Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:6]([Br:7])=[CH:5][S:4][CH:3]=1.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>C(O)C.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>[Br:7][C:6]1[C:2]([C:13]2[CH:14]=[CH:15][C:10]([O:9][CH3:8])=[CH:11][CH:12]=2)=[CH:3][S:4][CH:5]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Brc1cscc1Br
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: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(-c2cscc2Br)cc1
Temperature: 75 °C
Reaction time: 13 h
Yield: 30.5 %

Procedure:
To a mixture of 3,4-dibromothiophene (Scheme I, 1) (5 g, 20.7 mmol), 4-methoxyphenylboronic acid (Scheme I, 2, X1=4-methoxyphenyl) (3.14 g, 20.7 mmol), sodium carbonate (4.38 g, 41.3 mmol), toluene (100 mL), in a mixture of ethanol (60 mL) and water (40 mL) was added Pd(PPh3)4 (2.02 g, 1.75 mmol) under nitrogen. The mixture was stirred at 75° C. for 13 h, poured into water (60 mL), and extracted with ethyl acetate (60 mL×3). The organic extracts were dried over anhydrous magnesium sulfate (10 g), evaporated, and purified by column chromatography on silica gel (petroleum ether/ethyl acetate=150:1) to give 3-bromo-4-(4-methoxyphenyl)thiophene (Scheme I, 2, X1=4-methoxyphenyl) (1.7 g, yield 30.6%). 1H NMR (DMSO-d6 400 MHz): δ 7.84 (d, J=3.2 Hz, 1H), 7.64 (d, J=3.2 Hz, 1H), 7.42 (d, J=8.8 Hz, 2H), 6.97 (d, J=8.8 Hz, 2H), 3.78 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][C:14](=[O:16])[CH3:15])[CH2:10][C@@H:9]1[C:17](=S)[NH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:28]([NH:31][NH2:32])(=O)[CH3:29]>C(#N)C.C([O-])(=O)C.[Hg+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][C:14](=[O:16])[CH3:15])[CH2:10][C@@H:9]1[C:17]1[N:18]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[C:28]([CH3:29])=[N:31][N:32]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1C[C@H](C(=S)NCc2ccc(Cl)cc2)N(C(=O)OC(C)(C)C)C1
Reactant: CC(=O)NN
Agent: CC(=O)[O-]
Agent: [Hg+2]
Solvent: CC#N
Product: CC(=O)O[C@@H]1C[C@H](c2nnc(C)n2Cc2ccc(Cl)cc2)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of (2R,4R)-tert-butyl-2-((4-chlorobenzyl)carbamothioyl)-4-acetoxypyrrolidine-1-carboxylate from Step C (1.6 g, 3.88 mmol) and acetic hydrazide (575 mg, 7.76 mmol) in acetonitrile (18 ml) was added mercury (II) acetate (1.85 g, 5.82 mmol). The reaction mixture was stirred at room temperature for 16 h. The mixture was filtered through a plug of celite and washed with acetonitrile. The combined filtrates were concentrated, the resulting residue taken up in EtOAc (200 ml), then washed with H2O (75 ml), dried (Na2SO4), filtered and concentrated. Flash chromatography purification (Hex/EtOAc gradient, 10-100% EtOAc) provided the desired product.
Reaction SMILES: I[CH:2]1[C:8](=[O:9])[NH:7][C:6]2[N:10]=[CH:11][CH:12]=[CH:13][C:5]=2[CH2:4][CH2:3]1.[N-:14]=[N+:15]=[N-:16].[Na+].O.ClCCl>CN(C)C=O>[N:14]([CH:2]1[C:8](=[O:9])[NH:7][C:6]2[N:10]=[CH:11][CH:12]=[CH:13][C:5]=2[CH2:4][CH2:3]1)=[N+:15]=[N-:16]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1Nc2ncccc2CCC1I
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC1CCc2cccnc2NC1=O
Temperature: 20 °C
Yield: 94.9 %

