Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([C:13]2[CH:14]=[CH:15][C:16]3[O:25][C:24]4[CH2:23][CH2:22][N:21]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:20][C:19]=4[C:17]=3[CH:18]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([S:10]([C:13]2[CH:14]=[CH:15][C:16]3[O:25][C:24]4[CH2:23][CH2:22][N:21]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:20][C:19]=4[C:17]=3[CH:18]=2)(=[O:11])=[O:12])=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCc2oc3ccc(S(=O)(=O)c4ccc([N+](=O)[O-])cc4)cc3c2C1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2oc3ccc(S(=O)(=O)c4ccc(N)cc4)cc3c2C1
Yield: 88.7 %

Procedure:
To a solution of product from step A (96 mg, 0.20 mmol) in ethanol (4.0 mL) and water (2.0 mL) was added iron powder (57 mg, 1.02 mmol) and ammonium chloride (12 mg, 0.22 mmol). After refluxing for 3 h, the reaction mixture was filtered through a bed of celite and the celite bed washed repeatedly with ethyl acetate. The filtrate was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a crude product which was purified by flash column chromatography (SiO2, 3:2 hexanes/ethyl acetate) to give the product tert-butyl 8-(4-aminophenylsulfonyl)-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (76 mg, 87%) as an off-white solid: 1H NMR (CDCl3, 300 MHz) δ 8.22-8.19 (m, 1H), 7.88 (dd, J=8.7, 1.8 Hz, 1H), 7.81-7.75 (m, 2H), 7.67 (d, J=8.4 Hz, 1H), 6.97-6.91 (m, 2H), 4.48 (s, 2H), 3.54-3.52 (m, 2H), 3.23-3.16 (m, 2H), 1.55 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.CC1(C)C(C)(C)OB([C:36]2[CH:37]=[C:38]([S:42]([NH2:45])(=[O:44])=[O:43])[CH:39]=[CH:40][CH:41]=2)O1>>[F:15][C:14]([F:16])([F:17])[C:12]1[CH:11]=[C:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:26])([F:25])[F:27])=[CH:20][CH:19]=2)[N:9]=[C:8]([C:4]2[CH:3]=[C:2]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([S:42]([NH2:45])(=[O:44])=[O:43])[CH:37]=3)[CH:7]=[CH:6][CH:5]=2)[CH:13]=1
Reactant: CC1(C)OB(c2cccc(S(N)(=O)=O)c2)OC1(C)C
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)cc(-c3cccc(Br)c3)n2)cc1
Product: NS(=O)(=O)c1cccc(-c2cccc(-c3cc(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)n3)c2)c1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridine (example E.20) (0.223 g, 0.5 mmol) and commercially available 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-benzenesulfonamide [CAS-No. 486422-08-6] (0.283 g, 1.0 mmol) according to the general procedure VI. Obtained as a light brown solid (0.125 g, 43%). MS (ISP) 523.3 [(M+H)+]; mp 176-179° C.
Reaction SMILES: C([O:8][P:9]([NH:19][C:20]1[CH:25]=[C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:23]=[CH:22][C:21]=1[N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)(=[O:18])[O:10]CC1C=CC=CC=1)C1C=CC=CC=1>[Pd].CO>[C:26]([C:24]1[CH:23]=[CH:22][C:21]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[C:20]([NH:19][P:9](=[O:8])([OH:10])[OH:18])[CH:25]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)c1ccc(N2CCOCC2)c(NP(=O)(OCc2ccccc2)OCc2ccccc2)c1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)c1ccc(N2CCOCC2)c(NP(=O)(O)O)c1
Yield: 70 %

Procedure:
A solution of 1 g. of dibenzyl N-(5-tert.-butyl-2-morpholinophenyl) phosphoramidic acid dissolved in 100 ml. of dry methanol and 0.4 g. of palladium on carbon catalyst (wetted in monoglyme) was hydrogenated for 1/2 hour in a hydrogenation bottle. The resultant reaction mixture was filtered through Celite and the filtrate evaporated to dryness under reduced pressure. The product was obtained as a gray, crystalline solid residue (0.7 g.; 70% yield) melting at 79°-83° C.
Reaction SMILES: Br[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3].[NH2:10][C:11]1[C:16]([OH:17])=[CH:15][CH:14]=[CH:13][N:12]=1.O>[OH-].[Na+].ClCCl.CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-]>[NH2:10][C:11]1[C:16]([O:17][CH:2]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH3:3])=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: CC(Br)c1ccccc1
Reactant: Nc1ncccc1O
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(Oc1cccnc1N)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.2 %

