Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:31])[N:10]([C:12]1[CH:13]=[C:14]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:20][C:19]=2[OH:30])[CH:15]=[CH:16][CH:17]=1)[CH3:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH2:32]([N:34]([CH2:38][CH3:39])[CH2:35][CH2:36]O)[CH3:33].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:32]([N:34]([CH2:38][CH3:39])[CH2:35][CH2:36][O:30][C:19]1[CH:20]=[C:21]([CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH:22]=[CH:23][C:18]=1[C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([N:10]([CH3:11])[C:9]([NH:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[O:31])[CH:13]=1)[CH3:33]
Reactant: CCN(CC)CCO
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2O)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2OCCN(CC)CC)c1
Yield: 79.7 %

Procedure:
A solution of 500 mg (1.17 mmol, 1 eq) of methyl 3-[3′-(3-heptyl-1-methylureido)-2-hydroxybiphenyl-4-yl]propanoate (prepared in Example 15f) in 5 ml of tetrahydrofuran in the presence of 150 mg (1.29 mmol, 1.1 eq) of 2-diethylaminoethanol, 460 mg (1.76 mmol, 1.5 eq) of triphenylphosphine and 280 μL (1.76 mmol, 1.5 eq) of diethyl azodicarboxylate (DEAD) is stirred at room temperature for 24 hours. The reaction medium is concentrated and the residue is then chromatographed on silica gel (40/60 heptane/ethyl acetate). 490 mg of methyl 3-[2-(2-diethylaminoethoxy)-3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoate are obtained. Yield=80%
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:10]=1[CH:11]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][CH2:19][C:20]1[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=1.[BH4-].[Na+].C(O)(=O)C>C(O)C.O>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:10]=1[CH2:11][NH:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:29][CH:30]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cc(Br)ccc1OCc1ccccc1
Reactant: CCOC(=O)c1ccc(CN)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1ccc(CNCc2cc(Br)ccc2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-Benzyloxy-5-bromobenzaldehyde and ethyl 4-aminomethylbenzoate were heated together at 100° C. for 1 hour. The mixture was cooled, dissolved in ethanol (100 ml) and sodium borohydride (1.3 g) was added. The mixture was stirred for 18 hours at ambient temperature, acidified with acetic acid and water (200 ml) was added. The mixture was extracted with diethyl ether (4×100 ml), the extracts washed with saturated aqueous NaHCO3, dried (MgSO4), filtered and evaporated to give ethyl 4-[N-(2-benzyloxy-5-bromobenzyl)aminomethyl]benzoate which was purified by chromatography on silica gel eluting with CH2Cl2 then 5% ethyl acetate/CH2Cl2 (yield 11.4 g).
Reaction SMILES: Br[C:2]1[C:6]2[N:7]=[C:8]([Cl:12])[N:9]=[C:10]([NH2:11])[C:5]=2[S:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].B([C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25]([OH:27])=[O:26])(O)O.CC(C1C=C(C(C)C)C(C2C(P(C(C)(C)C)C(C)(C)C)=CC=CC=2)=C(C(C)C)C=1)C>O1CCOCC1>[NH2:11][C:10]1[C:5]2[S:4][CH:3]=[C:2]([C:22]3[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=3)[C:25]([OH:27])=[O:26])[C:6]=2[N:7]=[C:8]([Cl:12])[N:9]=1
Reactant: O=C(O)c1cccc(B(O)O)c1
Reactant: Nc1nc(Cl)nc2c(Br)csc12
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Nc1nc(Cl)nc2c(-c3cccc(C(=O)O)c3)csc12
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 65.4 %