Procedure:
To 333 mg of the intermediate obtained in Step G in 6 mL of dimethylformamide (DMF) was added 600 mg of sodium azide. The mixture was stirred at 20° C. 20 h before addition of water and extraction with dichloromethane. The extracts were combined and dried over sodium sulfate. Evaporation of the solvent gave 223 mg of the product characterized by its NMR and mass spectra.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[CH2:36])[CH2:4][O:5][C:6]1[CH:35]=[CH:34][C:9]([CH2:10][NH:11][C:12]2[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[N:15]=[C:14]([NH:24][C:25]3[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=3)[N:13]=2)=[CH:8][CH:7]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[C:59]([O:63][C:64](=[O:72])[NH:65][CH2:66][C:67]([CH3:71])([CH3:70])[CH2:68][NH2:69])([CH3:62])([CH3:61])[CH3:60].CCN(C(C)C)C(C)C>CN1C(=O)CCC1.O>[Cl:1][CH2:2][C:3](=[CH2:36])[CH2:4][O:5][C:6]1[CH:35]=[CH:34][C:9]([CH2:10][NH:11][C:12]2[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:21])[F:22])[N:15]=[C:14]([NH:24][C:25]3[CH:26]=[CH:27][C:28]([C:29]([NH:69][CH2:68][C:67]([CH3:71])([CH3:70])[CH2:66][NH:65][C:64](=[O:72])[O:63][C:59]([CH3:61])([CH3:60])[CH3:62])=[O:30])=[CH:32][CH:33]=3)[N:13]=2)=[CH:8][CH:7]=1
Reactant: CC(C)(CN)CNC(=O)OC(C)(C)C
Reactant: C=C(CCl)COc1ccc(CNc2nc(Nc3ccc(C(=O)O)cc3)nc(OCC(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN1CCCC1=O
Product: C=C(CCl)COc1ccc(CNc2nc(Nc3ccc(C(=O)NCC(C)(C)CNC(=O)OC(C)(C)C)cc3)nc(OCC(F)(F)F)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.3 %

Procedure:
To a solution of 4-((4-((4-((2-(chloromethyl)allyl)oxy)benzyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzoic acid (1.1 g) and TBTU (0.74 g) in NMP (10 mL) was added tert-butyl(3-amino-2,2-dimethylpropyl)carbamate (0.51 g) and DIPEA (1.47 mL). After stirring at room temperature for 2 hours, the mixture was diluted with 100 mL of water and extracted with EtOAc (2×150 mL). The organic layer were combined, washed with brine (100 mL), dried over MgSO4 and concentrated. The residue was purified by silica gel column to give tert-butyl 3-(4-(4-(4-(2-(chloromethyl)allyloxy)benzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-2,2-dimethylpropylcarbamate (1 g).
Reaction SMILES: O.[ClH:2].Cl.[NH2:4][CH2:5][C:6]([CH2:8][NH2:9])=O.Cl.[CH2:11]([O:14][NH2:15])[C:12]#[CH:13].[CH3:16]O>>[ClH:2].[CH2:11]([O:14][N:15]=[C:6]1[CH2:8][NH:9][CH:16]=[N:4][CH2:5]1)[C:12]#[CH:13]
Reactant: NCC(=O)CN
Reactant: C#CCON
Reactant: CO
Agent: Cl
Solvent: O
Product: C#CCON=C1CN=CNC1
Yield: 36 %

Procedure:
1,3-diaminoacetone dihydrochloride monohydrate (1.10 g, 6.14 mmol) was dissolved in refluxing methanol and O-(2-propynyl)hydroxylamine hydrochloride (0.730 g, 6.75 mmol) was added. After refluxing for 48 hours the solvent was evaporated. The crude product was dissolved in methanol and an excess of trimethylorthoformate was added to the reaction mixture and heated to reflux. After 24 hours the solvent was removed in vacuo. Crystallization from methanol/ethyl acetate afforded 410 mg (36%) of light-brown material. Mp. 205.0° C.
Reaction SMILES: [CH:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.C(N(CC)CC)C.[NH2:17][C:18]1[CH:40]=[CH:39][C:21]([C:22]([N:24]2[CH2:30][C:29]3[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=3[CH2:27][C:26]3[CH:35]=[CH:36][CH:37]=[CH:38][C:25]2=3)=[O:23])=[CH:20][CH:19]=1>C(Cl)Cl>[CH:35]1[C:26]2[CH2:27][C:28]3[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=3[CH2:30][N:24]([C:22]([C:21]3[CH:20]=[CH:19][C:18]([NH:17][C:7]([CH:1]4[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]4)=[O:8])=[CH:40][CH:39]=3)=[O:23])[C:25]=2[CH:38]=[CH:37][CH:36]=1
Reactant: O=C(Cl)C1CC=CCC1
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1)C1CC=CCC1
Reaction time: 18 h
Yield: 67.1 %

