Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18].[NH2:21][C:22]1[C:26]([C:27]#[N:28])=[CH:25][NH:24][N:23]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[N:23]3[N:24]=[CH:25][C:26]([C:27]#[N:28])=[C:22]3[N:21]=2)=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18]
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(F)c(C(F)(F)F)c1
Reactant: N#Cc1c[nH]nc1N
Product: N#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(F)c(C(F)(F)F)c3)nc12
Yield: 38.5 %

Procedure:
Reaction of 1-(4-fluoro-3-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (302 mg, 1.0 mmol), prepared from commercially available 4-fluoro3-trifluoromethyl-acetophenone according to general procedure A, and 3-amino-4-cyano-pyrazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as an off-white solid (144 mg, 38%). MS (ISP) 375.0 [(M+H)+]; mp 204° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.C(N(CC)CC)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>C(Cl)Cl.O>[CH3:1][O:2][C:3](=[O:33])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][C:14]=2[CH2:23][N:24]([S:42]([CH3:41])(=[O:44])=[O:43])[CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CNCCc2ccccc2)c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CCc2ccccc2)S(C)(=O)=O)c1
Reaction time: 1 h

Procedure:
To [6-methoxy-2′-(phenethylamino-methyl)-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid methyl ester (0.068 g, 0.15 mmol) and triethylamine (0.02 mL, 0.16 mmol) in CH2Cl2 (1 mL) was added methanesulfonyl chloride (0.01 mL, 0.16 mmol), and the mixture was stirred for 1 hour. Starting material was still present by analytical LCMS, so additional methanesulfonyl chloride was added, and the reaction was stirred overnight at room temperature. Additional methanesulfonyl chloride and triethylamine was added after 20 hours to push the reaction to completion. The solution was then diluted with CH2Cl2 and H2O, and the aqueous layer was separated and extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated, and the residue was purified by silica gel chromatography to give the title compound.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][OH:23])[CH2:16][CH2:15]1.[H-].[Na+]>CN(C=O)C>[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][O:23][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=2)[CH2:16][CH2:15]1
Reactant: CN1CCN(CCCO)CC1
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(OCCCN2CCN(C)CC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 4-fluoro-2-(methyloxy)-1-nitrobenzene (1 g, 5.8 mmol) in 20 mL of anhydrous DMF was added 3-(4-methyl-1-piperazinyl)-1-propanol (1.2 g, 7.59 mmol). Sodium hydride (60%) (467 mg, 11.68 mmol) was added portionwise and the reaction was stirred at rt for 90 min at which time it was quenched with a solution of saturated NH4Cl (5 mL) and most of the DMF was removed under reduced pressure. The residue was diluted with ethyl acetate and washed with a minimum amount of water and a saturated sodium chloride solution, dried over Na2SO4 and filtered. Solvents were removed under reduced pressure to give 1-methyl-4-(3-{[3-(methyloxy)-4-nitrophenyl]oxy}propyl)piperazine as a yellow solid (1.8 g total isolated, some residual DMF in product) (ESIMS (M+H)+=311)
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:16])[C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.C(OC([NH:28][CH2:29][C:30]1([CH3:35])[CH2:34][CH2:33][NH:32][CH2:31]1)=O)(C)(C)C.C(N(CC)CC)C>C(#N)C>[NH2:28][CH2:29][C:30]1([CH3:35])[CH2:34][CH2:33][N:32]([C:11]2[CH:12]=[C:13]3[C:8]([C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[C:9]([CH3:16])[C:10]=2[F:15])[CH2:31]1
Reactant: CC1(CNC(=O)OC(C)(C)C)CCNC1
Reactant: Cc1c(F)c(F)cc2c1c(=O)c(C(=O)O)cn2C1CC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1c(F)c(N2CCC(C)(CN)C2)cc2c1c(=O)c(C(=O)O)cn2C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.9 %

