Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:14]([O-:16])=[O:15])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][C:11]([CH3:13])=[CH2:12].[OH-].[Na+].[CH:19]([Cl:22])(Cl)[Cl:20]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:1][C:2]1[CH:3]=[C:4]([N+:14]([O-:16])=[O:15])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][C:11]1([CH3:13])[CH2:12][C:19]1([Cl:22])[Cl:20]
Reactant: ClC(Cl)Cl
Reactant: C=C(C)CCOc1ccc([N+](=O)[O-])cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Product: CC1(CCOc2ccc([N+](=O)[O-])cc2Cl)CC1(Cl)Cl
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 85 %

Procedure:
Into a solution of 17 g of 3-chloro-4-(3-methyl-3-butenyloxy)nitrobenzene and 0.4 g of tetra-n-butylammonium bromide in chloroform (29.4 g), a 50% sodium hydroxide solution (78.2 g) was dropwise added while stirring at room temperature, and stirring was continued at 50° C. for 2.5 hours. The resultant mixture was poured into ice-water and extracted with chloroform. The extract was concentrated under reduced pressure, and the precipitated crystals were subjected to filtration by a glass filter and washed with ether to give 19.4 g of 3-chloro-4-[2-(1-methyl-2,2-dichlorocyclopropyl)ethoxy]nitrobenzene.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].F[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15].[CH2:17]([N:24]1[CH2:29][C@@H:28]2[C@@H:26]([CH:27]2[NH2:30])[CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O>[CH2:17]([N:24]1[CH2:29][C@@H:28]2[C@@H:26]([CH:27]2[NH:30][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])[CH2:25]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: NC1[C@H]2CN(Cc3ccccc3)C[C@@H]12
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1NC1[C@H]2CN(Cc3ccccc3)C[C@@H]12
Temperature: 130 °C
Reaction time: 18 h

Procedure:
Potassium carbonate (4.59 g, 33.2 mmol), followed by 1-fluoro-2-nitrobenzene (1.87 g, 13.3 mmol) were added to a solution of (1R,5S)-3-benzyl-3-azabicyclo[3.1.0]hex-6-ylamine (WO 9318001), (2.50 g, 13.3 mmol) in N,N-dimethylformamide (40 ml), and the reaction mixture stirred at 130° C. for 18 hours. The cooled mixture was filtered, and the filtrate concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water, the phases separated, and the aqueous layer extracted with ethyl acetate (3×). The combined organic solutions were washed with brine, dried (MgSO4), filtered and evaporated under reduced pressure. The residual brown oil was purified by column chromatography on silica gel using an elution gradient of pentane:ethyl acetate (95:5 to 90:10) to afford the title compound as an orange crystalline foam, 3.11 g.
Reaction SMILES: Cl.[CH2:2]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([NH2:13])=[NH:12])[CH2:7][CH2:6]1)[CH2:3][CH3:4].C([O:16][CH:17]=[C:18]([C:24](OCC)=O)[C:19]([O:21][CH2:22][CH3:23])=[O:20])C.CC[O-].[Na+].[Na]>C(O)C>[OH:16][C:17]1[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:24][N:13]=[C:11]([C@H:8]2[CH2:9][CH2:10][C@H:5]([CH2:2][CH2:3][CH3:4])[CH2:6][CH2:7]2)[N:12]=1
Reactant: CCC[C@H]1CC[C@H](C(=N)N)CC1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCC[C@H]1CC[C@H](c2ncc(C(=O)OCC)c(O)n2)CC1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
23.9 g of trans-4-propylcyclohexanecarboxamidine hydrochloride and 25.2 g of diethyl ethoxymethylene-malonate are added to a sodium ethylate solution prepared from 5.4 g of sodium and 210 ml of ethanol and the mixture is diluted with 150 ml of ethanol. The mixture is stirred at room temperature for 50 minutes and at boiling temperature for 50 minutes and, after cooling, evaporated in vacuo. The viscid residue is suspended in 600 ml of water and acidified with 60 ml of glacial acetic acid. Subsequently, the suspension is stirred for 1.5 hours in an ice-bath and suction filtered. The material on the suction filter is washed with water and dried at 50° C. in vacuo over potassium hydroxide. There are obtained 33 g of ethyl trans-4-hydroxy-2-(4-propylcyclohexyl)-5-pyrimidinecarboxylate; m.p. 156°-157° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]([F:22])([F:21])[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[N:3]=1.[I-].[K+].CCN(C(C)C)C(C)C.[CH3:34][C:35]1[NH:39][N:38]=[C:37]([NH2:40])[CH:36]=1>CN(C=O)C.O>[F:21][C:13]([F:22])([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[C:4]1[N:3]=[C:2]([NH:40][C:37]2[CH:36]=[C:35]([CH3:34])[NH:39][N:38]=2)[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=1
Reactant: Fc1ccc(C(F)(F)c2nc(Cl)c3ccc(F)cc3n2)cc1
Reactant: Cc1cc(N)n[nH]1
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2nc(C(F)(F)c3ccc(F)cc3)nc3cc(F)ccc23)n[nH]1
Temperature: 50 °C
Reaction time: 8 h
Yield: 18.9 %

