Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C1C=C(Cl)C=C(C(OO)=[O:18])C=1>C(Cl)(Cl)Cl>[O:1]1[C:9]2[C:4](=[N+:5]([O-:18])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1cnc2ccoc2c1
Solvent: ClC(Cl)Cl
Product: [O-][n+]1cccc2occc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.8 %

Procedure:
To a solution of Furo[3,2-b]pyridine (1.5 g, 13.0 mmol) in CHCl3 (30 mL) was added MCPBA (2.9 g, 17.0 mmol). The mixture was stirred at room temperature for 16 hours. Then the mixture was filtered through a alumina (140 g, basic) and washed with ethyl acetate/hexane (1:1) and DCM/MeOH (20:1) to give Furo[3,2-b]pyridine 4-oxide (1.49 g, 88%). 1H NMR (CDCl3, 400 MHz) δ 8.25 (m, 1H), 7.81 (m, 1H), 7.51 (m, 1H), 7.23 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH:13]([CH3:15])[CH3:14])=[C:11]([C:16]([O:18]C)=[O:17])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.O.[OH-].[Li+].O.Cl>CO.C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH:13]([CH3:15])[CH3:14])=[C:11]([C:16]([OH:18])=[O:17])[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1cnn(-c2ccc(Cl)cc2)c1C(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1c(C(=O)O)cnn1-c1ccc(Cl)cc1
Temperature: 80 °C
Yield: 93.8 %

Procedure:
A mixture of methyl 1-(4-chlorophenyl)-5-isopropyl-pyrazole-4-carboxylate (26.0 g, 96.7 mmol) and lithium hydroxide monohydrate (10.0 g, 238 mml) in MeOH (60 mL), THF (60 mL), and H2O (30 mL) was heated at 80° C. for 3 h. The reaction mixture was cooled to room temperature, acidified with 1 N aqueous HCl, and extracted with EtOAc (600 ml). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated in vacuo to yield 1-(4-chlorophenyl)-5-isopropylpyrazole-4-carboxylic acid (24.0 g, 97%).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]2[N:11]([C:12]=1[C:13]([C:15]1[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=1)[N:21]([CH3:25])[CH:20]=[C:19]([C:26]([O:28]CC)=[O:27])[C:18]3=[O:31])=[O:14])[CH:10]=[CH:9][CH:8]=[CH:7]2.C(O)(C)(C)C.Cl>O>[CH3:3][C:4]1[CH:5]=[C:6]2[N:11]([C:12]=1[C:13]([C:15]1[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=1)[N:21]([CH3:25])[CH:20]=[C:19]([C:26]([OH:28])=[O:27])[C:18]3=[O:31])=[O:14])[CH:10]=[CH:9][CH:8]=[CH:7]2
Reactant: CCOC(=O)c1cn(C)c2ccc(C(=O)c3c(C)cc4ccccn34)cc2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: O
Product: Cc1cc2ccccn2c1C(=O)c1ccc2c(c1)c(=O)c(C(=O)O)cn2C
Yield: 96.4 %

Procedure:
0.27 ml (3.22 mmol) of a 1N aqueous solution of sodium hydroxide is added, at ambient temperature, to 0.5 g (1.29 mmol) of ethyl 6-[(2-methylindolizin-3-yl)carbonyl]-1-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylate in 9 ml of a mixture of t-butanol and water (1/1). The reaction medium is refluxed for 1 hour, acidified with a 1N aqueous solution of hydrochloric acid at ambient temperature, and then extracted with dichloromethane. The organic phase is washed with water, dried over sodium sulphate, and concentrated under reduced pressure. The residue obtained is rinsed with ether and then dried under reduced pressure at 50° C. 448 mg of a yellow solid are obtained.
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][C:17]([O:26][CH3:27])=[CH:18][C:19]=3[O:24][CH3:25])[N:14]=2)=[CH:9][CH:8]=1)C.C1COCC1.CO.[OH-].[K+]>O>[CH3:25][O:24][C:19]1[CH:18]=[C:17]([O:26][CH3:27])[CH:16]=[C:15]2[C:20]=1[C:21](=[O:23])[NH:22][C:13]([C:10]1[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][C:4]([OH:28])=[O:3])=[CH:12][CH:11]=1)=[N:14]2
Reactant: CCOC(=O)CCc1ccc(-c2nc3cc(OC)cc(OC)c3c(=O)[nH]2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(CCC(=O)O)cc3)nc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.8 %