Procedure:
A mixture of 1-bromoethylbenzene (55 g, 0.296 mol) and 2-amino-3-hydroxypyridine (29.6 g, 0.269 mol) in 40% aqueous sodium hydroxide solution (200 ml) and dichloromethane (200 ml) was treated with Adogen 464 (10 ml) and stirred vigorously at room temperature for 16 hours. A further 200 ml of water was added and the product extracted into dichloromethane, dried, and the solvent evaporated. Chromatography (silica gel, chloroform-methanol) gave the product as a crystalline solid (37.6 g, 63%), m.p. 79°-83° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](Br)[CH:6]=[CH:7][CH:8]=1.[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1B(O)O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:10][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(Br)c1
Reactant: OB(O)c1cccs1
Product: COc1cccc(-c2cccs2)c1

Procedure:
3-Methoxybromobenzene and thiophene-2-boronic acid were treated in a manner similar to Reference Example 26-(2) to give 2-(3-methoxyphenyl)thiophene as a yellow liquid. APCI-Mass m/Z 191 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[N:15]1[C:19](CC(N)=O)=[CH:18][C:17]([O:24][CH2:25][C:26]([F:32])([F:31])[C:27]([F:30])([F:29])[F:28])=[N:16]1.[CH2:33]([N:35](CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCCC1>[C:33]([C:19]1[N:15]([C:3]2[CH:4]=[C:5]([S:9][CH2:10][C:11]([F:12])([F:13])[F:14])[C:6]([CH3:8])=[CH:7][C:2]=2[F:1])[N:16]=[C:17]([O:24][CH2:25][C:26]([F:31])([F:32])[C:27]([F:28])([F:30])[F:29])[CH:18]=1)#[N:35]
Reactant: Cc1cc(F)c(-n2nc(OCC(F)(F)C(F)(F)F)cc2CC(N)=O)cc1SCC(F)(F)F
Reactant: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Cc1cc(F)c(-n2nc(OCC(F)(F)C(F)(F)F)cc2C#N)cc1SCC(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.2 %

Procedure:
0.80 g of 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-(2,2,3,3,3-pentafluoropropoxy)pyrazole-5-carboxyamide was dissolved in 20 mL of tetrahydrofuran, 0.42 g of triethylamine was added, and 0.52 g of trifluoroacetic anhydride was slowly dropwise added under cooling with ice. After stirring at room temperature for 2 hours, the solvent was distilled off under reduced pressure, and extraction with ethyl acetate was carried out. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:4) to obtain 0.60 g of 5-cyano-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-(2,2,3,3,3-pentafluoropropoxy)pyrazole.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]3[CH2:14][CH2:13][CH2:12][C:11]=13)[N:8](C(OC(C)(C)C)=O)[C:7]([CH3:23])([CH3:22])[C:6](=[O:24])[C:5]2([CH3:26])[CH3:25].FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]3[CH2:14][CH2:13][CH2:12][C:11]=13)[NH:8][C:7]([CH3:22])([CH3:23])[C:6](=[O:24])[C:5]2([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1c2c(cc(Br)c3c2CCC3)C(C)(C)C(=O)C1(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)Nc2c(cc(Br)c3c2CCC3)C(C)(C)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
To a solution of tert-butyl 6-bromo-2,2,4,4-tetramethyl-2,3,4,7,8,9-hexahydro-1H-cyclopenta[h]quinolin-3-one-1-carboxylate (1.0 g) obtained in Example 1, 8) in CH2Cl2 (10 ml) was added trifluoroacetic acid (10 ml), and the mixture was stirred at room temperature for 1 hr. The reaction solution was neutralized with 1N aqueous sodium hydroxide solution, and the mixture was extracted with CHCl3. The organic layer was washed with water and saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to normal phase chromatography (elution solvent hexane→hexane-ethyl acetate=7:3) to give the title compound (760 mg, 100%).
Reaction SMILES: NC1CCC2C(=CC(OC)=C([O:12]C)C=2)C1.[CH:16]1([N:22]=[C:23]=[N:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C(NCC(O)=O)(OC(C)(C)C)=O>C(Cl)Cl>[C:23]([NH:22][CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1)([NH:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:12]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: COc1cc2c(cc1OC)CC(N)CC2
Agent: CC(C)(C)OC(=O)NCC(=O)O
Solvent: ClCCl
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 2 h

