Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][CH:7]=[C:8]([I:10])[CH:9]=1)=[O:4].C(N(CC)CC)C.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](O)(=[O:26])=[O:25])=[CH:20][CH:19]=1>ClCCl.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]([C:5]1[N:6]([S:24]([C:21]2[CH:22]=[CH:23][C:18]([CH3:28])=[CH:19][CH:20]=2)(=[O:26])=[O:25])[CH:7]=[C:8]([I:10])[CH:9]=1)=[O:4]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COC(=O)c1cc(I)c[nH]1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(I)cn1S(=O)(=O)c1ccc(C)cc1
Yield: 80.2 %

Procedure:
4-Iodo-1H-pyrrole-2-carboxylic acid methyl ester 57d (25.1 g, 100 mmol) was dissolved in 150 mL of dichloromethane followed by addition of triethylamine (30.6 mL, 220 mmol), 4-dimethylaminopyridine (1.22 g, 10 mmol) and p-toluenesulfonic acid (21 g, 110 mmol). The reaction mixture was reacted at 20° C. overnight. The reaction was monitored by TLC until the disappearance of the starting materials and quenched by addition of 30 mL of hydrochloric acid (1 N). The mixture was extracted with dichloromethane (50 mL×3). The combined organic extracts were washed with saturated aqueous sodium carbonate and saturated brine successively, dried over anhydrous sodium sulfate, filtered to remove the drying agent and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound 4-iodo-1-(toluene-4-sulfonyl)-1H-pyrrole-2-carboxylic acid methyl ester 57e (32.5 g, yield 80.2%) as a white solid.
Reaction SMILES: [O:1]=[C:2]1[CH:7]2[CH2:8][CH2:9][CH2:10][CH:3]1[CH2:4][CH:5]([C:11]([O:13][CH3:14])=[O:12])[CH2:6]2.[BH4-].[Na+]>CO>[OH:1][CH:2]1[CH:7]2[CH2:8][CH2:9][CH2:10][CH:3]1[CH2:4][CH:5]([C:11]([O:13][CH3:14])=[O:12])[CH2:6]2
Reactant: COC(=O)C1CC2CCCC(C1)C2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1CC2CCCC(C1)C2O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 9-oxobicyclo[3.3.1]nonane-3-carboxylate (190 mg, 0.97 mmol) in methanol was added NaBH4 (76 mg, 2 mmol) at 0° C. The mixture was stirred at rt for 2 h, and concentrated. The residue was diluted with water, and the mixture was extracted with Et2O. The organic layer was concentrated to give methyl 9-hydroxybicyclo-[3.3.1]nonane-3-carboxylate, which was used in the next step directly without purification (140 mg, crude).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[C:10](=[CH:18][N:19]([CH3:22])[C:20]=2[CH3:21])[N:11]([CH3:17])[C:12](=[O:16])[CH:13](O)[N:14]=1.S(Cl)(Cl)=O.Cl.[CH2:28]([O:30][C:31](=[O:36])[CH2:32][CH2:33][CH2:34][NH2:35])[CH3:29]>C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[C:10](=[CH:18][N:19]([CH3:22])[C:20]=2[CH3:21])[N:11]([CH3:17])[C:12](=[O:16])[CH:13]([NH:35][CH2:34][CH2:33][CH2:32][C:31]([O:30][CH2:28][CH3:29])=[O:36])[N:14]=1
Reactant: CCOC(=O)CCCN
Reactant: Cc1c2c(cn1C)N(C)C(=O)C(O)N=C2c1ccccc1Cl
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCNC1N=C(c2ccccc2Cl)c2c(cn(C)c2C)N(C)C1=O
Reaction time: 24 h
Yield: 70.3 %

Procedure:
A mixture of 5-(2-chlorophenyl)-1,7-dihydro-3-hydroxy-1,6,7-trimethyl-pyrrolo[3,4-e][1,4]diazepin-2(3H)-one (6.3 g, 0.0198 mole) and thionyl chloride (18 mole) is allowed to stand at room temperature for one night. The 3-chloro derivative which forms is precipitated by the addition of ethyl ether, recovered by filtration and washed on filter with ethyl ether. The obtained intermediate is dissolved in chloroform (100 ml) and triethylamine (8 g) and γ-aminobutyric acid ethyl ester hydrochloride (6.4 g, 0.0382 mole) are gradually added to the obtained solution. The reaction mixture is allowed to stand, at room temperature for one day, then chloroform is evaporated, the residue is taken up with water acidified with HCl and the undissolved oil is extracted with chloroform. The chloroform solution is neutralized by washing with aqueous NaHCO3, dried over Na2SO4, filtered and concentrated to dryness yielding 6 g of an oily residue.
