Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([NH2:11])=[N:8][C:7]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:5])[CH3:2].[CH3:18][O:19][CH:20]([O:31][CH3:32])[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[C:23](F)[CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>O>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][C:23]2[CH:22]=[C:21]([CH:20]([O:31][CH3:32])[O:19][CH3:18])[CH:26]=[CH:25][C:24]=2[N+:27]([O-:29])=[O:28])=[N:8][C:7]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:5])[CH3:2]
Reactant: COC(OC)c1ccc([N+](=O)[O-])c(F)c1
Reactant: CCOC(=O)c1sc(N)nc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc(Nc2cc(C(OC)OC)ccc2[N+](=O)[O-])nc1-c1ccccc1
Yield: 54.1 %

Procedure:
A mixture of 0.250 g (1 mmole) of 2-amino-4-phenyl-thiazole-5-carboxylic acid ethyl ester (V.1), 0.215 g (1 mmole) of 4-dimethoxymethyl-2-fluoro-1-nitro-benzene, 0.488 g (1.5 mmole) of cesium carbonate and 5 mL of dimethylformamide was heated at 100 degrees overnight. The cooled mixture was diluted with 30 mL of water and then extracted three times with 20 mL of ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with ethyl acetate-hexanes (gradient 0:100-10:90) to give 0.240 g of 2-(5-dimethoxymethyl-2-nitro-phenylamino)-4-phenyl-thiazole-5-carboxylic acid ethyl ester (VIA a) as an orange solid.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([I:15])[N:12]=[C:11]1[CH:16]([CH3:18])[CH3:17])(C)(C)C.[ClH:20].O1CCOCC1>C(Cl)Cl>[I:15][C:13]1[N:12]=[C:11]([CH:16]([CH3:18])[CH3:17])[N:10]([CH2:9][CH2:8][NH2:7])[CH:14]=1.[ClH:20]
Reactant: CC(C)c1nc(I)cn1CCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)c1nc(I)cn1CCN
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To an ice-cooled solution of [2-(4-iodo-2-isopropyl-imidazol-1-yl)-ethyl]-carbamic acid tert-butyl ester (3.011 g; 7.941 mmol) in DCM (75 ml) was added slowly 4N HCl in dioxane (40 ml; 160 mmol). The resulting suspension was stirred at 0° C. for 15 min., then at rt for 2 h45. The volatiles were removed under reduced pressure, then under HV. The product 2-(4-iodo-2-isopropyl-imidazol-1-yl)-ethylamine was obtained as a colorless solid (2.720 g; 100%; presence of 2 eq. of HCl). LC-MS: tR=0.19 min.; [M+H]+=280.17 g/mol.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C@@H:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)=[N:7][CH:8]=1.[C:23]([CH:28]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:25][CH2:26][CH3:27])=[O:24]>O1CCOCC1.[O-2].[Mn+4].[O-2]>[CH2:26]([O:25][C:23](=[O:24])/[CH:28]=[CH:2]/[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C@@H:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)=[N:7][CH:8]=1)[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2ccc(CO)cn2)C1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Product: CCOC(=O)/C=C/c1ccc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)nc1
Reaction time: 18 h
Yield: 89.3 %