Procedure:
7-Bromo-2-chlorothieno[3,2-d]pyrimidin-4-amine (500 mg, 1.90 mmol) was dissolved in dioxane (10 mL) and 2.0 N sodium carbonate (2.85 mL, 5.70 mmol) and 3-boronobenzoic acid (316 mg, 1.90 mmol) were added. Nitrogen was flown to the mixture solution for 10 minutes and then Pd2(PPh3)Cl2 (80 mg, 0.11 mmol) and t-ButylXphos (73 mg, 0.17 mmol) were added. The reaction mixture solution was stirred at 90° C. for 6 hours and then filtered with celite. The organic layer was concentrated and then 2.0 N sodium hydroxide solution was added until the pH reached 10. After extracting with ethyl acetate, the aqueous layer was adjusted to pH 5 by adding 2.0 N hydrochloric acid solution. Thus prepared white solid was filtered and dried using nitrogen gas. The resultant target compound (380 mg, 65% yield) was used in the following reaction without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:27][CH3:28])=[C:17]([NH:20][C:21](=[O:26])[CH:22]=[CH:23][CH2:24]Br)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[F:8].[OH:31][CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:27][CH3:28])=[C:17]([NH:20][C:21](=[O:26])[CH:22]=[CH:23][CH2:24][N:35]4[CH2:36][CH2:37][CH:32]([OH:31])[CH2:33][CH2:34]4)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCBr
Reactant: OC1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCN1CCC(O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 40.7 %

Procedure:
A mixture of 250 mg (0.51 mmol) of the 4-bromo-but-2-enoic acid[4-(3-chloro-4-fluoro-phenylamino)-3-cyano-7-methoxy-quinolin-6-yl]-amide, and 103.2 mg (1.02 mmol) of 4-hydroxypiperidine in 2.25 ml dimethylformamide was stirred at room temperature for 3 hr. Saturated sodium bicarbonate was added and the precipitate was filtered and washed with hexane to give the first crop of product. The filtrate was extracted with ethyl acetate and the organic layer with purified by preparative TLC to yield the second crop. The two crops were combined to give 105.8 mg (41%) tan solid: mp >215° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[NH:8])[NH:4][N+:5]([O-:7])=[O:6].Cl.N[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[N:16][CH:17]=1.[OH-].[Na+]>O>[CH3:1][O:2][C:3](=[N:4][N+:5]([O-:7])=[O:6])[NH:8][CH2:11][C:12]1[CH:17]=[N:16][C:15]([Cl:18])=[CH:14][CH:13]=1
Reactant: COC(=N)N[N+](=O)[O-]
Reactant: NCc1ccc(Cl)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=N[N+](=O)[O-])NCc1ccc(Cl)nc1
Yield: 47.3 %

Procedure:
To a mixture of O-methyl-N-nitroisourea (1.25 g, 10.53 mmol), water (20 ml) and concentrated hydrochloric acid (0.85 ml, 10.03 mmol) was added 5-(aminomethyl)-2-chloropyridine (1.43 g, 10.03 mmol) dropwise over 5 minutes at room temperature with stirring. The reaction mixture was neutralized with 40% aqueous sodium hydroxide solution and adjusted to pH 7.2. After 17 hours of stirring at room temperature, the resulting crystals were collected. The crystals were washed with water and dried. As a result, 1.16 g (47.3% yield) of O-methyl-N-(6-chloro-3-pyridylmethyl)-N'-nitroisourea was obtained as white crystals. M.p. 112-113° C.
Reaction SMILES: CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.[OH:14][CH:15]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:16]#[C:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>CC(C)=O.O>[CH3:26][CH:24]([CH3:25])[CH2:23][C:15](=[O:14])[C:16]#[C:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)C#CC(O)CC(C)C
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)C#CC(=O)CC(C)C
Yield: 74.5 %