Procedure:
2-amino-6,7-dimethoxy tetraline (0.4 g; 2.07 mmoles) was dissolved in 20 ml CH2Cl2. Dicyclohexylcarbodiimide (0.4 g; 2.07 mmoles) and carbotertbutoxyglycine (0.36 g; 2.07 mmoles) were added to the solution. The solution was kept under stirring for 2 hours. Dicyclohexylurea that formed was then filtered off. The filtrate was extracted with a saturated solution of NaHCO3, diluted HCl and H2O till neutrality was reached. The organic phase separated and dried was concentrated under vacuum. The residue thus obtained was chromatographed on a silica gel column, eluting with CHCl3 --AcOEt, 1:1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@H:11]3[CH2:16][CH2:15][CH2:14][CH2:13][C@@:12]3([OH:18])[CH3:17])=[C:8]([C:19]([NH2:21])=[O:20])[CH:7]=[N:6][N:5]2[CH:22]=1.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[OH:18][C@@:12]1([CH3:17])[CH2:13][CH2:14][CH2:15][CH2:16][C@@H:11]1[NH:10][C:9]1[C:4]2[N:5]([CH:22]=[C:2]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:3]=2)[N:6]=[CH:7][C:8]=1[C:19]([NH2:21])=[O:20]
Reactant: OB(O)c1ccccc1
Reactant: C[C@]1(O)CCCC[C@@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CN(C)C=O
Product: C[C@]1(O)CCCC[C@@H]1Nc1c(C(N)=O)cnn2cc(-c3ccccc3)cc12
Temperature: 130 °C
Yield: 57.2 %

Procedure:
A mixture of 6-bromo-4-((1S,2S)-2-hydroxy-2-methylcyclohexylamino)pyrrolo[1,2-b]pyridazine-3-carboxamide (31 mg, 0.084 mmol), phenylboronic acid (21 mg, 0.17 mmol), Pd(OAc)2 (1.0 mg, 0.004 mmol), and dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (X-Phos, 4 mg, 0.0084 mmol) in DMF (0.5 mL) were added 2M K3PO4 (0.13 mL, 0.25 mmol) and the solution degassed via N2 sparging. The mixture was sealed and heated at 130° C. for 30 min. The reaction was cooled and the product was isolated via preparative HPLC to afford the title compound (17.5 mg, 52% yield) as a pale yellow solid. LCMS: 365.15 (M+H)+; HPLC (condition L): retention time=8.34 min; 1H NMR (methanol-d4, 400 MHz) δ 8.16 (s, 1H), 7.94 (d, J=1.7 Hz, 1H), 7.70 (m, 2H), 7.41 (t, J=7.5 Hz, 2H), 7.27 (m, 2H), 4.35 (m, 1H), 2.21 (m, 2H), 1.50-1.88 (m, 6H), 1.35 (s, 3H).
Reaction SMILES: [CH2:1]([C:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([O:19]C)=[O:18])=[CH:14][CH:15]=2)[N:10]([CH3:21])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[Li].O>C1COCC1.O>[CH2:1]([C:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([OH:19])=[O:18])=[CH:14][CH:15]=2)[N:10]([CH3:21])[CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc2c(Cc3ccccc3)cn(C)c2c1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(Cc2ccccc2)c2ccc(C(=O)O)cc21
Yield: 108.2 %

Procedure:
To a solution compound 56c (168 mg, 0.60 mmol), and LiOH.H2O (101 mg, 2.41 mmol) in THF/H2O (3/3 mL) was stirred at room temperature for 6 h. Concentrated the resulted mixture, extracted the residue with CH2Cl2, H2O, acidified the water layer with 1N HCl(aq) to pH˜4. The organic solution was dried over Na2SO4 and concentrated to give 56d (172.2 mg), which was used in the next reaction without further purification. MS m/z (M+H+) 266.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C@H:4]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)[NH:5][C:6](=[O:19])[C@H:7]([CH:16]([CH3:18])[CH3:17])[NH:8]C(OC(C)(C)C)=O.[ClH:29]>C(O)(=O)C.O1CCOCC1>[ClH:29].[CH3:1][O:2][C:3](=[O:28])[C@H:4]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)[NH:5][C:6](=[O:19])[C@H:7]([CH:16]([CH3:18])[CH3:17])[NH2:8]
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](N)C(C)C
Reaction time: 0.08 h

