Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[C:9]1([Mg]Cl)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Cl-].[NH4+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1([B-](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([PH+](C(C)(C)C)C)(C)(C)C.O1CCCC1>[C:9]1([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCCCCCCBr
Reactant: Cl[Mg]c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: C[PH+](C(C)(C)C)C(C)(C)C
Solvent: C1CCOC1
Product: CCCCCCCc1ccccc1

Procedure:
A 50-ml four-necked flask was equipped with a stirrer, a thermometer, a dropping funnel and a reflux condenser. 0.045 g (0.2 mmol) of palladium (II) acetate and 2 ml of tetrahydrofuran were weighed in the flask, followed by stirring. Further, 0.096 g (0.2 mmol) of di-tert-butylmethylphosphonium tetraphenylborate obtained in Example B-1 was weighed in air and added into the flask. The flask was purged with argon, followed by stirring at 22° C. for 30 minutes. 3.582 g (20 mmol) of n-heptyl bromide was added, followed by stirring at 22° C. for 30 minutes. 10 ml (22 mmol) of 2.2M tetrahydrofuran solution of phenylmagnesium chloride was added dropwise at 30° C. over a period of 10 minutes, followed by stirring at 30° C. for 3 hours. After the completion of the reaction, 10 ml of saturated aqueous ammonium chloride solution was added, followed by separation. The organic phase was purified by column chromatography to afford 2.997 g of 1-phenylheptane (yield: 85 mol % based on n-heptyl bromide). The identification of the product was made by mass spectroscopy.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:18][N:19]2[C:27]3[C:22](=[CH:23][C:24]([C:28]([OH:30])=O)=[CH:25][CH:26]=3)[CH:21]=[CH:20]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[N+:31]([C:34]1[CH:39]=[CH:38][C:37]([C@@H:40]([NH2:42])[CH3:41])=[CH:36][CH:35]=1)([O-:33])=[O:32]>>[N+:31]([C:34]1[CH:35]=[CH:36][C:37]([C@@H:40]([NH:42][C:28]([C:24]2[CH:23]=[C:22]3[C:27](=[CH:26][CH:25]=2)[N:19]([CH2:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:9]2[CH:8]=[CH:7][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:11][CH:10]=2)[CH:20]=[CH:21]3)=[O:30])[CH3:41])=[CH:38][CH:39]=1)([O-:33])=[O:32]
Reactant: C[C@H](N)c1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)c1ccc(-c2ccccc2Cn2ccc3cc(C(=O)O)ccc32)cc1
Product: CCOC(=O)c1ccc(-c2ccccc2Cn2ccc3cc(C(=O)N[C@@H](C)c4ccc([N+](=O)[O-])cc4)ccc32)cc1

Procedure:
The title compound was prepared following the same protocol as described in Step 8, Example 1, using the 1-((4′-(ethoxycarbonyl)-[1,1′-biphenyl]-2-yl)methyl)-1H-indole-5-carboxylic acid instead of the 1-((2′-(tert-Butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid and the (S)-1-(4-nitrophenyl)ethanamine instead of the (S)-1-(4-bromophenyl)ethanamine.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1)=O.[OH:13][CH2:14][CH2:15][NH:16][C:17]([NH2:19])=[S:18]>C(O)C>[OH:13][CH2:14][CH2:15][NH:16][C:17]1[S:18][CH:2]=[C:3]([C:5]2[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=2)[N:19]=1
Reactant: NC(=S)NCCO
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Solvent: CCO
Product: N#Cc1ccc(-c2csc(NCCO)n2)cc1
Yield: 39 %

Procedure:
In the same manner as described in step 3 of Example 81, a solution of 4-(2-bromo-acetyl)-benzonitrile (3.8 g, 17.1 mmol) and (2-hydroxy-ethyl)-thiourea, prepared in the previous step, in 50 mL of ethanol was heated at reflux for 2 h. The reaction was concentrated to a residue. The residue was dissolved in ethyl acetate and washed with saturated NaHCO3. The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo to give 6.2 g of crude product. The crude product was purified on silica gel using a stepwise gradient of 3:1 to 2:1 hexane:ethyl acetate to give 4-{2-[(2-hydroxyethyl)amino]-1,3-thiazol-4-yl}benzonitrile (1.6 g, 39%), mp 80-82° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:31])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[CH2:13][C:14]([C:16]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([CH3:23])[CH:17]=2)=O)=[CH:8][CH:7]=1.Cl.[NH2:33][OH:34].C([O-])(O)=O.[Na+]>>[OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:31])[C:6]1[CH:7]=[CH:8][C:9]([CH:12]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[CH2:13]/[C:14](=[N:33]\[OH:34])/[C:16]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([CH3:23])[CH:17]=2)=[CH:10][CH:11]=1
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)NCCO)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(C(=O)NCCO)cc1