Procedure:
To a solution of tert-butyl (3R)-3-{[5-(hydroxymethyl)-2-pyridinyl]amino}-1-piperidinecarboxylate (3.65 g, 11.9 mmol) in dioxane (50 mL) was added manganese(IV) oxide (7.7 g, 89 mmol) and, (carbethoxymethylene)triphenylphosphorane (6.2 g, 17.8 mmol). After stirring for 18 hrs at 60, a resulting precipitate was filtered and the filtrate was evaporated in vacuo and the residue was partitioned between water and EtOAc. The organic layer was separated, washed water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (CHCl3/methanol=95/5) to give tert-butyl (3R)-3-({5-[(1E)-3-ethoxy-3-oxo-1-propen-1-yl]-2-pyridinyl}amino)-1-piperidinecarboxylate (3.99 g, 89%).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[N:17]=[C:16]([C:26]([F:29])([F:28])[F:27])[CH:15]=2)=[CH:10][CH:9]=1)(=O)=O.[C:30]1(=[O:40])[NH:34][C:33](=[O:35])[C:32]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:31]12.[K]>>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([N:18]2[C:14]([C:11]3[CH:12]=[CH:13][C:8]([CH2:7][CH2:6][N:34]4[C:30](=[O:40])[C:31]5[C:32](=[CH:36][CH:37]=[CH:38][CH:39]=5)[C:33]4=[O:35])=[CH:9][CH:10]=3)=[CH:15][C:16]([C:26]([F:28])([F:27])[F:29])=[N:17]2)=[CH:20][CH:21]=1
Reactant: CS(=O)(=O)OCCc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(Cl)cc2)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Product: O=C1c2ccccc2C(=O)N1CCc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(Cl)cc2)cc1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
A mixture of 2-{4-[1-(4-chlorophenyl)-3-(trifluorom ethyl)-1H-pyrazol-5-yl]phenyl}ethyl methanesulfonate obtained by Example 51 (3.2 g) and Potassium phthalimide (1.6 g) was stirred at 80° C. for 5 hrs.
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:20]([C:22]3[N:26]([CH3:27])[N:25]=[C:24]([CH3:28])[CH:23]=3)=[O:21])[CH:14]=2)=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][N:3]=1.[CH3:29][S:30]([C:33]1[CH:34]=[C:35]([CH:40]=[CH:41][CH:42]=1)[C:36]([O:38][CH3:39])=[O:37])(=[NH:32])=[O:31].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([N:32]=[S:30]([C:33]2[CH:34]=[C:35]([CH:40]=[CH:41][CH:42]=2)[C:36]([O:38][CH3:39])=[O:37])([CH3:29])=[O:31])=[O:7])=[CH:9][C:10]=1[C:11]#[C:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:20]([C:22]2[N:26]([CH3:27])[N:25]=[C:24]([CH3:28])[CH:23]=2)=[O:21])[CH:14]=1
Reactant: Cc1cc(C(=O)Nc2cccc(C#Cc3cc(C(=O)O)cnc3N)c2)n(C)n1
Reactant: COC(=O)c1cccc(S(C)(=N)=O)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(S(C)(=O)=NC(=O)c2cnc(N)c(C#Cc3cccc(NC(=O)c4cc(C)nn4C)c3)c2)c1
Temperature: 60 °C
Reaction time: 16.5 h

Procedure:
To a solution of 6-amino-5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]nicotinic acid (68 mg, 0.18 mmol), methyl 3-(S-methylsulfonimidoyl)benzoate (42 mg, 0.198 mmol), and N,N-diisopropylethylamine (0.063 ml, 0.36 mmol) in 1.5 ml DMF at room temperature was added benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate (88 mg, 0.198 mmol). The reaction was heated at 60° C. for 3.5 hours, then at 48° C. for 16.5 hours. The mixture was partitioned between EtOAc and dilute brine. The EtOAc layer was washed with NaHCO3 solution, dilute HCl, NaHCO3 solution, brine, dried with anhydrous Na2SO4 and rotary evaporated. The dark foam was chromatographed eluting with hexane/acetone yielding light pink solid (38 mg, 37%).
Reaction SMILES: [CH2:1]1[C@H:7]2[NH:8][C@H:3]([CH2:4][CH:5]([OH:9])[CH2:6]2)[CH2:2]1.Br[CH2:11][CH2:12][CH2:13][F:14].C(N(CC)CC)C>CN(C=O)C>[F:14][CH2:13][CH2:12][CH2:11][N:8]1[CH:7]2[CH2:1][CH2:2][CH:3]1[CH2:4][CH:5]([OH:9])[CH2:6]2
Reactant: OC1C[C@H]2CC[C@@H](C1)N2
Reactant: FCCCBr
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: OC1CC2CCC(C1)N2CCCF
Temperature: 60 °C
Reaction time: 10 h

Procedure:
A mixture of nortropine (381.6 mg), 1-bromo-3-fluoropropane (634.4 mg) and triethylamine (0.42 ml) in DMF (7.5 ml) was heated to 60° C. and stirred at this temperature for 10 h. The solvent was then removed in vacuo. The product with the molecular weight of 187.26 (C10H18FNO) was obtained in this way; MS (ESI): 188 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[O:15][CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[N:5]=[C:4]([NH2:23])[N:3]=1.[Cl:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1>>[Cl:14][C:12]1[CH:11]=[CH:10][C:9]([O:15][CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[C:8]([C:6]2[N:5]=[C:4]([NH2:23])[N:3]=[C:2]([NH:29][C:28]3[CH:30]=[CH:31][C:25]([Cl:24])=[CH:26][CH:27]=3)[CH:7]=2)[CH:13]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: Nc1nc(Cl)cc(-c2cc(Cl)ccc2OCC2CCCCC2)n1
Product: Nc1nc(Nc2ccc(Cl)cc2)cc(-c2cc(Cl)ccc2OCC2CCCCC2)n1
Yield: 98 %

