Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH:11]1[CH2:15][CH2:14][CH2:13][O:12]1)[NH2:5].[S-:16][C:17]#[N:18].[NH4+].BrBr.N>C(O)(=O)C>[Br:1][C:2]1[C:8]([O:9][CH2:10][CH:11]2[CH2:15][CH2:14][CH2:13][O:12]2)=[CH:7][C:6]2[S:16][C:17]([NH2:18])=[N:5][C:4]=2[CH:3]=1
Reactant: Nc1ccc(OCC2CCCO2)c(Br)c1
Reactant: N#C[S-]
Agent: BrBr
Agent: N
Agent: [NH4+]
Solvent: CC(=O)O
Product: Nc1nc2cc(Br)c(OCC3CCCO3)cc2s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 26.1 %

Procedure:
To a solution of ii (3.0 g, 11.62 mmol) in acetic acid (50 mL) was added ammonium thiocynate (4.18 g, 55.11 mmol) at RT. The resulting mixture was stirred at RT for 15 min followed by the addition of bromine (0.68 mL, 13.22 mmol) in acetic acid (5 mL). The mixture was stirred at RT for 5 h. The pH was adjusted to >7 with ammonia solution followed by extraction with EtOAc (2×200 mL). The combined organics were washed with H2O, brine solution, dried (Na2SO4) and concentrated in vacuo. The residue was purified over silica (60% EtOAc-Hexanes) to obtain iii (1.0 g, 26%). 1HNMR (DMSO-d6, 400 MHz): δ 7.50 (s, 1H), 7.49 (s, 1H), 7.43 (br s, 2H), 4.18 (m, 1H), 3.96 (m, 2H), 3.80 (m, 1H), 3.69 (m, 1H), 1.96 (m, 2H) and 1.78 (m, 2H). MS: 329.0 [M+H]+.
Reaction SMILES: [Cl:1][CH2:2][C:3]([OH:5])=O.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:48][N:49]([CH3:53])[CH2:50][CH2:51][NH2:52]>C(Cl)Cl>[Cl:1][CH2:2][C:3]([NH:52][CH2:51][CH2:50][N:49]([CH3:53])[CH3:48])=[O:5]
Reactant: CN(C)CCN
Reactant: O=C(O)CCl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCNC(=O)CCl
Temperature: 25 °C
Reaction time: 0.21 h

Procedure:
A suspension of 2-chloroacetic acid (214 mg, 2.27 mmol), PyBOP® (1.18, 2.27 mmol), DIEA (1.18 mL, 6.81 mmol) in CH2Cl2 (1 mL) was stirred at RT for 10-15 minutes. This solution of activated acid was added to a suspension of N1,N1-dimethylethane-1,2-diamine (249 μL, 2.27 mmol) and CH2Cl2 (4 mL). The reaction mixture was stirred at RT for 1.5 h. Diluted with more CH2Cl2 and extracted with H2O (3×). Organic layer was dried under Na2SO4 and concentrated in vacuo to give the desired product 2-chloro-N-(2-(dimethylamino)ethyl)acetamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[C:18]([F:19])=[CH:17][CH:16]=[C:15]([F:20])[C:11]=2[C:12]([OH:14])=[O:13])=O)=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22].ClCCl.N1C(F)=NC(F)=NC=1[F:29]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([F:29])[C:10]3[C:18]([F:19])=[CH:17][CH:16]=[C:15]([F:20])[C:11]=3[C:12](=[O:14])[O:13]2)=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22]
Reactant: Fc1nc(F)nc(F)n1
Reactant: O=C(O)c1c(F)ccc(F)c1C(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: O
Product: O=C1OC(F)(c2ccc(Cl)c([N+](=O)[O-])c2)c2c(F)ccc(F)c21
Temperature: 0 °C
Reaction time: 2 h
Yield: 76.3 %