Procedure:
In analogy to example 151, step 3, N-(2-hydroxy-ethyl)-4-[3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-1-o-tolyl-propyl]-benzamide was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound as a colorless solid, MS (ESI+): m/z=434.4 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[H-].[Na+].Br[CH2:9][C:10]1[C:14]2[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=2[O:12][C:11]=1[C:20]([O:22][CH3:23])=[O:21].[Cl-].[NH4+]>CN(C)C=O>[F:19][C:16]1[CH:17]=[CH:18][C:13]2[O:12][C:11]([C:20]([O:22][CH3:23])=[O:21])=[C:10]([CH2:9][O:5][CH2:4][CH2:3][O:2][CH3:1])[C:14]=2[CH:15]=1
Reactant: COCCO
Reactant: COC(=O)c1oc2ccc(F)cc2c1CBr
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COCCOCc1c(C(=O)OC)oc2ccc(F)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31 %

Procedure:
To a solution (25 mL) of 2-methoxyethanol (2.74 mL) in N,N-dimethylformamide was added sodium hydride (60%, oily, 835 mg) at 0° C., and the mixture was stirred at room temperature for 30 min. After stirring, a solution (25 mL) of methyl 3-(bromomethyl)-5-fluoro-1-benzofuran-2-carboxylate (5.00 g) synthesized in Example A47(2) in N,N-dimethylformamide was added at 0° C. The reaction mixture was stirred at 80° C. for 5 hr, then saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-40% ethyl acetate/hexane) to give the title object compound (1.54 g, 31%) as a pale-yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1([C:15]2[C:16]([F:42])=[CH:17][C:18]3[C:35](=[O:36])[C:34]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:33][N:20]4[CH:21]([CH2:25][O:26]C5CCCCO5)[CH2:22][O:23][C:24]=2[C:19]=34)[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH2:1]([O:8][C:9]([NH:11][C:12]1([C:15]2[C:16]([F:42])=[CH:17][C:18]3[C:35](=[O:36])[C:34]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:33][N:20]4[CH:21]([CH2:25][OH:26])[CH2:22][O:23][C:24]=2[C:19]=34)[CH2:13][CH2:14]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cn2c3c(c(C4(NC(=O)OCc5ccccc5)CC4)c(F)cc3c1=O)OCC2COC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cn2c3c(c(C4(NC(=O)OCc5ccccc5)CC4)c(F)cc3c1=O)OCC2CO
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.1 %

Procedure:
In 2 ml of ethanol was dissolved 90 mg of ethyl 10-(1-benzyloxycarbonylaminocyclopropyl)-9-fluoro-3-(2-tetrahydropyranyloxymethyl)-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylate. To the resulting solution was added 10 mg of p-toluenesulfonic acid monohydrate. The resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure. Ethanol was added to the residue obtained, and the resulting crystals were collected by filtration to obtain 47 mg (yield: 61.0%) of ethyl 10-(1-benzyloxycarbonylaminocyclopropyl)-9-fluoro-3-hydroxymethyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24](O)=[O:25]>>[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:25]
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: O=C(O)c1ccccn1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccccn4)cc23)CC1
Yield: 84.9 %