Procedure:
A mixture of 0.61 g (2.18 mmol) of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 0.56 g (2.61 mmol) of 3-[(t-butoxycarbonyl)aminomethyl]-3-methylpyrrolidine, 0.66 g (6.54 mmol) of triethylamine, and 25 mL of acetonitrile was refluxed for 6 hours, then stirred overnight at room temperature. The precipitate was collected by filtration and washed with acetonitrile and ether. The crude product was suspended in 20 mL of 6N hydrochloric acid and 20 mL of glacial acetic acid and was stirred at room temperature for 3 hours. The solution was concentrated and the residue was triturated with ether. The solid was removed by filtration, washed with ether, and dried to give 0.61 g of the title compound as the hydrochloride, mp 250°-252° C.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17](C2C=CC(CCN(CC3C=CC=CC=3)C[C@H](O)C3C=CC=CC=3)=CC=2)=[CH:16][CH:15]=1)=[O:12].[H][H].[CH2:47]([OH:49])[CH3:48]>[C].[Pd]>[NH:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=[C:2]1[CH2:10][C:11]([NH:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:10][CH2:2][NH:1][CH2:48][C@H:47]([OH:49])[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH:18][CH:19]=1)=[O:12]
Reactant: CCO
Reactant: [H][H]
Reactant: O=C(Cc1nc2ccccc2[nH]1)Nc1ccc(-c2ccc(CCN(Cc3ccccc3)C[C@H](O)c3ccccc3)cc2)cc1
Agent: [Pd]
Product: O=C(Cc1nc2ccccc2[nH]1)Nc1ccc(CCNC[C@H](O)c2ccccc2)cc1

Procedure:
(R)-2-(1H-Benzimidazol-2-yl)-4′-[4-[2-[N-benzyl-N-(2-hydroxy-2-phenylethyl)amino]ethyl]phenyl]acetanilide (240 mg) was dissolved in 30 ml of ethanol, then 170 mg of 10% palladium-carbon was added thereto and the mixture was stirred for nine hours in a hydrogen atmosphere under atmospheric pressure. The catalyst was filtered off, the solvent was evaporated in vacuo, and the residue was washed with ethanol-ethyl acetate to give 200 mg of (R)-2-(1H-benzimidazol-2-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]-ethyl]acetanilide.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]1([C:11]2[CH:20]=[C:19]([CH2:21][CH2:22][CH2:23][C:24]([OH:26])=O)[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:27]([NH:29][CH2:30][CH3:31])[CH3:28].O>C(Cl)(Cl)Cl>[CH2:27]([N:29]([CH2:30][CH3:31])[C:24](=[O:26])[CH2:23][CH2:22][CH2:21][C:19]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:20]=1)[CH3:28]
Reactant: O=C(O)CCCc1cc(-c2ccccc2)nc2ccccc12
Reactant: CCNCC
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: O=S(Cl)Cl
Product: CCN(CC)C(=O)CCCc1cc(-c2ccccc2)nc2ccccc12
Temperature: 20 °C
Reaction time: 3 h

Procedure:
Thionyl chloride (1.02 cc) is added to a solution of 2-phenyl-4-quinolinebutanoic acid (3.7 g) in chloroform (60 cc), and the mixture is heated under reflux for 15 minutes. The solvents are evaporated off under reduced pressure. The residue obtained is dissolved in chloroform (40 cc). Diethylamine (6 cc) is added slowly to this solution in the course of 20 minutes. The mixture is stirred for 3 hours at room temperature (approximately 20° C.) and taken up with water (40 cc). The organic phase is decanted, washed with water (40 cc), dried over magnesium sulphate and evaporated under reduced pressure. The residue is chromatographed on silica gel, using a cyclohexane/ethyl acetate (50:50 by volume) mixture as eluant. N,N-Diethyl-2-phenyl-4-quinolinebutanamide (3.3 g) is thereby obtained, and this is converted to the monohydrochloride in acetone. The hydrochloride melts at 130° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[CH:7]=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:9]2)=[CH:4][CH:3]=1.Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]Cl.[OH:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[OH:26][CH:27]1[CH2:32][CH2:31][N:30]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:1][C:2]2[CH:3]=[CH:4][C:5]3[C:6](=[O:18])[CH:7]=[C:8]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[O:9][C:10]=3[CH:11]=2)[CH2:29][CH2:28]1
Reactant: O=c1cc(-c2ccccc2)oc2cc(O)ccc12
Reactant: ClCCCCCBr
Reactant: OC1CCNCC1
Product: O=c1cc(-c2ccccc2)oc2cc(OCCCCCN3CCC(O)CC3)ccc12