Procedure:
To a solution of 2-[(4-chloro-3-nitrophenyl)carbonyl]-3,6-difluorobenzoic acid (7.0 g, 22.00 mmol) at 0° C. in anhydrous dichloromethane (40 mL) pyridine (1.70 ml, 22.00 mmol) was added, followed by the addition of cyanuric fluoride (1.90 ml, 24.20 mmol). The reaction mixture was stirred for 120 minutes at 0° C. Water (35 mL) was added to the reaction mixture and it was stirred for 10 min at 0° C. The resulting slurry was filtered through a pad of Celite and washed with dichloromethane. The filtrate was partitioned with water and the organic layer was washed with water. It was dried over anhydrous sodium sulfate. Filtration and concentration gave a crystalline product. It was collected by filtration and dried in vacuo, to give 3-(4-chloro-3-nitrophenyl)-3,4,7-trifluoro-2-benzofuran-1(3H)-one (5.77 g, 82% yield). MS (EI) for C14H5ClF3NO4: 342 (M−).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[C:7]2[C:8](=[O:17])[CH:9]=[CH:10][CH:11]=[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:6]23[CH2:5][CH:4]=1.CO.[BH4-].[Na+]>O.[OH-].[Na+]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:16]=[CH:15][C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[CH:8]([OH:17])[C:7]=2[CH:18]=1
Reactant: COC1=CCC23C=CC=CC2=CC=CC(=O)C3=C1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc2c(c1)C(O)c1ccccc1C=C2

Procedure:
The 3-methoxy-5H-dibenzo[a,b]cyclohepten-5-one intermediate (6.4 grams, 0.027 mole) was dissolved 140 milliliters of methanol and added to and caused to react with a solution of 2.57 grams (0.0678 mole) of sodium borohydride in 29 milliliters of water and 0.1 milliliter of 10N sodium hydroxide at reflux temperature to obtain 3-methoxy-5H-dibenzo[a,d]cyclohepten-5-ol intermediate which was recovered by vaporizing some of the methanol in vacuo and chilling to obtain a solid which after filtering and drying amounted to 5.3 grams.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12](=[O:17])[N:11]([CH3:18])[C:10]=3[N:9]=[C:8]2[S:19]([NH:22][CH:23]([CH3:25])[CH3:24])(=[O:21])=[O:20])=[CH:4][CH:3]=1.Br[CH2:29][CH2:30][CH2:31][O:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][O:34]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:29][CH2:30][CH2:31][O:32][CH:33]4[CH2:38][CH2:37][CH2:36][CH2:35][O:34]4)[C:12](=[O:17])[N:11]([CH3:18])[C:10]=3[N:9]=[C:8]2[S:19]([NH:22][CH:23]([CH3:24])[CH3:25])(=[O:21])=[O:20])=[CH:26][CH:27]=1
Reactant: CC(C)NS(=O)(=O)c1nc2c(c(=O)[nH]c(=O)n2C)n1Cc1ccc(Cl)cc1
Reactant: BrCCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)NS(=O)(=O)c1nc2c(c(=O)n(CCCOC3CCCCO3)c(=O)n2C)n1Cc1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
To a solution of 7-(4-chlorobenzyl)-N-isopropyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-sulfonamide (59 mg, 0.143 mmol) in DMF (3 mL) was added 2-(3-bromopropoxy)tetrahydro-2H-pyran (32 mg, 0.143 mmol) followed by potassium carbonate (30 mg, 0.214 mmol) and the mixture was stirred at 60° C. for 4 h. The reaction was diluted with ethyl acetate and washed with brine and saturated aqueous ammonium chloride. The organic phase was dried and concentrated to give 7-(4-chlorobenzyl)-N-isopropyl-3-methyl-2,6-dioxo-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-2,3,6,7-tetrahydro-1H-purine-8-sulfonamide (61 mg, 77% yield) as yellow solid. LCMS retention time 1.805 min; LCMS MH+-THP 470.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]([O:23][C:24]([F:43])([F:42])[C:25]([F:41])([F:40])[O:26][C:27]([F:39])([F:38])[C:28]([F:37])([F:36])[C:29]([F:35])([F:34])[C:30]([F:33])([F:32])[F:31])([F:22])[F:21])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.Br[CH2:45][CH2:46][O:47][CH2:48][CH2:49][O:50][CH2:51][CH2:52][CH2:53][CH3:54]>>[CH2:51]([O:50][CH2:49][CH2:48][O:47][CH2:46][CH2:45][O:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]([O:23][C:24]([F:43])([F:42])[C:25]([F:40])([F:41])[O:26][C:27]([F:38])([F:39])[C:28]([F:36])([F:37])[C:29]([F:34])([F:35])[C:30]([F:31])([F:32])[F:33])([F:22])[F:21])=[CH:12][CH:13]=2)=[N:4][CH:3]=1)[CH2:52][CH2:53][CH3:54]
Reactant: CCCCOCCOCCBr
Reactant: Oc1cnc(-c2ccc(OCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2)nc1
Product: CCCCOCCOCCOc1cnc(-c2ccc(OCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2)nc1