Reaction SMILES: [C:1]([C:3]1[CH:40]=[CH:39][C:6]2[N:7](COCC[Si](C)(C)C)[C:8]([CH:10]([OH:30])[C:11]3[C:19]([O:20][CH3:21])=[CH:18][C:17]([CH3:22])=[C:16]4[C:12]=3[CH:13]=[CH:14][N:15]4C(OC(C)(C)C)=O)=[N:9][C:5]=2[CH:4]=1)#[N:2].C(C1C=CC2N=C(C(O)C3C(OC)=CC(C)=C4C=3C=CN4C(OC(C)(C)C)=O)N(COCC[Si](C)(C)C)C=2C=1)#N.CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Cl-].[NH4+].C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.C(OCC)(=O)C.CO>[OH:30][CH:10]([C:11]1[C:19]([O:20][CH3:21])=[CH:18][C:17]([CH3:22])=[C:16]2[C:12]=1[CH:13]=[CH:14][NH:15]2)[C:8]1[NH:7][C:6]2[CH:39]=[CH:40][C:3]([C:1]#[N:2])=[CH:4][C:5]=2[N:9]=1
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(O)c1nc2cc(C#N)ccc2n1COCC[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(O)c1nc2ccc(C#N)cc2n1COCC[Si](C)(C)C
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(C)c2[nH]ccc2c1C(O)c1nc2cc(C#N)ccc2[nH]1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
A mixture of (±)-tert-butyl 4-((5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(hydroxy)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-((6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(hydroxy)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (0.3 g, 0.533 mmol) was dissolved in THF (5.33 mL). TBAF (5.34 mL, 5.34 mmol) was added to the solution and the reaction was stirred at 50° C. for 5 hours. The reaction was diluted with ethyl acetate and then with 20 mL of a saturated aq. solution of ammonium chloride. The ethyl acetate layer was separated, washed with water, dried and concentrated. The resulting residue was dissolved in MeOH (4 mL) to which cesium carbonate (0.87 g, 2.67 mmol) was added. The reaction was heated at 50° C. for 1 hour. The reaction was then concentrated and directly purified by flash chromatography (0-10% MeOH in DCM) to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.93 (d, J=3.54 Hz, 1H) 10.86 (br. s., 1H) 7.81-7.95 (m, 1H) 7.60 (m) 7.40-7.56 (m) 7.14 (t, J=2.78 Hz, 1H) 6.75 (s, 1H) 6.53-6.62 (m, 1H) 6.19-6.31 (m, 2H) 3.81 (s, 3H) 2.40-2.47 (m, 3H). HRMS calcd. for C19H16N4O2 (M+H)+ 333.1346. found 333.1355.
