Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:4]=1)=O.[C:19]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)(=[O:21])[CH3:20].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CC(O)=O.C(Cl)Cl>[C:19]([N:22]1[CH2:27][CH2:26][N:25]([CH2:1][C:3]2[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:4]=2)[CH2:24][CH2:23]1)(=[O:21])[CH3:20]
Reactant: COc1cc(C=O)cc(NC(=O)OC(C)(C)C)n1
Reactant: CC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1cc(CN2CCN(C(C)=O)CC2)cc(NC(=O)OC(C)(C)C)n1

Procedure:
To a solution of tert-butyl 4-formyl-6-methoxypyridin-2-ylcarbamate (15-3, 292 mg, 1.16 mmole) and 1-acetylpiperazine (178 mg, 1.39 mmole) in 2% glacial HOAc in CH2Cl2 (5 mL) was added NaBH(OAc)3 (270 mg, 1.27 mmole) at RT. After 1.5 hr the mixture was quenched with saturated NaHCO3 and extracted with CH2Cl2 (3×). The combined organic layers were dried (MgSO4), filtered, and concentrated. Flash column chromatography (gradient, 0-5% EtOH/EtOAc) gave the titled compound as a white foam. 1H-NMR (500 MHz, CDCl3) δ7.41 (s, 1H), 7.00 (bs, 1H), 6.43 (s, 1H), 3.83 (s, 3H), 3.63 (bs, 2H), 3.46 (bs, 4H), 2.41 (m, 4H), 2.08 (s, 3H), 1.52 (s, 9H); MS (ES) (M+H)+365.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[CH:7][C:6]([C:13]([OH:15])=O)=[C:5]2[OH:16].C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][NH2:35])=[CH:32][CH:31]=1>CC(N(C)C)=O.O>[Cl:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][NH:35][C:13]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[OH:16])=[CH:3][C:2]([F:1])=[C:11]([F:12])[CH:10]=3)=[O:15])=[CH:32][CH:31]=1
Reactant: O=C(O)c1cnc2cc(F)c(F)cc2c1O
Reactant: NCc1ccc(Cl)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2cc(F)c(F)cc2c1O
Temperature: 25 °C
Reaction time: 26 h

Procedure:
A mixture of 0.5 g of 6,7-difluoro-4-hydroxy-3-quinolinecarboxylic acid from preparation No. 15 and 0.435 g of carbonyldiimidazole in 8 mL of anhydrous dimethylacetamide is stirred 4 h at 65° C. The reaction mixture is cooled to 25° C. and 2 drops of distilled water is added. After an additional 10 min 0.34 mL of 4-chlorobenzylamine is added. The mixture is stirred 26 h at 25° C. and then diluted with 10 mL of distilled water. After standing for an additional 30 min the precipitate is collected by filtration and washed with three 10 mL portions of distilled water. The solid is dried in a stream of air and then at 20 torr/120° C./3 days. The yield is 0.51 g (70%) of a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([Cl:9])=[CH:4][C:3]=1[OH:10].C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:23](O)=[O:24].S(=O)(=O)(O)O>O>[OH:10][C:3]1[C:2]([Br:1])=[CH:7][C:6]([F:8])=[C:5]([Cl:9])[C:4]=1[CH:23]=[O:24]
Reactant: O=C(O)C(F)(F)F
Reactant: Oc1cc(Cl)c(F)cc1Br
Agent: C1N2CN3CN1CN(C2)C3
Agent: O=S(=O)(O)O
Solvent: O
Product: O=Cc1c(O)c(Br)cc(F)c1Cl
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 62 %