Procedure:
Jones' reagent (from chromium trioxide, 4 g) was added dropwise with stirring to ethyl 4-hydroxy-6-methyl-2-heptynoate (9.5 g) in acetone (30 ml) in an ice bath, with the temperature being maintained at about 10°. After 0.5 hour the reaction was diluted with water (300 ml) and extracted with diethyl ether thrice. The organic phase was washed with brine, dried, and evaporated to give ethyl 6-methyl-4-oxo-2-heptynoate as an oil (7.0 g).
Reaction SMILES: [CH:1](NC(C)C)(C)[CH3:2].C([Li])CCC.C([N-]C(C)C)(C)C.[Li+].[CH:21]1([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:25][CH:24]=[CH:23][CH2:22]1.ICC>C1COCC1>[CH2:1]([C:21]1([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:25][CH:24]=[CH:23][CH2:22]1)[CH3:2]
Reactant: CC(C)NC(C)C
Reactant: CCOC(=O)C1CC=CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCI
Product: CCOC(=O)C1(CC)CC=CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
To a solution of diisopropylamine (10 mL, 72 mmol) in anhydrous THF (50 mL) was added n-butyl lithium (29 mL, 72 mmol, 2.5 M solution in hexane) over 20 min at −78° C. The mixture was stirred at 0° C. under nitrogen for 1 h. The freshly prepared lithium diisopropylamide was added to a mixture of ethyl cyclopent-3-enecarboxylate (6.7 g, 47.9 mmol) in anhydrous THF (50 mL) over 20 minutes at −78° C. After another 1 hour at this temperature, iodoethane (11.2 g, 72 mmol) was added over 20 min. Then the mixture was stirred at room temperature for 2 h and quenched with saturated aqueous ammonium chloride solution. The aqueous layer was extracted with ether (3×100 mL). The combined organic layers were washed with diluted hydrochloric acid (1 N), then washed with brine, dried over anhydrous sodium sulfate and filtered. Concentration gave the titled compound (7 g crude) which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ ppm 5.60 (s, 2H), 4.21-4.12 (m, 2H), 2.92-2.84 (m, 2H), 2.31-2.25 (m, 2H), 1.75-1.67 (m, 2H), 1.29-1.24 (m, 3H), 0.88-0.82 (m, 3H).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20](O)=[O:21])=[CH:11][CH:10]=2)=[C:4]([O:26][CH3:27])[CH:3]=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1.Cl.[CH2:59]([O:61][C:62](=[O:66])[CH2:63][NH:64][CH3:65])[CH3:60]>C(Cl)Cl.O.CCOC(C)=O>[CH2:59]([O:61][C:62](=[O:66])[CH2:63][N:64]([C:20](=[O:21])[C:19]1[CH:23]=[CH:24][CH:25]=[C:17]([CH2:16][O:15][C:12]2[CH:11]=[CH:10][C:9]([C:5]3[CH:6]=[C:7]([F:8])[C:2]([F:1])=[CH:3][C:4]=3[O:26][CH3:27])=[CH:14][CH:13]=2)[CH:18]=1)[CH3:65])[CH3:60]
Reactant: COc1cc(F)c(F)cc1-c1ccc(OCc2cccc(C(=O)O)c2)cc1
Reactant: CCOC(=O)CNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CN(C)C(=O)c1cccc(COc2ccc(-c3cc(F)c(F)cc3OC)cc2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 3-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-benzoic acid (20 g, 54 mmol), DIEA (38 mL, 216 mmol), EDCI (15.47 g, 81 mmol) and HOAT (11 g, 81 mmol) in methylene chloride (800 mL) was stirred at room temperature for 1 h, followed by addition of N-methyl glycine ethyl ester hydrochloride (12.44 g, 81 mmol). The resulting mixture was stirred at room temperature for 24 h, then treated with EtOAc (1.5 L) and water (1.5 L). The organic layer was separated, washed with water and brine, dried over sodium sulfate, filtered and evaporated. The oily residue was purified by column (0-35% EtOAc in hexane) to give {[3-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-benzoyl]-methyl-amino}-acetic acid ethyl ester, 17 g (67%). LC-MS (ES) calculated for C26H25F2NO5, 469; found m/z 470 [M+H]+.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[CH2:7]([O:9][C:10]([NH:12][CH2:13][CH2:14][S:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:11])[CH3:8]>O.CO>[CH2:7]([O:9][C:10]([NH:12][CH2:13][CH2:14][S:15]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:2])=[O:11])[CH3:8]
Reactant: CCOC(=O)CSCCNC(=O)OCC
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCOC(=O)CS(=O)CCNC(=O)OCC
Yield: 78.8 %