Procedure:
To a solution of 4-chloro-2-(difluoro(4-fluorophenyl)methyl)-7-fluoroquinazoline (0.160 g, 0.492 mmol) in DMF (2 mL) at rt were added potassium iodide (0.082 g, 0.492 mmol), DIEA (0.094 mL, 0.541 mmol) and 5-methyl-1H-pyrazol-3-amine (0.048 g, 0.492 mmol). After stirring the reaction mixture at 50° C. overnight, the mixture was cooled to rt and H2O (15 mL) was added. The precipitate was collected by filtration and washed with H2O. The crude product was purified on HPLC (Phenomenex phenylhexyl reverse phase column, eluted with gradient of solvent B=0.05% HOAc/CH3CN and solvent A=0.05% HOAc/H2O) to afford 2-(difluoro(4-fluorophenyl)methyl)-7-fluoro-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine as a white powder (36 mg, 19%). 1H NMR (300 MHz, DMSO-d6) δ 2.26 (s, 3H), 6.27 (s, 1H), 7.35 (t, 2H), 7.56 (m, 1H), 7.72-763 (m, 3H), 8.78 (m, 1H), 10.82 (s, 1H), 12.23 (s, 1H); LC-MS (ESI) m/z 388 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)([OH:19])[C:13]2[N:17]([CH3:18])[CH:16]=[N:15][CH:14]=2)=[CH:8][C:7]=1[C:27](=[O:35])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=1)=[O:4].[N-:36]=[N+:37]=[N-:38].[Na+]>CO>[N:36]([CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)([OH:19])[C:13]2[N:17]([CH3:18])[CH:16]=[N:15][CH:14]=2)=[CH:8][C:7]=1[C:27](=[O:35])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=1)=[O:4])=[N+:37]=[N-:38]
Reactant: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc(NC(=O)CBr)c(C(=O)c2cccc(Cl)c2)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CO
Product: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc(NC(=O)CN=[N+]=[N-])c(C(=O)c2cccc(Cl)c2)c1

Procedure:
A mixture of intermediate (4) (0.0161 mol) and NaN3 (0.0161 mol) in methanol (25 ml) was stirred and refluxed overnight.The product was used without further purification, yielding 2-azido-N-[2-(3-chlorobenzoyl)-4-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]phenyl]-acetamide (intermediate 5).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([C@H:14]([CH3:31])[C@:15]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])([OH:22])[CH2:16][N:17]3[CH:21]=[N:20][CH:19]=[N:18]3)[S:12][CH:13]=2)=[CH:5][CH:4]=1)#[N:2].[H-].[K+].Cl[C:35]([O:37][CH2:38][Cl:39])=[O:36]>C1COCC1.CCOC(C)=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([C@H:14]([CH3:31])[C@:15]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])([O:22][C:35]([O:37][CH2:38][Cl:39])=[O:36])[CH2:16][N:17]3[CH:21]=[N:20][CH:19]=[N:18]3)[S:12][CH:13]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: C[C@@H](c1nc(-c2ccc(C#N)cc2)cs1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: O=C(Cl)OCCl
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@@H](c1nc(-c2ccc(C#N)cc2)cs1)[C@@](Cn1cncn1)(OC(=O)OCCl)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 111.6 %