Procedure:
A mixture of 90.4 gm (0.40 mole) 2-bromo-4-fluoro-5-chlorophenol (containing 10% 2-bromo-3-chloro-4-fluorophenol) and 64 gm (0.45 mole) hexamethylenetetramine was cooled in an ice bath. To this cooled mixture were added 306 mL trifluoroacetic acid. After stirring at about 0° C. for 15 minutes, the reaction mixture was heated at reflux for 1.5 hours. The reaction mixture was then cooled in an ice bath and treated with 439 mL of water followed by 220 mL 50% sulfuric acid. The reaction mixture was stirred without cooling for two hours. The reaction mixture was then diluted with 500 mL water and the resulting solid collected by filtration. The solid was washed with water until the wash was neutral (pH about 7). The solid was dried under reduced pressure and was then subjected to silica gel chromatography, eluting with a gradient of hexane containing from 0–2% ethyl acetate. Fractions containing the desired compound were combined and concentrated under reduced pressure to provide 57 gm (62%) 2-hydroxy-3-bromo-5-fluoro-6-chlorobenzaldehyde.
Reaction SMILES: [I:1]Cl.[CH2:3]([N:5]1[C:9]([CH2:10][C:11]([OH:14])([CH3:13])[CH3:12])=[CH:8][C:7]([C:15]#[N:16])=[N:6]1)[CH3:4].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH2:3]([N:5]1[C:9]([CH2:10][C:11]([OH:14])([CH3:12])[CH3:13])=[C:8]([I:1])[C:7]([C:15]#[N:16])=[N:6]1)[CH3:4]
Reactant: CCn1nc(C#N)cc1CC(C)(C)O
Reactant: ClI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCn1nc(C#N)c(I)c1CC(C)(C)O
Reaction time: 18 h

Procedure:
A solution of iodine monochloride in dichloromethane (10.8 mL of 2 M, 21.6 mmol) was added to a mixture of 1-ethyl-5-(2-hydroxy-2-methylpropyl)-1H-pyrazole-3-carbonitrile (2.0 g, 10.3 mmol), dichloromethane (17 mL) and freshly ground potassium carbonate (2.9 g, 22 mmol). The reaction was stirred for 18 hours. The work-up and purification procedures described in Part D of Example 588 were followed to provide 1.8 g of 1-ethyl-5-(2-hydroxy-2-methylpropyl)-4-iodo-1H-pyrazole-3-carbonitrile as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:18])[CH2:9][S:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.[OH:19]O.CSC>C(O)(=O)C>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:18])[CH2:9][S:10]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:19]
Reactant: OO
Reactant: O=C(CSc1ccc(O)cc1)c1ccccc1O
Solvent: CC(=O)O
Solvent: CSC
Product: O=C(CS(=O)c1ccc(O)cc1)c1ccccc1O
Temperature: 25 °C
Reaction time: 12 h
Yield: 71 %

Procedure:
6.0 g (23.1 mmol) of 2′-hydroxy-2-(4-hydroxyphenylthio) acetophenone and 50 mL of acetic acid were added under a room temperature into a 100 mL flask with four inlets and attached with a stirrer and a thermometer. To the resultant solution, 2.8 g (24.7 mmol) of 30% aqueous solution of hydrogen peroxide was added, and the solution was stirred for 12 hours at a room temperature. Following to the completion of the reaction, 0.5 g of dimethyl sulfide was added into the solution, and then, the solution was extracted with MIBK. The MIBK layer was washed several times with water, and followed by washing with sodium hydrogencarbonate. The MIBK in the solution was distilled out under reduced pressure, and the resultant residue was subjected to recrystallization with ethyl acetate to obtain 4.5 g of 2′-hydroxy-2-(4-hydroxyphenylsulfinyl) acetophenone. The yield was 71% and the melting point of the compound was in a range of 166 to 167° C.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1([CH2:12][OH:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)([O-:5])=[O:4].[C:14]([O:17][CH2:18][CH2:19]Br)(=[O:16])[CH3:15].Cl>O.CN(C=O)C>[N+:3]([C:6]1([CH2:12][O:13][CH2:15][C:14]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)([O-:5])=[O:4]
Reactant: O=[N+]([O-])C1(CO)CCCCC1
Reactant: CC(=O)OCCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COCC1([N+](=O)[O-])CCCCC1
Reaction time: 0.33 h

Procedure:
Under the nitrogen gas atmosphere, NaH (2.32 g, 58 mmol) was added in the DMF (70 mL) solution of (1-nitro-cyclohexyl)-methanol (6.96 g, 35 mmol) which had been obtained in 1) while cooling the solution with ice, and the mixture was stirred for 20 minutes while making the temperature rise naturally. Bromoethyl acetate (9.96 g, 58.0 mmol) was dropped, and the mixture was stirred at room temperature over-night. The reaction mixture was diluted with water (200 mL), 2M hydrochloric acid (20 mL, 40 mmol) was added, and the mixture was extracted with ethyl acetate (50 mL) two times. The organic layer was washed with 5% sodium bicarbonate aqueous solution (20 mL) and water (50 mL), and then dried with anhydrous sodium sulfate. The solvents were removed by distillation under reduced pressure, the residue was refined with silica gel column chromatography (Highflash 4L, manufactured by Yamazen Corporation, the mixture of hexane and ethyl acetate of 5:1 in mixing ratio), and pale yellow oily ethyl (1-nitro-cyclohexylmethoxy)-acetate (5.47 g, 57%) was obtained.
Reaction SMILES: CS(Cl)(=O)=O.O[CH:7]1[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=2[O:10][CH2:9][CH2:8]1.C(N(CC)CC)C.[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>C(Cl)Cl>[CH3:18][O:17][C:16]1[C:11]2[O:10][CH2:9][CH2:8][CH:7]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[C:12]=2[CH:13]=[CH:14][CH:15]=1
Reactant: COc1cccc2c1OCCC2O
Reactant: C1CCNCC1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc2c1OCCC2N1CCCCC1
Reaction time: 2 h