Procedure:
The title compound was prepared essentially as in Example 1 by combining 5-hydroxy-2-[4-(3-(2-(2-(nonafluorobutoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)propoxy)phenyl]pyrimidine (1.22 g, 1.85 mmol, Example 10) and 1-bromo-2-(2-butoxyethoxy) ethane (0.81 g, 3.62 mmol). The resulting crude product was isolated and further purified essentially as described in Example 3, eluting with 30 volume percent ethyl acetate/hexane, to yield 1.13 g of purified product.
Reaction SMILES: [Br:1][C:2]1[C:11]([F:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH:6]([CH3:13])[NH:7]2.[OH-].[Na+].[C:16](OC(=O)C)(=[O:18])[CH3:17]>S(=O)(=O)(O)O>[C:16]([N:7]1[C:8]2[C:3](=[C:2]([Br:1])[C:11]([F:12])=[CH:10][CH:9]=2)[CH2:4][CH2:5][CH:6]1[CH3:13])(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: CC1CCc2c(ccc(F)c2Br)N1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)N1c2ccc(F)c(Br)c2CCC1C
Temperature: 20 °C

Procedure:
To 6.0 g of 5-bromo-6-fluoro-1,2,3,4-tetrahydroquinaldine was added 50 ml of acetic anhydride and one drop of concentrated sulfuric acid. The solution was heated on a steam bath for two hours, then cooled to about 20° C. The solution was basified with 10% sodium hydroxide solution. The solution was extracted with chloroform, and the chloroform extracts were evaporated to provide an oil which was distilled in vacuo to provide N-acetyl-5-bromo-6-fluoro-1,2,3,4-tetrahydroquinaldine. The structural assignment was supported by nuclear magnetic resonance spectral analysis.
Reaction SMILES: [CH:1]1([NH:8][C:9]2[N:19]=[CH:18][CH:17]=[CH:16][C:10]=2[C:11]([O:13][CH2:14]C)=[O:12])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(C(CC)CNC1N=CC=CC=1C(OCC)=[O:28])C>>[CH:1]1([N:8]2[C:9]3[N:19]=[CH:18][CH:17]=[CH:16][C:10]=3[C:11](=[O:12])[O:13][C:14]2=[O:28])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cccnc1NCC(CC)CC
Reactant: CCOC(=O)c1cccnc1NC1CCCCCC1
Product: O=c1oc(=O)n(C2CCCCCC2)c2ncccc12

Procedure:
The title compound was prepared according to the procedure of Example 3B substituting the product of Example 71A for the product of Example 3A (0.205 g, 55%). MS (ESI+) m/z 249.1 (M+H)+; 1H NMR (300 MHz, CDCl3) δ 1.63 (m, 6H), 1.84 (m, 4H), 2.43 (m, 2H), 5.39 (s, 1H), 7.24 (dd, J=7.72, 4.78 Hz, 1H), 8.40 (m, 1H), 8.71 (dd, J=4.78, 1.84 Hz, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[F:11][C:12]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:13]=1[NH2:14].C(O)(=O)C>O>[F:11][C:12]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:13]=1[NH:14][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: Nc1ccc(F)cc1F
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cccnc1Nc1ccc(F)cc1F
Temperature: 110 °C
Reaction time: 1 h