Procedure:
There was dissolved 149.7 g (0.7 mol) of sodium metaperiodate in 1400 ml of water, and thereto was added dropwise a solution of 164.5 g (0.7 mol) of ethyl 2-[2-(ethoxycarbonylamino)ethylthio]acetate in 125 ml of methanol under cooling with ice. After dropping the mixture was stirred for, hours under cooling with ice. The precipitate was removed by filtration and washed with water and with chloroform, successively. The filtrate was extracted with chloroform and dried over anhydrous sodium sulfate. Then the solvent was removed under reduced pressure to give 138.6 g of white solid. The solid was recrystallized from ethanol-n-hexane (1:4) to give 113.5 g of the titled compound.
Reaction SMILES: [Br-].[CH3:2][N:3]([CH3:14])[NH:4][C:5]([N:7]1[CH2:11][CH2:10][CH:9]([PH3+])[C:8]1=[O:13])=[O:6].[C:15]([C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:26]=1[OH:27])[CH:22]=O)([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C>>[CH3:2][N:3]([CH3:14])[NH:4][C:5]([N:7]1[CH2:11][CH2:10][C:9](=[CH:22][C:21]2[CH:20]=[C:19]([C:15]([CH3:16])([CH3:18])[CH3:17])[C:26]([OH:27])=[C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:24]=2)[C:8]1=[O:13])=[O:6]
Reactant: CN(C)NC(=O)N1CCC([PH3+])C1=O
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Agent: [Br-]
Solvent: CCN(CC)CC
Product: CN(C)NC(=O)N1CCC(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Yield: 46.4 %

Procedure:
Substantially in the same manner as in Example 39 (3), 8.31 g of the thus obtained {1-(N-dimethylaminocarbamoyl)-2-oxopyrrolidin-3-yl}phosphonium bromide, 3.79 g (16.2 mmol) of 3,5-di-tert-butyl-4-hydroxybenzaldehyde and 4.51 ml (32.4 mmol) of triethylamine were treated to give 2.91 g of the objective compound (Ia-26) in 46.4% yield.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[N:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C@@H:15]1[CH2:20][CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16]1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[N:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C@@H:15]1[CH2:20][CH2:19][CH2:18][NH:17][CH2:16]1
Reactant: COCCCn1c([C@@H]2CCCN(C(=O)OC(C)(C)C)C2)nc2ccncc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCCn1c([C@@H]2CCCNC2)nc2ccncc21

Procedure:
(R)-tert-Butyl 3-(3-(3-methoxypropyl)-3H-imidazo[4,5-c]pyridin-2-yl)piperidine-1-carboxylate (36D) (0.279 mmol, 0.105 g) was added to a 10 mL round-bottomed flask equipped for stirring under nitrogen. Dichloromethane (1 mL) and trifluoroacetic acid (1 mL) were then added and the resultant solution was allowed to stir under nitrogen for 4 hr. The reaction was then concentrated and dried in-vacuo affording (R)-3-(3-Methoxypropyl)-2-(piperidin-3-yl)-3H-imidazo[4,5-c]pyridine (35E) as a clear oil that was used without further purification. ESI-MS: m/z 275.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][C:12]([CH3:15])([CH3:14])[CH2:11][CH2:10][C:9]=2[CH:16]([OH:18])[CH3:17])=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl.CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:13][C:12]([CH3:14])([CH3:15])[CH2:11][CH2:10][C:9]=2[C:16](=[O:18])[CH3:17])=[CH:6][CH:7]=1
Reactant: CC(O)C1=C(c2ccc(Cl)cc2)CC(C)(C)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOCC
Product: CC(=O)C1=C(c2ccc(Cl)cc2)CC(C)(C)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of EXAMPLE 253A (1.18 g) in dichloromethane (20 ml) was slowly added Dess-Martin Periodinane (2.457 g). The reaction mixture was stirred at room temperature for 3 hours and diluted with ether. The resulting mixture was washed with aqueous NaOH and water. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by flash chromatography, eluting with 0-100% dichloromethane in hexane to provide the title compound.
Reaction SMILES: C([O:3][C:4](=[O:30])[C:5]([CH3:29])([CH3:28])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:27])[N:12]1[CH2:17][CH2:16][C:15]2[NH:18][CH:19]=[CH:20][C:14]=2[CH2:13]1)C.C(O)C.[OH-].[Na+]>O>[Cl:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH:11]([N:12]1[CH2:17][CH2:16][C:15]2[NH:18][CH:19]=[CH:20][C:14]=2[CH2:13]1)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]([CH3:29])([CH3:28])[C:4]([OH:30])=[O:3]
Reactant: CCOC(=O)C(C)(C)CCCCCC(c1ccccc1Cl)N1CCc2[nH]ccc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(CCCCCC(c1ccccc1Cl)N1CCc2[nH]ccc2C1)C(=O)O
Temperature: 96.5 °C
Yield: 59.6 %