Procedure:
Following the method described in Example 72, 4-chloro-6-(5-chloro-2-cyclohexylmethoxy-phenyl)-pyrimidin-2-yl-amine and 4-chloro-aniline provided the title compound (98% yield). 1H NMR (DMSO-d6) δ 1.15-1.19 (m, 4H, CH2) δ 1.65-1.73 (m, 6H, CH2), 3.89 (d, 2H, J=5.7 Hz, Ar), 6.49 (s, 1H, Ar), 7.27 (d, 1H, J=8.4 Hz, Ar), 7.46 (d, 2H, J=8.7 Hz, Ar), 7.61 (d, 2H, J=8.5 Hz, Ar), 7.82-7.85 (m, 2H, Ar).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[C:13]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH3:13][O:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[CH:9][CH:8]=[C:7]2[OH:12]
Reactant: O=C([O-])[O-]
Reactant: Oc1cccc2c(O)cccc12
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1cccc2c(O)cccc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 44.1 %

Procedure:
To a stirred solution of 1,5-dihydroxy naphthalene (40 g, 0.25 mol) in dry acetone (200 mL) was added, K2CO3 (34.5 g, 0.25 mol) and the mixture was stirred at RT for 3 h, and then cooled to 0° C. To this, a solution of methyl iodide (124.5 mL, 2 mol) in dry acetone (100 mL) was added drop wise and the reaction mixture was stirred for 2 h at 0° C. and then for 10 h at RT. After completion (TLC), the mixture was filtered and washed with EtOAc. The solvent was removed under reduced pressure and the crude product was purified by column chromatography (8% EtOAc:Hexanes) to afford the desired compound (19.2 g, 44%) as a light green solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:20]=[C:19]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[CH:18]=[CH:17][C:5]=1[C:6]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10](O)=[O:11])=[O:7])[CH3:2].[CH3:26][N:27]([CH3:37])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N:34]([CH3:36])[CH3:35])[CH:29]=1.C(OC(=O)C)(=O)C.Cl>>[CH3:35][N:34]([CH3:36])[C:30]1[CH:29]=[C:28]([N:27]([CH3:37])[CH3:26])[CH:33]=[CH:32][C:31]=1[C:6]1([C:5]2[CH:17]=[CH:18][C:19]([N:21]([CH2:22][CH3:23])[CH2:24][CH3:25])=[CH:20][C:4]=2[O:3][CH2:1][CH3:2])[C:8]2[C:9](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:10](=[O:11])[O:7]1
Reactant: CN(C)c1cccc(N(C)C)c1
Reactant: CCOc1cc(N(CC)CC)ccc1C(=O)c1ccccc1C(=O)O
Agent: Cl
Solvent: CC(=O)OC(C)=O
Product: CCOc1cc(N(CC)CC)ccc1C1(c2ccc(N(C)C)cc2N(C)C)OC(=O)c2ccccc21
Reaction time: 8 h

Procedure:
A mixture of 2-(2-ethoxy-4-(diethylamino)benzoyl)-benzoic acid (6.82 g.), N,N,N',N'-tetramethyl-m-phenylenediamine (2.80 g.) and acetic anhydride (20 g.) was heated (70°-75° C.) during one hour, let stand overnight and poured into dilute hydrochloric acid. The resulting mixture was basified. Recrystallization of the resulting red precipitate from hexane followed by slurrying in alkaline water afforded 3-(2,4-bis(dimethylamino)phenyl)-3-(2-ethoxy-4 -(diethylamino)phenyl)phthalide (I: X= (CH3)2N, Y2 = CH3CH2O, Y4 = (CH3CH2)2N, Z4 = Z5 = Z6 = Z7 = H) (m.p. 146°-150° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:27][CH3:28])=[C:17]([NH:20][C:21](=[O:26])[CH:22]=[CH:23][CH2:24]Br)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[F:8].[S:31]1[CH2:35][CH2:34][NH:33][CH2:32]1>CN(C)C=O.C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:27][CH3:28])=[C:17]([NH:20][C:21](=[O:26])[CH:22]=[CH:23][CH2:24][N:33]4[CH2:34][CH2:35][S:31][CH2:32]4)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCBr
Reactant: C1CSCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCN1CCSC1
Temperature: 25 °C
Reaction time: 19.5 h
Yield: 37.6 %