Procedure:
Methane sulfonyl chloride (14.9 ml) is added dropwise to a solution of the product obtained in Step 1. (31.6 g) and triethylamine (29.3 ml) in methylene chloride (750 ml) cooled to 0° C. under nitrogen. The reaction mixture is stirred for 11/2 hours; piperidine (175 ml) is added and the reaction mixture is stirred under nitrogen overnight. The reaction mixture is washed with sat'd aq. sodium bicarbonate, sat'd NaCl, dried, filtered and evaporated in vacuo yielding the desired product as its hydrochloride salt.
Reaction SMILES: [F:1][OH:2].[S:3](Cl)([C:6]1[CH:12]=[CH:11][C:9]([CH3:10])=[CH:8][CH:7]=1)(=[O:5])=[O:4]>N1C=CC=CC=1>[S:3]([C:6]1[CH:12]=[CH:11][C:9]([CH3:10])=[CH:8][CH:7]=1)([O:2][F:1])(=[O:5])=[O:4]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OF
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OF)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
The solution of 9.8 g of partial-fluoro alcohol in 40 ml of pyridine was cooled down to 0° C. in ice-salt water and 6 g of TsCl was added in small portion. After addition the resulting mixture was stirred at 0° C. for two hours and then placed in freezer (−20° C.) for two days. The reaction mixture was poured into ice water and the product was extracted with ethyl acetate twice. The combined organic phase was washed with brine, 10% HCl and again brine three times, and then dried over MgSO4. After evaporation of solvent, pure partial-fluoro tosylate was obtained in yield of 98%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[CH2:8][CH2:7][CH2:6]2.Cl.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23]N)=[CH:19][CH:18]=1.Cl.O>C(O)C>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:9]3[NH:23][C:20]4[C:21]([C:8]=3[CH2:7][CH2:6][C:5]=2[CH:4]=1)=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=4
Reactant: COc1ccc2c(c1)CCCC2=O
Reactant: COc1ccc(NN)cc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1ccc2c(c1)CCc1c-2[nH]c2ccc(OC)cc12
Yield: 74 %

Procedure:
10.0 g (57 mmol) of 6-methoxy-1-tetralone in 125 ml of ethanol is added in drops within 35 minutes to a boiling solution of 10.0 g (57 mmol) of p-methoxyphenylhydrazine-hydrochloride and 5.0 ml of concentrated hydrochloric acid in 180 ml of ethanol. Then, it is refluxed for 5 hours. After 370 ml of hot water is added, it is allowed to cool. The almost colorless reaction product is suctioned off and recrystallized from ethanol. Yield 74%, melting point 189-191° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:23]4[C:24]5[CH:36]=[CH:35][CH:34]=[N:33][C:25]=5[NH:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[C:22]4=[N:21][C:20]=3[CH2:37][C:38]([OH:40])=O)=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C(N=C=NCCCN(C)C)C.C(N(C(C)C)CC)(C)C>ClCCl>[O:40]=[C:38]([NH:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[CH2:37][C:20]1[N:21]=[C:22]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[NH:26][C:25]3[N:33]=[CH:34][CH:35]=[CH:36][C:24]=3[N:23]2[C:19]=1[C:16]1[CH:15]=[CH:14][C:13]([C:9]2([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:10][CH2:11][CH2:12]2)=[CH:18][CH:17]=1
Reactant: Nc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(CC(=O)O)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(CC(=O)Nc4ccccc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 48.3 %