Reaction SMILES: NC1C=CC=CC=1.Cl.N(OCCC(C)C)=[O:10].C([O-])(=O)C.[Na+].C1(C=CC=C(O)C=1)O.[C:30]1([N:36]=[N:37][C:38]2[C:44](O)=[C:43]([N:46]=[N:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH:42]=[CH:41][C:39]=2[OH:40])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O>[C:30]1([N:36]=[N:37][C:38]2[C:39]([OH:40])=[CH:41][C:42]([OH:10])=[C:43]([N:46]=[N:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH:44]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)CCON=O
Reactant: Oc1ccc(N=Nc2ccccc2)c(O)c1N=Nc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: Oc1cccc(O)c1
Solvent: Nc1ccccc1
Solvent: O
Product: Oc1cc(O)c(N=Nc2ccccc2)cc1N=Nc1ccccc1
Temperature: 5 °C
Reaction time: 2 h

Procedure:
Bis(phenylazo)resorcinol isomers were prepared according to a procedure similar to that described in Helvetica Chimica Acta, pp. 1816-1823 (1958). In a 2 liter flask, 37.2 g of aniline was added to 120 ml of water, and to this solution was added 100 ml of concentrated HCl and the solution was cooled to 5° C. 58.58 g of isoamyl nitrite was then added slowly. In a second 3 liter flask, 160 g of sodium acetate was added to a stirred solution of 44.4 g of resorcinol in 440 ml of water and dissolved. Then, the above diazonium solution was added in a thin stream to the resorcinol solution with vigorous stirring. Stirring continued for 2 hours, and an orange-red product precipitated out. Since reaction above occurs in acid solution, the predominant amount of the isomer in the orange red product is the 2,4-bis(phenylazo) resorcinol isomer (see FIG. 1 in Helvetica Chimica Acta identified above.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11].C=O.[C:14]1(B(O)O)C=CC=CC=1.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=[CH2:14])[C:6]2=[O:11]
Reactant: OB(O)c1ccccc1
Reactant: O=C1CCc2c(F)cccc21
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: C=C1Cc2c(F)cccc2C1=O
Temperature: 25 °C
Yield: 71.8 %

Procedure:
To a 1000 mL round bottle flask were charged 4-fluoro-2,3-dihydro-1H-inden-1-one (249a) (5.04 g, 33.6 mmol), paraformaldehyde (10.08 g, 336 mmol), phenylboronic acid (4.92 g, 40.3 mmol) followed by toluene (235 mL), to the suspension was added TFA 2.6 mL, 33.6 mmol), and the resulting suspension was refluxed for 4 hrs, which resulted a clear yellowish solution. The solution was cooled to room temperature, and the pH was adjusted to 7-8 by adding saturated NaHCO3. After extracting with ethyl acetate, the organic layers were combined, and evaporated. The residue was purified by flash chromatography (0 to 30% EtOAc/Hexane) to give 4-fluoro-2-methylene-2,3-dihydro-1H-inden-1-one (249b) (3.91 g, 72%). LC-MS tR=1.49 min in 3 min chromatography, MS (ESI) m/z 163 [M+H]+
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH3:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].Cl.[CH2:13]([O:15][C:16](=[O:28])[CH2:17][C@@H:18]([NH2:27])[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:14].CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[CH2:13]([O:15][C:16](=[O:28])[CH2:17][C@@H:18]([NH:27][C:2]1[CH:3]=[C:4]([CH3:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9])[CH2:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH3:14]
Reactant: CCOC(=O)C[C@@H](N)CCc1ccccc1
Reactant: Cc1ccc([N+](=O)[O-])c(F)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@H](CCc1ccccc1)Nc1cc(C)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 56.1 %

Procedure:
To a solution of 3-Fluoro-4-nitrotoluene (0.7 g, 4.5 mmol) in DMF (5 mL) were added (S)-3-Amino-5-phenyl-pentanoic acid ethyl ester hydrochloride (1.2 g, 4.5 mmol) and DIPEA (1.6 g, 9.0 mmol). The reaction mixture was stirred at room temperature for 48 h. The reaction mixture was then diluted with ethyl acetate and washed with water (×4). The organic phase was then dried over Na2SO4 and concentrated to afford an orange solid. The resulting residue was Purified by silica gel prep TLC using 4:1 Hexanes:ethyl acetate as an eluent to afford 0.9 g of the desired product.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]([OH:12])=O)=[N:2]1.[C:13]([O:17][C:18]([N:20]1[C@H:27]([CH2:28][NH2:29])[CH2:26][C@H:25]2[C@@H:21]1[CH2:22][CH2:23][CH2:24]2)=[O:19])([CH3:16])([CH3:15])[CH3:14]>>[C:13]([O:17][C:18]([N:20]1[C@H:27]([CH2:28][NH:29][C:10]([C:3]2[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[O:1][N:2]=2)=[O:12])[CH2:26][C@H:25]2[C@@H:21]1[CH2:22][CH2:23][CH2:24]2)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1[C@H](CN)C[C@@H]2CCC[C@@H]21
Reactant: O=C(O)c1noc2ccccc12
Product: CC(C)(C)OC(=O)N1[C@H](CNC(=O)c2noc3ccccc23)C[C@@H]2CCC[C@@H]21

Procedure:
prepared by reaction of Benzo[d]isoxazole-3-carboxylic acid with (1S,3S,5S)-3-aminomethyl-2-azabicyclo[3.3.0]octane-2-carboxylic acid tert-butyl ester. LC-MS: tR=1.11 min; [M+H]+=386.6.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]([OH:10])[N:4]=1)[NH2:2].[OH-].[Na+].[C:13](=S)=[S:14]>C(O)C>[OH:10][C:5]1[N:4]2[C:13]([SH:14])=[N:2][N:1]=[C:3]2[CH:8]=[C:7]([CH3:9])[N:6]=1
Reactant: Cc1cc(NN)nc(O)n1
Reactant: S=C=S
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc2nnc(S)n2c(O)n1
Yield: 53.8 %

Procedure:
The product obtained in Step 2 (1.0 g) was added to a solution of 0.29 g of sodium hydroxide in 20 ml of 80% ethanol, 1.31 g of carbon disulfide was further added, and the mixture was refluxed for 24 hours. After concentrating under reduced pressure, the residue was dissolved in 10 ml of water and the pH was adjusted to 2.0 with 1N hydrochloric acid. The formed crystals were collected by filtration and washed with 10 ml of water and 10 ml of ethanol, affording 0.7 g of the objective compound as pink crystals.
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([C:6](/[N:8]=[C:9]2\[NH:10][C:11]3[CH:29]=[CH:28][C:27]([CH2:30][OH:31])=[CH:26][C:12]=3[N:13]\2[C@H:14]2[CH2:19][CH2:18][C@@H:17]([C:20](=[O:25])[NH:21][CH:22]([CH3:24])[CH3:23])[CH2:16][CH2:15]2)=[O:7])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:38][O-].[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6](/[N:8]=[C:9]2\[NH:10][C:11]3[CH:29]=[CH:28][C:27]([CH2:30][O:31][CH3:38])=[CH:26][C:12]=3[N:13]\2[C@H:14]2[CH2:19][CH2:18][C@@H:17]([C:20](=[O:25])[NH:21][CH:22]([CH3:23])[CH3:24])[CH2:16][CH2:15]2)=[O:7])=[CH:32][CH:33]=1
Reactant: C[O-]
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(CO)cc32)CC1
Agent: [Na+]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COCc1ccc2[nH]/c(=N\C(=O)c3ccc(F)cc3)n([C@H]3CC[C@@H](C(=O)NC(C)C)CC3)c2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a 0° C. cooled solution of (E)-4-fluoro-N-(6-(hydroxymethyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide (100 mg, 0.221 mmol) in DCM (2.5 mL) was added thionyl chloride (0.081 mL, 1.105 mmol) dropwise, and the reaction was stirred at 0° C. for 30 minutes. The solvent was removed and the residue was resuspended in ACN (2 mL), cooled to 0° C., and sodium methoxide (478 mg, 2.210 mmol) was added. The reaction was stirred overnight at RT. The solvent was removed on a rotovap, and the residue was partitioned between water and DCM. The aqueous layer was neutralized (pH approximately 8) with concentrated HCl and extracted with DCM. The combined organic layers were concentrated, adsorbed onto a plug of silica gel, and purified by column chromatography, eluting with 0-10% MeOH in DCM, to provide (E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(methoxymethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide as a white powder (45 mg, 43.6% yield). MS, m/z (C26H31FN4O3): calcd, 466.2. found, 466.8 [M+H].
