1.10 mmol), the same procedure was followed as in Step 9c of Example 9 to give 52.7 mg (19%) of the desired compound as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]2[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:5]=2[CH:4]=1.[F:14][C:15]([F:26])([F:25])[C:16]1[CH:17]=[C:18]([N:22]=[C:23]=[O:24])[CH:19]=[CH:20][CH:21]=1.CCCCCC>CCOCC>[F:14][C:15]([F:25])([F:26])[C:16]1[CH:17]=[C:18]([NH:22][C:23]([N:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:13]=[CH:12][C:6]2=3)=[O:24])[CH:19]=[CH:20][CH:21]=1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: COc1ccc2c(c1)CCCCN2
Solvent: CCCCCC
Solvent: CCOCC
Product: COc1ccc2c(c1)CCCCN2C(=O)Nc1cccc(C(F)(F)F)c1

Procedure:
A solution of 2.0 g (11.3 mMol) of 7-methoxy-2,3,4,5-tetrahydro-1H-benzo[b]azepine [Monatsheft Chemie, 97 (1966),150] and 2.28 g (97%; 11.8 mMol) of 3-trifluoromethyl-phenyl-isocyanate in 20 ml ether is stirred for 30 min in a icebath. After addition of hexane, the mixture is concentrated partially in vacuo and the crystallized product filtered off: m.p.: 108° C.; MS: [M+1]+=365; Anal.: C,H,N,F.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:7][C@@H:6]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[NH:24][C:25](=[O:45])[C@H:26]([CH:32]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[NH:27][C:28]([O:30][CH3:31])=[O:29])[O:5][CH2:4]1.N1C=CC=CC=1.[C:52]1([S:58](Cl)(=[O:60])=[O:59])[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>C(Cl)Cl>[CH3:31][O:30][C:28]([NH:27][C@H:26]([C:25]([NH:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][CH2:16][C@H:6]1[O:5][CH2:4][C@@H:3]([CH2:2][NH:1][S:58]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)(=[O:60])=[O:59])[N:8]([C:9]([O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:10])[CH2:7]1)=[O:45])[CH:32]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:29]
Reactant: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](CN)CO1)C(c1ccccc1)c1ccccc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](CNS(=O)(=O)c2ccccc2)CO1)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of tert-butyl (2R,5R)-5-(aminomethyl)-2-[2-(2-{[N-(methoxycarbonyl)-β-phenyl-L-phenylalanyl]amino}phenyl)ethyl]morpholine-4-carboxylate (1 eq.) in DCM (0.1M) were added pyridine (3 eq) and benzene sulfonyl chloride (1.3 eq). The reaction mixture was stirred for 4 hrs at room temperature, diluted with CH2Cl2 and the organic layer was washed with aqueous saturated sodium bicarbonate. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by automated silica gel flash chromatography system eluted with a gradient 10% to 100% of EtOAc/Hex to afford title compound.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][C@@H:9]1[CH2:12][C@H:11]([C:13]([OH:15])=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCCCC1.ClC(OCC(C)C)=O.Cl.[CH3:32][NH:33][O:34][CH3:35]>ClCCl>[C:1]([O:5][C:6](=[O:7])[CH2:8][C@H:9]1[CH2:10][C@@H:11]([C:13](=[O:15])[N:33]([O:34][CH3:35])[CH3:32])[CH2:12]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](C(=O)O)C1
Reactant: CNOC
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCCCC1
Product: CON(C)C(=O)[C@H]1C[C@@H](CC(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 99.5 %

Procedure:
To an ice cold solution of 1.74 g of cis-3-tert-butoxycarbonylmethyl-cyclobutanecarboxylic acid, 3 mL of N-methyl-piperidine, and 50 mL of dichloromethane was added 1.7 mL of isobutyl chloroformate drop-wise over 5 min. After an additional 5 min, 1.6 g of N-methyl-N-methoxy-amine hydrochloride was added and the mixture allowed to warm with stirring overnight. The resulting mixture was diluted with 100 mL of dichloromethane, washed with 100 mL of water, 100 mL of 0.1 N HCl, 50 mL of saturated sodium carbonate and dried over magnesium sulfate. The solution was diluted with 50 mL of toluene and concentrated under reduced pressure. Drying under vacuum overnight gave 2.08 g of product as a colorless thick oil: MS (m+1)=258.3; 1H NMR (400 MHz, CDCl3) 3.62 (s, 3H), 3.16 (s, 3H), 2.35 (d, 2H), 2.0 (dd, 1H), 1.4 (s, 9H).