Procedure:
To a round-bottomed flask were added 2-amino-4,6-dimethoxy-benzamide (0.161 g, 0.82 mmol), 3-(4-formyl-phenyl)-propionic acid ethyl ester (0.170 g, 0.82 mmol), sodium bisulfite (0.160 g, 0.902 mmol), p-toluenesulfonic acid (0.016 g, 0.082 mmol) and N,N-dimethylacetamide (10 mL). The reaction mixture was refluxed at 155° C. for 16 h before being cooled to room temperature. Water was added and the precipitated solid was filtered off and washed with water and methanol to obtain 3-[4-(5,7-dimethoxy-4-oxo-3,4-dihydro-quinazolin-2-yl)-phenyl]-propionic acid ethyl ester (0.304 g, 97%). The compound 3-[4-(5,7-dimethoxy-4-oxo-3,4-dihydro-quinazolin-2-yl)-phenyl]-propionic acid ethyl ester (0.304 g, 0.795 mmol) was taken up in a 1:1 mixture of THF and methanol (6 mL). A solution of potassium hydroxide (0.089 g, 1.59 mmol) in water (6 mL) was added to the reaction mixture and stirred at room temperature for 16 h. The solvent was removed and the reaction mixture was acidified with 1 N hydrochloric acid. The precipitated solid was filtered off and washed with water and methanol. The solid was further washed with methanol to obtain 3-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)propanoic acid (0.143 g, 51%). Selected data: MS (ES) m/z: 355.0; MP 250.6-251.1° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([NH2:16])[CH:12]=[CH:13][C:14]=1[F:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O:23][CH2:24][CH3:25])(=[O:22])[CH2:18][C:19]([CH3:21])=O.O.C([O-])(O)=O.[Na+]>C1CCCCC1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:24]([O:23][C:17](=[O:22])[CH:18]=[C:19]([NH:16][C:11]1[CH:12]=[CH:13][C:14]([F:15])=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]=1)[CH3:21])[CH3:25]
Reactant: Nc1ccc(F)c(OCc2ccccc2)c1
Reactant: CCOC(=O)CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCCCC1
Product: CCOC(=O)C=C(C)Nc1ccc(F)c(OCc2ccccc2)c1
Temperature: 25 °C
Yield: 98.9 %

Procedure:
92.7 g (0.43 mol) of 3-Benzyloxy-4-fluoro-phenylamine, 57 ml (0.45 mol) of ethyl acetoacetate and 0.81 g (4 mmol) of p-toluenesulfonic acid monohydrate in 370 ml of cyclohexane were heated at reflux for 3 h in the presence of a water separator funnel. The reaction mixture was cooled to RT, ACOEt (1 l) and saturated aqueous NaHCO3 solution (0.5 l) were added, the layers were separated and the organic layer once extracted with AcOEt (0.3 l). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo to give 140 g (100%) of the desired 3-(3-benzyloxy-4-fluoro-phenylamino)-but-2-enoic acid ethyl ester as yellow-orange crystalline solid. Melting point: 79° C.-80° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH2:7][CH2:8][C@H:9]([NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C:10]([OH:12])=O)([CH3:4])([CH3:3])[CH3:2].[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.CN1CCOCC1.[F:54][C:55]([F:69])([F:68])[C:56]1[CH:57]=[C:58]([N:62]2[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]2)[CH:59]=[CH:60][CH:61]=1>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:24])[CH2:7][CH2:8][C@H:9]([NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C:10](=[O:12])[N:65]1[CH2:64][CH2:63][N:62]([C:58]2[CH:59]=[CH:60][CH:61]=[C:56]([C:55]([F:68])([F:69])[F:54])[CH:57]=2)[CH2:67][CH2:66]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCN(c2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 170.5 %

Procedure:
2.53 g of (S)-2-Benzyloxycarbonylamino-pentanedioic acid 5-tert-butyl ester and 2.46 g of TOTU was dissolved in 15 ml of DMF. The, 3.29 ml of N-Methylmorpholine was added and the mixture was stirred for 30 min at RT. 1.72 g of 1-(3-Trifluoromethyl-phenyl)-piperazine was added and stirring was continued for 5 h. The mixture was diluted with ethyl acetate and washed with saturated sodium hydrogen carbonate solution. Drying of the organic phase over sodium sulfate and evaporation of the solvents under reduced pressure afforded a brownish powder that was purified by chromatography over silica gel eluting with ethyl acetate/heptane 1:2 to 100% ethyl acetate to give 7 g of the desired product.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]=O)=[CH:7][C:6]=2[CH:12]=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH2:21][CH2:22][NH2:23])[CH:17]=[CH:18][C:19]=1[Cl:20]>>[Cl:13][C:14]1[CH:15]=[C:16]([CH2:21][CH2:22][NH:23][CH2:10][C:8]2[O:9][C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:12][C:6]=3[CH:7]=2)[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: Cc1ccc2oc(C=O)cc2c1
Reactant: NCCc1ccc(Cl)c(Cl)c1
Product: Cc1ccc2oc(CNCCc3ccc(Cl)c(Cl)c3)cc2c1
Yield: 89.3 %

