Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(S(F)(F)[F:7])CC.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[CH2:15][N:16]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([CH2:27]O)[CH:23]=2)[N:18]([CH:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[C:17]1=[O:35].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[CH2:15][N:16]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([CH2:27][F:7])[CH:23]=2)[N:18]([CH:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[C:17]1=[O:35]
Reactant: COc1ccc(Cn2c(=O)c3cc(CO)ccc3n(C3CCOCC3)c2=O)cc1OC
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(Cn2c(=O)c3cc(CF)ccc3n(C3CCOCC3)c2=O)cc1OC
Temperature: -78 °C
Reaction time: 2 h

Procedure:
0.11 ml of DAST is added dropwise to a solution of 0.1 g of the compound obtained in Step 14.3 in 2 ml of DCM cooled to −78° C. The reaction medium is stirred for 2 hours at −78° C. and then allowed to warm to room temperature. It is neutralized with saturated NaHCO3 solution. The resulting mixture is extracted with DCM. The organic phase is dried over Na2SO4, filtered and evaporated under reduced pressure. The residue is chromatographed on silica gel, eluting with a DCM/EtOAc mixture from (95/5, v/v) to (30/70, v/v) to give 0.032 g of the expected product.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:15]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:14](=[O:29])[N:13]2C)=[O:11])=[CH:5][CH:4]=1.[CH3:33]N1C(=O)C(C2C=CC=CC=2)C(C2C=CC=CC=2)N1.FC(F)(F)C1C=CC(N=C=O)=CC=1>>[F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:15]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:14]([O:29][CH3:33])=[N:13]2)=[O:11])=[CH:5][CH:4]=1
Reactant: CN1C(=O)C(c2ccccc2)C(c2ccccc2)N1C(=O)Nc1ccc(C(F)(F)F)cc1
Reactant: CN1NC(c2ccccc2)C(c2ccccc2)C1=O
Agent: O=C=Nc1ccc(C(F)(F)F)cc1
Product: COC1=NN(C(=O)Nc2ccc(C(F)(F)F)cc2)C(c2ccccc2)C1c1ccccc1

Procedure:
Also isolated was 1-[(4-trifluoromethylphenyl)-aminocarbonyl]-2-methyl-4,5-diphenyl-3-pyrazolidinone, corresponding to a product prepared, according to the method of Example 1, from 2-methyl-4,5-diphenyl-3-pyrazolidinone and 4-trifluoromethylphenylisocyanate.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]=O)=[CH:10][C:5]=2[O:4][CH2:3]C1.[CH2:13]([N:17]1[C:21]([CH2:22][NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][CH3:33])[CH:26]=2)=[C:20]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[NH:19][CH:18]1[I:40])[CH2:14][CH2:15][CH3:16].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C(O)(=O)C>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:23]([CH2:22][C:21]3[N:17]([CH2:13][CH2:14][CH2:15][CH3:16])[CH:18]([I:40])[NH:19][C:20]=3[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][CH3:33])[CH:26]=3)=[CH:10][C:5]=2[O:4][CH2:3]1
Reactant: O=Cc1ccc2c(c1)OCCO2
Reactant: CCCCN1C(CNCc2cccc(OCC)c2)=C(c2ccccc2)NC1I
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCCCN1C(CN(Cc2cccc(OCC)c2)Cc2ccc3c(c2)OCO3)=C(c2ccccc2)NC1I
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2,3-Dihydro-benzo[1,4]dioxine-6-carbaldehyde (503 mg) is added to a solution of (1-butyl-2-iodo-4-phenyl-3H-imidazol-5-ylmethyl)-(3-ethoxy-benzyl)-amine (750 mg) in 10 mL of 1,2-dichlorethane followed by the addition of 10 drops of acetyl alcohol. The resulting mixture is stirred at room temperature for 2 hours. 2 Equivalents of NaBH(OAc)3 are added and the stirring is continued overnight. The reaction is quenched with 10 mL water. The organic phase is collected, washed with water and brine, and dried over Na2SO4. Concentration and purification via flash chromatography provides benzo[1,3]dioxol-5-ylmethyl-(1-butyl-2-iodo-4-phenyl-3H-imidazol-5-ylmethyl)-(3-ethoxy-benzyl)-amine (compound 4).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:12][O:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:16]([O:17]C)[C:15]=1[Cl:22].[Al+3].[Cl-].[Cl-].[Cl-].Cl>ClCCCl>[Cl:22][C:15]1[C:16]([OH:17])=[C:19]([CH:20]=[CH:21][C:14]=1[O:13][CH3:12])[C:4]([C:3]1[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:2]=1[F:1])=[O:5]
Reactant: O=C(Cl)c1cc(F)ccc1F
Reactant: COc1cccc(OC)c1Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1ccc(C(=O)c2cc(F)ccc2F)c(O)c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 21 g of 2,5-difluorobenzoyl chloride and 20.4 g of 2-chlororesorcinol dimethyl ether in 250 ml of 1,2-dichloroethane at 5°-10° C. 15.7 g of AlCl3 is added in portions. The mixture is allowed to warm to room temperature and is then refluxed for 30 minutes. The mixture is poured into concentrated HCl and ice and stirred for approximately one hour. The product is extracted with ethyl acetate, dried over Na2SO4 and evaporated to give 3-chloro-2',5'-difluoro-2-hydroxy-4-methoxybenzophenone, mp 178°-180° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=2)[C:10]=1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:22]1([CH2:29][CH2:30][O:31][C:32]2[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+]>[Cu].N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=2)[C:10]=1[O:38][C:35]1[CH:34]=[CH:33][C:32]([O:31][CH2:30][CH2:29][N:22]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:37][CH:36]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(OCCN2CCCCCC2)cc1
Reactant: COc1ccc2c(Br)c(OCc3ccccc3)ccc2c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: COc1ccc2c(Oc3ccc(OCCN4CCCCCC4)cc3)c(OCc3ccccc3)ccc2c1
Yield: 42.4 %