Procedure:
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (5.8 mmol) was added to a suspension of potassium hydride (7 mmol) in THF at 0° C. and was allowed to stir for 0.5 hours. Choromethyl chloroformate (5.8 mmol, in 2 mL THF) was added dropwise and the reaction was allowed to warm to room temperature and stirred for 4 hours. The crude reaction was diluted with EtOAc, and was sequentially washed with H2O, 0.1N HCl, H2O, and brine. The organic layer was dried over MgSO4 and was concentrated to afford 3.43 g of the subtitled product as a pale yellow solid. 1H NMR (DMSO) δ8.47 (s, 1H), 8.29 (s, 1H), 8.08 (s, 1H), 7.97 (d, 2H, J=8), 7.88 (d, 2H, J=8), 7.26-7.12 (m, 3H), 5.93 (d, 1H, J=6), 5.90 (d, 1H, J=6), 5.70 (d, J=1H, J=15), 5.36 (d, 1H, J=15), 4.02 (q, 1H, J=7), and 1.48 (d, 3H, J=7); MS (MH+=530).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][C:12]([F:17])=[CH:11][CH:10]=2)=[O:5])[CH3:2].C(N(C(C)C)CC)(C)C.[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([F:17])=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2ccc(F)cc2c1Cl
Reactant: [H][H]
Agent: [Pd]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOC(=O)c1cnc2ccc(F)cc2c1

Procedure:
A solution of 4-chloro-6-fluoro-quinoline-3-carboxylic acid ethyl ester (4.2 g, 16.6 mmol) and diisopropylethylamine (8.7 mL, 50 mmol) in ethanol (50 mL) was hydrogenated over 10% palladium on carbon (0.2 g) at 1 atmosphere of hydrogen for 1 day. Additional catalyst (0.3 g) was added and the hydrogenation was continued at 50 psi of hydrogen for 2 hours. The catalyst was removed by filtration. The solvent was evaporated in vacuo, and the residue was partitioned between water and dichloromethane. The organic layer was dried over sodium sulfate. The product was preabsorbed onto silica gel and purified by flash chromatography, using a gradient of ethyl acetate (0% to 30%) in heptanes as the eluant, to give the product as a yellow solid, 2.2 g (60%). MS: m/z 219.9 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:33]1([NH2:36])[CH2:35][CH2:34]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([NH:36][CH:33]3[CH2:35][CH2:34]3)=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Reactant: NC1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(Cn1c(-c2ccc(Cl)cc2)nc2cccnc21)NC1CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.5 %

Procedure:
Under nitrogen bubbling, a mixture of 2-(4chlorophenyl)-3H-imidazo [4,5-b]pyridine-3-acetic acid (4.0 g, 0.014 mole) and 1,1'-carbonyldiimidazole (2.27 g, 0.014 mole) in 150 ml of tetrahydrofuran was stirred at room temperature for 3 hours. Then, under nitrogen atmosphere, cyclopropylamine (2.40 g, 0.042 mole) was added and the reaction mixture was allowed to stir at room temperature overnight. The tetrahydrofuran was evaporated and the residue was recrystallized from isopropyl alcohol with refrigeration. The solid was collected by filtration, washed with cold isopropyl alcohol and water, and dried under high vacuum at 50° C. over the weekend to give 2.4 g (53%) of title compound, mp 231°-232° C.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[CH2:12]([O:14][C:15](=[O:29])[CH:16]([CH2:20][C:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:17](=O)[CH3:18])[CH3:13].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C.C(Cl)(Cl)Cl>[CH2:12]([O:14][C:15]([C:16]1[CH:20]=[C:21]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:6]([C:5]2[CH:7]=[CH:8][CH:9]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=2)[C:17]=1[CH3:18])=[O:29])[CH3:13]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)C(CC(=O)c1ccccc1)C(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cc(-c2ccccc2)n(-c2cccc(C(F)(F)F)c2)c1C