Procedure:
A mixture of 250 mg (0.51 mmol) of 4-bromo-but-2-enoic acid[4-(3-chloro-4-fluoro-phenylamino)-3-cyano-7-methoxy-quinolin-6-yl]-amide, and 80 μL (1.02 mmol) of thiazolidine in 2.25 ml dimethylformamide was stirred at room temperature for 19.5 hr. After the mixture was cooled, the suspension was diluted with saturated sodium bicarbonate solution and extracted with ethyl acetate. The extracts were evaporated to an oil and purified by preparative TLC to yield 95.6 mg (38%) yellow solid: mp 135-138° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][C:12]([C:15]([OH:17])=O)=[CH:11][N:10]=1.C(N(C(C)C)CC)(C)C.[CH3:27][NH:28][S:29]([C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35][NH2:36])(=[O:31])=[O:30]>CN(C=O)C>[CH3:27][NH:28][S:29]([C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35][NH:36][C:15]([C:12]1[CH:13]=[N:14][C:9]([C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[F:1])=[N:10][CH:11]=1)=[O:17])(=[O:30])=[O:31]
Reactant: O=C(O)c1cnc(-c2cc(F)ccc2F)nc1
Reactant: CNS(=O)(=O)c1cccc(CN)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNS(=O)(=O)c1cccc(CNC(=O)c2cnc(-c3cc(F)ccc3F)nc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
A mixture of 2-(2,5-difluoro-phenyl)-pyrimidine-5-carboxylic acid (118 mg, 0.5 mmol, prepared according to the general procedure described in Example 2, steps 1 and 2), and 0-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (190 mg, 0.5 mmol) in dry DMF (5 mL) is treated with 0.09 mL of diisopropylethylamine and stirred at room temperature for 30 minutes. A solution of 3-methylsulfamoylbenzylamine (150 mg, 0.75 mmol) in dry DMF (1 mL) is added and the mixture stirred at room temperature for 24 hours. The solvent is removed and the residue partitioned between EtOAc and saturated NaHCO3. The organic phase is separated and washed with water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by column chromatography eluting with 20% EtOAc in DCM to afford 2-(2,5-difluoro-phenyl)-pyrimidine-5-carboxylic acid 3-methylsulfamoyl-benzylamide (135 mg, 65%) as a solid. MS: 419 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 2.41 (d, 3H), 4.64 (d, 2H), 7.43-7.78 (m, 5H), 7.89 (s, 1H) 7.90 (t, 1H), 9.37 (s, 2H), 9.60 (t, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:9]2)=[CH:4][CH:3]=1.[Na].[OH-].[Na+].S(OC)(O[CH3:23])(=O)=O>O.C(O)C>[CH3:23][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([S:12]([OH:15])(=[O:13])=[O:14])=[CH:9]2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(O)c1ccc2ccc(O)cc2c1
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc2ccc(S(=O)(=O)O)cc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of 7-hydroxynaphthalene-2-sulfonic acid, sodium salt (15 g, 60.9 mmol) in H2O/ethanol (150 mL, 2:1) is added solid NaOH (2.68 g, 67 mmol)at room temperature. The mixture is stirred until a homogenous solution forms and dimethyl sulfate (6.34 mL, 67 mmol) is then added. A precipitate slowly forms and the mixture is stirred over a period of 16 hours. The crude mixture is concentrated in vacuo and the residue is stirred in absolute EtOH (100 mL) as a slurry for 2 hours. The precipitate is filtered and dried. The solid is heated at reflux in 95% EtOH (100 mL) for 2 h, allowed to cool to room temperature, filtered and dried to give 12.6 g of crude 7-methoxynaphthalene-2-sulfonic acid, sodium salt. A mixture of the sulfonic acid, sodium salt (12.6 g, 48.6 mmol) in phosphorous oxychloride (20 mL) and phosphorous pentachloride (13.2 g, 63.2 mmol) is heated slowly to 60° C. until a homogenous solution forms and then is heated at 120° C. for 4 hours. The resulting mixture is cooled in an ice bath and a mixture of ice/ice water is added slowly with stirring. The mixture is diluted with water and extracted with CHCl3 (2×100 mL). The combined organic layers are washed successively with water, saturated NaHCO3 solution and saturated NaCl. The organic phase is dried over anhydrous MgSO4, filtered and concentrated to give 10 g of a crude oil. The crude product is purified by column chromatography in a gradient of 5% EtOAc/hexanes to 30% EtOAc/hexanes to afford the title compound (3.8 g, 14.8 mmol) as a white crystalline solid.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:15]([O:17][C:18]([C@@H:20]1[CH2:22][C@H:21]1[C:23]1[CH:28]=[C:27]([F:29])[C:26]([NH2:30])=[CH:25][C:24]=1[F:31])=[O:19])[CH3:16].[O:32]([C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][CH:46]=1)[CH:42]=O)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(OCC)(=O)C>ClC(Cl)C>[CH2:15]([O:17][C:18]([C@@H:20]1[CH2:22][C@H:21]1[C:23]1[CH:28]=[C:27]([F:29])[C:26]([NH:30][CH2:42][C:41]2[CH:44]=[CH:45][CH:46]=[C:39]([O:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:40]=2)=[CH:25][C:24]=1[F:31])=[O:19])[CH3:16]
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Reactant: CCOC(=O)[C@@H]1C[C@H]1c1cc(F)c(N)cc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: CCOC(=O)[C@@H]1C[C@H]1c1cc(F)c(NCc2cccc(Oc3ccccc3)c2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.2 %