Procedure:
A mixture of 208 mg of 3-cyclohexene-1-carbonyl chloride (prepared from 3-cyclohexene-1-carboxylic acid and thionyl chloride) and 145 mg of triethylamine in 3 ml of methylene chloride is added to a solution of 377 mg of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine in 7 ml of methylene chloride. The mixture is stirred for 18 hours, washed with water, 1N HCl, water, 1M NaHCO3 and brine then dried with Na2 SO4. The organic layer is passed through a short column of hydrous magnesium silicate and hexane added to the filtrate at the boil to give 340 mg of the desired product as a crystalline solid, m.p. 234°-236° C.
Reaction SMILES: [C:1]([NH:9][CH:10]([C:16]#[N:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:27])=CC=1>N1C=CC=CC=1>[NH2:17][C:16]1[S:27][C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:9][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C(C#N)NC(=O)c1ccccc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: c1ccncc1
Product: CCOC(=O)c1nc(-c2ccccc2)sc1N
Yield: 40.3 %

Procedure:
To a stirred solution of compound ethyl 2-benzamido-2-cyanoacetate (0.46 g, 2 mmol) in pyridine (20 mL) was added Lawesson's reagent (0.81 g, 2 mmol). The reaction mixture was heated at reflux for 15 hr. It was then concentrated and diluted with EtOAc (40 mL). The diluted mixture was washed with water (3×20 mL), brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (10:1 PE/EtOAc) to afford ethyl 5-amino-2-phenylthiazole-4-carboxylate (0.2 g, 40%) as yellow solid: 1H-NMR (CDCl3, 500 MHz) δ (ppm): 7.80 (d, J=6.5 Hz, 1H), 7.36-7.41 (m, 3H), 4.43 (q, J=7.0 Hz, 2H), 1.44 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 249 [M+H+].
Reaction SMILES: [CH2:1]1[C@@H:5]2[CH2:6][CH2:7][C@@H:8]([NH:9][C:10](=[O:25])[C@H:11]([CH2:21][CH:22]([CH3:24])[CH3:23])[N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH3:13])[C@@H:4]2[CH2:3][NH:2]1.C(N(CC)CC)C.[F:33][C:34]([F:46])([F:45])[C:35]1[CH:36]=[C:37]([S:41](Cl)(=[O:43])=[O:42])[CH:38]=[CH:39][CH:40]=1>ClCCl>[C:17]([O:16][C:14]([N:12]([CH3:13])[C@H:11]([C:10]([NH:9][C@H:8]1[C@H:4]2[C@H:5]([CH2:1][N:2]([S:41]([C:37]3[CH:38]=[CH:39][CH:40]=[C:35]([C:34]([F:33])([F:45])[F:46])[CH:36]=3)(=[O:43])=[O:42])[CH2:3]2)[CH2:6][CH2:7]1)=[O:25])[CH2:21][CH:22]([CH3:23])[CH3:24])=[O:15])([CH3:18])([CH3:19])[CH3:20]
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: CC(C)C[C@@H](C(=O)N[C@@H]1CC[C@H]2CNC[C@H]21)N(C)C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C[C@@H](C(=O)N[C@@H]1CC[C@H]2CN(S(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@H]21)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To N1-[(3aS,4R,6aR)-Octahydrocyclopenta[c]pyrrol-4-yl]-N2-(tert-butyloxycarbonyl)-N2-methyl-L-leucinamide from Step A (220 mg, 0.622 mmol) in dichloromethane (5.0 mL) was added triethylamine (0.130 mL, 0.934 mmol) followed by 3-(trifluoromethyl)benzene-1-sulfonyl chloride (0.110 ml, 0.685 mmol) and the reaction mixture was stirred at room temperature overnight. The reaction was reduced in volume and loaded onto a silica gel cartridge (Analogix®, Burlington, Wis., RS-24). The title compound was eluted with a gradient of 0% to 10% methanol (2 N ammonia)/dichloromethane over 20 minutes to give N2-(tert-butyloxycarbonyl)-N2-methyl-N1-((3aS,4R,6aR)-2-{[3-(trifluoromethyl)phenyl]sulfonyl}octahydrocyclopenta[c]pyrrol-4-yl)-L-leucinamide: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.32 (bs, 1H), 8.18-8.13 (m, 1H), 8.02-7.95 (m, 1H), 7.90-7.84 (m, 1H), 7.68 (t, J=7.9, 1H), 4.17-4.09 (m, 1H), 3.77-3.69 (m, 1H), 3.20-3.11 (m, 2H), 3.05-2.97 (m, 4H), 2.53-2.47 (m, 2H), 1.98-1.88 (m, 1H), 1.87-1.71 (m, 3H), 1.62-1.48 (m, 3H), 1.46 (s, 9H), 1.32-1.22 (m, 1H), 0.87 (dd, J=6.6, 15.5, 6H).
Reaction SMILES: CCOC([C:6]([C:10]1[CH:11]=[CH:12][C:13]([O:27][CH3:28])=[C:14]([CH2:16][C:17]([O:19]CC2C=CC=CC=2)=[O:18])[CH:15]=1)=[CH:7][CH2:8][CH3:9])=O.[O:29]1[CH2:33]C[CH2:31][CH2:30]1.C([OH:36])C>[Pd]>[CH3:31][CH2:30][O:29][C:33]([CH2:9][CH2:8][CH2:7][CH2:6][C:10]1[CH:11]=[CH:12][C:13]([O:27][CH3:28])=[C:14]([CH2:16][C:17]([OH:19])=[O:18])[CH:15]=1)=[O:36]
Reactant: C1CCOC1
Reactant: CCO
Reactant: CCC=C(C(=O)OCC)c1ccc(OC)c(CC(=O)OCc2ccccc2)c1
Agent: [Pd]
Product: CCOC(=O)CCCCc1ccc(OC)c(CC(=O)O)c1
Reaction time: 8 h
Yield: 100 %