Procedure:
29.6 g of t-butoxycarbonylvalyltyrosine methyl ester is dissolved in 255 ml of acetic acid. To this solution is added 128 ml of 6 N hydrochloric acid in dioxane. The reaction is allowed to stand for five minutes and the solution is removed under vacuum. The residue is triturated with ethyl ether. The resultant precipitate is filtered, washed with ethyl ether and dried in a vacuum oven at 55° C. to afford valyltyrosine methyl ester hydrochloride.
Reaction SMILES: [N:1]1C=CC=[CH:3][CH:2]=1.C(N)C.[NH2:10][C:11]1[C:12]([F:37])=[CH:13][C:14]([F:36])=[C:15]([N:17]2[C:26]3[C:21](=[CH:22][C:23]([N+:29]([O-:31])=[O:30])=[C:24](F)[C:25]=3[CH3:27])[C:20](=[O:32])[C:19]([C:33]([OH:35])=[O:34])=[CH:18]2)[CH:16]=1>C(OCC)C>[NH2:10][C:11]1[C:12]([F:37])=[CH:13][C:14]([F:36])=[C:15]([N:17]2[C:26]3[C:21](=[CH:22][C:23]([N+:29]([O-:31])=[O:30])=[C:24]([NH:1][CH2:2][CH3:3])[C:25]=3[CH3:27])[C:20](=[O:32])[C:19]([C:33]([OH:35])=[O:34])=[CH:18]2)[CH:16]=1
Reactant: Cc1c(F)c([N+](=O)[O-])cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c12
Reactant: c1ccncc1
Agent: CCN
Solvent: CCOCC
Product: CCNc1c([N+](=O)[O-])cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c2c1C
Temperature: 50 °C
Reaction time: 3 h
Yield: 64.1 %

Procedure:
Pyridine (300 mg) and a 70% aqueous solution (150 mg) of ethylamine were added to 1-(5-amino-2,4-difluorophenyl)-7-fluoro-8-methyl-6-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (110 mg), and the mixture was stirred at 50° C. for 3 hours. Diethyl ether was added to the reaction mixture, followed by stirring. A supernatant liquid was removed, and solids deposited were recrystallized from N,N-dimethylformamide. The solids were collected by filtration and washed with ethanol to obtain the title compound (75 mg) as a reddish brown powder.
Reaction SMILES: C1(C)C=CC=CC=1.[Cl:8][C:9]1[CH:37]=[CH:36][C:12]([CH2:13][N:14]2[CH:19]=[N:18][C:17]([NH:20][CH:21]3[CH2:25][CH2:24][C:23]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)(O)[CH:22]3[OH:34])=[N:16][C:15]2=[O:35])=[CH:11][CH:10]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(N(CC)CC)C>[Cl:8][C:9]1[CH:37]=[CH:36][C:12]([CH2:13][N:14]2[CH:19]=[N:18][C:17]([NH:20][CH:21]3[CH2:25][CH:24]=[C:23]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)[CH:22]3[OH:34])=[N:16][C:15]2=[O:35])=[CH:11][CH:10]=1
Reactant: O=c1nc(NC2CCC(O)(c3ccc(F)cc3)C2O)ncn1Cc1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: Cc1ccccc1
Product: O=c1nc(NC2CC=C(c3ccc(F)cc3)C2O)ncn1Cc1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 52.2 %

