Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.C([Li])CCC.[NH2:12][C:13]1[CH:24]=[CH:23][C:22]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])=[CH:21][C:14]=1[C:15](N(OC)C)=[O:16].Cl>COC.CCCCCC.O1CCCC1>[NH2:12][C:13]1[CH:24]=[CH:23][C:22]([O:25][Si:26]([C:29]([CH3:30])([CH3:31])[CH3:32])([CH3:28])[CH3:27])=[CH:21][C:14]=1[C:15]([C:2]1[S:3][CH:4]=[CH:5][CH:6]=1)=[O:16]
Reactant: CON(C)C(=O)c1cc(O[Si](C)(C)C(C)(C)C)ccc1N
Reactant: Brc1cccs1
Agent: COC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(N)c(C(=O)c2cccs2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 45.9 %

Procedure:
To a solution of 2-bromothiophene (2.7 g, 16 mmol) in dimethyl ether (30 ml) was added dropwise 1.6 M solution (8.9 ml) of n-butyllithium in n-hexane at −78° C. The reaction mixture was stirred at −78° C. for 30 min. and a solution of 2-amino-5-{[tert-butyl(dimethyl)silyl]oxy}-N-methoxy-N-methylbenzamide (2.0 g, 6.4 mmol) in tetrahydrofuran (10 ml) was added dropwise. The reaction mixture was stirred at −78° C. for 30 min. and 0.1N hydrochloric acid was added. The mixture was extracted with ethyl acetate and the extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give (2-amino-5-{[tert-butyl(dimethyl)silyl]oxy}phenyl)(thien-2-yl)methanone (0.98 g, yield 46%) as a yellow oil.
Reaction SMILES: CN1CCOCC1.[C:8]([C:10]1[CH:11]=[C:12]([NH:16][CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18]([OH:20])=O)[CH:13]=[CH:14][CH:15]=1)#[N:9].[N:27]1([C:33]2[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=2)[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.Cl.CN(C)CCCN=C=NCC.O.OC1C2N=NNC=2C=CC=1>CN(C=O)C.O>[C:8]([C:10]1[CH:11]=[C:12]([NH:16][CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18]([NH:37][C:36]2[CH:35]=[CH:34][C:33]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[CH:39][CH:38]=2)=[O:20])[CH:13]=[CH:14][CH:15]=1)#[N:9]
Reactant: N#Cc1cccc(NC(C(=O)O)c2ccccc2)c1
Reactant: Nc1ccc(N2CCOCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cccc(NC(C(=O)Nc2ccc(N3CCOCC3)cc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
87 μl (0.793 mmol) of 4-methylmorpholine are added to a solution of 200 mg (0.793 mmol) of (3-cyanophenylamino)-2-phenylacetic acid, 141 mg (0.793 mmol) of 4-morpholin-4-ylaniline, 152 mg (0.793 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (DAPECI) and 121 mg (0.793 mmol) of hydroxybenzotriazole hydrate (HOBt) in 3 ml of DMF, and the mixture is stirred at room temperature for 48 hours. The reaction mixture is introduced into water, and the precipitate is filtered off, giving 2-(3-cyanophenylamino)-N-(4-morpholin-4-ylphenyl)-2-phenylacetamide as a colourless solid; ESI 413.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4][CH2:3]1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:9]([N:8]([CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C@H:5]1[CH2:6][CH2:7][C@H:2]([N:1]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:3][CH2:4]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: BrCCCCCBr
Reactant: N[C@H]1CC[C@H](N(Cc2ccccc2)Cc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(CN(Cc2ccccc2)[C@H]2CC[C@H](N3CCCCC3)CC2)cc1

Procedure:
2.0 g (6.8 mmol) of trans-1amino-4-dibenzylaminocyclohexane (see Example 2) is dissolved in 50 mL DMF and stirred for 48 h at RT with 1.6 g (7 mmol) of 1,5-dibromopentane and 2 g of potassium carbonate. The mixture is cooled, combined with water, extracted twice with 100 mL of dichloromethane, dried and the solvent is eliminated in vacuo. The residue is purified over a column (about 100 mL silica gel, about 500 mL ethyl acetate 80/methanol 20+1% concentrated ammonia). The desired fractions are evaporated down in vacuo and crystallised from petroleum ether. Yield: 1.2 g (49%).
Reaction SMILES: BrCCO[C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[C:7]([O:13][CH3:14])[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH2:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25][NH:24]1.[CH3:33][C:34](C)=[O:35]>>[CH2:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25][N:24]1[CH2:33][CH2:34][O:35][C:6]1[C:7]([O:13][CH3:14])=[C:8]([CH:11]=[CH:12][CH:5]=1)[CH:9]=[O:10]
Reactant: c1ccc2c(c1)CCNC2
Reactant: CC(C)=O
Reactant: COc1cc(OCCBr)ccc1C=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: COc1c(C=O)cccc1OCCN1CCc2ccccc2C1