Procedure:
Beginning with 12.0 mg (0.05 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 19.0 mg (0.15 mMol) pyridine-2-carboxylic acid, 14.2 mg (85%) of the title compound were recovered.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=[C:4]([CH2:11]O)[CH:3]=1.O=S(Cl)[Cl:15]>ClCCl>[Cl:1][C:2]1[C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=[C:4]([CH2:11][Cl:15])[CH:3]=1
Reactant: OCc1cc(Cl)c2c(c1)OCO2
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: ClCc1cc(Cl)c2c(c1)OCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (7-chlorobenzo[d][1,3]-dioxol-5-yl)methanol (5.5 g, 30 mmol) and SOCl2 (5.0 mL, 67 mmol) in dichloromethane (20 mL) was stirred at room temperature for 1 h and was then poured into ice water. The organic layer was separated and the aqueous phase was extracted with dichloromethane (50 mL×3). The combined extracts were washed with water and aqueous NaHCO3 solution, dried over Na2SO4 and evaporated under reduced pressure to afford 4-chloro-6-(chloromethyl)benzo[d][1,3]dioxole, which was directly used in the next step.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[N:12]=[C:11]([C:13]3[CH2:14][CH2:15][N:16]([S:19]([C:22]4[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=4)(=[O:21])=[O:20])[CH2:17][CH:18]=3)[CH:10]=[CH:9][CH:8]=2)=[O:6])[CH2:3][CH2:2]1.FC(F)(F)C1C=C(S([Cl:44])(=O)=O)C=CC=1>>[CH:1]1([NH:4][C:5]([C:7]2[N:12]=[C:11]([C:13]3[CH2:18][CH2:17][N:16]([S:19]([C:22]4[CH:23]=[CH:24][C:25]([O:28][C:29]([F:31])([F:30])[F:32])=[CH:26][CH:27]=4)(=[O:21])=[O:20])[CH2:15][CH:14]=3)[CH:10]=[CH:9][C:8]=2[Cl:44])=[O:6])[CH2:3][CH2:2]1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: O=C(NC1CC1)c1cccc(C2=CCN(S(=O)(=O)c3ccc(OC(F)(F)F)cc3)CC2)n1
Product: O=C(NC1CC1)c1nc(C2=CCN(S(=O)(=O)c3ccc(OC(F)(F)F)cc3)CC2)ccc1Cl

Procedure:
Similarly, 5-chloro-1′-(4-trifluoromethoxybenzenesulfonyl)-1′,2′,3′,6′-tetra-hydro-[2,4′]bipyridinyl-6-carboxylic acid cyclopropylamide was synthesized using 4-trifluoromethoxybenzenesulfonyl chloride at the last step instead of 3-trifluoromethylbenzenesulfonyl chloride. 1H NMR (400 MHz, CD3OD): δ 7.99 (m, 2H), 7.85 (d, 1H, J=8.4 Hz), 7.59 (d, 1H, J=8.4 Hz), 7.54 (m, 2H), 6.72 (m, 1H), 3.87 (m, 2H), 3.39 (t, 2H, J=5.6 Hz), 2.87 (m, 1H), 2.73 (m, 2H), 0.83 (m, 2H), 0.66 (m, 2H); MS: 502 (M+H+).
Reaction SMILES: [CH3:1][CH:2]([C:6]1[S:10][C:9]([NH:11][C:12](=[O:29])[CH:13]([NH:17][C:18](=[O:28])[CH2:19][C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=2)[CH2:14][CH2:15][CH3:16])=[N:8][N:7]=1)[CH2:3][CH:4]=O.[CH:30]([NH2:33])([CH3:32])[CH3:31].C([BH3-])#N.[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>ClC(Cl)C.C(Cl)Cl.C(O)(=O)C>[CH:30]([NH:33][CH2:4][CH2:3][CH:2]([C:6]1[S:10][C:9]([NH:11][C:12](=[O:29])[CH:13]([NH:17][C:18](=[O:28])[CH2:19][C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=2)[CH2:14][CH2:15][CH3:16])=[N:8][N:7]=1)[CH3:1])([CH3:32])[CH3:31]
Reactant: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1nnc(C(C)CC=O)s1
Reactant: CC(C)N
Agent: O=S(=O)([O-])[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1nnc(C(C)CCNC(C)C)s1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 2-[2-(3,5-difluoro-phenyl)-acetylamino]-pentanoic acid [5-(1-methyl-3-oxo-propyl)-[1,3,4]thiadiazol-2-yl]-amide (63 mg, 0.148 mmol), isopropylamine (0.2 ml) in dichloroethane (1 ml) and methylene chloride (1 ml) was stirred at r.t. for 10 min. Sodium cyanoborohydride (70 mg), acetic acid (0.1 ml), and sodium sulphate were added and the resulting mixture was stirred at 45-50° C. overnight. The mixture was quenched with water, basified with saturated sodium carbonate, extracted with methylene chloride. The organic layer was separated, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by Shimadzu HPLC to give the title compound LC-MS RT=1.7 min, M+1=467.9.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:13])=[C:4]([OH:12])[C:5]([O:9][CH2:10][CH3:11])=[CH:6][C:7]=1[Br:8].CI.[C:16](=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:8][C:7]1[CH:6]=[C:5]([O:9][CH2:10][CH3:11])[C:4]([O:12][CH3:16])=[C:3]([F:13])[C:2]=1[Br:1]
Reactant: O=C([O-])[O-]
Reactant: CCOc1cc(Br)c(Br)c(F)c1O
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: CCOc1cc(Br)c(Br)c(F)c1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.5 %