Procedure:
A toluene solution (200 μL) of 1-(4-chlorobenzyl)-4-{[3-(4-fluorophenyl)-2,3-dihydroxycyclopentyl]amino}-1,3,5-triazin-2(1H)-one (14.0 mg, 0.0325 mmol) synthesized in Synthesis Example 465 and p-toluenesulfonic acid monohydrate (6.18 mg, 0.0325 mmol) was stirred at 100° C. for 8 hours. After the completion of the reaction, to the reaction solution, triethylamine was added and the reaction solution was concentrated under reduced pressure, followed by purifying the resultant residue by silica gel column chromatography (chloroform/ethyl acetate=1/2) to obtain the title compound (7.00 mg, yield: 52%).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]1(=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][C:14]1=[O:19].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>CN1C2C(N=C(N)NC=2NCC1CNC1C=CC(C(NC(C(O)=O)CCC(O)=O)=O)=CC=1)=O>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][C:18]1[CH2:17][CH2:16][CH2:15][C:14](=[O:19])[C:13]=1[OH:20])[CH3:27]
Reactant: O=C1CCCCC1=O
Reactant: CCOC(=O)CBr
Agent: CN1c2c([nH]c(N)nc2=O)NCC1CNc1ccc(C(=O)NC(CCC(=O)O)C(=O)O)cc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Product: CCOC(=O)CC1=C(O)C(=O)CCC1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
n-Butyl lithium (101 mL, 161 mmol) was added to a stirred solution of diisopropylamine (22.96 mL) in methyl-THF (200 mL) at −10° C. The resulting solution was stirred at −10° C. for 15 mins. 1,2-cyclohexanedione (8.6 g) was added to the reaction mixture as a solution in methyl-THF (28 mL). During the addition the internal temperature of the reaction was maintained between −15° C. and −5° C. by modulation of delivery rate. The resulting dark orange/brown solution was stirred at −10° C. for a further 15 mins. The reaction mixture was then cooled to −78° C. and ethyl bromoacetate (12.76 mL) was added dropwise via syringe. Further ethyl bromoacetate (0.8 mL) was added, no further evolution of heat was observed therefore the reaction was left to stir at −60 to −70° C. (internal temp) for 1 hour 15 minutes. The reaction mixture was quenched at −78° C. with 0.5 M HCl (400 ml), allowed to warm to RT and extracted with diethyl ether (200 ml). The organic layer was washed with water (300 mL) and saturated brine. The crude reaction mixture was purified by flash column chromatography (100 g, silica, ethyl acetate/cyclohexane, 0-50%) to give the title compound (7.1 g). LC/MS MH+ 199, Rt 1.78 mins (5 min system).
Reaction SMILES: [NH2:1][C:2]1([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.CCN(CC)CC.[N:22]([C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[CH:27][CH:26]=1)=[C:23]=[O:24]>C(Cl)Cl>[CH3:8][N:5]1[CH2:4][CH2:3][C:2]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])([NH:1][C:23]([NH:22][C:25]2[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[CH:27][CH:26]=2)=[O:24])[CH2:7][CH2:6]1
Reactant: CCOC(=O)CC1(N)CCN(C)CC1
Reactant: CCCCCCCCc1ccc(N=C=O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCc1ccc(NC(=O)NC2(CC(=O)OCC)CCN(C)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.7 %

Procedure:
A stirred solution of ethyl 2-(4-amino-1-methylpiperidin-4-yl)acetate (62 mg, 0.308 mmol) in CH2Cl2 (2 mL) was treated with NEt3 (0.13 mL, 0.924 mmol.), and 1-isocyanato-4-octylbenzene (0.071 mL, 0.308 mmol). The reaction was stirred overnight, at room temperature, then the solvent removed in vacuo and the product purified by column chromatography to obtain the title compound (94 mg, 71%). 1H NMR (400 MHz, CDCl3) δ 7.19 (d, 2H, J=8.4 Hz), 7.12 (d, 2H, J=8.4 Hz), 6.45 (bs, 1H), 4.78 (bs, 1H), 4.09 (q, 2H, J=7.2 Hz), 2.90 (s, 2H), 2.58-2.48 (m, 4H), 2.39-2.19 (m, 4H), 2.25 (s, 3H), 1.75-1.70 (m, 2H), 1.60-1.54 (m, 2H), 1.30-1.23 (m, 13H), 0.80 (t, 3H, 6.4 Hz); MS ESI 432.4 [M+H]+, calcd for [C25H41N3O3+H]+ 432.62.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[C@@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17]([Si:21](Cl)([CH3:23])[CH3:22])([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][Si:21]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:23])[CH3:22])[C@@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)[C@@H]1C(=O)O
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1C(=O)O
Reaction time: 16 h
Yield: 95.4 %