Procedure:
The compound was prepared by a method similar to Example 3 from 7-hydroxyflavone, 1-bromo-5-chloropentane, and 4-hydroxypiperidine: mp 94°-95° C.
Reaction SMILES: Cl[C:2]1[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[C:40]1([CH3:46])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:46][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[C:2]1[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: Cc1ccccc1
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)c1ccc(C(=O)OCC)c(Cl)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(-c2ccccc2C)c(C(=O)OCC)cc1-c1ccccc1

Procedure:
40 g (115 mmol) of diethyl chloroterephthalate, 19.7 g (162 mmol) of benzeneboronic acid, 389 mg (1.73 mmol) of Pd(OAc)2, 3.36 ml (3.4 mmol) of 1 M tri-tert-butylphosphine in toluene and 75 g (231 mmol) of Cs2 CO3 are heated at the boil for 4 h in 300 ml of 1,4-dioxane. The mixture is subsequently partitioned between toluene and water, and the org. phase is washed three times with water, dried over Na2SO4 and evaporated in a rotary evaporator. The yield is 47 g (115 mmol, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:21][CH2:22][CH3:23])=[C:15]([O:18][CH2:19][CH3:20])[CH:16]=3)[CH:11]=[C:10]([C:24](O)=[O:25])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.CO.[OH-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:21][CH2:22][CH3:23])=[C:15]([O:18][CH2:19][CH3:20])[CH:16]=3)[CH:11]=[C:10]([CH2:24][OH:25])[CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CCOc1cc2cc(C(=O)O)cc(-c3ccnc(Cl)c3)c2cc1OCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1cc2cc(CO)cc(-c3ccnc(Cl)c3)c2cc1OCC
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a suspension of 1-(2-chloro-4-pyridyl)-3-carboxy-6,7-diethoxynaphthalene in tetrahydrofuran (50 ml) is added dropwise a solution of 70% sodium aluminum bis(2-methoxyethoxy) hydride (70% toluene solution, 29.4 ml) in tetrahydrofuran (50 ml) at a temperature below 5° C. under nitrogen atmosphere, and the mixture is reacted at the same temperature for one hour. After the reaction is complete, to the mixture is added methanol (12 ml), and further thereto is added a 6.25 M aqueous sodium hydroxide solution (48 ml), and the mixture is stirred at 50° C. for one hour. The tetrahydrofuran layer is separated from the mixture, and the aqueous solution is extracted with methylene chloride, and the methylene chloride layer is separated, and combined with the tetrahydrofuran layer, then concentrated under reduced pressure. The resultant is extracted again with methylene chloride, washed, dried, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (solvent; chloroform:ethyl acetate=4:1), and crystallized from ether to give 1-(2-chloro-4-pyridyl)-3-hydroxymethyl-6,7-diethoxynaphthalene (3.94 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:13][C@@H:12]([CH3:14])[S:11][N:10]([CH:15]([CH3:17])[CH3:16])[C@@H:9]2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:25](I)[CH:26]=C.[CH3:29][Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:13][C@@:12]([CH3:29])([CH2:14][CH:25]=[CH2:26])[S:11][N:10]([CH:15]([CH3:17])[CH3:16])[C@@H:9]2[C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)N1S[C@H](C)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: C=CCI
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC[C@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(C(C)C)S1
Temperature: 60 °C