Procedure:
To a solution of 2-(3-(4-(1-((tert-butoxycarbonyl)amino)cyclobutyl)phenyl)-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepin-2-yl)acetic acid (0.04 g, 1 eq.) in dichloromethane (2 mL) was added successively aniline (0.027 g, 4 eq.), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) (0.029 g, 2 eq.) and diisopropylethylamine (70 μL, 5 eq.). The reaction was stirred at room temperature for 20 hours. The reaction mixture was diluted with dichloromethane (10 mL), washed with water (2×10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by preparative HPLC (YMC PACK ODS-AM; AM12S05-1020WT; 100×20 mm ID; CAN/0.1% TFA, 30 mL/min) gave tert-butyl (1-(4-(2-(2-oxo-2-(phenylamino)ethyl)-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepin-3-yl)phenyl)cyclobutyl)carbamate (0.022 g, 48%). LCMS: 613 [M+H].
Reaction SMILES: [OH-].[Na+].C([O:6][C:7]1[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][C:8]=1[C:9]([NH:11][C@H:12]([C:20](=[O:36])[NH:21][C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])(=O)C.Cl>CO.O1CCCC1>[Cl:41][C:38]1[CH:39]=[CH:40][C:7]([OH:6])=[C:8]([CH:37]=1)[C:9]([NH:11][C@H:12]([C:20](=[O:36])[NH:21][C:22]1[CH:27]=[C:26]([C:28]([F:29])([F:31])[F:30])[CH:25]=[C:24]([C:32]([F:33])([F:34])[F:35])[CH:23]=1)[CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:10]
Reactant: CC(=O)Oc1ccc(Cl)cc1C(=O)N[C@@H](Cc1ccccc1)C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(Cl)ccc1O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 56.1 %

Procedure:
5N Aqueous sodium hydroxide (0.2 mL) was added to a solution of (S)-2-acetoxy-5-chloro-N-(2-phenyl-1-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-ethyl)benzamide (141.4 mg, 0.25 mmol) in a mixed solvent of methanol/tetrahydrofuran (2 mL+2 mL), and the mixture was stirred at room temperature for 20 minutes. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. After the ethyl acetate layer was washed successively with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was crystallized by ethyl acetate/isopropyl ether/n-hexane to give the title compound (74.4 mg, 56.8%) as a white powder.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5](Cl)=[CH:4][C:3]=1[S:9]([NH:12][CH2:13][C:14]1[CH:15]=[C:16]([C:20]2[CH:21]=[C:22]3[C:26](=[C:27]([C:29]([NH2:31])=[O:30])[CH:28]=2)[NH:25][CH:24]=[C:23]3[CH:32]2[CH2:37][CH2:36][N:35]([S:38]([CH2:41][CH3:42])(=[O:40])=[O:39])[CH2:34][CH2:33]2)[CH:17]=[CH:18][CH:19]=1)(=[O:11])=[O:10].[Cl:43]C1C=CC(Cl)=CC=1S(Cl)(=O)=O>>[Cl:43][C:6]1[CH:7]=[CH:2][C:3]([S:9]([NH:12][CH2:13][C:14]2[CH:15]=[C:16]([C:20]3[CH:21]=[C:22]4[C:26](=[C:27]([C:29]([NH2:31])=[O:30])[CH:28]=3)[NH:25][CH:24]=[C:23]4[CH:32]3[CH2:37][CH2:36][N:35]([S:38]([CH2:41][CH3:42])(=[O:39])=[O:40])[CH2:34][CH2:33]3)[CH:17]=[CH:18][CH:19]=2)(=[O:11])=[O:10])=[CH:4][CH:5]=1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CNS(=O)(=O)c5cc(Cl)ccc5Cl)c4)cc23)CC1
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CNS(=O)(=O)c5ccc(Cl)cc5)c4)cc23)CC1
Yield: 13 %

Procedure:
The title compound was prepared according to the general procedure of 5-[3-({[(2,5-dichlorophenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide substituting (2E,4E)-5-chloro-2,4,6-heptatriene-2-sulfonyl chloride (80 mg, 0.352 mmol) for 2,5-dichlorobenzenesulfonyl chloride. Reaction mixture was then concentrated and purified by Gilson Preparatory HPLC to give 7.5 mg the title compound (13%).
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:15][CH3:16])[CH2:9][C:8]2[CH:10]=[C:11]([OH:14])[CH:12]=[CH:13][C:7]=2[O:6]1)=[O:4].[Cl:17][C:18]1[CH:23]=[C:22]([C:24]([CH3:28])([CH3:27])[CH2:25][CH3:26])[CH:21]=[CH:20][C:19]=1[O:29][CH2:30][CH2:31][CH2:32]I>>[Cl:17][C:18]1[CH:23]=[C:22]([C:24]([CH3:27])([CH3:28])[CH2:25][CH3:26])[CH:21]=[CH:20][C:19]=1[O:29][CH2:30][CH2:31][CH2:32][O:14][C:11]1[CH:12]=[CH:13][C:7]2[O:6][C:5]([CH2:15][CH3:16])([C:3]([OH:2])=[O:4])[CH2:9][C:8]=2[CH:10]=1
Reactant: CCC1(C(=O)OC)Cc2cc(O)ccc2O1
Reactant: CCC(C)(C)c1ccc(OCCCI)c(Cl)c1
Product: CCC1(C(=O)O)Cc2cc(OCCCOc3ccc(C(C)(C)CC)cc3Cl)ccc2O1