Procedure:
The above 4-(2-bromoethoxy)-2-methoxybenzaldehyde (16.8 g, 65 mmol) ([building block 2]) was dissolved in acetone (300 ml) and potassium carbonate (44.9 g, 0.33 mol), potassium iodide (2 g) were added followed by addition of 1,2,3,4-tetrahydroisoquinoline (9.07 g, 72 mmol). The resulting mixture was stirred vigorously at reflux temperature for 16 hours. After cooling, the mixture was filtered and the inorganic precipitate was washed with acetone (100 ml). The combined acetone filtrates were concentrated in vacuo. The residue was dissolved in ethyl acetate (50 ml) and washed with water (2×20 ml) saturated sodium chloride (20 ml), dried over MgSO4 and concentrated in vacuo. The residue (23 g) was purified by column chromatography on silica gel (400 g) eluting first with a mixture of ethyl acetate and heptane (1:1, 2 liters) then with a mixture of ethyl acetate and heptane (2:1, 5 liters) to afford 12 9 (60%) of 4-[2-(1,2,3,4-tetrahydroisoquinolin-2-yl)ethoxyl-2-methoxybenzaldehyde as a solid.
Reaction SMILES: [CH3:1][N:2]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]3[CH2:18][NH:17][CH2:16][CH2:15][C:13]3=2)[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[CH:19]([O:22][C:23]1[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][C:24]=1[C:25](O)=[O:26])([CH3:21])[CH3:20]>>[CH:19]([O:22][C:23]1[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][C:24]=1[C:25]([N:17]1[CH2:16][CH2:15][C:13]2=[C:14]3[C:9](=[CH:10][CH:11]=[C:12]2[CH2:18]1)[C:8]1[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=1)[N:2]3[CH3:1])=[O:26])([CH3:21])[CH3:20]
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: Cn1c2ccccc2c2ccc3c(c21)CCNC3
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCc2c(ccc3c4ccccc4n(C)c23)C1

Procedure:
Prepared in analogy to example 1.1 from 11-methyl-2,3,4,11-tetrahydro-1H-pyrido[4,3-a] carbazole and 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.1).
Reaction SMILES: [C:1]1(=[O:8])[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C1CCCCC1)C.[C:18](Cl)(=[O:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>C1(C)C=CC=CC=1>[C:18]([N:7]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]1=[O:8])(=[O:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: O=C1CCCCCN1
Reactant: CCCCCCCC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C1CCCCC1
Product: CCCCCCCC(=O)N1CCCCCC1=O
Temperature: 67.5 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
113 g (1 mol) of ε-caprolactam (purity >99% by weight) are dissolved in 200 ml of toluene in a round-bottom flask. 127 g (1 mol) of N,N-dimethylcyclohexylamine are introduced into this. Then, at 40-70° C., 164.2 g (1 mol) of octanoyl chloride (purity 99% by weight) are added dropwise. The reaction mixture is then stirred at 65-70° C. for one hour. Then, to remove the ammonium salt produced, it is washed first once with 130 ml of hot water and then with 10 ml of concentrated HCl dissolved in 130 ml of hot water. It is subsequently washed 3 more times with 130 ml of hot water in order to maintain a pH of 5-7 in the reaction mixture. The solvent is distilled off under reduced pressure (water pump) at 70-80° C. N-octanoylcaprolactam is obtained as a yellow liquid in 93% yield with a purity of 98%.
Reaction SMILES: [O:1]=[S:2]1(=[O:26])[C:7]2[CH:8]=[C:9]([O:12][C:13]3[CH:14]=[C:15]([C:19](=[N:21][OH:22])[NH2:20])[CH:16]=[CH:17][CH:18]=3)[CH:10]=[CH:11][C:6]=2[N:5]2[CH2:23][CH2:24][CH2:25][C:4]2=[N:3]1.N1C=CC=CC=1.[S:33](Cl)(Cl)=[O:34]>C1COCC1.C(Cl)Cl>[O:34]=[S:33]1[NH:20][C:19]([C:15]2[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=2)[O:12][C:9]2[CH:10]=[CH:11][C:6]3[N:5]4[CH2:23][CH2:24][CH2:25][C:4]4=[N:3][S:2](=[O:1])(=[O:26])[C:7]=3[CH:8]=2)=[N:21][O:22]1
Reactant: O=S(Cl)Cl
Reactant: NC(=NO)c1cccc(Oc2ccc3c(c2)S(=O)(=O)N=C2CCCN23)c1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=S1NC(c2cccc(Oc3ccc4c(c3)S(=O)(=O)N=C3CCCN34)c2)=NO1
Reaction time: 0.5 h