Procedure:
After dissolving 3,4-dibromo-6-ethoxy-2-fluorophenol (3.8 g, 12 mmol) in dimethylformamide (30 ml), methyl iodide (1.5 ml, 24 mmol) and potassium carbonate (3.3 g, 24 mmol) were added and the mixture was stirred at room temperature for 18 hours. Water (80 ml) was added, extraction was performed with diethyl ether (60 ml×2), and then after washing the combined organic layers with brine (80 ml) and drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (1.83 g, 46.7%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:10][CH2:9][CH2:8][C:5]2=[N:6][CH:7]=1.C([O-])(=O)C.[K+].C(O)(=O)C.[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CCOC(C)=O>[CH:20](=[C:8]1/[CH2:9][CH2:10][C:4]2[C:5]/1=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=2)/[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=Cc1ccccc1
Reactant: Brc1cnc2c(c1)CCC2
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Brc1cnc2c(c1)CC/C2=C\c1ccccc1
Temperature: 145 °C
Yield: 59.4 %

Procedure:
To a mixture of 3-bromo-6,7-dihydro-5H-cyclopenta[b]pyridine (1.83 g, 9.24 mmol) and potassium acetate (0.980 g, 9.99 mmol) in acetic acid (30 mL, 520 mmol) was added benzaldehyde (1.90 ml, 18.7 mmol). The reaction mixture was heated to 145° C. (oil bath temperature) in a sealed pressure tube for 3 d, cooled to room temperature and additional benzaldehyde (4 mL) and KOAc (1.83 g) were added. The reaction mixture was heated to 145° C. (oil bath temperature) in a sealed pressure tube for 2 d and cooled to room temperature. The reaction mixture was diluted with EtOAc. The organic phase was washed with 5 M NaOH, water and brine and dried over MgSO4. The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel (5% to 10% EtOAc in heptane) to give (E)-7-benzylidene-3-bromo-6,7-dihydro-5H-cyclopenta[b]pyridine (1.57 g, 5.49 mmol, 59% yield) as a yellow solid. MS m/z=286.0 [M+H]+. Calculated for C15H12BrN 285.0.
Reaction SMILES: [CH2:1]([S:5][S:6][CH2:7][C:8]([OH:10])=O)[CH:2]([CH3:4])[CH3:3].ClC(OCC(C)C)=O.CN1CCOCC1.[NH2:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[N:33]=[CH:32][N:31]=[C:30]2[NH:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([Br:44])[CH:39]=1>O1CCCC1.C(Cl)Cl.CO>[Br:44][C:40]1[CH:39]=[C:38]([NH:37][C:30]2[C:29]3[C:34](=[CH:35][CH:36]=[C:27]([NH:26][C:8](=[O:10])[CH2:7][S:6][S:5][CH2:1][CH:2]([CH3:3])[CH3:4])[CH:28]=3)[N:33]=[CH:32][N:31]=2)[CH:43]=[CH:42][CH:41]=1
Reactant: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Reactant: CC(C)CSSCC(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)CSSCC(=O)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 11.6 %