Procedure:
A mixture of (7.9 g., 0.05 mole) 2-chloro-3-nitropyridine and 12.9 g. (0.10 mole) of 2,4-difluoroaniline was purged with nitrogen and heated in an oil bath to 110° C. when the temperature rose spontaneously to 135° C. Heating was continued to 145° C. when a second spontaneous temperature rise occurred requiring temperature control with ice. The maximum internal temperature was 185° C. After slight cooling, 40 ml. of acetic acid and 60 ml. of water was added. After stirring one hour the crystalline precipitate was collected (11.1 g., m.p. 110° C.) and recrystallized from hexane to give 2-(2,4-difluoroanilino)-3-nitropyridine, m.p. 112°-114° C.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3]([O-:6])(=[O:5])=[O:4].[F:9][C:10]1[CH:15]=[C:14]([C:16]([O:18]C)=[O:17])[CH:13]=[CH:12][C:11]=1[N+:20]([CH3:23])([CH3:22])[CH3:21].FC(F)(F)C(O)=O>O>[F:1][C:2]([F:8])([F:7])[S:3]([O-:6])(=[O:5])=[O:4].[C:16]([C:14]1[CH:13]=[CH:12][C:11]([N+:20]([CH3:22])([CH3:21])[CH3:23])=[C:10]([F:9])[CH:15]=1)([OH:18])=[O:17]
Reactant: COC(=O)c1ccc([N+](C)(C)C)c(F)c1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: C[N+](C)(C)c1ccc(C(=O)O)cc1F

Procedure:
A solution of 4.00 g (11.1 mmol) 10, 96 ml dest. water and 96 ml trifluoroacetic acid was refluxed for 2 days. The reaction mixture was evaporated, dried by use of oil pump vacuum over night and treated with diethyl ether. The resulting solid was filtered, washed extensively with diethyl ether and dried by oil pump vacuum. The solid crude product 11 was obtained in 92% yield (3.54 g, 10.2 mmol) and crude compound 11 was used for the next step without purification.
Reaction SMILES: I[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1.C([Sn](CCCC)(CCCC)[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=1[N+:25]([O-:27])=[O:26])CCC.O1CCCC1>CN1CCCC1=O.S1C=CC=C1C([O-])=O.[Cu+]>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([CH:2]=[CH:3][C:4]2[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=2)=[C:18]([N+:25]([O-:27])=[O:26])[CH:19]=1
Reactant: COc1ccc(C=CI)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(OC)cc1[N+](=O)[O-]
Agent: [Cu+]
Agent: O=C([O-])c1cccs1
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: COc1ccc(C=Cc2ccc(OC)cc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 72.8 %