Procedure:
In analogy to example S1) 111 mg (0.69 mmol) of 5-methyl-benzofuran-2-carbaldehyde and 144 mg (0.76 mmol) of 2-(3,4-dichloro-phenyl)-ethylamine were reacted to yield 206 mg (89%) of [2-(3,4-dichloro-phenyl)-ethyl]-(5-methyl-benzofuran-2-ylmethyl)-amine as light brown oil. 1HNMR (CDCl3, 300 MHz): δ 2.42 (s, 3H), 2.77 (t, J=6.7 Hz, 2H), 2.89 (t, J=6.7 Hz, 2H), 3.91 (s, 2H), 6.46 (s, 1H), 7.04 (m, 2H), 7.32 (m, 4H).
Reaction SMILES: CS(O[CH2:6][CH:7]1[CH2:11][N:10]([C:12]([OH:14])=[O:13])[C:9]2[CH:15]=[C:16]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:17]3[NH:18][CH:19]=[C:20]([CH3:22])[C:21]=3[C:8]1=2)(=O)=O.S([O-])(=O)(=O)C.[Cl-:36].[Li+]>CN(C=O)C>[Cl:36][CH2:6][CH:7]1[CH2:11][N:10]([C:12]([OH:14])=[O:13])[C:9]2[CH:15]=[C:16]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:17]3[NH:18][CH:19]=[C:20]([CH3:22])[C:21]=3[C:8]1=2
Reactant: [Cl-]
Reactant: Cc1c[nH]c2c(OCc3ccccc3)cc3c(c12)C(COS(C)(=O)=O)CN3C(=O)O
Agent: CS(=O)(=O)[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: Cc1c[nH]c2c(OCc3ccccc3)cc3c(c12)C(CCl)CN3C(=O)O
Temperature: 25 °C

Procedure:
200mg (0.29 mmol max) of the product of step 3A, 1,1-dimethylethyl ester of 1-(methanesulfonyloxymethyl) -1,6-dihydro-8-methyl-5-(phenylmethoxy)-benzo[1,2-b:4,3-b']dipyrrole-3(2H)-carboxylic acid, the crude mesylate, is stirred under nitrogen at 80° C. in 3 ml DMF and 40 mg lithium chloride for 25 minutes, when TLC shows the reaction to be complete. The reaction mixture is cooled to room temperature, and partitioned between methylene chloride and water. The layers are separated and the aqueous layer reextracted with methylene chloride. The organic layers are combined, dried over sodium sulfate and evaporated under high vacuum. The crude product is chromatographed over 10 g silica gel, eluting with ethyl acetatehexane (20:80). Fraction of 5 ml are collected and the product found by TLC in fractions 7-17, which upon combining and evaporating yield compound 7, 1,1-dtmethylethyl ester of 1-(chloromethyl) -1,6-dihydro-8-methyl-5-(phenylmethoxy)-benzo[1,2-b:4,3-b']dipyrrole-3(2 H)-carboxylic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].[H-].[Na+].Br[CH2:16][C:17]#[N:18].O>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:16][C:17]#[N:18])[CH:8]=[CH:7]2)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Reactant: N#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCn1ccc2cc([N+](=O)[O-])ccc21
Yield: 97 %