Procedure:
8-(2-Chlorophenyl)-2,2 dimethyl-8-(1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-yl)-octanoic acid ethyl ester (0.11 g, 0.25 mmol) was added to a mixture of ethanol (15 mL), water (1.35 mL), and sodium hydroxide (0.07 g, 1.75 mmol). The mixture was heated to reflux (95-98° C. oil bath) for 11 hours. After cooling to room temperature, the solvent was evaporated under reduced pressure. Water (10 mL) was added to the residue and adjusted to pH=6 with 10 N hydrochloric acid. The product was extracted with dichloromethane (3×10 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried over Na2SO4. After filtration, the dichloromethane solution was concentrated under reduced pressure to obtain crude product. The crude product was purified by column chromatography (silica gel, ethyl acetate/heptane=3/7) to afford 8-(2-chlorophenyl)-2,2 dimethyl-8-(1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-yl)-octanoic acid (Compound Iq, 0.06 g, 59.8% yield) as a yellow oil. 1NMR (Field: 300 MHz, Solvent: CD3OD/TMS) δ (ppm): 7.60 (d, 1H, J=7.5 Hz), 7.48 (d, 1H, J=7.8 Hz), 7.41-7.30 (m, 2H), 6.58 (d, 1H, J=2.7 Hz), 5.89 (d, 1H, J=2.7 Hz), 4.56-4.52 (m, 1H), 3.96 (d, 1H, J=13.5 Hz), 3.65 (d, 1H, J=13.5 Hz), 2.97-2.65 (m, 4H), 2.00-1.87 (m, 2H), 1.43-1.39 (m, 2H), 1.28-1.18 (m, 6H), 1.11 (s, 6H). 13C NMR (Field: 75 MHz, Solvent: CD3OD/TMS) δ (ppm) 183.09, 136.97, 136.77, 131.03, 130.05, 130.31, 128.80, 124.29, 118.35, 113.24, 105.71, 65.49, 50.79, 49.81, 43.48, 42.01, 33.13, 30.39, 26.74, 26.19, 25.98, 23.34.
Reaction SMILES: [NH2:1][C@H:2]([C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].Cl.CCN(CC)CC.[NH:36]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[C@H:37]([C:42]([NH:44][C@H:45]([C:50](O)=[O:51])[CH2:46][CH:47]([CH3:49])[CH3:48])=[O:43])[CH2:38][CH:39]([CH3:41])[CH3:40].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C.C(O)(=O)C>[NH:36]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[C@H:37]([C:42]([NH:44][C@H:45]([C:50]([NH:1][C@H:2]([C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9])=[O:51])[CH2:46][CH:47]([CH3:48])[CH3:49])=[O:43])[CH2:38][CH:39]([CH3:41])[CH3:40]
Reactant: N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reactant: CC(C)C[C@H](NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reaction time: 4 h
Yield: 93.6 %

Procedure:
A solution of H-Lys(Z)-OBzl.HCl (20.35 g, 50 mmol) in DMF (50.0 g) was treated with Et3N (5.26 g, 51 mmol) at 25 to 30° C. Boc-Leu-Leu-OH (17.57 g, 51 mmol) and HOBt (1.08 g, 8 mmol) were added followed by an additional portion of DMF (7.0 g). A solution of DCC (11.35 g, 55 mmol) in DMF (25.0 g) was added dropwise over a period of 30 min at 20° C. The reaction mixture was stirred for 4 h and the temperature was allowed to rise (to ca. 34° C.). Acetic acid (0.2 g) was added, the resulting suspension was filtered and the filter cake was rinsed with DMF (15.0 g). Acetone (126.0 g) was added to the filtrate, followed by two portions of H2O (66.5 g, 89.5 g-30 min apart). The resulting precipitate was filtered and the filter cake was washed with acetone (53.0 g) and H2O (212.0 g). The crude solid was triturated with a mixture of acetone (100 g) and H2O (400 g), filtered, washed with H2O and dried in vacuo at 40° C. to give Boc-Leu-Leu-Lys(Z)-OBzl (32.6 g, 93.4%).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]([C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH2:26][CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])[CH:18]=2)=[O:16])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].C(C1C=CC(C(CCC)CCCCCCC(C2C3C(=CC=CC=3)N(CCCC(OCC)=O)C=2)=O)=CC=1)C(C)C>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]([C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])[CH:18]=2)=[O:16])=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CCOC(=O)CCCn1cc(C(=O)CCCCc2ccc(CC(C)C)cc2)c2ccccc21
Agent: CCCC(CCCCCCC(=O)c1cn(CCCC(=O)OCC)c2ccccc12)c1ccc(CC(C)C)cc1
Product: CC(C)Cc1ccc(CCCCC(=O)c2cn(CCCC(=O)O)c3ccccc23)cc1

