Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([OH:19])=O)[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:21]([O:25][C:26](=[O:33])[C@H:27]([CH2:29][CH:30]([CH3:32])[CH3:31])[NH2:28])([CH3:24])([CH3:23])[CH3:22].ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.CN1CCOCC1>C(Cl)Cl>[C:21]([O:25][C:26](=[O:33])[C@H:27]([CH2:29][CH:30]([CH3:31])[CH3:32])[NH:28][C:17](=[O:19])[C@H:12]([CH2:13][CH:14]([CH3:15])[CH3:16])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)C[C@H](N)C(=O)OC(C)(C)C
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CC(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 99.5 %

Procedure:
Under atmosphere of argon, to a solution of N-benzyloxycarbonylleucine (26.5 g) and leucine t-butyl ester hydrochloride (22.4 g) in methylene chloride (20.0 ml.) were added 1-hydroxybenzotriazole (HOBt) (14.2 g) and 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDC) hydrochloride (20.1 g) at 0° C. Thereto was added N-methylmorpholine (11.5 ml) over a period of 5 minutes and the mixture was stirred for 20 hours at room temperature. The reaction solution was concentrated and to the residue were added ice-water and ethyl acetate. In order to dissolve HOBt that appeared, was added sodium bicarbonate. The aqueous layer was extracted with ethyl acetate and combined organic layer was washed with 10% aqueous solution of citric acid, a saturated aqueous solution of sodium bicarbonate and saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and was concentrated to give the title compound (43.2 g) having the following physical data.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[C:9]([O:17]CC)(=O)[CH2:10][C:11]([O:13]CC)=O>C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:11](=[O:13])[CH2:10][C:9]([NH:5][C:4]2[CH:6]=[CH:7][CH:8]=[C:2]([Cl:1])[CH:3]=2)=[O:17])[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Nc1cccc(Cl)c1
Solvent: CCOCC
Product: O=C(CC(=O)Nc1cccc(Cl)c1)Nc1cccc(Cl)c1
Temperature: 220 °C
Reaction time: 18 h

Procedure:
3-chloroaniline (5.01 g) and diethyl malonate (2.51 ml) were combined in a flask and heated to 220° C. utilizing a short path condenser with nitrogen bleed over the reaction to remove reaction ethanol. The reaction was stirred for 18 hours and then cooled to room temperature. The solid that had formed in the flask was broken up in diethyl ether 30 mL to give free flowing orange solid upon filtration and washing with ether (3.75 g). LRMS (ES+) m/z (M+H)+ 322.9.
Reaction SMILES: [H][H].[CH3:3][CH2:4][O:5][C:6]([N:8]1[CH2:13][CH:12]=[CH:11][CH2:10][N:9]1C(OCC1C=CC=CC=1)=O)=[O:7]>C(O)C.[C].[Pd]>[CH2:4]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][NH:9]1)=[O:7])[CH3:3]
Reactant: [H][H]
Reactant: CCOC(=O)N1CC=CCN1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)N1CCCCN1

Procedure:
In a hydrogen atmosphere, 10% palladium-carbon (3.2 g) was added to the above-obtained 1,2,3,6-tetrahydropyridazine-1,2-dicarboxylic acid 1-benzyl ester 2-ethyl ester (32 g) in ethanol (100 mL), and the resultant mixture was stirred at 40° C. for 24 hours, and then cooled in air. The reaction mixture was filtered, and the solvent of the filtrate was removed under reduced pressure, and the residue was purified by distillation (boiling point 81° C./1 mmHg), to thereby give hexahydropyridazine-1-carboxylic acid ethyl ester as an oily product (5.96 g, yield from the 2 processes: 31.1%).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:15]([NH:22][CH2:23][CH2:24][C:25]1[CH:40]=[CH:39][C:28]([O:29][C:30]2[CH:38]=[CH:37][C:33]([C:34]([NH2:36])=[O:35])=[CH:32][N:31]=2)=[CH:27][CH:26]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH:41](=O)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C(O)(=O)C.[OH-].[Na+]>ClCCCl>[CH2:15]([N:22]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[CH2:23][CH2:24][C:25]1[CH:40]=[CH:39][C:28]([O:29][C:30]2[CH:38]=[CH:37][C:33]([C:34]([NH2:36])=[O:35])=[CH:32][N:31]=2)=[CH:27][CH:26]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: NC(=O)c1ccc(Oc2ccc(CCNCc3ccccc3)cc2)nc1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: NC(=O)c1ccc(Oc2ccc(CCN(Cc3ccccc3)Cc3ccccc3)cc2)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.9 %