Procedure:
To a solution of 5-nitroindole (1.62 g, 10 mmole) in DMF (15 ml) was added sodium hydride (60% in oil, 0.440 g, 11 mmole). The reaction mixture was stirred for 30 minutes at room temperature after which time bromoacetonitrile (1.25 g, 10.5 mmole) was added via syringe. After 1 h reaction time at the same temperature, the mixture was poured into 200 ml of water. The precipitate, (5-nitro-indol-1-yl)-acetonitrile, was collected (1.96, 97% yield) and was used without further purification.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([CH2:10][C:11]2[N:12]=[CH:13][N:14]([C:16]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:15]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH2:35]([C:37]1([C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([OH:51])[CH:46]=2)[CH2:43][CH2:42][CH2:41][CH2:40][NH:39][C:38]1=[O:44])[CH3:36].[F-].[K+].[CH2:54]1OCCOCCOCCOCCOCCOC1>CC#N>[CH2:35]([C:37]1([C:45]2[CH:46]=[C:47]([CH:48]=[CH:49][CH:50]=2)[O:51][C:2]2[CH:9]=[C:8]([CH2:10][C:11]3[N:12]=[CH:13][N:14]([C:16]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:15]=3)[CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH2:43][CH2:42][CH2:41][CH2:40][N:39]([CH3:54])[C:38]1=[O:44])[CH3:36]
Reactant: N#Cc1ccc(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1F
Reactant: C1COCCOCCOCCOCCOCCO1
Reactant: CCC1(c2cccc(O)c2)CCCCNC1=O
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Product: CCC1(c2cccc(Oc3cc(Cc4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)cn4)ccc3C#N)c2)CCCCN(C)C1=O

Procedure:
2-Fluoro-4-(1-trityl-1H-imidazol-4-ylmethyl)-benzonitrile (as described in Step A above) (0.348 g, 0.784 mmol), 3-ethyl-3-(3-hydroxy-phenyl)-1-methyl-azepan-2-one (as described in Example 8, Step B) (0.194 mg, 0.784 mmol), KF.Al2O3 (0.232 g) and 18-Crown-6 (0.020 g, 0.076 mmol) were refluxed in CH3CN (15 mL) under Ar for 48 h. The solution was concentrated in vacuo, diluted with EtOAc, washed with 1N NaOH solution, water, brine, dried (MgSO4), concentrated and purified using SiO2 chromatography (1.0% MeOH/CH2Cl2) to give the title compound.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:13][CH2:12][CH2:11][CH2:10][C:7]2([CH2:9][CH2:8]2)[CH:6]1OC(=O)C)=O.N12CCCN=C1CCCCC2.O.Cl>C1(C)C=CC=CC=1>[CH2:9]1[C:7]2([CH2:10][CH2:11][CH2:12][CH2:13][C:5]([CH2:3][OH:2])=[CH:6]2)[CH2:8]1
Reactant: COC(=O)C1CCCCC2(CC2)C1OC(C)=O
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: Cc1ccccc1
Product: OCC1=CC2(CCCC1)CC2
Temperature: 120 °C
Reaction time: 5.5 h
Yield: 47.7 %

Procedure:
To a solution of 4-acetoxy-spiro[2.6]nonane-5-carboxylic acid methyl ester (1.06 g) obtained in Step 3 in toluene (11 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (3.3 mL), followed by stirring the reaction mixture at 120° C. for 5.5 hours. After ice-cooling the reaction mixture, water (25 mL) and 1N aqueous hydrochloric acid solution (25 mL) were added thereto, followed by extraction with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium bicarbonate solution and saturated brine, dried and concentrated. The residue was purified by column chromatography on silica gel (diethyl ether:hexane (volume ratio)=1:20) to give spiro[2.6]non-4-en-5-yl-methanol (0.32 g).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([N:13]2[C:18](=[O:19])[C:17]3[CH2:20][CH2:21][CH2:22][C:16]=3[NH:15][C:14]2=[O:23])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].Br[CH2:25][C:26]#[CH:27]>>[Cl:1][C:2]1[CH:12]=[CH:11][C:10]([N:13]2[C:18](=[O:19])[C:17]3[CH2:20][CH2:21][CH2:22][C:16]=3[N:15]([CH2:27][C:26]#[CH:25])[C:14]2=[O:23])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: C#CCBr
Reactant: CCOC(=O)c1cc(-n2c(=O)[nH]c3c(c2=O)CCC3)ccc1Cl
Product: C#CCn1c2c(c(=O)n(-c3ccc(Cl)c(C(=O)OCC)c3)c1=O)CCC2