Procedure:
By referring to the synthetic method of J. Org. Chem., 1997, 62, 199, to a solution of lithium acetate (280 mg) in water (3 ml) was added acetonitrile (90 ml), the solution was stirred at room temperature, then 4-methoxycinnamic acid (7.5 g), N-iodosuccinimide (10 g) were sequentially added thereto, the solution was stirred for 2 hours at room temperature, and then neutralized with a saturated aqueous solution of sodium bicarbonate. The solution was extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide 1-(2-iodovinyl)-4-methoxybenzene (8.0 g). By referring to the synthetic method of J. Am. Chem. Soc., 1996, 118, 2748, to a solution of 1-(2-iodovinyl)-4-methoxybenzene (7.1 g) and tributyl(4-methoxy-2-nitrophenyl)tin (10 g) in 1-methyl-2-pyrrolidone (100 ml) was added copper(I) thiophene-2-carboxylate (6.6 g) on an ice bath under a nitrogen atmosphere, and the solution was stirred for 25 minutes at room temperature. Tetrahydrofuran was added thereto, the solution was stirred, then filtered through alumina, extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (4.7 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9]Br)[C:5]([Cl:8])=[N:6][CH:7]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:21])[CH3:20])=[C:14]([CH:22]=[CH2:23])[CH:13]=1.ClC1C(CN(C2C=CC=CC=2C=C)C(=O)C)=CC(F)=C(Cl)N=1>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][N:18]([C:15]2[CH:16]=[CH:17][C:12]([Cl:11])=[CH:13][C:14]=2[CH:22]=[CH2:23])[C:19](=[O:21])[CH3:20])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: C=Cc1cc(Cl)ccc1NC(C)=O
Reactant: Clc1ncc(Br)cc1CBr
Agent: C=Cc1ccccc1N(Cc1cc(F)c(Cl)nc1Cl)C(C)=O
Product: C=Cc1cc(Cl)ccc1N(Cc1cc(Br)cnc1Cl)C(C)=O
Yield: 93.1 %

Procedure:
Compound 76C (0.19 g, 94%) was prepared from 76B (0.145 g, 0.51 mmol) and 9B (0.1 mg, 0.51 mmol) using a procedure similar to the synthesis of 1C.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Mg]Br.[C:13]1([CH3:21])[CH:18]=[CH:17][C:16]([CH:19]=[O:20])=[CH:15][CH:14]=1.FC(F)(F)C1C=C(Cl)C=CC=1C(O)C1C=CC=CC=1>>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:19]([OH:20])[C:16]1[CH:17]=[CH:18][C:13]([CH3:21])=[CH:14][CH:15]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: FC(F)(F)c1ccccc1[Mg]Br
Agent: OC(c1ccccc1)c1ccc(Cl)cc1C(F)(F)F
Product: Cc1ccc(C(O)c2ccccc2C(F)(F)F)cc1

Procedure:
This material was prepared from 2-(trifluoromethyl)phenylmagnesium bromide (16 mmol) and p-tolualdehyde (1.82 mL, 15 mmol) using the procedure described for compound (96) (4.28 g, 100%).
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([C:19]2[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=2[F:26])[O:7][C:8]=1[NH:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=1)(=[O:3])[NH2:2].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[NH:60]1[CH2:66][CH2:65][CH2:64][C@@H:61]1[CH2:62][OH:63]>CN(C=O)C>[F:26][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]([F:25])[C:19]=1[C:6]1[O:7][C:8]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([C:14]([N:60]3[CH2:66][CH2:65][CH2:64][C@@H:61]3[CH2:62][OH:63])=[O:15])=[CH:17][CH:18]=2)=[C:4]([C:1]([NH2:2])=[O:3])[N:5]=1
Reactant: OC[C@H]1CCCN1
Reactant: NC(=O)c1nc(-c2c(F)cccc2F)oc1Nc1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[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: NC(=O)c1nc(-c2c(F)cccc2F)oc1Nc1ccc(C(=O)N2CCC[C@@H]2CO)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 36 %