Procedure:
To a suspension, cooled to 0° C., of the product obtained in Step A of Example 13 (250 mg, 0.67 mmol) in 15 ml of THF there are added 109 μl (1.34 mmol) of pyridine and then, dropwise, 72 μl (1.01 mmol) of thionyl chloride dissolved in 3 ml of CH2Cl2. Stirring is carried out at 0° C. for 30 minutes and the mixture is allowed to come back to ambient temperature whilst stirring for a further hour. Evaporation to dryness is carried out and the residue is made more solid by triturating it in water. The precipitate is filtered off to yield the title product.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.[NH2:32][C:33]1[CH:42]=[CH:41][C:36]([O:37][CH2:38][CH2:39][OH:40])=[CH:35][CH:34]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[OH:40][CH2:39][CH2:38][O:37][C:36]1[CH:41]=[CH:42][C:33]([NH:32][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[NH:10]2)=[O:30])=[CH:34][CH:35]=1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: Nc1ccc(OCCO)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(OCCO)cc2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 77.2 %

Procedure:
In a manner similar to the method described in Examples 1e, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (0.4 g, 0.86 mmol) was reacted with 2-(4-amino-phenoxy)-ethanol (0.24 g, 1.5 mmol), HATU (0.58 g, 1.5 mmol) and iPr2NEt (0.3 mL, 1.7 mmol) in CH2Cl2 (20 mL) at room temperature for 20 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(2-hydroxy-ethoxy)-phenyl]-amide as a white solid (0.4 g, 78%).
Reaction SMILES: [OH-:1].[K+].Cl.[NH2:4]O.C[O:7][C:8](=O)[C@H:9]([CH2:14][S:15][CH3:16])[NH:10][C:11](=[O:13])[CH3:12].Cl>CO.C(Cl)(Cl)Cl.C(OCC)(=O)C>[CH3:16][S:15][CH2:14][C@@H:9]([C:8]([NH:4][OH:1])=[O:7])[NH:10][C:11](=[O:13])[CH3:12]
Reactant: NO
Reactant: [OH-]
Reactant: COC(=O)[C@H](CSC)NC(C)=O
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CSC[C@H](NC(C)=O)C(=O)NO
Reaction time: 72 h
Yield: 87.4 %

Procedure:
A solution of 1.32 g (20 mmole) of potassium hydroxide (85%) in 15 ml of methanol was added dropwise to a solution of 832 mg (12 mmole) of hydroxylamine hydrochloride in 20 ml of methanol under ice cooling sufficient to keep the temperature at +9° to +10° C. Similarly under ice cooling, a solution of 1.91 g (10 mmole) of S-methyl-N-acetyl-L-cysteine methyl ester in 15 ml of methanol was added dropwise. After completion of the dropwise addition, the temperature was allowed to rise to room temperature and the mixture was allowed to stand for 3 days as it was. Thereafter ethyl acetate which contained hydrogen chloride gas was added to attain a pH of about 4. The resulting precipitate was filtered off and the filtrate was concentrated in vacuo by distilling off the methanol. The residue thus obtained was subjected to chromatography on silica gel column (developing solvent: 10% methanol-containing chloroform) to give 1.68 g (88% yield) of N-(S-methyl-N-acetylcysteinyl)-hydroxylamine.
Reaction SMILES: [F:1][C:2]1([F:17])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14](O)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.S(Cl)([Cl:20])=O.CN(C)C=O>>[F:1][C:2]1([F:17])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([Cl:20])=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Solvent: CN(C)C=O
Product: O=C(Cl)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (600 mg, 2.5 mmol) in thionyl chloride (540 □L, 7.4 mmol) was added N,N-dimethylformamide (60 □L, 0.60 mmol). The reaction mixture was stirred at room temperature for one hour. Excess thionyl chloride and N,N-dimethylformamide were removed in vacuo and the resulting acid chloride was used without further purification.
Reaction SMILES: [CH2:1]([Mg]Cl)[CH:2]=C.Cl[C:7]1([CH3:28])[CH2:12][CH2:11][C:10]2[C:13]([CH3:27])=[C:14]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]([CH3:18])=[C:16]([CH3:17])[C:9]=2[O:8]1.O1CCC[CH2:30]1>CCOCC>[C:21]1([CH2:20][O:19][C:14]2[C:15]([CH3:18])=[C:16]([CH3:17])[C:9]3[O:8][C:7]([CH2:28][CH:1]=[CH2:2])([CH3:30])[CH2:12][CH2:11][C:10]=3[C:13]=2[CH3:27])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CCC(C)(Cl)O2
Reactant: C=CC[Mg]Cl
Reactant: C1CCOC1
Solvent: CCOCC
Product: C=CCC1(C)CCc2c(C)c(OCc3ccccc3)c(C)c(C)c2O1
Yield: 57.2 %