Procedure:
m-Trifluoromethylaniline (5 mmol, 0.8 g), 3-oxo-2-(2-oxo-2-phenyl-ethyl)-butyric acid ethyl ester (5 mmol, 1.2 g), and tosic acid (0.1 g) were combined in ethanol, then heated under reflux. The crude material was resuspended in chloroform and washed with water, then with brine. The organic layer was dried over NaSO4. The solids were separated and the solvents removed under vacuum. The resulting oil was purified over silica gel to yield the named product, 1H-NMR (CDCl3, ppm): 1.37 t (3H), 2.42 s (3H), 4.32 q (2H), 6.80 s (1H), 7.0-7.6 bm (9H).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH:13]([N:15]=[C:16]=[O:17])[CH3:14])[CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][N:19]([CH3:21])[NH2:20].C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH3:18][N:19]([CH3:21])[NH:20][C:16]([NH:15][CH:13]([C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=1)[CH3:14])=[O:17]
Reactant: CC(N=C=O)c1cccc(-c2ccccc2)c1
Reactant: CN(C)N
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(NC(=O)NN(C)C)c1cccc(-c2ccccc2)c1
Reaction time: 1.5 h
Yield: 78.8 %

Procedure:
To a solution of 2.29 g of 1-(3-phenylphenyl)ethylisocyanate in 8 ml of toluene was added dropwise 0.78 g (13 mmol) of N,N-dimethylhydrazine with ice-cooling. The mixture was removed from an ice bath and stirred for 1.5 hours. The reaction solution was concentrated, and the residue (2.89 g) was subjected to silica gel column chromatography (eluted with n-hexane:ethyl acetate=2:1and then 1:1 and then 1:2) to obtain 2.29 g (8.08 mmol) of 1,1-dimethyl-4-{1-(3-phenylphenyl)ethyl}semicarbazide as a viscous oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:16])[CH2:5][CH:6]1[CH2:15][CH2:14][C:9]2(OCC[O:10]2)[CH2:8][CH2:7]1>CC(C)=O>[CH3:2][O:3][C:4](=[O:16])[CH2:5][CH:6]1[CH2:15][CH2:14][C:9](=[O:10])[CH2:8][CH2:7]1
Reactant: COC(=O)CC1CCC2(CC1)OCCO2
Agent: Cl
Solvent: CC(C)=O
Product: COC(=O)CC1CCC(=O)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 108.5 %

Procedure:
A 1 N aqueous hydrochloric acid solution (50 mL)/acetone (200 ml) mixture of (1,4-dioxa-spiro[4.5]dec-8-yl)-acetic acid methyl ester (4.99 g) obtained in Example (1b) was stirred at room temperature for 15 hours. The organic solvent was removed using an evaporator. The remaining aqueous solution was subjected to two extractions with ethyl acetate. The organic layer was washed with saturated brine, then dried over sodium sulfate, and then concentrated to obtain the title compound (4.30 g, quantitative yield) as a colorless oil.
Reaction SMILES: [OH:1][C:2]1([C:15]([N:17]2[CH2:24][CH2:23][CH2:22][C@H:18]2[C:19](O)=[O:20])=[O:16])[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([N:34]2[CH:38]=[N:37][N:36]=[N:35]2)=[C:30]([CH2:32][NH2:33])[CH:31]=1>>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([N:34]2[CH:38]=[N:37][N:36]=[N:35]2)=[C:30]([CH:31]=1)[CH2:32][NH:33][C:19](=[O:20])[C@H:18]1[CH2:22][CH2:23][CH2:24][N:17]1[C:15]([C:2]1([OH:1])[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:16]
Reactant: NCc1cc(Cl)ccc1-n1cnnn1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)C1(O)c2ccccc2-c2ccccc21
Product: O=C(NCc1cc(Cl)ccc1-n1cnnn1)[C@H]1CCCN1C(=O)C1(O)c2ccccc2-c2ccccc21