Reaction SMILES: C(N)(C)(C)C.[Br:6]Br.[CH2:8]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[OH:22])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1(C)C=CC=CC=1.C(Cl)Cl.CCOCC.O>[CH2:8]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Br:6])[C:17]=1[OH:22])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Oc1ccccc1OCc1ccccc1
Reactant: BrBr
Solvent: ClCCl
Solvent: CCOCC
Solvent: CC(C)(C)N
Product: Oc1c(Br)cccc1OCc1ccccc1
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
Tert-butyl amine (2 eq) was dissolved in toluene (1M) and the solution was cooled to −30° C. Br2 (1 eq) was added dropwise maintaining the temperature. The mixture was left stirring for 30 min, then it was cooled to −78° C. A solution of 2-benzyloxyphenol (1 eq) in DCM (6M) was added dropwise. The mixture was allowed to reach RT over the course of 3 h. The mixture was diluted with Et2O and H2O was added. The mixture was washed with 1N HCl, sat. aq. Na2S2O3 and brine. After drying over Na2SO4 all volatiles were evaporated in vacuo. The residue was purified by FC (PE:EtOAc, 9:1). The colourless oil was used without further characterization in the next reaction. (ES−) m/z 277, 279 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]([NH:20][CH:21]=[C:22]([CH3:24])[CH3:23])[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:13][CH:14]=2)=[CH:4][CH:3]=1.Cl[C:26](=[O:33])[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].ClCCl.C(=O)(O)[O-].[Na+]>ClCCCl>[CH2:31]([O:30][C:28](=[O:29])[CH2:27][C:26]([N:20]([CH2:21][CH:22]([CH3:23])[CH3:24])[C:11]1[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:13][CH:14]=[C:9]([CH2:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH:10]=1)=[O:33])[CH3:32]
Reactant: CCOC(=O)CC(=O)Cl
Reactant: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1NC=C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: CCOC(=O)CC(=O)N(CC(C)C)c1cc(Cc2ccc(F)cc2)cnc1C(=O)OCC
Temperature: 25 °C
Yield: 53.5 %

Procedure:
To a solution of ethyl 5-[(4-fluorophenyl)methyl]-3-3-[(2-methylpropyl)amino]-3-2-pyridinecarboxylate and ethyl 5-[(4-fluorophenyl)methyl]-3-[(2-methyl-1-propen-1-yl)amino]-2-pyridinecarboxylate (˜1.7:1 mixture, 419 mg, 1.3 mmol) in 1,2-dichloroethane (15 mL) was added ethyl 3-chloro-3-oxopropanoate (0.25 mL, 90%, 1.9 mmol). The resultant solution was heated at 85° C. for 5 hours. Upon cooling to room temperature, dichloromethane and saturated aqueous sodium bicarbonate were added and the layers separated. The organic layer was washed with brine. The aqueous layers were extracted with dichloromethane and the combined organics dried over sodium sulfate. Filtration and concentration followed by silica gel chromatography provided ethyl 3-[[3-(ethyloxy)-3-oxopropanoyl](2-methylpropyl)amino]-5-[(4-fluorophenyl)methyl]-2-pyridinecarboxylate (309 mg, 55%). 1H NMR (CDCl3) δ 8.56 (s, 1 H), 7.45 (s, 1 H), 7.10 (m, 2 H), 6.99 (m, 2 H), 4.39 (q, J=7.2 Hz, 2 H), 4.02-3.97 (m, 5 H), 3.15 (d, J=15.6 Hz, 1 H), 3.04 (d, J=15.6 Hz, 1 H), 2.81 (dd, J=13.6, 6.0 Hz, 1 H), 1.62 (m, 1 H), 1.36 (t, J=7.2 Hz, 3 H), 1.16 (t, J=6.8 Hz, 3 H), 0.90 (d, J=6.4 Hz, 3 H), 0.81 (d, J=6.4 Hz, 3 H); MS: m/z 445 (M+1). Further elution provided ethyl 3-[[3-(ethyloxy)-3-oxopropanoyl](2-methyl-1-propen-1-yl)amino]-5-[(4-fluorophenyl)methyl]-2-pyridinecarboxylate (115 mg, 21%). 1H NMR (CDCl3) δ 8.37 (s, 1 H), 7.32 (s, 1 H), 7.07 (m, 2 H), 6.97 (m, 2 H), 6.15 (s, 1 H), 4.39 (q, J=7.2 Hz, 2 H), 4.18 (q, J=7.2 Hz, 2 H), 3.48 (s, 2 H), 1.70 (s, 3 H), 1.59 (s, 3 H), 1.38 (t, J=7.2 Hz, 3 H), 1.25 (t, J=7.2 Hz, 3 H); MS: m/z 445 (M+1).