Procedure:
Add sodium triacetoxyborohydride (0.2600 g, 1.227 mmol) to a stirred solution of 6-[4-(2-benzylamino-ethyl)-phenoxy]-nicotinamide (0.3058 g, 0.8802 mmol), benzaldehyde (0.092 mL, 0.905 mmol), glacial acetic acid (0.052 mL, 0.908 mmol) and 1,2-dichloroethane (8 mL). Stir for 18 h at room temperature under nitrogen. Pour the reaction into 1N sodium hydroxide (50 mL) and extract with diethyl ether (3×50 mL). Wash the diethyl ether extracts with brine, dry over magnesium sulfate, filter, and concentrate on a rotary evaporator to give the crude product. The crude product is purified by flash chromatography on silica gel eluting with 75% ethyl acetate/hexanes to yield 0.2501 g (65%) of 6-[4-(2-dibenzylamino-ethyl)-phenoxy]-nicotinamide: HPLC (30/70 to 90/10 ACN/(0.1% TFA in water) Zorbax SB-Phenyl Column 4.6 mm×15 cm×5 micron: Retention time: 8.14 minutes, Purity: 99.7%; mass spectrum (ion spray): m/z=438.0 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:3]=1[CH2:4][O:5][CH2:6][C@@H:7]1[CH2:11][C@@H:10]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][NH:8]1.Cl[C:39]1[N:44]=[CH:43][CH:42]=[CH:41][N:40]=1.C(N(C(C)C)C(C)C)C>>[F:1][C:2]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:3]=1[CH2:4][O:5][CH2:6][C@@H:7]1[CH2:11][C@@H:10]([S:12][C:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:9][N:8]1[C:39]1[N:44]=[CH:43][CH:42]=[CH:41][N:40]=1
Reactant: Fc1cc(F)c(COC[C@@H]2C[C@@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)CN2)cc1F
Reactant: Clc1ncccn1
Solvent: CCN(C(C)C)C(C)C
Product: Fc1cc(F)c(COC[C@@H]2C[C@@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)CN2c2ncccn2)cc1F
Temperature: 80 °C
Yield: 71.1 %

Procedure:
A mixture of 2.08 g (4 mmol)(2S,4R)-2-(2,4,5-Trifluoro-benzyloxymethyl)-4-tritylsulfanyl-pyrrolidine, 0.687 g (6 mmol) 2-chloropyrimidine and 1.16 ml (6.8 mmol) N-ethyldiisopropylamine was heated for 3 h at 80° C. The reaction was cooled and partitioned between H2O/Et2O (3×300). The organic phases were washed with aqueous saturated NaHCO3, aqueous 10% NaCl, dried (NaSO4) and evaporated. Flash chromatography on silica gel (CH2Cl2/EtOAc 97.5:2.5) gave 1.7 g (71%) (2S,4R)-2-[2-(2,4,5-Trifluoro-benzyloxymethyl)-4-tritylsulfanyl-pyrrolidin-1-yl]-pyrimidine, MS: 598 (MH+).
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[CH3:32][NH:33][CH2:34][CH3:35].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH2:34]([N:33]([CH2:27][C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=2)[NH:14][CH:13]=[C:12]3[CH:9]2[CH2:8][CH2:7][N:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH2:11][CH2:10]2)[CH:26]=[CH:25][CH:24]=1)[CH3:32])[CH3:35]
Reactant: CCNC
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCN(C)Cc1cccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)c1
Yield: 21.3 %