Procedure:
Combine 2-benzyloxy-1-bromo-6-methoxy-naphthalene (31 g, 90 mmol), 4-(2-azepan-1-yl-ethoxy)-phenol (31 g, 132 mmol), copper bronze (12 g, 189 mmol), potassium carbonate (25 g, 181 mmol) and pyridine (400 mL). Heat the reaction mixture to reflux for 85 hours. Cool and filter the residue with celite and elute with methanol and methylene chloride (500 mL, V/V=1:5). Evaporate solvent under reduced pressure and chromatograph the residue on a silica gel column eluting the material with a step gradient of methanol/dichloromethane (0 to 10%) to get 19 g (43%) of 1-{2-[4-(2-benzyloxy-6-methoxy-naphthalen-1-yloxy)-phenoxy]-ethyl}-azepane. Dissolve 1-{2-[4-(2-benzyloxy-6-methoxy-naphthalen-1-yloxy)-phenoxy]-ethyl}-azepane (19 g, 38 mmol) in ethyl acetate (500 mL) and methanol (600 mL). Heat the mixture to obtain a clear solution. Cool to room temperature. Add ammonium formate (30 g, 476 mmol) and palladium on carbon (2 g, 1.9 mmol). Heat to reflux for 30 minutes. Add ammonium formate (7 g, 111 mmol) and palladium on carbon (0.7 g, 0.7 mmol). Heat to reflux for 30 minutes. Filter the suspension through a pad of celite and elute with ethyl acetate (500 mL). Evaporate solvent under reduced pressure and add water (100 mL). Dilute the mixture with ethyl acetate (500 mL) and separate layers. Wash the organic layer with saturated sodium bicarbonate solution (2×200 mL), dry with magnesium sulfate, filter and evaporate solvent under reduced pressure to give 15.1 g (97%) of 1-[4-(2-azepan-1-yl-ethoxy)-phenoxy]-6-methoxy-naphthalen-2-ol.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:17][CH3:18])=[C:9]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:10]=2)[CH:5]=[C:4]([NH:19][C:20]2[CH:24]=[C:23]([CH3:25])[NH:22][N:21]=2)[N:3]=1.[C:26](B1OC(C)(C)C(C)(C)O1)([CH3:28])=[CH2:27].C([O-])([O-])=O.[Na+].[Na+].CN(C=O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[C:26]([C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:17][CH3:18])=[C:9]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:10]=2)[CH:5]=[C:4]([NH:19][C:20]2[CH:24]=[C:23]([CH3:25])[NH:22][N:21]=2)[N:3]=1)([CH3:28])=[CH2:27]
Reactant: COCCOc1cc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2cc1OC
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(C)c1nc(Nc2cc(C)[nH]n2)cc2cc(OC)c(OCCOC)cc12
Temperature: 180 °C