Procedure:
using ethyl 2-chloro-5-(1,2,4,5,6,7-hexahydro-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoate and 3-bromo-1-propyne there is obtained ethyl 2-chloro-5-{1,2,4,5,6,7-hexahydro-1-(2-propynyl)-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl}-benzoate, m.p. 121°-123° C.,
Reaction SMILES: [CH2:1]([C:8]1[C:13]2[O:14][CH:15]([CH3:19])[C:16](=[O:18])[NH:17][C:12]=2[CH:11]=[C:10]([CH:20]=O)[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][NH:23][C:24](=[O:37])[C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:27][CH:26]=1>>[CH2:1]([C:8]1[C:13]2[O:14][CH:15]([CH3:19])[C:16](=[O:18])[NH:17][C:12]=2[CH:11]=[C:10]([CH2:20][N:34]2[CH2:35][CH2:36][N:31]([C:28]3[CH:27]=[CH:26][C:25]([C:24]([NH:23][CH3:22])=[O:37])=[CH:30][CH:29]=3)[CH2:32][CH2:33]2)[CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1Oc2c(Cc3ccccc3)cc(C=O)cc2NC1=O
Reactant: CNC(=O)c1ccc(N2CCNCC2)cc1
Product: CNC(=O)c1ccc(N2CCN(Cc3cc(Cc4ccccc4)c4c(c3)NC(=O)C(C)O4)CC2)cc1

Procedure:
Using 353A and N-methyl-4-(piperazin-1-yl)benzamide 282 in the general procedure for reductive aminations, the title compound was obtained as a light grey solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.32 (d, J=6.82 Hz, 3H) 2.42-2.49 (m, 4H) 2.74 (d, J=4.29 Hz, 3H) 3.16-3.28 (m, 4H) 3.38 (s, 2 H) 3.89 (s, 2H) 4.54-4.60 (m, 1H) 6.73-6.82 (m, 2H) 6.92 (m, 2H) 7.14-7.19 (m, 1H) 7.19-7.23 (m, 2H) 7.24-7.30 (m, 2H) 7.70 (m, 2H) 8.14 (q, J=4.29 Hz, 1H) 10.60 (s, 1H). ESI-MS: m/z 485.4 (M+H)+. mp=227.0-230.9° C.
Reaction SMILES: [CH3:1][Mg]I.[C:4]([C:7]1[C:8]([F:47])=[CH:9][C:10]([O:45][CH3:46])=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][N:24]2[C@@H:28]([CH3:29])[C@@H:27]([C:30]3[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[C:32]([C:40]([F:43])([F:42])[F:41])[CH:31]=3)[O:26][C:25]2=[O:44])[CH:12]=1)(=O)[CH3:5]>C(OCC)C>[F:39][C:36]([F:37])([F:38])[C:34]1[CH:35]=[C:30]([C@H:27]2[O:26][C:25](=[O:44])[N:24]([CH2:23][C:14]3[CH:15]=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:17]=[CH:18][C:13]=3[C:11]3[CH:12]=[C:7]([C:4]([CH3:5])=[CH2:1])[C:8]([F:47])=[CH:9][C:10]=3[O:45][CH3:46])[C@H:28]2[CH3:29])[CH:31]=[C:32]([C:40]([F:43])([F:42])[F:41])[CH:33]=1
Reactant: COc1cc(F)c(C(C)=O)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Reactant: C[Mg]I
Solvent: CCOCC
Product: C=C(C)c1cc(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c(OC)cc1F

Procedure:
Methyl magnesium iodide (29 μL, 0.085 mmol) was added dropwise to a solution of (4S,5R)-3-{[5′-acetyl-4′-fluoro-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (30 mg, 0.047 mmol) in diethyl ether (2 mL) at room temperature. The reaction was carefully heated at reflux 4 h. Additional methyl magnesium iodide (63 μL, 0.19 mmol) and ether (1 mL) was added and the reaction was refluxed for 3 h. The reaction was quenched with sat. NH4Cl and extracted with EtOAc (3×25 mL). The combined extracts were washed with brine (25 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by flash silica gel chromatography (0-25% EtOAc/hexanes gradient) to afford (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4′-fluoro-5′-isopropenyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one as a clear glass. LCMS=636.3 (M+1)+. 1H NMR (benzene-d6, 500 MHz, mixture of atropisomers): δ 7.59 (s, 1 H), 7.55 (s, 1 H), 7.35 (d, J=8 Hz, 1 H), 7.30-7.27 (m, 2 H), 6.99-6.96 (m, 2 H), 6.45 (d, J=12.9 Hz, 1 H), 5.32 (d, J=16.9 Hz, 1 H), 5.16-5.15 (m, 1 H), 4.90 (d, J=16.3 Hz, 1 H), 4.48 (d, J=7.7 Hz, 1 H), 3.70 (d, J=6.4 Hz, 1 H), 3.16 (s, 3 H), 2.85-2.79 (m, 1 H), 2.12 (s, 3 H), −0.025 (d, J=6.5 Hz, 3 H).
Reaction SMILES: [NH:1]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C@H:2]([C:19]([O:21]CC1C=CC=CC=1)=[O:20])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][P:11]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:5]=1.C([O-])=O.[NH4+]>CO.C(O)(=O)C.[Pd]>[NH:1]([C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])[C@H:2]([C:19]([OH:21])=[O:20])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][P:11]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][CH:9]=1
Reactant: CCOP(=O)(OCC)Oc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)OCc2ccccc2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOP(=O)(OCC)Oc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1