Procedure:
Following the general procedure of example 1, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-indole-7-carboxamide (50.0 mg, 0.112 mmol), N-methylethanamine (50.7 mg, 0.86 mmol) and NaBH(OAc)3 (58.0 mg, 0.303 mmol) were reacted to give the title compound (11.5 mg, 21%).
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:13]([CH2:15][N:16]([CH2:33][C:34](=[O:48])[NH:35][CH2:36][C:37]2[CH:42]=[CH:41][C:40]([C:43](=[O:46])[NH:44][OH:45])=[C:39]([OH:47])[CH:38]=2)[C:17](=[O:32])[CH2:18][CH2:19][CH2:20][C:21]([NH:23][NH:24]C(OC(C)(C)C)=O)=[O:22])=[O:14])=[CH:7][C:6]=1[OH:49])=[O:4].FC(F)(F)C(O)=O>ClC(Cl)C>[OH:45][NH:44][C:43]([C:40]1[CH:41]=[CH:42][C:37]([CH2:36][NH:35][C:34]([CH2:33][N:16]([CH2:15][C:13](=[O:14])[NH:12][CH2:11][C:8]2[CH:9]=[CH:10][C:5]([C:3](=[O:4])[NH:2][OH:1])=[C:6]([OH:49])[CH:7]=2)[C:17](=[O:32])[CH2:18][CH2:19][CH2:20][C:21]([NH:23][NH2:24])=[O:22])=[O:48])=[CH:38][C:39]=1[OH:47])=[O:46]
Reactant: CC(C)(C)OC(=O)NNC(=O)CCCC(=O)N(CC(=O)NCc1ccc(C(=O)NO)c(O)c1)CC(=O)NCc1ccc(C(=O)NO)c(O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(Cl)Cl
Product: NNC(=O)CCCC(=O)N(CC(=O)NCc1ccc(C(=O)NO)c(O)c1)CC(=O)NCc1ccc(C(=O)NO)c(O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 68 %

Procedure:
The crude N,N-bis-({N-[(4-(N-hydroxycarbamoyl)-3-hydroxyphenyl)methyl]-carbamoyl}methyl)-N'-[(tert-butoxy)carbonylamino]pentane-1,5-diamide from above was suspended in 20 mL of dichloroethane and 10 mL of trifluoroacetic acid was added. The deprotection reaction was stirred for 4 hours at room temperature. Dichloroethane and trifluoroacetic acid were removed in vacuo, and the resulting residue was dissolved in 10 mL of methanol, which was added dropwise to 150 mL of stirred ethyl acetate. A precipitate formed which was collected by filtration, washed with ethyl acetate and then dried in vacuo under a high vacuum. Obtained 1.41 grams (68% yield) of product as a white powder.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH2:27][CH3:28])[CH:24]=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:15]=3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.[C:35](Cl)(=[O:38])[CH2:36][CH3:37]>>[CH:31]1([CH2:30][O:29][C:22]2[CH:23]=[CH:24][C:25]([CH2:27][CH3:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:34])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:35](=[O:38])[CH2:36][CH3:37])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:32][CH2:33]1
Reactant: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c1
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(CC)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-ethylphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f50) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: C[Si](C)(C)[N:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8].[Li+].CC([N-]C(C)C)C.[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[CH2:27]Cl.O>C1COCC1>[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[CH2:27][CH:5]1[CH2:6][CH2:7][NH:3][C:4]1=[O:8]
Reactant: C[Si](C)(C)N1CCCC1=O
Reactant: ClCc1ccc(Cl)cc1Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: O=C1NCCC1Cc1ccc(Cl)cc1Cl
Temperature: -78 °C
Yield: 66.6 %

Procedure:
Charge a flask with 1-trimethylsilanyl-pyrrolidin-2-one (5.0 g, 32 mmol), dissolve in THF (150 mL) and cool to −78° C. under nitrogen. Add LDA (2M, 19 mL, 38 mmol) and stir at −78° C. for 10 minutes. Add 2,4-dichloro-1-chloromethyl-benzene (8.1 g, 41 mmol) and warm to room temperature. Pour into water after 2 hours and extract with methylene chloride. Dry over sodium sulfate, filter and concentrate. Purify the residue over silica gel (1:1 hexanes:ethylacetate to 100% ethyl acetate) to afford 5.2 g (67%) of the title compound as a white solid. 1H NMR (CDCl3) δ 7.38 (d, 1H), 7.23 (d, 1H), 7.18 (dd, 1H), 6.01 (bs, 1H), 3.31 (m, 3H), 2.75 (m, 2H), 2.13 (m, 1H), 1.84 (m, 1H).
Reaction SMILES: [CH2:1]1[O:11][C:4]2([CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]2)[O:3][CH2:2]1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([Mg]Br)=[CH:15][CH:14]=1>C(OCC)C>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:7]2([OH:10])[CH2:6][CH2:5][C:4]3([O:3][CH2:2][CH2:1][O:11]3)[CH2:9][CH2:8]2)=[CH:15][CH:14]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: O=C1CCC2(CC1)OCCO2
Solvent: CCOCC
Product: OC1(c2ccc(F)cc2)CCC2(CC1)OCCO2
Temperature: 25 °C
Yield: 94.1 %