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1([CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.Cl.[CH:27]([C@@H:29]1[C@@H:33]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:32][N:31]([C@H:40]([CH:53]2[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]2)[C:41]([O:43]CC2C=CC(OC)=CC=2)=[O:42])[CH2:30]1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[F:10][C:11]1([CH2:17][CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:16][CH2:15][N:14]([CH2:27][C@@H:29]2[C@@H:33]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:32][N:31]([C@H:40]([CH:53]3[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]3)[C:41]([OH:43])=[O:42])[CH2:30]2)[CH2:13][CH2:12]1
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](c3ccccc3)[C@@H](C=O)C2)cc1
Reactant: FC1(CCCc2ccccc2)CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)[C@@H](C1CCCCC1)N1C[C@H](CN2CCC(F)(CCCc3ccccc3)CC2)[C@@H](c2ccccc2)C1
Reaction time: 16 h
Yield: 48 %

Procedure:
To a solution of DIEA (0.019 mL, 0.11 mmol) in 0.5 mL of 1,2-dichloroethane was added 4fluoro-4-(3-phenylpropyl) piperidine.HCl (21 mg, 0.08 mmol) To this solution, a solution of 2-(R)-((3-(R)-formyl)-4-(S)-phenylpyrrolidin-1-yl)-2-(cyclohexyl)acetic acid, (4-methoxy) benzyl ester (25 mg, 0.052 mmol, from EXAMPLE 33, Step E) was added. A slurry of sodium triacetoxyborohydride (35 mg, 0.17 mmol) in 0.5 mL of 1,2-dichloroethane was then added. The reaction mixture was allowed to stand at rt for 16 hours. The solvent was removed and the product was purified by preprative HPLC (column: YMC Combiprep ODS-A 20×50 mm, gradient: 10% acetonitrile/H2O w/0.1% TFA for 1.5 min then ramp to 90% acetonitrile/H2O w/0.1% TFA over 7.5 min, flow: 20 mL/min). The isolated material was stirred in 3 mL formic acid for 16 h. After removal of solvent, the residue was purified by ion exchange chromatography (0.5 grams Varian SCX resin, 100% MeOH→2.0 M NH3/MeOH) to give 13 mg (48%) of the title compound: 1H NMR (400 MHz, CD3OD) δ 1.15-1.37 (m, 4H), 1.41-1.59 (m, 5H), 1.62-1.69 (m, 5H), 1.72-1.91 (m, 5H), 2.04 (t, J=10, 1H), 2.24 (t, J=11, 1H), 2.32 (dd, J=4.5, 13, 1H), 2.46 (dd, J=10, 13 Hz, 2H), 2.58 (t, J=7.5 Hz, 2H), 2.62-2.65 (m, 1H), 2.77 (m, 1H), 3.16 (dd, J=11, 19, 1H), 3.45 (m, 2H), 3.51 (d, J=3.9, 1H), 3.58-3.64 (m, 2H), 7.12-7.16 (m, 3H), 7.22-7.29 (m, 3H), 7.33-7.37 (m, 4H); ESI-MS: 521 (M+H); HPLC A: 2.65 min.