Procedure:
The title compound was prepared by reaction of crude BocTyr(PO3Et2)OBzl (1 mmol) and ammonium formate (4 mmol) with 10% Pd on charcoal for 20 min. at 50° C. in methanol/acetic acid mixture. After the filtration of the catalyst the solvent was concentrated in vacuo and the residue was dissolved in EtOAc and washed several times with a solution of satured NaCl. The organic phase was dried (Na2SO4) and concentrated, giving an oil 270 mg (70% yield), that was used without purification for the next step. FAB mass spectroscopy: m/z 409 [MNa]+. H1NMR (200 mhz, DMSO-d6) d (ppm)=7.3-7 (dd, 4H, aromatics), 4.1 (m, 4H, P—O—CH2—CH3), 3-2.7 (m, 2H, CH—CH2—F), 1.4-1.2 (m, 15H, CH3—CH2+tBu).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1([F:17])[O:16][C:7]2=[CH:8][C:9]3[NH:13][C:12]([SH:14])=[N:11][C:10]=3[CH:15]=[C:6]2[O:5]1.[Cl-].Cl[CH2:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[CH:23][NH+:22]=1>C(O)C.O>[F:17][C:4]1([F:3])[O:16][C:7]2=[CH:8][C:9]3[NH:13][C:12]([S:14][CH2:20][C:21]4[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[CH:23][N:22]=4)=[N:11][C:10]=3[CH:15]=[C:6]2[O:5]1
Reactant: COc1c[nH+]c(CCl)cc1OC
Reactant: FC1(F)Oc2cc3nc(S)[nH]c3cc2O1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cnc(CSc2nc3cc4c(cc3[nH]2)OC(F)(F)O4)cc1OC
Temperature: 20 °C
Reaction time: 5 h

Procedure:
6.3 ml of 1N sodium hydroxide solution are added dropwise to a solution, warmed to 50° C., of 0.69 g of 2,2-difluoro-5H-[1,3]-dioxolo[4,5-f]benzimidazole-6-thiol and 0.67 g of 2-chloromethyl-4,5-dimethoxypyridinium chloride in 9 ml of ethanol and 4 ml of water in the course of one minute. On cooling the clear reaction mixture to 20° C., a colorless precipitate separates out after a short time. The mixture is stirred at 20° C. for a further 5 hours and the precipitate is filtered off with suction over a suction filter, rinsed with 1N sodium hydroxide solution and water and dried to constant weight. The beige solid is dissolved in 10 ml of methylene chloride, insoluble constituents are filtered off, the filtrate is concentrated and the residue is made to crystallize by addition of diisopropyl ether after cooling. 1.02 g (90% of theory) of the title compound of m.p. 189°-191° C. are obtained.
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1.Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19]>C(O)C>[OH:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: OCCCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=Cc1ccc(OCCCCCCO)cc1
Yield: 55.7 %

Procedure:
A solution of potassium hydroxide (13.2 g) and 4-hydroxybenzaldehyde (20.6 g, 169 mmol) in ethanol (320 ml) was refluxed for 30 min. 6-Bromohexanol (24.5 g, 135 mmol) dissolved in ethanol (30 ml) were added and the reaction mixture was refluxed for 16 h. The solvent was then removed in vacuo. Dichloromethane (400 ml) was added no the residue. The organic layer was washed with aqueous sodium hydroxide (1 M, 300 ml), water (500 ml) and brine (250 ml), filtered, dried over anhydrous sodium sulfate and concentrated in vacuo. Recritstallisation of the residue from dichloromethane/petroleum ether yielded (13) as a pale yellow solid (16.7 g, 45%). The analytical data was in accordance with that reported by C. Noel, C. Friedrich, V. Leonard, P. LeBarney, G. Ravaux, and J. C. Dubois, Makromol. Chem., Macromol. Symp., 1989, 24, 283.