Procedure:
To a solution of 1,4-cyclohexanedione mono-ethylene ketal (25 g, 0.16 mol) in diethylether (750 ml), cooled to -78° C. was added 4-fluorophenyl magnesium bromide (1 M in tetrahydrofuran, 190 ml, 0.19 mol) dropwise. The reaction mixture was warmed to room temperature, quenched with water and extracted twice with ethyl acetate. Washing with brine, drying and solvent evaporation gave 8-(4-fluorophenyl)-1,4-dioxa-spiro[4.5]decan-8-ol (38 g, 95%).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[O:5][CH2:4][C@H:3]1[NH:10][C:11](=[O:19])[O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C.[S:27](Cl)([CH3:30])(=[O:29])=[O:28]>ClCCl>[CH3:30][S:27]([O:1][C@H:2]1[C@H:3]([NH:10][C:11]([O:12][CH2:13][CH2:14][Si:15]([CH3:17])([CH3:16])[CH3:18])=[O:19])[CH2:4][O:5][C:6]([CH3:9])([CH3:8])[CH2:7]1)(=[O:29])=[O:28]
Reactant: CC1(C)C[C@@H](O)[C@H](NC(=O)OCC[Si](C)(C)C)CO1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)C[C@@H](OS(C)(=O)=O)[C@H](NC(=O)OCC[Si](C)(C)C)CO1
Temperature: 25 °C
Reaction time: 4 h
Yield: 119.7 %

Procedure:
To a solution of 2-(trimethylsilyl)ethyl (3R,4R)-4-hydroxy-6,6-dimethyl-tetrahydro-2H-pyran-3-ylcarbamate (360 mg, 1.25 mmol) and triethylamine (378 mg, 3.75 mmol) in dichloromethane (5 mL) was dropwise added mesyl chloride (213 mg, 1.87 mmol) at 0° C. The reaction mixture was stirred at room temperature for 4 h, and then diluted with dichloromethane (100 mL). The organic layer was washed with water (50 mL) and brine (50 mL), dried over sodium sulfate, filtered and concentrated to afford the title compound (550 mg, crude) as a yellow oil, which was directly used in the next step without further purification.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:39])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[C:33]([CH3:38])=[N:34][CH:35]=[CH:36][CH:37]=2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:16][N:14]([CH3:15])[C:12]1[C:11]([C:17]([F:18])([F:20])[F:19])=[CH:10][C:9]2[NH:21][C:22](=[O:39])[CH2:23][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]4[C:33]([CH3:38])=[N:34][CH:35]=[CH:36][CH:37]=4)[CH:27]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1ncccc1-c1cccc(C(=O)CC(=O)Nc2cc(C(F)(F)F)c(N(C)C)cc2NC(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ncccc1-c1cccc(C2=Nc3cc(N(C)C)c(C(F)(F)F)cc3NC(=O)C2)c1

Procedure:
The title compound was prepared from (5-dimethylamino-2-{3-[3-(2-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M10) (380 mg, 0.683 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (215 mg).
Reaction SMILES: [F:1][C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[C:24](=[O:29])N(OC)C)=[O:17])([CH3:14])([CH3:13])[CH3:12]>>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[C:24]([C:9]1[O:10][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[C:7]=2[CH:8]=1)=[O:29])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: Fc1cccc2occc12
Reactant: CON(C)C(=O)C1CCCCN1C(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)N1CCCCC1C(=O)c1cc2c(F)cccc2o1

Procedure:
The title compound (500 mg) was prepared from 4-fluoro-benzofuran (450 mg) and (RS)-1-(tert-butyloxycarbonyl)-2-(N-methoxy-N-methylcarbamoyl)-piperidine, D1 (900 mg) according to a procedure similar to that for Description 2.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[NH:6][C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=2[C:13](=[O:15])[CH:14]=1)[CH3:4].Br[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([B:24]([OH:26])[OH:25])=[CH:20][CH:19]=1.O>CN(C=O)C>[CH2:3]([C:5]1[CH:14]=[C:13]([O:15][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([B:24]([OH:26])[OH:25])=[CH:20][CH:19]=2)[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[N:6]=1)[CH3:4]
Reactant: OB(O)c1ccc(CBr)cc1
Reactant: CCc1cc(=O)c2c([nH]1)CCCC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1cc(OCc2ccc(B(O)O)cc2)c2c(n1)CCCC2
Reaction time: 40 h
Yield: 99.3 %