Procedure:
The title compound was prepared following the general procedure described in Example 1, Step 4 employing the phenol prepared in Example 4, Step 1 and the iodide prepared in Step 1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][OH:14])[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15]I>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][O:14][CH3:15])[CH:10]([CH3:11])[CH3:12])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CI
Reactant: CC(C)[C@H](CO)NC(=O)OC(C)(C)C
Product: COC[C@H](NC(=O)OC(C)(C)C)C(C)C
Yield: 67 %

Procedure:
The title compound has been prepared in 67% yield from the alcohol of Example 6, Step B and methyl iodide following the alkylation method given in Example 6, Step C.
Reaction SMILES: [O:1]=[C:2]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[CH2:3][NH:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)=[O:6].[C:25]1(=[O:35])[O:30][C:28](=[O:29])[C:27]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]12>C1(C)C=CC=CC=1>[C:10]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]=[CH:8][C:7]([C:5]([NH:4][CH2:3][C:2]([N:19]2[CH2:24][CH2:23][N:22]([C:25]([C:26]3[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=3[C:28]([OH:30])=[O:29])=[O:35])[CH2:21][CH2:20]2)=[O:1])=[O:6])=[CH:12][CH:11]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(=O)O)CC1)c1ccc(-c2ccccc2)cc1
Yield: 48.9 %

Procedure:
Biphenyl-4-carboxylic acid (2-oxo-2-piperazin-1-yl-ethyl)-amide (150 mg, 0.46 mmol) and phthalic anhydride (69 mg, 0.46 mmol) in toluene (20 mL) were heated to reflux for 2 hours. The reaction mixture was then concentrated under reduced pressure. The resulting residue was purified by Preparative TLC (using silicagel 60F254 coated glass plate (20×20 cm, 1 mm (thickness) as the stationary phase with the mobile phase being 10% MeOH in Chloroform) to afford 106 mg (48.5% yield) of 2-(4-{2-[(biphenyl-4-carbonyl)-amino]-acetyl}-piperazine-1-carbonyl)-benzoic acid, LC-MS purity: 86.97%, 1H NMR: (DMSO) δ 8.6 (t, 1H), 7.9 (d, 2H), 7.85-7.7 (m, 4H), 7.5 (t, 2H), 7.4 (t, 1H), 7.3-7.2 (bs, 2H), 7.0 (bs, 1H), 4.25-4.05 (m, 2H), 3.75-3.4 (m, 6H), 3.1-3.0 (bs, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[OH-].[Na+].Cl.Cl[CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1>CO>[N:16]1[CH:17]=[CH:18][CH:19]=[C:14]([CH2:13][S:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)[CH:15]=1
Reactant: ClCc1cccnc1
Reactant: Nc1ccc(S)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1ccc(SCc2cccnc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.8 %

Procedure:
4-aminothiophenol (10 g) was dissolved in methanol (200 ml), aqueous solution of sodium hydroxide (15.7 g, 60 ml) was added to the mixture, 3-(chloromethyl)pyridine hydrochloride (14.4 g) was added to the mixture at 0° C., and the mixture was stirred for 2 hours at room temperature. The solvent was removed under reduced pressure, and the obtained residue was added to water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure and the obtained residue was washed with hexane/ethyl acetate, to give 4-[(3-pyridinylmethyl)sulfanyl]aniline (13.1 g).
Reaction SMILES: [CH:1]1([CH2:7][CH:8]2[CH2:13][CH:12]([C:14](=[O:21])[CH2:15][C:16](OCC)=[O:17])[CH2:11][CH2:10][N:9]2[C:22]([O:24][CH3:25])=[O:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl.[NH2:29]O.Cl>CO.CO.O.O>[CH:1]1([CH2:7][C@@H:8]2[CH2:13][C@@H:12]([C:14]3[O:21][NH:29][C:16](=[O:17])[CH:15]=3)[CH2:11][CH2:10][N:9]2[C:22]([O:24][CH3:25])=[O:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CC(=O)C1CCN(C(=O)OC)C(CC2CCCCC2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@H]1CC1CCCCC1
Reaction time: 0.5 h
Yield: 8.1 %