Procedure:
To a degassed solution of 174.7 mg (0.424 mmol) of (3S,4R,6R)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-6-methyl-2-(2-propanyl)-1,2-thiazinan (Example 120, Step A) in THF (1.5 mL) was added allyl iodide (0.55 mL, 6.02 mmol). The resulting solution was heated to 60° C. for 10 minutes, then a 1 M solution of lithium bis(trimethylsilyl)-amide in THF (2.0 mL, 2.00 mmol) was added dropwise, over one minute. After heating at 60° C. for 17 hours, the reaction was cooled to room temperature, quenched with water (2 mL), and then concentrated under reduced pressure. Purification by reverse-phase preparative HPLC using an Agilent Eclipse Plus C18 column (Agilent Technologies, Santa, Clara, Calif.), 0.1% TFA in MeCN/H2O, gradient 40% to 95% over 25 minutes, provided the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][N:5]2[CH:11]=1.[I:12]N1C(=O)CCC1=O.C(Cl)(Cl)Cl>CC#N>[Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][N:5]2[C:11]=1[I:12]
Reactant: Clc1ccc2nc(Cl)cn2c1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: Clc1ccc2nc(Cl)c(I)n2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a suspension of 2,6-dichloro-imidazo[1,2-a]pyridine, compound 12 (4.0 g, 0.02 mol) in dry CH3CN (50 mL) was added N-iodosuccinimide (NIS, 5.3 g, 0.024 mol) and the mixture stirred at room temperature for 1 h. The reaction mixture was heated at reflux for 10 min and then cooled to room temperature. Chloroform (200 mL) was added to the reaction mixture and the organic phase washed successively with 10% NaOH (100 mL), sodium thiosulfate (100 mL) and water (2×100 mL) then dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The resulting solid was suspended in MeOH and filtered to give 5.0 g (80%) of compound 19 as white crystalline solid.
Reaction SMILES: [CH2:1]([O:4][C@@H:5]1[CH2:25][C@@H:24]2[C@:11]([CH3:29])([CH2:12][C@H:13]([OH:28])[C@H:14]3[C@H:23]2[CH2:22][CH2:21][C:20]2[C@:15]3([CH3:27])[CH2:16][CH2:17][C:18](=[O:26])[CH:19]=2)[C@@:6]1([OH:30])[C:7](=[O:10])[CH2:8]O)[CH:2]=[CH2:3].[Cl-:31].[Li+]>CN(C)C=O.O>[CH2:1]([O:4][C@@H:5]1[CH2:25][C@@H:24]2[C@:11]([CH3:29])([CH2:12][C@H:13]([OH:28])[C@H:14]3[C@H:23]2[CH2:22][CH2:21][C:20]2[C@:15]3([CH3:27])[CH2:16][CH2:17][C:18](=[O:26])[CH:19]=2)[C@@:6]1([OH:30])[C:7](=[O:10])[CH2:8][Cl:31])[CH:2]=[CH2:3]
Reactant: [Cl-]
Reactant: C=CCO[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CO
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCO[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CCl

Procedure:
A solution of 16α-allyloxy-11β,17,21-trihydroxypregn-4-ene-3,20-dione, 21-methanesulfonate (4.6 mmoles) in 60 ml of dimethylformamide is refluxed for 1 hour under nitrogen with 5 g of lithium chloride. The solution is cooled, diluted with water and filtered. The solid is dissolved in chloroform, washed with 5% hydrochloric acid, water, dried, and evaporated in vacuo to yield the title compound.
Reaction SMILES: [CH2:1]([NH:8][C@@H:9]([CH2:14][CH:15]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:10]([O:12][CH3:13])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:23][C:24]([C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[C:29]([F:34])[CH:28]=1)=[N:25][OH:26].C(=O)([O-])[O-].[K+].[K+].C1COCC1>C(OCC)(=O)C.O>[CH2:1]([N:8]([CH2:23][C:24]([C:27]1[CH:28]=[C:29]([F:34])[CH:30]=[C:31]([F:33])[CH:32]=1)=[N:25][OH:26])[C@@H:9]([CH2:14][CH:15]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:10]([O:12][CH3:13])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H](CC1CCCCCC1)NCc1ccccc1
Reactant: ON=C(CBr)c1cc(F)cc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CC1CCCCCC1)N(CC(=NO)c1cc(F)cc(F)c1)Cc1ccccc1