Procedure:
Sodium hydride (60% dispersion in oil; 180 mg) was added to a mixture of 2-ethyl-5,6,7,8-tetrahydro-4(1H)-quinolone (660 mg) and 4-bromomethylphenylboronic acid (800 mg) (obtained as described in J. Amer. Chem. Soc. 1958, 80, 835) in DMF (12 ml) under an atmosphere of argon. The mixture was stirred for 40 hours and then water (0.2 ml) was added. Volatile material was removed by evaporation and the residue was dissolved in warm 0.5M sodium hydroxide solution (10 ml). Insoluble material was removed by filtration and the filtrate was acidified to pH 4 with 20% citric acid solution. The precipitate solid was collected by filtration, washed with water (20 ml) and dried under high vacuum to give 4-[(2-ethyl-5,6,7,8-tetrahydroquinolin-4-yl)oxymethyl]phenylboronic acid (C) (1.15 g), m.p. 229°-231° C.; NMR (d6 -DMSO): 1.3(t,3H), 1.6-1.9(m,4H), 2.5-2.7(m,2H), 2.75-2.95(m,4H), 5.4(s,2H), 7.3(d,2H), 7.4(s,1H, 7.5(d,2H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=1)=[O:3].Br.[OH2:15]>CS(C)=O>[O:3]=[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:11])([F:12])[F:13])[CH:5]=1)[CH:1]=[O:15]
Reactant: O
Reactant: CC(=O)c1cccc(C(F)(F)F)c1
Agent: Br
Solvent: CS(C)=O
Product: O=CC(=O)c1cccc(C(F)(F)F)c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 128 %

Procedure:
3-Trifluoromethylacetophenone (11.80 mmol, 2.22 g) was dissolved in dimethyl sulfoxide (13 mL), and 48% hydrobromic acid (5.4 mL) was gradually added at room temperature. After overnight stirring at 70° C., the reactor was cooled to room temperature. After addition of water, the reaction solution was extracted with chloroform, and the extract was dried and filtered, and the solvent was evaporated to give the desired product as a yellow liquid (3.04 g (crude), yield 128%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH:15]=[C:14]([CH3:17])[CH:13]=[C:12]([NH:18][CH2:19][C:20]4([C:23]([F:26])([F:25])[F:24])[CH2:22][O:21]4)[C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH2:27]([NH2:29])[CH3:28]>ClCCl>[CH2:27]([NH:29][CH2:22][C:20]([CH2:19][NH:18][C:12]1[CH:13]=[C:14]([CH3:17])[CH:15]=[C:16]2[C:11]=1[CH:10]=[N:9][N:8]2[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)([OH:21])[C:23]([F:25])([F:24])[F:26])[CH3:28]
Reactant: CCN
Reactant: Cc1cc(NCC2(C(F)(F)F)CO2)c2cnn(-c3ccc(F)cc3)c2c1
Solvent: ClCCl
Product: CCNCC(O)(CNc1cc(C)cc2c1cnn2-c1ccc(F)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.7 %

Procedure:
A solution of 1-(4-fluorophenyl)-6-methyl-N-{[2-(trifluoromethyl)-2-oxiranyl]methyl}-1H-indazol-4-amine (1.52 g, 4.16 mmol) in dichloromethane (30 ml) was added to ethylamine (2M in tetrahydrofuran) (70 ml, 140 mmol). The reaction was stirred at room temperature overnight and then evaporated in vacuo. The crude product was purified on a 70 g silica Bond Elut cartridge using a 0-100% ethyl acetate in dichloromethane gradient over 60 mins to give the title compound (1.463 g).
Reaction SMILES: C([O:3][C:4](=[O:26])[C:5]([O:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[C:27]1([C:33]2[O:34][C:35]([CH3:51])=[C:36]([CH2:38][CH2:39]OS(C3C=CC(C)=CC=3)(=O)=O)[N:37]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH3:25][S:22]([C:19]1[CH:18]=[CH:17][C:16]([O:15][C@@:5]([CH3:14])([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:39][CH2:38][C:36]3[N:37]=[C:33]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[O:34][C:35]=3[CH3:51])=[CH:9][CH:8]=2)[C:4]([OH:3])=[O:26])=[CH:21][CH:20]=1)(=[O:24])=[O:23]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccccc3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(S(C)(=O)=O)cc1
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C[C@](C)(Oc2ccc(S(C)(=O)=O)cc2)C(=O)O)cc1