Procedure:
A solution of 3.0 grams of disulfide acid from Example 76 in 50 mL of tetrahydrofuran was cooled in an ice bath. A 2.1 mL portion of isobutyl chloroformate followed by a 1.8 mL portion of N-methyl morpholine were added. After stirring for 5 minutes at 0° C., 0.85 grams of 6-amino 4-(3-bromoanilino)quinazoline was added. The mixture was stirred for 3 hours at 0° C. and then allowed to warm to room temperature. The reaction was quenched with water and the tetrahydrofuran was evaporated under vacuum. Addition of methylene chloride followed by washing the methylene chloride layer with water and evaporation of the solvent gave a crude product. Silica gel chromatography with methanol in methylene chloride gave 0.15 grams white solid of product.
Reaction SMILES: [Br:1][C:2]1[C:13]([CH3:14])=[CH:12][C:5]([O:6][C@@H:7]2[CH2:11][CH2:10][O:9][CH2:8]2)=[CH:4][C:3]=1[CH2:15]Br.[C:17]([O-:20])(=[O:19])[CH3:18].[K+].O>CN(C)C=O>[C:17]([O:20][CH2:15][C:3]1[CH:4]=[C:5]([O:6][C@@H:7]2[CH2:11][CH2:10][O:9][CH2:8]2)[CH:12]=[C:13]([CH3:14])[C:2]=1[Br:1])(=[O:19])[CH3:18]
Reactant: CC(=O)[O-]
Reactant: Cc1cc(O[C@@H]2CCOC2)cc(CBr)c1Br
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OCc1cc(O[C@@H]2CCOC2)cc(C)c1Br
Temperature: 50 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
(R)-3-(4-Bromo-3-(bromomethyl)-5-methylphenoxy)tetrahydrofuran 35b (700 mg, 2 mmol) was dissolved in 15 mL of N,N-dimethylformamide, followed by addition of potassium acetate (197 mg, 2 mmol). The reaction solution was heated to 50° C. and stirred for 1 hour. The resulting solution was cooled down to room temperature, mixed with 100 mL of water and extracted with ethyl acetate (20 mL×2). The combined organic extracts were washed with saturated sodium chloride solution (30 mL), dried with anhydrous magnesium sulphate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude title compound (R)-2-bromo-3-methyl-5-((tetrahydrofuran-3-yl)oxy)benzyl acetate 35c (658 mg) as a yellow oil, which was used directly in the next step without further purification.
Reaction SMILES: O.[N:2](=[CH:4][C:5](=[O:17])[CH2:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[OH:3].[CH2:18](O)[CH2:19][OH:20].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:19]1[O:20][C:5]([CH:4]=[N:2][OH:3])([CH2:6][C:7]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:8])[O:17][CH2:18]1
Reactant: OCCO
Reactant: O=C(C=NO)CC(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: O=C(CC1(C=NO)OCCO1)OCc1ccccc1
Yield: 94 %

Procedure:
In a two liter flask fitted with a Dean Stark water separator and a condenser were placed in 186.5 g. (0.85 mole) of benzyl oximino-acetoacetate [1.1], 62 g. (1 mole) of ethylene glycol, 800 ml. of benzene (reagent grade) and 2 g. (10.5 mmole) of p-toluenesulfonic acid monohydrate. The reaction mixture was boiled at reflux until 15 ml. of water was removed (3 hours). The benzene solution was washed once with saturated sodium bicarbonate solution and once with brine. After drying over anhydrous sodium sulfate, the benzene solution was evaporated, leaving 212 g. (94% yield) of benzyl oximino-acetoacetate ethylene ketal [2.1] as a light yellow oil! Its NMR spectrum was consistent with the assigned structure. Generally, the product was used as such in subsequent reactions but one of the isomers can be crystallized2 from toluene-petroleum either (b.p. 30°-60° C.); m.p. 52° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:29]([F:32])([F:31])[F:30])[CH2:14][CH2:13][N:12]([C:15]3[S:16][C:17]([C:24]([O:26]CC)=[O:25])=[C:18]([C:20]([F:23])([F:22])[F:21])[N:19]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].[OH-].[Na+].Cl>O1CCOCC1>[Cl:9][C:6]1[CH:5]=[C:4]([C:10]2([C:29]([F:32])([F:30])[F:31])[CH2:14][CH2:13][N:12]([C:15]3[S:16][C:17]([C:24]([OH:26])=[O:25])=[C:18]([C:20]([F:23])([F:21])[F:22])[N:19]=3)[CH2:11]2)[CH:3]=[C:2]([Cl:1])[C:7]=1[Cl:8]
Reactant: CCOC(=O)c1sc(N2CCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)nc1C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1sc(N2CCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)nc1C(F)(F)F
Temperature: 80 °C
Yield: 98.9 %