Procedure:
A mixture of [1-Chloro-6-methoxy-7-(2-methoxy-ethoxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine (150 mg), isopropenyl boronic acid pinacol ester (70 μl), Na2CO3 (70 mg), Tetrakis(triphenylphosphine)palladium(0) (10 mg), DMF (0.5 ml) and water (0.5 ml) was heated at 180° C. for 30 minutes under microwave irradiation. After reaction finished, the reaction mixture was purified by preparative LC-MS to give [1-Isopropenyl-6-methoxy-7-(2-methoxy-ethoxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine (120 mg). LC-MS: m/e 369(MH+).
Reaction SMILES: N1N(C2C=CC(C(F)(F)F)=CC=2C(O)=O)N=CC=1.N1(C2C=CC(C(F)(F)F)=CC=2C(O)=O)C=CN=N1.[N:37]1[NH:38][N:39]=[CH:40][CH:41]=1.[F:42][C:43]1[C:51]([F:52])=[CH:50][CH:49]=[C:48](I)[C:44]=1[C:45]([OH:47])=[O:46]>O1CCOCC1.O>[F:42][C:43]1[C:51]([F:52])=[CH:50][CH:49]=[C:48]([N:38]2[N:39]=[CH:40][CH:41]=[N:37]2)[C:44]=1[C:45]([OH:47])=[O:46]
Reactant: O=C(O)c1c(I)ccc(F)c1F
Reactant: c1cn[nH]n1
Agent: O=C(O)c1cc(C(F)(F)F)ccc1-n1ccnn1
Agent: O=C(O)c1cc(C(F)(F)F)ccc1-n1nccn1
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1c(-n2nccn2)ccc(F)c1F

Procedure:
Prepared according to the procedure for 2-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)benzoic acid (Intermediate 37a) and 2-(1H-1,2,3-triazol-1-yl)-5-(trifluoromethyl)benzoic acid (Intermediate 37b) from 2H-1,2,3-triazole (CAS number 288-36-8; 0.75 g, 10.86 mmol) and 2,3-difluoro-6-iodobenzoic acid (CAS number 333780-75-9; 1.54 g, 5.43 mmol) in 1,4-dioxane (10 ml) and water (0.2 ml). The crude solid was purified by column chromatography (silica, 0-3% methanol/DCM) to afford 2,3-difluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid (Intermediate 39a). The mixed fractions were further purified by column chromatography (silica, 0-3% methanol/DCM) followed by reverse phase preparative HPLC (eluted with acetonitrile/water containing 0.1% formic acid) to afford 2,3-difluoro-6-(1H-1,2,3-triazol-1-yl)benzoic acid (Intermediate 39b).
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:17]3[CH:18]=[CH:19][S:20][C:16]=3[C:15]3[CH:14]=[CH:13][C:12]([C:21]([OH:23])=O)=[CH:11][C:10]=3[N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:24][S:25]([NH2:28])(=[O:27])=[O:26].CCN=C=NCCCN(C)C.O>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:24][S:25]([NH:28][C:21]([C:12]1[CH:13]=[CH:14][C:15]2[C:16]3[S:20][CH:19]=[CH:18][C:17]=3[C:8]([NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[N:9][C:10]=2[CH:11]=1)=[O:23])(=[O:27])=[O:26]
Reactant: CS(N)(=O)=O
Reactant: O=C(O)c1ccc2c(c1)nc(Nc1ccccc1)c1ccsc12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)NC(=O)c1ccc2c(c1)nc(Nc1ccccc1)c1ccsc12
Reaction time: 5 h
Yield: 80.6 %