Procedure:
The procedure of Ex. 16 was repeated except that ethyl 4-[3-[5-(4-isobutylphenyl)valeryl]-1-indolyl]butyrate obtained in Ex. 23 was used in place of ethyl 4-[3-[8-(4-isobutylphenyl)undecanoyl]-1-indolyl]butyrate to give 4-[3-[5-(4-isobutylphenyl)valeryl]-1-indolyl]butyric acid.
Reaction SMILES: [CH3:1][N:2]([CH2:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)[C:3]([C:5]1[S:13][C:12]2[C:7](=[N:8][CH:9]=[CH:10][C:11]=2Cl)[CH:6]=1)=[O:4].[CH3:22][C:23]1[NH:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([NH2:32])=[CH:27][CH:26]=2>>[CH3:1][N:2]([CH2:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)[C:3]([C:5]1[S:13][C:12]2[C:7](=[N:8][CH:9]=[CH:10][C:11]=2[NH:32][C:28]2[CH:29]=[C:30]3[C:25](=[CH:26][CH:27]=2)[NH:24][C:23]([CH3:22])=[CH:31]3)[CH:6]=1)=[O:4]
Reactant: CN(Cc1ccncc1)C(=O)c1cc2nccc(Cl)c2s1
Reactant: Cc1cc2cc(N)ccc2[nH]1
Product: Cc1cc2cc(Nc3ccnc4cc(C(=O)N(C)Cc5ccncc5)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from 7-chloro-thieno[3,2-b]pyridine-2-carboxylic acid methyl-pyridin-4-ylmethyl-amide and 2-methyl-1H-indol-5-ylamine by a method analogous to Example 1C. MS: 428 (MH+); HPLC Rf: 4.26 min; HPLC purity: 93%.
Reaction SMILES: [Br-].[CH2:2]([N+:9]1[CH:18]=[CH:17][C:16]2[C:11](=[N:12][C:13]([NH:34][CH:35]([CH3:37])[CH3:36])=[C:14]([N:19]3[CH2:24][CH2:23][CH:22]([O:25][C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=4[F:33])[CH2:21][CH2:20]3)[N:15]=2)[CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH2:2]([N:9]1[CH2:18][CH2:17][C:16]2[C:11](=[N:12][C:13]([NH:34][CH:35]([CH3:37])[CH3:36])=[C:14]([N:19]3[CH2:24][CH2:23][CH:22]([O:25][C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=4[F:33])[CH2:21][CH2:20]3)[N:15]=2)[CH2:10]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)Nc1nc2c[n+](Cc3ccccc3)ccc2nc1N1CCC(Oc2ccc(F)cc2F)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCN(Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 72 h
Yield: 103.2 %

Procedure:
To a solution of 6-benzyl-2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-3-(isopropylamino)pyrido[3,4-b]pyrazin-6-ium bromide (7.2 g, 12.62 mmol) in DCM (126 ml) was added NaBH(OAc)3 (16.05 g, 76 mmol). The resulting solution was stirred at room temperature for 3 days. After DCM was removed under vacuum, EtOAc (200 mL) was added to re-dissolve the residue. Then saturated NaHCO3 (150 mL) was added and the mixture was vigorously stirred for 30 min. The organic layer was washed with water (50 mL) and brine (50 mL), and dried with anhydrous Na2SO4 overnight. Removal of the solvent gave the title compound (6.43 g) as a yellow solid, which was used without further purification. ESI-MS m/z [M+H]+ 494.10.