Procedure:
Ethyl 2-[3-(3,4,5-trichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]-4-(tri-fluoromethyl)-1,3-thiazole-5-carboxylate (2.4 g) was added to a mixture solution comprising 1,4-dioxane (40 mL) and an aqueous solution (40 mL) of sodium hydroxide (2.0 g), followed by heating at 80° C. for ten hours. After cooling, the reaction solution was poured over ice water, acidified by adding concentrated hydrochloric acid, and then extracted with ethyl acetate. The organic layer was dried over magnesium sulfate. The solvent was evaporated off under reduced pressure to obtain the title compound (2.25 g, 99%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:10].C1C(=O)N([Br:18])C(=O)C1>C(O)(C(F)(F)F)=O>[Br:18][C:6]1[CH:5]=[CH:4][C:3]([OH:10])=[C:2]([Cl:1])[C:7]=1[CH2:8][OH:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: OCc1cccc(O)c1Cl
Solvent: O=C(O)C(F)(F)F
Product: OCc1c(Br)ccc(O)c1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a flask charged with 2-chloro-3-(hydroxymethyl)phenol and a stir bar was added NBS (10.8 g, 60.5 mmol) and TFA (50 mL). The reaction was allowed to stir for 16 hours at RT, then the solvent was removed under vacuum. The residue was re-dissolved in EtOAc, washed with water, and purified by silica gel flash chromatography. A pair of regio-isomers was collected from the separation. The less polar spot was the desired 4-bromo-2-chloro-3-(hydroxymethyl)phenol according to NMR analysis.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][N:8]=[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:18][CH2:19][C:20](Cl)=[O:21].Cl.[CH2:24]([NH2:26])C>C(Cl)Cl.[OH-].[Na+]>[CH3:24][NH:26][C:20](=[O:21])[CH2:19][O:18][C:3]1[CH:4]=[CH:5][C:6]2[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])=[N:8][O:9][C:10]=2[C:2]=1[Cl:1]
Reactant: CCN
Reactant: O=C(Cl)COc1ccc2c(-c3ccccc3F)noc2c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CNC(=O)COc1ccc2c(-c3ccccc3F)noc2c1Cl
Reaction time: 18 h

Procedure:
A solution of 4.0 g of {[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetyl chloride in methylene chloride is added drop-wise to a solution of 0.9 g of ethylamine hydrochloride in 50 ml methylene chloride and 25 ml of 15% sodium hydroxide solution at 0° C. After 18 hr at room temperature the reaction mixture is acidified, filtered, and the filtrate partitioned. The aqueous solution is washed with methylene chloride. The organic solutions are combined, washed with saturated sodium chloride solution and dried over magnesium sulfate. Removal of the solution gives N-methyl-{[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetamide, mp 164° C.
Reaction SMILES: O1C=C(CN)N=C1.[S:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:13][NH2:14].[F:15][C:16]1[CH:37]=[CH:36][C:19]([CH2:20][N:21]2[CH2:25][CH2:24][N:23]([C:26]3[CH:27]=[C:28]([CH:32]=[CH:33][N:34]=3)[C:29](O)=[O:30])[C:22]2=[O:35])=[CH:18][CH:17]=1>>[F:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:20][N:21]2[CH2:25][CH2:24][N:23]([C:26]3[CH:27]=[C:28]([CH:32]=[CH:33][N:34]=3)[C:29]([NH:14][CH2:13][C:9]3[S:8][CH:12]=[CH:11][N:10]=3)=[O:30])[C:22]2=[O:35])=[CH:36][CH:37]=1
Reactant: O=C(O)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Reactant: NCc1nccs1
Agent: NCc1cocn1
Product: O=C(NCc1nccs1)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Yield: 88 %

Procedure:
Following the procedure as described in Example 14, making variations as required to replace oxazol-4-ylmethanamine with thiazol-2-ylmethanamine to react with 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinic acid, 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-N-(thiazol-2-ylmethyl)isonicotinamide was obtained as a colorless solid in 88% yield: mp 123-125° C.; NMR (300 MHz, CDCl3) δ 8.64 (s, 1H), 8.35 (d, J=5.1 Hz, 1H), 7.70 (d, J=2.7 Hz, 1H), 7.39-7.21 (m, 5H), 7.04-6.99 (m, 2H), 4.93 (d, J=5.7 Hz, 2H), 4.42 (s, 2H), 4.02 (t, J=8.1 Hz, 2H), 3.36 (t, J=8.1 Hz, 2H); MS (ES+) m/z 411.9 (M+1).