Procedure:
4-(phenylamino)thieno[3,2-c]quinoline-7-carboxylic acid (6 mg) was reacted with methyl sulfonamide (120 mg), EDCI (80 mg) and DMAP (20 mg) in anhydrous DMF (0.5 ml). After 5 hours, water was added and the solution subjected to preparative HPLC. Genevac evaporation provided N-(methylsulfonyl)-4-(phenylamino)thieno[3,2-c]quinoline-7-carboxamide as a solid (6 mg, 81% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][C@H:23]([CH2:27][OH:28])[CH2:22]2)[NH:12][C:11]([C:29]2[S:30][CH:31]=[CH:32][N:33]=2)=[N:10]1.C(OC([NH:41][C@@H:42]([CH:46]([CH3:48])[CH3:47])[C:43](O)=[O:44])=O)(C)(C)C>>[NH2:41][C@@H:42]([CH:46]([CH3:48])[CH3:47])[C:43]([O:28][CH2:27][C@@H:23]1[CH2:22][N:21]([CH2:20][C:13]2[NH:12][C:11]([C:29]3[S:30][CH:31]=[CH:32][N:33]=3)=[N:10][CH:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[Br:1])[C:14]=2[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:26][CH2:25][O:24]1)=[O:44]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCOC(=O)C1=C(CN2CCO[C@H](CO)C2)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Product: CCOC(=O)C1=C(CN2CCO[C@H](COC(=O)[C@@H](N)C(C)C)C2)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Yield: 47 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(((S)-2-(hydroxymethyl)morpholino)methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (1 g, 1.9 mmol) was reacted with (S)-2-((tert-butoxycarbonyl)amino)-3-methylbutanoic acid (0.63 g, 2.9 mmol) according to the procedure as described in Example 49 to give the title compound as a yellow solid (0.57 g, 47%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([NH:13][CH2:14][CH2:15][OH:16])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.N1C=CN=C1.[C:24]([Si:28]([CH3:31])([CH3:30])Cl)([CH3:27])([CH3:26])[CH3:25].O>CC(N(C)C)=O>[Si:28]([O:16][CH2:15][CH2:14][NH:13][C:5]1[CH:4]=[C:3]([C:2]([F:17])([F:18])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:6]=1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:31])[CH3:30]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCNc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)[Si](C)(C)OCCNc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 89.1 %

Procedure:
A solution of the compound (0.38 g) obtained in step 1, imidazole (0.12 g) and tert-butyldimethylchlorosilane (0.26 g) in DMAc (5 mL) was stirred at room temperature for 14 hr, poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous ammonium chloride solution and saturated brine, dried and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (solvent gradient; 3→10% ethyl acetate/hexane) to give N-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3,5-bis(trifluoromethyl)aniline (0.48 g, 89%) as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:18])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]=[CH:8][C:7]=2[CH:11]=1.C([Li])CCC.B(OC(C)C)(OC(C)C)OC(C)C.Br[C:38]1[CH:53]=[CH:52][C:41]([CH2:42][N:43]2[CH2:46][CH:45]([C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH2:44]2)=[CH:40][C:39]=1[F:54].FC(F)(C1C=CC=CC=1)C1C=CC2OC(B(O)O)=CC=2C=1>C1COCC1>[F:18][C:2]([F:1])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:38]3[CH:53]=[CH:52][C:41]([CH2:42][N:43]4[CH2:46][CH:45]([C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH2:44]4)=[CH:40][C:39]=3[F:54])=[CH:8][C:7]=2[CH:11]=1
Reactant: CCOC(=O)C1CN(Cc2ccc(Br)c(F)c2)C1
Reactant: FC(F)(c1ccccc1)c1ccc2occc2c1
Agent: CC(C)OB(OC(C)C)OC(C)C
Agent: OB(O)c1cc2cc(C(F)(F)c3ccccc3)ccc2o1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C1CN(Cc2ccc(-c3cc4cc(C(F)(F)c5ccccc5)ccc4o3)c(F)c2)C1
Reaction time: 0.5 h

Procedure:
To a solution of 5-(difluoro(phenyl)methyl)benzofuran (0.684 g, 2.8 mmol) in 28 mL THF at −78° C. under nitrogen was added butyllithium, 2.5M solution in hexanes (1.3 mL, 3.4 mmol) dropwise. The clear solution was allowed to stir for 30 min, at which point triisopropyl borate (0.97 mL, 4.2 mmol) was added. After 30 min, the bath was removed and the reaction allowed reaching ambient temperature. After 30 min, 28 mL 2N HCl was added, and the reaction was diluted with MTBE. The organic layer was washed with brine and dried with anhyd sodium sulfate, filtered, and concentrated to a ] clear oil. Hexanes was added to give a white solid, which was collected by filtration. A portion of the unpurified material was carried forward as follows: ethyl 1-(4-bromo-3-fluorobenzyl)azetidine-3-carboxylate (0.150 g, 0.474 mmol) and 5-(difluoro(phenyl)methyl)benzofuran-2-ylboronic acid (0.273 g, 0.949 mmol) were reacted according to Scheme B2 and general procedure F to give ethyl 1-((4-(5-(difluoro(phenyl)methyl)benzofuran-2-yl)-3-fluorophenyl)methyl)azetidine-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.94 (t, J=8.0 Hz, 1H), 7.89 (s, 1H), 7.76 (d, J=8.5 Hz, 1H), 7.45-7.60 (m, 6H), 7.38 (d, J=3.0 Hz, 1H), 7.26-7.33 (m, 2H), 4.10 (q, J=7.0 Hz, 2H), 3.63 (s, 2H), 3.43-3.51 (m, 2H), 3.20-3.38 (m, 3H), 1.19 (t, J=7.0 Hz, 3H).
Reaction SMILES: [C:1]([C:3]1([OH:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[CH:2].[Na].Cl[C:12]([O:14][CH3:15])=[O:13]>C1C=CC=CC=1.C1(C)C=CC=CC=1>[C:12](=[O:13])([O:9][C:3]1([C:1]#[CH:2])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)[O:14][CH3:15]
Reactant: C#CC1(O)CCCCC1
Reactant: COC(=O)Cl
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: C#CC1(OC(=O)OC)CCCCC1
Temperature: 25 °C