Procedure:
To a solution of 4-(4-carbamoyl-2-(2,6-difluorophenyl)oxazol-5-ylamino)benzoic acid (0.040 g, 0.111 mmol), O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.042 g, 0.111 mmol), and diisopropylethylamine (0.038 mL, 0.222 mmol) in DMF (0.35 mL) was added D-prolinol (0.011 mL, 0.111 mmol) and the reaction mixture stirred at room temperature for 6 hours. The reaction was reduced in vacuo. The residue was purified by preparative HPLC to afford the white solid (R)-2-(2,6-difluorophenyl)-5-(4-(2-(hydroxymethyl)pyrrolidine-1-carbonyl)phenylamino)oxazole-4-carboxamide (0.018 g, 0.040 mmol, 36%). 1H NMR (DMSO) δ 1.68 (1H, m), 1.90 (3H, m), 3.61-3.32 (4H, m), 4.13 (1H, br s), 4.75 (1H, t), 7.50-7.31 (8H, m), 7.64 (1H, m), 9.50 (1H, br s). LCMS (2) Rt: 2.10 min; m/z (ES+) 443.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:15]=[CH:16][C:17]2[O:22][CH2:21][CH2:20][CH:19]([C:23]([O:25][CH3:26])=[O:24])[C:18]=2[CH:27]=1.C1C[O:31][CH2:30]C1>CCCCCC>[F:13][C:14]1[CH:15]=[CH:16][C:17]2[O:22][CH2:21][CH2:20][C:19]([CH2:30][OH:31])([C:23]([O:25][CH3:26])=[O:24])[C:18]=2[CH:27]=1
Reactant: COC(=O)C1CCOc2ccc(F)cc21
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: COC(=O)C1(CO)CCOc2ccc(F)cc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 5 mL (0.035 mole) of diisopropylamine in 100 mL of THF was cooled to 0° C. and 22.1 mL (0.35 mole) of 1.6M butyllithium in hexane was added dropwise. After stirring for 30 minutes at 0° C. the resulting solution was cooled to -78° C. A solution of 6.2 g (0.0295 mole) of Methyl 6-fluoro-2,3-dihydro-4H-benzopyran-4-carboxylate in 20 mL of THF was then added dropwise while maintaining the temperature below -66° C. The resulting solution was stirred at -78° C. for 3 hours. Gaseous formaldehyde was then bubbled into the solution for 5 minutes. The reaction was allowed to warm to room temperature, then diluted with water and extracted with EtOAc. The EtOAc layer was dried over Na2SO4, filtered and evaporated to give 7.6 g of crude product as an oil. NMR (CDCl3) ppm (delta): 2.20-2.60 (m, 2H), 3.8 (s, 3H), 4.26 (t, 2H, J=5 Hz), 4.90 (m, 2H), 6.80-7.20 (m, 3H).
Reaction SMILES: I[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)=[N:4][N:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[CH:6]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:31][C:32]1[C:37](B(O)O)=[CH:36][CH:35]=[CH:34][N:33]=1>O1CCOCC1.O.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>[F:31][C:32]1[CH:37]=[C:36]([C:2]2[C:3]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=3)=[N:4][N:5]([CH2:7][C:8]3[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=3)[CH:6]=2)[CH:35]=[CH:34][N:33]=1
Reactant: OB(O)c1cccnc1F
Reactant: COc1ccc(Cn2cc(I)c(-c3cccc([N+](=O)[O-])c3)n2)cc1
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(Cn2cc(-c3ccnc(F)c3)c(-c3cccc([N+](=O)[O-])c3)n2)cc1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
1 g (2.3 mmol) of 4-iodo-1-(4-methoxybenzyl)-3-(3-nitrophenyl)-1H-pyrazole (prepared as described in Example 27) were dissolved in a mixture of 20 ml of dioxane and 5 ml of water in a nitrogen atmosphere. 750 mg (2.3 mmol) of cesium carbonate, 350 mg (0.3 mmol) of palladium tetrakis and 486 mg (3.45 mmol) of 2-fluoro-pyridyl boronic acid were added and the reaction stirred at 100° C. for 4 hours. The mixture was then filtered through a celite pad and the filtrate evaporated under reduced pressure. The residue was re-dissolved with dichloromethane and washed with water. The organic layer was dried over sodium sulphate and evaporated. 680 mg (73%) of the title compound crystallized from diethylether.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([OH:14])[CH2:9][CH2:10][CH2:11][C:12]#[CH:13].C1(NC2CCCCC2)CCCCC1.C(#N)C>[Cu]I.CCOCC>[N:3]1[CH:4]=[CH:5][CH:6]=[N:7][C:2]=1[C:13]#[C:12][CH2:11][CH2:10][CH2:9][CH2:8][OH:14]
Reactant: C#CCCCCO
Reactant: Brc1ncccn1
Agent: [Cu]I
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: CC#N
Solvent: CCOCC
Product: OCCCCC#Cc1ncccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.1 %