Procedure:
Sodium triacetoxyborohydride (0.244 g, 1.15 mmol) was added to a solution of enantiomerically enriched-(trans)-ethyl-2-(4-amino-2,5-difluorophenyl)cyclopropanecarboxylate (III-1e) (0.110 g, 0.46 mmol) and 3-phenoxybenzaldehyde (0.091 g, 0.46 mmol) in 5 mL of dichloroethane. The mixture was stirred at room temperature for one hour. The reaction mixture was partitioned between chlroroform and water. The organic phase was washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate and the solvent evaporated. The residue was purified by chromatography on silica gel with hexane:ethyl acetate to give 0.127 g (65% yield) of the title compound as a colorless oil. 1HNMR (400 MHz, CDCl3) δ 7.32 (t, J=8.61Hz, 2H), 7.29 (t, J=7.69 Hz, 2H), 7.10 (t, J=7.14 Hz, 1H), 7.06 (d, J=7.69 Hz, 1H), 6.99 (d, J=7.51 Hz, 2H), 6.90 (dd, J=3.11, 8.06 Hz, 1H), 6.55 (dd, J=6.78, 12.09 Hz, 1H), 6.28 (dd, J=7.51, 11.72 Hz, H), 4.36 (br s, 1H), 4.29 (d, J=5.68 Hz, 2H), 4.15 (q, J=7.14 Hz, 2H), 2.50 (m, 1H), 7.79 (m, 1H), 1.53 (m, 1H), 1.27 (t, J=7.14 Hz, 3H), 1.22 (m, 1H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Cl[C:12]1[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:12]2[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=2)=[CH:6][CH:5]=1
Reactant: OCCc1ccc(O)cc1
Reactant: NC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1ccc(Oc2ccc(CCO)cc2)nc1
Temperature: 120 °C
Yield: 48.1 %