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][C:9]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:19](O)([C:21]([F:24])([F:23])[F:22])=O>>[N:13]1([C:9]2[CH:8]=[C:3]([C:4]([O:6][CH3:7])=[O:5])[C:2]3[NH:1][C:19]([C:21]([F:24])([F:23])[F:22])=[N:12][C:11]=3[CH:10]=2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: COC(=O)c1cc(N2CCOCC2)cc(N)c1N
Reactant: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(N2CCOCC2)cc2nc(C(F)(F)F)[nH]c12
Temperature: 25 °C

Procedure:
A mixture of methyl 2,3-diamino-5-(4-morpholinyl)benzoate (4.0 g) in CF3COOH (20 mL) was heated at reflux temperature for 8 h. When TLC analysis indicated consumption of starting material, the mixture was cooled to room temperature and the solvent was removed in-vacuo. The residue was diluted with aqueous NaHCO3 and extracted with EtOAc (250 mL×3). The combined organic layers were washed with brine (250 mL×2), dried over anhydrous Na2SO4. After filtration, the solvent was removed by rotary evaporator. The residue was then purified by silica gel chromatography eluted with EtOAc:petroleum ether=1:4 to afford the desired product as a pale solid. (4.3 g, 82.7%). 1H NMR (300 MHz, DMSO-d6): δ ppm 13.47 (s, 1H), 7.71 (s, 1H), 7.56 (s, 1H), 3.96 (s, 3H), 3.79 (t, 4H, J=4.5 Hz), 3.17 (s, 4H). LC-MS: m/e=330.1 [M+1]+.
Reaction SMILES: [Mg].[F:2][C:3]1[CH:4]=[C:5](Br)[CH:6]=[CH:7][CH:8]=1.[CH2:10]([CH:17]1[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].Cl>C1COCC1.C(OCC)(=O)C>[CH2:10]([CH:17]1[CH2:18][CH2:19][C:20]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([F:2])[CH:4]=2)([OH:23])[CH2:21][CH2:22]1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCC1CCC(=O)CC1
Reactant: Fc1cccc(Br)c1
Agent: Cl
Agent: [Mg]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCCCC1CCC(O)(c2cccc(F)c2)CC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 107.4 %

Procedure:
Well-dried magnesium (8.3 g) and THF (20 ml) were put in a reaction vessel under a nitrogen atmosphere, and heated to 50° C. 3-Fluorobromobenzene (8) (60.0 g) dissolved in THF (300 ml) was slowly added dropwise thereto in the temperature range of 40° C. to 60° C., and the mixture was stirred for another 60 minutes. Then, 4-heptylcyclohexanone (9) (50.0 g) dissolved in THF (150 ml) was slowly added dropwise thereto in the temperature range of 50° C. to 60° C., and the mixture was stirred for another 60 minutes. The reaction mixture obtained was cooled to 30° C., and then poured into a vessel containing an aqueous 1N—HCl solution (900 ml) and ethyl acetate (500 ml), and mixed. The mixture was then allowed to stand until it had separated into two phases of organic and aqueous phases, and an extractive operation was carried out. The organic phase obtained was fractionated, washed with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, giving 80.0 g of 4-heptyl-1-(3-fluorophenyl)-cyclohexanol (10). The compound (10) obtained was a yellow oil.
Reaction SMILES: Cl[CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:13].[N-:14]=[N+:15]=[N-:16].[Na+]>CS(C)=O>[N:14]([CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:13])=[N+:15]=[N-:16]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1Nc2ccccc2CCC1Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: [N-]=[N+]=NC1CCc2ccccc2NC1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-chloro-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (15.9 g, 0.08 mol) and sodium azide (6.36 g, 0.10 mol) in dimethylsulfoxide (320 ml) was maintained at 80° C. under an atmosphere of nitrogen for 3 hours. At this time, the IR spectrum of an aliquot showed a strong peak at 2150 cm-1 characteristic of the azide group. The reaction mixture was poured into 1000 ml of ice/water and the suspension was stirred for 30 min. The solid was filtered off, washed with water (250 ml) and dried to give 3-azido-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one, m.p. 142°-5°.