Procedure:
To (2R,3S)-1-(tert-butoxycarbonyl)-3-hydroxypyrrolidine-2-carboxylic acid (4.812 g, 20.81 mmol) in DMF (30 mL) at 0° C. was added tert-butylchlorodimethylsilane (9.409 g, 62.43 mmol) and triethylamine (10.53 g, 104.0 mmol). The cold bath was removed and the reaction mixture was stirred for 16 hours. The mixture was diluted with EtOAc (50 mL) and 10% NaOH (30 mL), and the phases were separated. The organic phase was washed with 10% NaOH. The combined aqueous phases were acidified with concentrated HCl until pH=2. The aqueous phase was extracted with DCM. The combined organic phases were dried (Na2SO4) and concentrated under reduced pressure to give the crude product 6.86 g).
Reaction SMILES: [ClH:1].Cl.[CH3:3][N:4]([CH3:29])[C@H:5]1[CH2:9][CH2:8][N:7](CC(C2(O)CCCCC2)C2C=CC=C(C(F)(F)F)C=2)[CH2:6]1.Cl.Cl.N[C@H]1CCN([CH2:38][CH:39]([C:50]2([OH:56])[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]2)[C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([C:46]([F:49])([F:48])[F:47])[CH:41]=2)C1>>[ClH:1].[ClH:1].[CH3:3][N:4]([CH3:29])[C@H:5]1[CH2:9][CH2:8][N:7]([CH:51]2[CH2:52][CH2:53][CH2:54][CH2:55][C:50]2([CH:39]([C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([C:46]([F:47])([F:49])[F:48])[CH:41]=2)[CH3:38])[OH:56])[CH2:6]1
Reactant: CN(C)[C@H]1CCN(CC(c2cccc(C(F)(F)F)c2)C2(O)CCCCC2)C1
Reactant: N[C@H]1CCN(CC(c2cccc(C(F)(F)F)c2)C2(O)CCCCC2)C1
Agent: Cl
Product: CC(c1cccc(C(F)(F)F)c1)C1(O)CCCCC1N1CC[C@H](N(C)C)C1

Procedure:
In an analogous manner to Example 36, 1-{2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-1-[3-(trifluoromethyl)phenyl]ethyl}cyclohexanol dihydrochloride was prepared from, 1-{2-[(3S)-3-aminopyrrolidin-1-yl]-1-[3-(trifluoromethyl)phenyl]ethyl}cyclohexanol (See Example 221). MS (ES) m/z 385.1; HRMS: calcd for C21H31F3N2O+H, 385.24667; found (ESI, [M+H]+), 385.2454.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([B:15]2[O:19][C:18]([CH3:21])([CH3:20])[C:17]([CH3:23])([CH3:22])[O:16]2)=[CH:11][CH:10]=1)(=O)=O.[NH2:24][C@@H:25]([CH3:35])[C@@H:26]([C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1)[OH:27].C(OCC)(=O)C>CN(C)C=O>[CH3:21][C:18]1([CH3:20])[C:17]([CH3:22])([CH3:23])[O:16][B:15]([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][NH:24][C@@H:25]([CH3:35])[C@@H:26]([C:28]3[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=3)[OH:27])=[CH:14][CH:13]=2)[O:19]1
Reactant: C[C@H](N)[C@H](O)c1ccc(O)cc1
Reactant: CC1(C)OB(c2ccc(OCCOS(C)(=O)=O)cc2)OC1(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@H](NCCOc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)[C@H](O)c1ccc(O)cc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 16.6 %

Procedure:
A mixture of 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]ethyl methanesulfonate (1.20 g) and 4-((1R,2S)-2-amino-1-hydroxypropyl)phenol (1.76 g) in N,N-dimethylformamide (20 mL) was stirred at 80° C. for 5 hrs. Ethyl acetate was added to the reaction mixture. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent:n-hexane/ethyl acetate=1/1, methylene chloride/methanol=9/1) to afford the title compound (0.24 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][C:3]=1[C:13](=[O:22])[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Br:23]N1C(=O)CCC1=O>CN(C=O)C.CCOCC>[Br:23][C:7]1[CH:6]=[C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH:4]=[C:3]([C:13](=[O:22])[CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:2]=1[OH:1]
Reactant: O=C(O)CCc1ccc(O)c(C(=O)CCc2ccccc2)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C(O)CCc1cc(Br)c(O)c(C(=O)CCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
The carboxylic acid 209, for example 3-[4-Hydroxy-3-(3-phenyl-propionyl)-phenyl]-propionic acid, (1.04 gm, 3.4 g mmol) was dissolved in DMF (7 mL) and N-bromosuccinimide (0.65 g, 3.66 mmol) was added to the solution. The mixture was stirred at ambient temperature for 2.5 h, diluted with ether and the organic layer was separated and washed with water and brine and then filtered through a pad of magnesium sulfate and concentrated. The residue was purified by flash chromatography (3.5:1.5:0.1 of hexane:ethyl acetate:acetic acid) to give 0.5 g of 3-[3-bromo-4-hydroxy-5-(3-phenyl-propionyl)-phenyl]-propionic acid 210 as a yellow-brown oil.