Procedure:
To 12 mL (24 mmol) of 2M allylmagnesium chloride in tetrahydrofuran, cooled in an ice bath, was added, with stirring, a solution of 4.95 g (14.98 mmol) of rac-2-chloro-3,4-dihydro-2,5,7,8-tetramethyl-6-(phenylmethoxy)-2H-1-benzopyran in 60 mL of anhydrous ether. The reaction mixture was stirred at 0° C. for 6 hr then worked up by being poured into cold, saturated NH4Cl solution and ether extraction. The product (5.4 g of a pale-yellow oil) was dissolved in 40 mL of methanol and 10 mL of ether containing 10 mg of p-toluenesulfonic acid monohydrate. The solution was stirred at room temperature for 21 hr then concentrated in vacuo. The residue was chromatographed on 75 g of silica gel. Elution with 40:1 parts by volume hexane-ether gave 2.88 g (57.2% yield) of rac-3,4-dihydro-6-(phenylmethoxy)-2-(2-propenyl)-2,5,7,8-tetramethyl-2H-1-benzopyran as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][S:10]([C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16]([OH:18])=O)(=[O:12])=[O:11].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:46]1[NH:51][CH2:50][CH2:49][N:48]2[CH2:52][CH2:53][CH2:54][C@H:47]12>CN(C)C(=O)C.CC1CCCO1>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[NH:9][S:10]([C:13]1[CH:21]=[CH:20][CH:19]=[C:15]([C:16]([N:51]2[CH2:50][CH2:49][N:48]3[CH2:52][CH2:53][CH2:54][C@@H:47]3[CH2:46]2)=[O:18])[CH:14]=1)(=[O:12])=[O:11]
Reactant: O=C(O)c1cccc(S(=O)(=O)Nc2c(F)cccc2F)c1
Reactant: C1C[C@@H]2CNCCN2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CC1CCCO1
Product: O=C(c1cccc(S(=O)(=O)Nc2c(F)cccc2F)c1)N1CCN2CCC[C@@H]2C1
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
To 3-{[(2,6-difluorophenyl)amino]sulfonyl}benzoic acid (0.96 g, 3.06 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (1.28 g, 3.37 mmol) in N,N-dimethylacetamide (7.4 mL) and 2-methyltetrahydrofuran (22 mL) was added (R)-octahydropyrrolo[1,2-a]pyrazine (0.54 g, 4.28 mmol). The reaction was stirred at ambient temperature for 5.5 hours, and then it was diluted with 2-methyltetrahydrofuran (15 mL). The organic solution was washed with 6% NaHCO3/6% NaCl (35 mL), and the aqueous layer was extracted with 2-methyltetrahydrofuran (50 mL). The organic layer was washed with 6% NaHCO3/6% NaCl (50 mL) and 1:1 saturated NaCl/water (6×15 mL), and then it was concentrated. The residue was concentrated from ethanol (2×10 mL) to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:10])=[CH:5][C:6]=1[C:7](Cl)=[O:8].[CH3:11][NH:12][CH3:13].O1CCOCC1>C1COCC1>[CH3:11][N:12]([CH3:13])[C:7]([C:6]1[CH:5]=[C:4]([CH3:10])[O:3][C:2]=1[CH3:1])=[O:8]
Reactant: CNC
Reactant: Cc1cc(C(=O)Cl)c(C)o1
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)N(C)C)c(C)o1
Reaction time: 1 h
Yield: 80 %