Procedure:
Standard Procedure (B) was utilized to prepare the title compound from 3-(4-hydroxyphenyl)-2-(4-methanesulfonyl-phenoxy)-2-methyl-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(2-phenyl-5-methyl-oxazol-4-yl)-ethyl ester. 1H NMR (400 MHz, CDCl3) δ 8.00 (d, 2H, J=7.04 Hz), 7.80 (d, 2H, J=9.00 Hz), 7.55-7.50 (m, 3H), 7.14 (d, 2H, J=8.60 Hz), 6.97 (d, 2H, J=9.00 Hz), 6.80 (d, 2H, J=8.21 Hz), 4.20 (t, 2H, J=5.87 Hz), 3.29 (d, 1H, J=14.08 Hz), 3.17 (d, 1H, J=14.08 Hz), 3.10 (t, 2H, J=5.87 Hz), 3.01 (s, 3H), 2.46 (s, 3H), 1.54 (s, 3H); HRMS (ES+) m/z exact mass calcd for C29H30NO7S 536.1743, found 536.1771.
Reaction SMILES: [OH:1][C:2]([CH3:20])([CH:9]=[CH:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[CH2:3][C:4]([O:6]CC)=[O:5].[OH-].[Na+].[Br:23]Br.C(=O)([O-])O.[Na+]>CO>[OH:1][C:2]1([CH3:20])[CH:9]([Br:23])[CH:10]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[O:6][C:4](=[O:5])[CH2:3]1
Reactant: CCOC(=O)CC(C)(O)C=CCCc1ccc(Cl)cc1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(O)CC(=O)OC(CCc2ccc(Cl)cc2)C1Br

Procedure:
The carboxylic acid (2.88 g) prepared by hydrolyzing 3.27 g of ethyl 3-hydroxy-3-methyl-7-(p-chlorophenyl)-4-heptenoate with 4 N sodium hydroxide solution in methanol, was treated with 1.3 g of bromine in an aqueous sodium hydrogen carbonate solution and the reaction mixture was worked up according to the method described in Example 1 (b). The product was purified by a column chromatography using silica gel affording 1.93 g of the desired compound melting at 116°-119° C.
Reaction SMILES: C([O:3][C:4](=[O:48])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:31]3[CH:36]=[CH:35][C:34]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH:33][CH:32]=3)[CH:25]=[C:26]([CH2:28][O:29][CH3:30])[CH:27]=2)[C:10]=1[CH2:41][CH2:42][C:43]([O:45]CC)=[O:44])C.[OH-].[Na+]>C1COCC1.C(O)C>[C:43]([CH2:42][CH2:41][C:10]1[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:31]3[CH:36]=[CH:35][C:34]([S:37]([CH3:40])(=[O:38])=[O:39])=[CH:33][CH:32]=3)[CH:25]=[C:26]([CH2:28][O:29][CH3:30])[CH:27]=2)=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:48])=[O:3])([OH:45])=[O:44]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(COC)cc(-c3ccc(S(C)(=O)=O)cc3)c2)c1CCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COCc1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccc(S(C)(=O)=O)cc2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.4 %

Procedure:
To a solution of the 4-{2-(2-ethoxycarbonyl-ethyl)-3-[6-(4′-methanesulfonyl-5-methoxymethyl-biphenyl-3-yloxy)-hexyl]-phenoxy}-butyric acid ethyl ester (195 mg, 0.29 mmol) in THF (5 mL) and ethanol (5 mL) was added aqueous 1.0 N sodium hydroxide (3 mL) at room temperature. The resulting suspension was stirred for 5 h at room temperature at which time TLC analysis of the mixture indicated the absence of starting material. Then, the reaction mixture was concentrated and the residue was diluted with water (20 mL) and extracted with diethyl ether (30 mL) to remove any neutral impurities. The aqueous layer was acidified with 1.0 N hydrochloric acid and the precipitated white organic compound was extracted into ethyl acetate (2×30 mL). The combined ethyl acetate extracts were washed with brine solution (50 mL) and the organic layers were dried over anhydrous magnesium sulfate. Filtration of the drying agent and removal of the solvent afforded 4-[2-(2-carboxy-ethyl)-3-[6-(-4′-methanesulfonyl-5-methoxymethyl-biphenyl-3-yloxy)-hexyl]-phenoxy]-butyric acid (168 mg, 94%) as a white solid: ES(+)-HRMS m/e calcd for C34H42O9S (M+Na)+ 649.2442. found 649.2440.