Procedure:
820 mg (2.83 mmol) methyl (S)-2-benzylamino-3-cycloheptyl-propionate were stirred overnight at RT together with 0.71 g (2.83 mmol) 2-bromo-1-(3,5-difluoro-phenyl)-ethanone-oxime, 0.51 g (3.68 mmol) potassium carbonate and 10 ml THF. After the addition of water and ethyl acetate the organic phases were combined, washed with water, dried and evaporated to dryness by rotary evaporation. The residue was purified by RP-HPLC. The product-containing fractions were combined, the organic solvent was removed and the aqueous residue was made alkaline with saturated, aqueous sodium hydrogen carbonate solution. It was extracted with ethyl acetate, the organic phase was dried and concentrated by rotary evaporation.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[C:5]([OH:33])([CH3:32])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][N:19]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[C:18](=[O:30])[N:17]2[CH3:31])=[CH:9][CH:8]=1)[CH3:2].[H-].[Na+].I[CH2:38][CH2:39][CH2:40][CH3:41].C1OCCOCCOCCOCCOCCOC1>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:34])[C:5]([O:33][CH2:38][CH2:39][CH2:40][CH3:41])([CH3:32])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][N:19]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=3)[C:18](=[O:30])[N:17]2[CH3:31])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCCCI
Reactant: CCOC(=O)C(C)(O)Cc1ccc(OCCC2CN(Cc3ccc(OC)cc3)C(=O)N2C)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCOC(C)(Cc1ccc(OCCC2CN(Cc3ccc(OC)cc3)C(=O)N2C)cc1)C(=O)OCC
Temperature: 0 °C
Reaction time: 18 h
Yield: 64.4 %

Procedure:
A slurry of 2-hydroxy-3-(4-{2-[1-(4-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-propionic acid ethyl ester (7.35 g, 15.62 mmol) and sodium hydride (2.5 g, 62.5 mmol, 60% dispersion on mineral oil) in DMF (50 mL) i stirred for 45 minutes, then cooled to 0° C. Iodobutane (36 mL, 312 mmol, d=1.617) and 18-crown-6 16.5 g, 62.5 mmol) are added, then the reaction mixture is stirred 18 h at ambient temperature and diluted with ethyl acetate. The organic layer is washed, then dried concentrated in vacuo, and diluted with ethanol (400 mL) and 5N NaOH (40 mL). The reaction mixture is refluxed for 1 h, cooled to ambient temperature, and concentrated in vacuo. The residue is washed, dried, concentrated, and re-dissolved in ethanol (300 mL). Concentrated H2SO4 (30 mL) is added to the reaction solution, then the mixture is refluxed 1 h, cooled to ambient temperature, concentrated, and diluted with ethyl acetate. The organic layer is washed, dried, and concentrated to provide the title compound (5.3 g, 65%). 1H NMR (400 MHz, CDCl3): δ 7.17 (d, 2H, J=8.8 Hz), 7.09 (d, 2H, J=8.8 Hz), 6.84 (d, 2H, J=8.8 Hz), 6.70 (d, 2H, J=8.8 Hz), 4.32, 4.28 (ABq, 2H, J=14.7 Hz), 4.17-4.11 (m, 2H), 3.93 (t, 2H, J=5.9 Hz), 3.78 (s, 3H), 3.61-3.53 (m, 3H), 3.40-3.31 (m, 3H), 2.97-2.89 (m, 3H), 2.97-2.89 (m, 3H), 2.81 (s, 3H), 2.25-2.15 (m, 1H), 1.89-1.81 (m, 1H), 1.59-1.49 (m, 2H), 1.42-1.33 (m, 2H), 1.29 (s, 3H), 1.24 (t, 3H, J=7.2 Hz), 0.91 (t, 3H, J=7.2 Hz). Rf=0.43 in 50% acetone in hexanes.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]([CH2:22][P:23](=[O:30])([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26])[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][CH2:17][CH2:16]3)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH:31]([N:34]([CH2:38]C)C(C)C)(C)C.C(Cl)(Cl)=[O:41].CN>ClCCl.C1(C)C=CC=CC=1.O1CCCC1.Cl>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]([CH2:22][P:23](=[O:30])([O:24][CH2:25][CH3:26])[O:27][CH2:28][CH3:29])[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([C:38](=[O:41])[NH:34][CH3:31])[CH2:17][CH2:16]3)(=[O:10])=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCOP(=O)(CN(c1ccc2c(c1)CCN2)S(=O)(=O)c1cc(Cl)cc(Cl)c1)OCC
Reactant: O=C(Cl)Cl
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOP(=O)(CN(c1ccc2c(c1)CCN2C(=O)NC)S(=O)(=O)c1cc(Cl)cc(Cl)c1)OCC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1.27 g diethyl {[(3,5-dichloro-phenylsulphonyl)-(2,3-dihydro-1H-indol-5-yl)-amino]-methyl}-phosphonate are dissolved in 10 ml dichloromethane and cooled to 0° C. To this are added 410 μl N,N-diisopropyl-ethylamine and 6.8 ml of a 20% solution of phosgene in toluene. The mixture is left for 1 hour with stirring and then the solvents are eliminated in a nitrogen current. The residue is taken up in 40 ml of tetrahydrofuran, 6.45 ml of a 2 M solution of methylamine in tetrahydrofuran are added and the mixture is stirred overnight at ambient temperature. Then it is diluted with dichloromethane and 1 N hydrochloric acid and washed with semisaturated sodium chloride solution. The organic phase is dried on magnesium sulphate, the solvents are eliminated in vacuo and the residue is purified by chromatography on silica gel (dichloromethane/methanol 95:5 to 60:40).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:30]=[CH:29][C:17]([O:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]([NH:27][CH3:28])=[O:26])[CH:20]=3)=[CH:16][C:15]=2[F:31])=[O:12])[N:7]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][OH:39])[CH:33]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)[P:43]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])C.ClC1C=C(C=CC=1)C(OO)=[O:61]>OS([O-])=O.[Na+]>[P:43]([O:39][CH2:38][C:34]1[CH:35]=[CH:36][CH:37]=[C:32]([N:7]2[C:8]([NH:10][C:11](=[O:12])[NH:13][C:14]3[CH:30]=[CH:29][C:17]([O:18][C:19]4[CH:24]=[CH:23][N:22]=[C:21]([C:25](=[O:26])[NH:27][CH3:28])[CH:20]=4)=[CH:16][C:15]=3[F:31])=[CH:9][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[N:6]2)[CH:33]=1)([O:44][C:45]([CH3:46])([CH3:47])[CH3:48])([O:49][C:50]([CH3:51])([CH3:52])[CH3:53])=[O:61]
Reactant: CCN(CC)P(OC(C)(C)C)OC(C)(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CNC(=O)c1cc(Oc2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3cccc(CO)c3)c(F)c2)ccn1
Agent: O=S([O-])O
Agent: [Na+]
Product: CNC(=O)c1cc(Oc2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3cccc(COP(=O)(OC(C)(C)C)OC(C)(C)C)c3)c(F)c2)ccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.3 %