Procedure:
A solution of 2,5-dimethylfuran-3-carbonylchloride (2.19 g; 13.8 mmol) in 10 ml of THF was added to a 2M solution of dimethylamine in dioxane (21 ml; 42 mmol) in 80 ml of THF at rt. After stirring for 1 hr, the volatiles were removed in vacuo and the residue was partitioned between EtOAc (100 ml) and water (100 ml). The organic layer was washed with saturated potassium bisulfate solution (100 ml), 1N NaOH (50 ml) and brine (50 ml). Drying over MgSO4 and concentration in vacuo afforded compound 866A (1.84 g, 80%) as an amber liquid. 1HNMR (CDCl3): δ2.23 (s, 3H), 2.33 (s, 3H), 3.04 (s, 6H), 5.96 (s, 1H).
Reaction SMILES: C([O:3][C:4](=[O:40])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])C.[OH-].[Li+].C(O)C.Cl>O>[F:39][C:36]([F:37])([F:38])[C:33]1[CH:34]=[CH:35][C:30]([C:27]2[CH:26]=[CH:25][C:24]([C:20]3[O:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:12]4[CH:11]=[CH:10][C:9]([O:8][C:5]([CH3:6])([CH3:7])[C:4]([OH:40])=[O:3])=[CH:14][CH:13]=4)[N:19]=3)=[CH:29][CH:28]=2)=[CH:31][CH:32]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4ccc(C(F)(F)F)cc4)cc3)oc2C)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1oc(-c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)nc1CCOc1ccc(OC(C)(C)C(=O)O)cc1

Procedure:
To a 20 mL round-bottomed flask equipped for magnetic stirring and fitted with a reflux condenser was added 2-(4-{2-[2-(4′-trifluoromethylbiphenyl-4-yl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid ethyl ester (0.268 mmoles), lithium hydroxide (0.535 mmoles, 0.268 mL of a 2N solution), and ethanol (5 mL). This solution was heated to reflux for 2 h. Distilled water was added to the mixture and the pH was adjusted to 3 using a 1 N HCl solution. The organic layer was extracted with ethyl acetate, washed with brine, and concentrated in-vacuo. This crude oil was re-solvated in pure ethyl acetate and filtered over a pad of Celite. The filtrate was concentrated in-vacuo, and the crude oil was crystallized using acetonitrile. The crystals were collected and dried in-vacuo affording 2-(4-{2-[2-(4′-trifluoromethylbiphenyl-4-yl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid. 1H NMR (400 MHz, CDCl3) 8.04 (2H, d), 7.92 (2H, d), 7.58 (2H, dd), 7.26 (2H, m), 6.91 (2H, d), 6.79 (2H, d), 4.17 (2H, t), 3.00 (2H, t) 2.39 (3H, s), 1.53 (6H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[Li+].CC([N-]C(C)C)C.[CH2:17]1[O:19][CH2:18]1>C1COCC1>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:8])[C:7]=1[CH2:17][CH2:18][OH:19]
Reactant: C1CO1
Reactant: Clc1cncc(Cl)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCc1c(Cl)cncc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3,5-dichloropyridine (4.0 g, 27.0 mmol) in THF (70 mL) was added LDA (1.8 M in THF/heptane/ethylbenzene, 22.0 mL, 39.6 mmol) at −78° C. and the mixture was stirred at the same temperature for 2 h, and then ethylene oxide (1.2 M in THF, 25 ml, 30.0 mmol) was added. The reaction mixture was allowed to warm to room temperature gradually and stirred for 1 h at room temperature. The reaction mixture was quenched by adding saturated aqueous NH4Cl solution and extracted with EtOAc. The organic layer was washed with brine (2 times) and dried over MgSO4. After the solvent was removed, the residue was purified by column chromatography on silica gel to give compound B1-1 (3.1 g, 60%) as a yellow solid.
Reaction SMILES: [Cl-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:9][O:10][CH3:11])C=CC=CC=1.[Br:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]2[CH2:36][CH2:35][C:34](=O)[CH2:33][CH2:32]2)=[CH:27][CH:26]=1.CCCCCC>COC(C)(C)C.O1CCCC1>[Br:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]2[CH2:36][CH2:35][C:34](=[CH:9][O:10][CH3:11])[CH2:33][CH2:32]2)=[CH:27][CH:26]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CCC(c2ccc(Br)cc2)CC1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: COC(C)(C)C
Product: COC=C1CCC(c2ccc(Br)cc2)CC1
Reaction time: 0.5 h
Yield: 93.6 %