Procedure:
A solution of methyl 2-(cyclohexylmethyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.5 g, 4.2 mmol) in MeOH (4 mL) was added to a solution of NaOH (221 mg, 5.5 mmol) in MeOH/H2O (4 mL/0.25 mL) at −30° C. After 10 minutes was added hydroxylamine-HCl (0.59 g, 8.5 mmol) and NaOH (0.339 g, 8.5 mmol) in MeOH (5 mL) and H2O (5 mL). Stirring was continued at −30° C. for 30 minutes. The reaction solution was poured into 6M HCl (6 mL) at 80° C. and heated for 30 minutes. The reaction mixture was partitioned between water and ethyl acetate. The organic phase was isolated, dried with Na2SO4, filtered through Celite® and the solvent was evaporated. Crude 1.7 g. Purification using reversed phase chromatography, which gave 0.3 g, yield 22%. Chiral separation using Chiralcel OJ, mobile phase heptane/ethanol 80/20 at 40° C. gave of (2R,4S)-methyl 2-(cyclohexylmethyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.11 g). 1H NMR (600 MHz, cdcl3) δ 0.91 (d, 2H), 1.06-1.39 (m, 5H), 1.68 (dt, 7H), 1.85 (s, 2H), 1.94 (s, 1H), 2.99 (t, 2H), 3.68 (s, 3H), 4.11 (d, 1H), 4.50 (d, 1H), 5.60 (s, 1H). [α]20D +3.2 (MeCN, c=1).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH:22]2[CH2:24][CH2:23]2)=[N:5][C:6]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[N:7][C:8]=1[CH2:9][O:10][CH3:11].[CH2:25]([O:27][C:28](=[O:40])[C:29]([O:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1)([CH3:31])[CH3:30])[CH3:26].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOCC>[CH2:25]([O:27][C:28](=[O:40])[C:29]([O:32][C:33]1[CH:34]=[CH:35][C:36]([O:39][CH2:2][C:3]2[C:4]([CH:22]3[CH2:24][CH2:23]3)=[N:5][C:6]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)=[N:7][C:8]=2[CH2:9][O:10][CH3:11])=[CH:37][CH:38]=1)([CH3:31])[CH3:30])[CH3:26]
Reactant: COCc1nc(-c2ccc(C(F)(F)F)cc2)nc(C2CC2)c1CCl
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2c(COC)nc(-c3ccc(C(F)(F)F)cc3)nc2C2CC2)cc1
Yield: 73.1 %

Procedure:
A solution of 200 mg (0.56 mmol) 5-chloromethyl-4-cyclopropyl-6-methoxymethyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 113H]), 125 mg (0.56 mmol) 2-(4-hydroxy-phenoxy)-2-methyl-propionic acid ethyl ester [Newman, Melvin S.; Cella, James A. Monoalkylation of hydroquinone. Journal of Organic Chemistry (1974), 39(2), p 214–15] and 237 mg (0.73 mmol) cesium carbonate in 3 ml DMF was stirred for 3 h at RT. The reaction mixture was taken up in ether and washed with 1N HCl and water. After purification of the crude product by chromatography over silica gel with AcOEt/heptane 1:3, 223 mg of pure 2-{4-[4-Cyclopropyl-6-methoxymethyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-phenoxy}-2-methyl-propionic acid ethyl ester was isolated.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]#[N:9].[Cl-].[OH:11][NH3+:12].C(N(CC)CC)C>>[OH:11][N:12]=[C:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[CH3:1])[NH2:9]
Reactant: [NH3+]O
Reactant: Cc1ccncc1C#N
Agent: [Cl-]
Solvent: CCN(CC)CC
Product: Cc1ccncc1C(N)=NO

Procedure:
850 mg (7.20 mmol) of 4-methylpyridine-3-carbonitrile, 750 mg (10.79 mmol) of hydroxylammonium chloride and 1.2 ml (8.6 mmol) of triethylamine were reacted according to the General Method 5A. Yield: 666 mg (61% of theory)