Procedure:
Prepared by procedures similar to that described above in Example 8 from 9-hydroxy-9-fluorenylcarbonyl-L-proline and 1-[5-chloro-2-(1H-tetraazol-1-yl)phenyl]methanamine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([O:16]C)[CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH:18]([CH3:33])[C:19]([C:25]1[CH:26]=[CH:27][C:28](=[O:32])[N:29]([CH3:31])[CH:30]=1)([OH:24])[C:20]([F:23])([F:22])[F:21].B(Br)(Br)Br>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([OH:16])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH:18]([CH3:33])[C:19]([C:25]1[CH:26]=[CH:27][C:28](=[O:32])[N:29]([CH3:31])[CH:30]=1)([OH:24])[C:20]([F:23])([F:21])[F:22]
Reactant: COc1cc(Oc2ccc(C(C)C(O)(c3ccc(=O)n(C)c3)C(F)(F)F)c(Cl)c2)ccc1F
Agent: BrB(Br)Br
Product: CC(c1ccc(Oc2ccc(F)c(O)c2)cc1Cl)C(O)(c1ccc(=O)n(C)c1)C(F)(F)F

Procedure:
In analogy to Example 183, 5-{2-[2-chloro-4-(4-fluoro-3-methoxy-phenoxy)-phenyl]-1-hydroxy-1-trifluoromethyl-propyl}-1-methyl-1H-pyridin-2-one (Example 199) was reacted with BBr3 to give the title compound as an off-white solid. MS (m/e)=472.2 [M+H+].
Reaction SMILES: [SH:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[Br:10]Br>C(OCC)(=O)C>[Br:10][C:8]1[C:3]2=[N:4][CH:5]=[CH:6][CH:7]=[C:2]2[S:1][N:9]=1
Reactant: BrBr
Reactant: N#Cc1ncccc1S
Solvent: CCOC(C)=O
Product: Brc1nsc2cccnc12
Temperature: 25 °C

Procedure:
To a solution of 3-mercaptopicolinonitrile (1.05 g, 7.72 mmol) in ethyl acetate (30 mL), bromine (3.00 g, 18.90 mmol) was added dropwise at 0° C. The reaction mixture was allowed to warm to room temperature and then refluxed for 3 h. The reaction mixture was concentrated under reduced pressure. Trituration with hexanes:methylene chloride (1:1 mixture) gave 3-bromoisothiazolo[4,5-b]pyridine, as light brown solid which was carried forward without further purification. MW=215 confirmed by LC-MS, tr=15.89 min (Method Y) MH+=216.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4](C)[CH2:5][NH:6][C:7]([C:9]1[O:10][C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[CH:13]=1)=[O:8].C[O:20][C:21](=[O:48])[C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([CH3:29])[C:23]=1[N:30]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[S:31]([C:34]1[CH:39]=[CH:38][C:37](F)=[CH:36][CH:35]=1)(=[O:33])=[O:32].[Li+].[OH-]>CN(C=O)C.C1COCC1.O.CO>[O:10]1[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[CH:13]=[C:9]1[C:7]([NH:6][CH2:5][CH2:4][O:3][C:37]1[CH:38]=[CH:39][C:34]([S:31]([N:30]([C:23]2[C:24]([CH3:29])=[CH:25][C:26]([CH3:28])=[CH:27][C:22]=2[C:21]([OH:48])=[O:20])[CH2:41][C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)(=[O:32])=[O:33])=[CH:35][CH:36]=1)=[O:8]
Reactant: COC(=O)c1cc(C)cc(C)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(F)cc1
Reactant: CC(O)CNC(=O)c1cc2ccccc2o1
Agent: [H-]
Agent: [Li+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C)c(N(Cc2ccccc2)S(=O)(=O)c2ccc(OCCNC(=O)c3cc4ccccc4o3)cc2)c(C(=O)O)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 15.4 %