Procedure:
To a room temperature solution of 1-H-tetrazole (0.45M in acetonitrile, 56 mL, 25.3 mmol, solvent removed in vacuo prior to using) in tetrahydrofuran (100 mL) was added example 1, (4-{4-[({3-tert-butyl-1-[3-(hydroxymethyl)phenyl]-1H-pyrazol-5-yl}carbamoyl)amino]-3-fluorophenoxy}-N-methylpyridine-2-carboxamide, (5.00 g, 9.39 mmol) and di-t-butyl N,N-diethylphosphoramidite (2.11 g, 8.45 mmol). The reaction mixture was allowed to stir at room temperature for 2 h. The reaction mixture was then cooled to −40° C. and a slurry of m-chloroperoxybenzoic acid (85% in CH2Cl2, 2.74 g, 12.2 mmol) was added while keeping the reaction temperature below 0° C. The reaction mixture was allowed to warm to room temperature and stir for 10 min and then an aqueous.solution of NaHSO3 (10%, 40 mL) was added. After stirring for an additional 1 h at room temperature, the reaction was transferred to a separatory funnel and extracted with EtOAc. The organic layer was washed with NaHCO3 (2×50 mL), dried (NaSO4) and concentrated. The crude material was purified via column chromatography (CH2Cl2:2 M NH3 in MeOH, 98:2), followed by recrystallization (CH2Cl2/hexanes) to afford 3.57 g (52%) of the desired product as a white crystalline material. MS m/z 724.9 (M+H)+; Retention time (LC-MS): 3.74 min.