Procedure:
A solution of 36.0 gm of 1-ethynylcyclohexanol in 50 ml of benzene was slowly added drop-by-drop to an agitated suspension, cooled to 0° to 5° C, of 5.5 gm of finely distributed sodium in 50 ml of absolute toluene and 250 ml of benzene, and was agitated at room temperature until reaction had been completed. 26.0 gm of methyl chloroformate were added under cooling to the sodium salt which has been formed. The mixture was allowed to react for 12 hours at room temperature and was washed several times with water and dried. After distilling off the solvent, the raw ester was fractionated by means of a 20 cm Vigreux column. The methyl 1 -ethynylcyclohexyl carbonate thus obtained constitutes a colorless liquid having a fruity, herbal, complex odor and a distinctive fragrance of dill, and has the following characteristic values;
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8](=[O:24])[N:9]([CH2:16][C:17]([O:19]C(C)(C)C)=[O:18])[C:10]2=[O:15])(=[O:4])=[O:3].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][S:2]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8](=[O:24])[N:9]([CH2:16][C:17]([OH:19])=[O:18])[C:10]2=[O:15])(=[O:3])=[O:4]
Reactant: CC(C)(C)OC(=O)CN1C(=O)c2cccc(NS(C)(=O)=O)c2C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cccc2c1C(=O)N(CC(=O)O)C2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of tert-butyl 2-(4-(methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetate (85 mg, 0.240 mmol) and TFA (370 μl, 4.80 mmol) in 5 ml of DCM was stirred at room temperature overnight. The mixture was evaporated to obtain 2-(4-(methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetic acid (72 mg, 0.240 mmol, 100% yield, MS/ESI+ 298.9 [MH]+) and used as such in the following reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]([F:13])([F:12])[F:11])[NH2:5].C(N(CC)CC)C.[CH3:21][C:22]1([C:25](Cl)=[O:26])[CH2:24][CH2:23]1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:25]([C:22]2([CH3:21])[CH2:24][CH2:23]2)=[O:26])[CH:6]=[CH:7][C:8]=1[O:9][C:10]([F:11])([F:12])[F:13]
Reactant: CC1(C(=O)Cl)CC1
Reactant: Nc1ccc(OC(F)(F)F)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C(=O)Nc2ccc(OC(F)(F)F)c(Cl)c2)CC1
Yield: 89.2 %