Procedure:
Sodium hydride (0.240 g, 5.99 mmol, 60% dispersion in mineral oil) was added to DMF (8 ml) and cooled to 0° C. A solution of N-(2-hydroxypropyl)-1-benzofuran-2-carboxamide (0.6 g, 2.92 mmol) in DMF (1.5 ml) was added and allowed to stir for 10 min at 0° C. and then for 15 min at rt. The product of Example 29 (0.383 g, 0.87 mmol) was then added in one portion and the reaction was allowed to stir overnight. The reaction was then quenched with water, extracted with EtOAc, washed with water, brine, dried over MgSO4, and concentrated in vacuo to provide an oil which was chromatographed using hexane to 2/1 hexane/EtOAc as eluant to provide the product as a mixture of esters which was used directly in the next reaction. The mixture of esters (233 mg) was dissolved in THF:MeOH:H2O (1.2 mL:0.7 mL:1.2 mL) and LiOH (13.7 mg, 0.32 mmol) was added. The reaction was heated at reflux overnight. The reaction was cooled to rt, quenched with 6M HCl and extracted with CH2Cl2. The organics were washed with brine, dried over Na2SO4, concentrated in vacuo to provide an oil which was chromatographed using hexane to 9/1 CH2Cl2/MeOH as eluant to provide 80 mg (44% yield) of the product acid. Electrospray Mass Spec: m/z 597.2 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][OH:13])=[CH:8][CH:7]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][O:13][C:15](=[O:17])[CH3:16])=[CH:8][CH:7]=1
Reactant: COC(=O)COc1ccc(CO)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COC(=O)COc1ccc(COC(C)=O)cc1
Temperature: 0 °C
Yield: 61.7 %

Procedure:
A solution of (4-hydroxymethyl-phenoxy)-acetic acid methyl ester 69 (100 grams, 509 mmol), acetic anhydride (250 mL) and pyridine (20 mL) was refluxed for 4 hours. Reaction mixture was poured in to ice water (1000 mL) and crude 70 was extracted into chloroform, dried over Na2SO4, and distilled. The crude was vacuum distilled to give pure 70 (75 grams, 61.7%) as a light yellow syrup, Bp15 206-210° C. The structure was confirmed with NMR. IHNMR (CDCl3) δ 2.05 (s, 3H,O═C—CH3), 3.78(s, 3H,ester), 4.62(s, 2H,OCH2), 5.02 (s, 2H, CH2), 6.88 (d,2H,Ar), 7.33 (d, 2H,Ar).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:29])[CH2:9][NH:10][CH:11]([CH3:28])[CH2:12][C:13]2[CH:27]=[CH:26][C:16]3[O:17][C:18]([C:23]([OH:25])=[O:24])([C:20]([OH:22])=[O:21])[O:19][C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:30][C:31]1([CH2:34]O)[CH2:33][CH2:32]1.Cl.[K+].[Br-]>C(Cl)(Cl)Cl>[CH3:30][C:31]1([CH2:34][O:24][C:23]([C:18]2([C:20]([O:22][CH2:30][C:31]3([CH3:34])[CH2:33][CH2:32]3)=[O:21])[O:17][C:16]3[CH:26]=[CH:27][C:13]([CH2:12][CH:11]([NH:10][CH2:9][CH:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[OH:29])[CH3:28])=[CH:14][C:15]=3[O:19]2)=[O:25])[CH2:33][CH2:32]1
Reactant: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)O)O2)NCC(O)c1cccc(Cl)c1
Reactant: CC1(CO)CC1
Agent: Cl
Agent: [Br-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CC(Cc1ccc2c(c1)OC(C(=O)OCC1(C)CC1)(C(=O)OCC1(C)CC1)O2)NCC(O)c1cccc(Cl)c1