Procedure:
Combine 4-(2-hydroxy-ethyl)-phenol (2.0 g, 14.5 mmol), 6-chloronicotinamide (2.3 g, 14.5 mmol) and K2CO3 (5.0 g, 36.2 mmol) in DMF (40 mL) under nitrogen, stir and heat at 120° C. overnight. Cool to ambient temperature and pour into water, extract the aqueous layer with ethyl acetate. Combine the organic layers and dry over Na2SO4. Eliminate the solvent and purify by flash chromatography on silica gel (eluent: CHCl3/7% EtOH/0.7% NH4OH) to give the title compound (1.8 g, 49%). Electrospray MS M+1 ion=259, 1H-NMR (DMSO-d6, 400 MHz): 8.58 (d, 1H, J=2.7 Hz), 8.22 (dd, 1H, J=2.7 and 8.8 Hz), 8.00 (bs, 1H), 7.46 (bs, 1H), 7.25 (m, 2H), 7.05-7.02 (m, 3H), 4.65 (t, 1H, J=5.3 Hz), 3.63-3.58 (m, 2H), 2.72 (t, 2H, J=6.9 Hz).
Reaction SMILES: N[C@H:2](C(OCC)=O)[CH2:3]CC(OCC)=O.CO.C([C:19]1[CH:40]=[CH:39][CH:38]=[CH:37][C:20]=1[C:21]([NH:23][C@H:24]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:22])#C.[K+].[Br-]>C(Cl)Cl>[C:2]([C:39]1[CH:40]=[CH:19][C:20]([C:21]([NH:23][C@H:24]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:22])=[CH:37][CH:38]=1)#[CH:3]
Reactant: CCOC(=O)CC[C@H](N)C(=O)OCC
Reactant: C#Cc1ccccc1C(=O)N[C@@H](CCC(=O)OCC)C(=O)OCC
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: C#Cc1ccc(C(=O)N[C@@H](CCC(=O)OCC)C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.55 g of 4-ethynylbenzoic acid (obtained from tert.-butyl 4-ethynylbenzoate in 84% yield by hydrolysis with trifluoroacetic acid) in 50 ml of anhydrous ether and 25 ml of anhydrous tetrahydrofuran is added 1.58 ml of triethylamine. This is followed by 1.00 g of phenyl N-phenylphosphoraminochloridate. After stirring the reaction mixture at room temperature under nitrogen for 0.5 hour, 0.90 g of diethyl L-glutamate is added in one portion. The mixture is allowed to stir for another 8 hrs. After a workup, the residue is subjected to column chromatography using a 1% methanol:methylene chloride mixture as the eluent. The major fraction isolated from the column contained 0.68 g (54%) of diethyl N-(ethynylbenzoyl)-L-glutamate as an oil which slowly solidified: NMR (CDCl3, 300 MHz) delta 1.25 (t, 3H, J=6.9 Hz), 1.33 (t, 3H, J=6.9 Hz), 2.11-2.60 (m, 4H), 3.23 (s, 1H), 4.09 (q, 2H, J=6.9 Hz), 4.27 (l, 2H, J=6.9 Hz), 4.80 (m, 1H), 7.12 (d, 1H, J=7.2 Hz), 7.59 (d, 2H, J=8.4 Hz), 7.81 (d, 2H, J=8.4 Hz); IR (KBr) 3330, 3280, 2990, 1735, 1640, 1520, 1380, 1200, 1105, 1020, 855, and 770 cm- 1.
Reaction SMILES: [Na:1].C(O[C:5](=O)[CH2:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)C.[CH2:16](Br)[CH:17]=C.[OH-].[K+]>C(O)C.O>[Na:1].[C:8]1([C:7]([CH2:6][CH2:5][CH:16]=[CH2:17])=[O:14])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: C=CCBr
Reactant: CCOC(=O)CC(=O)c1ccccc1
Agent: [K+]
Agent: [Na]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C=CCCC(=O)c1ccccc1
Yield: 98 %

Procedure:
A sodium solution of alcohol was prepared by dissolving 33 g of sodium in 1000 mL of ethanol. To the warm solution, 260 mL of benzoyl-acetic acid-ethylester was added and then 130 mL of allyl bromide was slowly dropped into the solution. The mixture was refluxed for 4 hrs. and then the solid removed in a vacuum. The resulting solid was then combined in an aqueous solution of potassium hydroxide prepared by combining 145 g of potassium hydroxide with 500 mL of water. This mixture was heated under reflux for 4 hrs. The mixture was then neutralized and extracted three times with 150 mL of diethylether. The organic layer was separated, washed twice with water, and dried. The solvent was removed in a vacuum to produce a 98 percent yield of phenyl-(but-3-enyl) ketone.
Reaction SMILES: [CH:1]([O:6][CH3:7])([O:4][CH3:5])OC.CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.C([C:25]1[CH:30]=[CH:29][C:28]([C:31]#[C:32][C:33]2[CH:43]=[CH:42][C:36]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:35][CH:34]=2)=[CH:27][CH:26]=1)=O.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.CO>[CH3:7][O:6][CH:1]([O:4][CH3:5])[C:25]1[CH:26]=[CH:27][C:28]([C:31]#[C:32][C:33]2[CH:34]=[CH:35][C:36]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:42][CH:43]=2)=[CH:29][CH:30]=1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc(C=O)cc2)cc1
Reactant: COC(OC)OC
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ccc(C#Cc2ccc(C(OC)OC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.7 %

Procedure:
Trimethyl orthoformate (51 g) and (+)-CSA (2.3 g) were added to a methanol (0.40 L)-chloroform (0.10 L) mixed solution of ethyl 4-[(4-formylphenyl)ethynyl]benzoate (27 g) as obtained in Example 10-(1), and the mixture was stirred for 3 hours at room temperature. A saturated aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and then the desiccant was filtered out. Then, the solvent was distilled off under reduced pressure, and the resulting residue was purified by OH type silica gel chromatography (gradient elution with hexane/ethyl acetate=95/5→80/20) to obtain ethyl 4-{[4-(dimethoxymethyl)phenyl]ethynyl}benzoate (white solid) (21 g, 67%).