Procedure:
To a solution of 3-chloro-4-trifluoromethoxyaniline (2.1 g) in methylene chloride (50 ml), triethylamine (1.1 g) was added, and a solution of 1-methylcyclopropanecarbonyl chloride (1.2 g) in methylene chloride was dropwise added thereto while stirring and ice-cooling. After stirring at room temperature for 1 hour, the reaction mixture was washed with 1 N hydrochloric acid, sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated. The crude crystals (2.9 g) were recrystallized from ethanol to give N-(3-chloro-4-trifluoromethoxyphenyl)-1-methylcyclopropanecarboxamide (2.6 g). M.P., 101°-102° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:17]=[C:16](Cl)[CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=[O:12])=[C:4]([F:19])[CH:3]=1.BrC1C=CC(N)=C(F)C=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].ClC1N=C(Cl)C=CC=1C(O)=[O:43]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[NH:17][C:16](=[O:43])[CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=[O:12])=[C:4]([F:19])[CH:3]=1
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Reactant: O=C(O)c1ccc(Cl)nc1Nc1ccc(Br)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Nc1ccc(Br)cc1F
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(=O)[nH]c1Nc1ccc(Br)cc1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
Preparation of 2-(4-bromo-2-fluorophenylamino)-6-chloronicotinic acid: To a solution of 4-bromo-2-fluorophenylamine (10.4 g, 54.7 mmol) in THF (25 mL) at −78° C. under N2 was added lithium bis(trimethylsilyl)amide (83.3 mL, 83.3 mmol, 1 M solution in hexanes) dropwise over 15 minutes. The reaction mixture was stirred for one hour at −78° C. 2,6-Dichloro-nicotinic acid (5.00 g, 26.0 mmol) was then added dropwise as a solution in THF (15 mL) and the reaction mixture was allowed to warm from −78° C. to room temperature and stir for 16 hours. The reaction mixture was quenched by the addition of H2O and the pH was adjusted to 0-2 with 6 N HCl and then diluted with EtOAc. The organic layer was separated and washed with H2O, saturated NaCl, dried (Na2SO4), and concentrated under reduced pressure. The crude product was triturated several times with ethyl acetate and the resulting solid was collected, washed with dichloromethane and dried under vacuum to yield 7.50 g (83%) pure desired product as a dark pink solid.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8].[CH2:9]([O:16][C:17]1[CH:18]=[C:19]([Mg]Br)[CH:20]=[C:21]([F:23])[CH:22]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(OC1C=C(Br)C=C(F)C=1)C1C=CC=CC=1.[Mg]>O1CCCC1>[CH2:9]([O:16][C:17]1[CH:18]=[C:19]([C:4]2([OH:8])[CH2:5][CH2:6][CH2:7][CH:3]2[O:2][CH3:1])[CH:20]=[C:21]([F:23])[CH:22]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Fc1cc(OCc2ccccc2)cc([Mg]Br)c1
Reactant: COC1CCCC1=O
Agent: Fc1cc(Br)cc(OCc2ccccc2)c1
Agent: [Mg]
Solvent: C1CCOC1
Product: COC1CCCC1(O)c1cc(F)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
After repetition of the above reaction, a solution of 2-methoxycyclopentanone (12.5 g) in tetrahydrofuran (10 ml) was added to a solution of 3-benzyloxy-5-fluorophenylmagnesium bromide [prepared by heating a mixture of 3-benzyloxy-5-fluorobromobenzene (31 g), magnesium powder (2.65 g) and tetrahydrofuran (20 ml) to 40° C. for 2 hours] and the mixture was stirred at ambient temperature for 2 hours. The mixture was evaporated and the residue was partitioned between diethyl ether and water. The organic layer was washed with water, dried (MgSO4) and evaporated. The residue was purified by column chromatography using a 9:1 v/v mixture of methylene chloride and diethyl ether as eluent. There was thus obtained, as a mixture of diastereoisomers, 1-(3-benzyloxy-5-fluorophenyl)-2-methoxycyclopentanol (21.7 g, 62%), as an oil.
Reaction SMILES: FC(F)(F)C1C=CC(CBr)=CC=1.Br[CH2:14][C:15]1[C:16]([CH3:26])=[N:17][O:18][C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[CH3:27][C:28]1[N:29]=[C:30]([N:38]2[CH2:42][CH2:41][NH:40][C:39]2=[O:43])[S:31][C:32]=1[C:33]([O:35][CH2:36][CH3:37])=[O:34]>>[CH3:27][C:28]1[N:29]=[C:30]([N:38]2[CH2:42][CH2:41][N:40]([CH2:14][C:15]3[C:16]([CH3:26])=[N:17][O:18][C:19]=3[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:39]2=[O:43])[S:31][C:32]=1[C:33]([O:35][CH2:36][CH3:37])=[O:34]
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Reactant: Cc1noc(-c2ccccc2)c1CBr
Agent: FC(F)(F)c1ccc(CBr)cc1
Product: CCOC(=O)c1sc(N2CCN(Cc3c(C)noc3-c3ccccc3)C2=O)nc1C
Yield: 87 %

Procedure:
Following the procedure as described in Example 13, making variations as required to replace 4-(trifluoromethyl)benzyl bromide with 4-(bromomethyl)-3-methyl-5-phenylisoxazole to react with ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained as a colorless solid in 87% yield: MS (ES+) m/z 427.2 (M+1).