Procedure:
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid and 1-methylcyclopropyl-methanol according to the procedure of Example 30 as a white solid (HCl salt); 1H NMR (CDCl3) δ 0.39 (m, 4H), 0.52 (m, 4H), 1.10, (s, 6H), 1.32 (d, J=6.5 Hz, 3H), 2.80 (m, 1H), 3.19 (m, 2H), 3.48 (m, 2H), 4.10 (s, 4H), 5.50 (bd, 1H), 5.70 (bs, 1H), 6.80 (m, 3H), 7.25 (m, 2H), 7.45 (s, 1H), 8.70 (bs, 1H), 10.10 (bs, 1H); IR (KBr): 1763 cm-1 (C=O); MS (ES) m/z 558 (MH+); [α]D25 -25° (c, 1.0, CHCl3). Anal. Calcd. for C30H36ClNO7 ·HCl: C, 60.61; H, 6.10; N, 2.36; Cl, 11.94. Found: C, 60.02; H, 6.58; N, 2.17; Cl, 11.20.
Reaction SMILES: O=[C:2]([CH3:14])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1.BrBr.[Cl:17][C:18]1[N:23]=[C:22]([NH:24][C:25]([NH2:27])=[S:26])[CH:21]=[N:20][CH:19]=1.[Br-]>O1CCOCC1.C(O)C>[Cl:17][C:18]1[N:23]=[C:22]([NH:24][C:25]2[S:26][C:3]([C:4]3[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=3)=[C:2]([CH3:14])[N:27]=2)[CH:21]=[N:20][CH:19]=1
Reactant: CC(=O)Cc1ccc(S(N)(=O)=O)cc1
Reactant: NC(=S)Nc1cncc(Cl)n1
Agent: BrBr
Agent: [Br-]
Solvent: CCO
Solvent: C1COCCO1
Product: Cc1nc(Nc2cncc(Cl)n2)sc1-c1ccc(S(N)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 88.2 %

Procedure:
4-(2-Oxo-propyl)-benzenesulfonamide (prepared as described in European patent specification EP 91749 A2) (0.63 g, 2.9 mmol) is dissolved in dry dioxan (70 ml) at 0° C. and bromine (0.121 ml, 2.4 mmol) is added dropwise. The mixture is stirred for 45 minutes at room temperature then the solvent is removed in vacuo. 6-Chloro-pyrazin-2-yl-thiourea (0.35 g, 1.87 mmol) is added to a solution of the above bromide (0.546 g, 1.87 mmol) in ethanol and the solution is heated at 60° C. for 4 hours. The reaction mixture is allowed to cool and the solvent removed under vacuum to give the title compound (0.63 g). MH+ (ES+): 382.1, 384.2 (3:1)
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7].C(=O)([O-])[O-].[K+].[K+].[Br:22][CH2:23][C:24](Br)=[O:25].C(OCC)(=O)C>ClCCl.O>[Br:22][CH2:23][C:24]([N:1]1[CH2:5][CH2:4][CH2:3][C:2]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:25]
Reactant: CCOC(=O)C1(C(=O)OCC)CCCN1
Reactant: O=C(Br)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C1(C(=O)OCC)CCCN1C(=O)CBr
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of diethyl 2,2-pyrrolidinedicarboxylate (D63, 900 mg) in dichloromethane (9 mL) at 0° C., potassium carbonate (0.5M solution, 12.5 mL) and bromoacetyl bromide (0.55 mL) were added. The resulting mixture was stirred at 0° C. for 2 hours. The mixture was then diluted with water and then allowed to reach r.t. Ethyl acetate (15 mL) was added and phases were separated. The aqueous phase was then extracted with ethyl acetate (2×10 mL) and washed with brine (20 mL). The organic phase was dried and concentrated in vacuo to give the desired compound (1.06 g) as orange oil.