Procedure:
A mixture of 2-bromopyrimidine (3.96 g), 5-hexynol (2.44 g), dicylohexylamine (4 g), BTPC (250 mg), copper (I) iodide (25 mg) and acetonitrile (40 ml) was stirred at ambient temperature under nitrogen for 1 h (temp. rose to ~45°). Ether (120 ml) was added, the mixture was filtered and the filtrate was evaporated in vacuo to an oil which was purified by FCC. Elution with ether followed by System C (17:3) gave the title compound as a pale yellow oil (3.64 g), t.l.c. (System C 17:3) Rf 0.34.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([O:7][C:8]2[C:9]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:10][C:11]([C:18]([OH:20])=O)=[CH:12][C:13]=2[S:14]([NH2:17])(=[O:16])=[O:15])=[CH:5][CH:6]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH2:40]([NH:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>CN(C=O)C>[CH2:48]([N:47]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:18](=[O:20])[C:11]1[CH:10]=[C:9]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[C:8]([O:7][C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)=[C:13]([S:14]([NH2:17])(=[O:16])=[O:15])[CH:12]=1)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc(N2CCCC2)c1Oc1ccccc1
Reactant: c1ccc(CNCc2ccccc2)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1cc(C(=O)N(Cc2ccccc2)Cc2ccccc2)cc(N2CCCC2)c1Oc1ccccc1

Procedure:
In a similar manner to Example 8, piretanide can be reacted with EDC, HOBt and dibenzylamine in DMF to yield N,N-dibenzyl 3-aminosulfonyl-4-phenoxy-5-(1-pyrrolidinyl) benzamide.
Reaction SMILES: CP(C)C.O.[N:6]([CH2:9][C:10]1[C:11]([F:27])=[C:12]([O:17][C:18]2[CH:19]=[C:20]([CH:23]=[C:24]([Cl:26])[CH:25]=2)[C:21]#[N:22])[C:13]([Br:16])=[CH:14][CH:15]=1)=[N+]=[N-]>C1COCC1>[NH2:6][CH2:9][C:10]1[C:11]([F:27])=[C:12]([O:17][C:18]2[CH:19]=[C:20]([CH:23]=[C:24]([Cl:26])[CH:25]=2)[C:21]#[N:22])[C:13]([Br:16])=[CH:14][CH:15]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Br)ccc(CN=[N+]=[N-])c2F)c1
Agent: CP(C)C
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cc(Cl)cc(Oc2c(Br)ccc(CN)c2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.7 %

Procedure:
Trimethylphosphine (1M in THF) (6.41 mL, 6.41 mmol) and water (0.384 mL, 21.36 mmol) were added to a solution of 3-{[3-(azidomethyl)-6-bromo-2-fluorophenyl]oxy}-5-chlorobenzonitrile (1.630 g, 4.27 mmol) in THF (30 mL) at RT. The mixture was stirred at RT overnight. The solvent was evaporated. The residue was purified by chromatography with dichloromethane:methanol to give the title compound (1.21 g, 79%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.80 (s, 1H), 7.60 (dd, 1H), 7.43-7.51 (m, 2H), 7.41 (t, 1H), 3.75 (s, 2H), 1.92 (br. s., 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:8]1[CH:12]=[CH:11][CH:10]=[C:9]1B(O)O>>[C:2]1([C:9]2[O:8][CH:12]=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccccc1
Reactant: OB(O)c1ccco1
Product: c1ccc(-c2ccco2)cc1

Procedure:
Bromobenzene (1.5 g, 9.55 mmol) was coupled to 2-furylboronic acid (1.75 g, 15.6 mmol) using Method E. The crude compound was purified by column chromatography using a stepped gradient of 5-10% EtOAc in heptane to give the title compound.