Procedure:
20.4 g of triphenyl-methoxymethyl-phosphonium chloride were suspended in 60 ml of t-butyl methyl ether while gassing with argon in a sulphonation flask having a thermometer, mechanical stirrer, dropping funnel and solid substance addition tube and treated at -10° C. within 10 minutes with 6.6 g of solid potassium t-butylate. After completion of the addition the mixture was stirred at -10° C. to 0° C. for 30 minutes, then the deep orange, heterogeneous reaction mixture was treated dropwise at 0° C. with a solution of 10 g of 4-(4-bromophenyl)cyclohexanone in 50 ml of absolute tetrahydrofuran, subsequently stirred at room temperature for 24 hours, poured into 500 ml of hexane and filtered. Low-pressure chromatography of the concentrated residue (13.9 g) on silica gel with hexane/ethyl acetate (vol. 9:1) gave 10.4 g of 1-bromo-4-[4-(methoxymethylidene)cyclohexyl]benzene as a colourless oil.
Reaction SMILES: CN(C)C(N(C)C)=N.[CH3:9][O:10][C:11](=[O:40])[CH:12](P(OC)(OC)=O)[NH:13][C:14](=[O:33])[C:15]1[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=2)=[O:22])=[CH:17][C:16]=1[Br:32].[CH:41]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:44]=[CH:43][C:42]=1[CH:51]=O.C(OCC)(=O)C>O1CCCC1>[CH3:9][O:10][C:11](=[O:40])/[C:12](/[NH:13][C:14](=[O:33])[C:15]1[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=2)=[O:22])=[CH:17][C:16]=1[Br:32])=[CH:51]/[C:42]1[CH:43]=[CH:44][C:45]2[C:50](=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH:41]=1
Reactant: COC(=O)C(NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Br)P(=O)(OC)OC
Reactant: O=Cc1ccc2ccccc2c1
Agent: CN(C)C(=N)N(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)/C(=C/c1ccc2ccccc2c1)NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Br
Temperature: -20 °C
Reaction time: 0.08 h
Yield: 78.7 %

Procedure:
1,1,3,3-Tetramethylguanidine (50.5 μL, 0.40 mmol) was added to a solution of rac.-N-[2-bromo-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]-2-(dimethoxyphosphinyl)glycine methyl ester (Example 130; 106.4 mg, 0.20 mmol) in tetrahydrofuran (1 mL) at −20° C. After 5 min, a solution of naphthalene-2-carboxaldehyde (31.4 mg, 0.20 mmol) in tetrahydrofuran (0.5 mL) was added. The solution was stirred at −20° C. for 1 h and then was stirred at room temperature for 4 h. Ethyl acetate (15 mL) was added and the solution was washed with 1N hydrochloric acid solution (10 mL) and brine (10 mL). The dried (MgSO4) organic phase was filtered, evaporated and the resulting residue was triturated with petroleum ether to furnish (Z)-2-[[2-bromo-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]-3-(naphthalen-2-yl)propenoic acid methyl ester (88 mg, 78% yield) as a yellow solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[CH2:11][NH:12][CH3:13].CCN(CC)CC.[C:21](Cl)(=[O:24])[CH:22]=[CH2:23]>C(Cl)Cl>[CH3:13][N:12]([CH2:11][C:3]1[N:2]([CH3:1])[C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:21](=[O:24])[CH:22]=[CH2:23]
Reactant: CNCc1cc2ccccc2n1C
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)N(C)Cc1cc2ccccc2n1C

Procedure:
To a stirred solution of 1-methyl-2-(methylaminomethyl)-1H-indole (13 g, 8.6 mmole) and Et3N (1.35 mL, 9.6 mmole) in CH2Cl2 (75 mL) at 0° C. was added dropwise acryloyl chloride (0.77 mL, 93 mmole) over 5 minutes. After 2 h the reaction was washed with cold H2O, brine, dried (MgSO4) and concentrated under vacuum. The residue was used without further purification.