Procedure:
Benzyl 2-[5-[1-(2-ethoxycarbonyl)butenyl]-2-methoxyphenyl]acetate (1.85 g, 4.84 mmol), 5% palladium on carbon (400 mg), tetrahydrofuran (50 mL) and ethanol (50 mL) were mixed and hydrogenation was carried out for 8 hours at room temperature. The catalyst was removed by filtration and the filtrate was concentrated to afford 1.42 g (100%) of the title compound as a yellow oily product.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:6]=1)=[O:4].[N-:21]=[N+:22]=[N-:23].[Na+].O.CO>C1COCC1>[N:21]([CH2:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:6]=1)=[O:4])=[N+:22]=[N-:23]
Reactant: CC(C)(C)OC(=O)n1cc(C(=O)CBr)c2ccccc21
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)n1cc(C(=O)CN=[N+]=[N-])c2ccccc21

Procedure:
To a stirred solution of 3-bromoacetyl-1-(tert-butoxycarbonyl)-indole, which may be prepared as described in Step (c) above, (0.01 mol), in THF is added a solution or suspension of sodium azide (0.01 to 0.05 mol) in THF, which optionally contains from 0% to 50% water or methanol, and the mixture is stirred. Reaction progress may be followed by TLC or HPLC. When a sufficient amount of desired product is formed, the mixture (or, optionally, the residue which is obtained after first rotary evaporating off the reaction solvent) is partitioned between ethyl acetate and water. The organic layer is washed with brine, dried over sodium sulfate, and rotary evaporated to give 3-azidoacetyl-1-(tert-butoxycarbonyl)-indole, which may be purified, if needed or desired, by chromatography on silica gel or crystallization.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][N:6]2[C:11]=1[C:10](Cl)=[N:9][CH:8]=[N:7]2.C([O-])(O)=O.[Na+].[O-:18]S([O-])(=O)=O.[Na+].[Na+].[F:25][C:26]1[CH:27]=[C:28]([CH:40]=[CH:41][CH:42]=1)[CH2:29][N:30]1[C:38]2[C:33](=[CH:34][C:35]([NH2:39])=[CH:36][CH:37]=2)[CH:32]=[N:31]1>C(#N)C.O>[F:25][C:26]1[CH:27]=[C:28]([CH:40]=[CH:41][CH:42]=1)[CH2:29][N:30]1[C:38]2[C:33](=[CH:34][C:35]([NH:39][C:10]3[C:11]4=[C:3]([CH2:2][OH:18])[CH:4]=[CH:5][N:6]4[N:7]=[CH:8][N:9]=3)=[CH:36][CH:37]=2)[CH:32]=[N:31]1
Reactant: O=S(=O)([O-])[O-]
Reactant: Clc1ncnn2ccc(CBr)c12
Reactant: Nc1ccc2c(cnn2Cc2cccc(F)c2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: OCc1ccn2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c12
Reaction time: 72 h
Yield: 65 %

Procedure:
A mixture of crude 5-bromomethyl-4-chloro-pyrrolo[2,1-f][1,2,4]triazine (3.69 gm, 0.015 moles and NaHCO3 (2.51 gm, 2 equiv) in a mixture of acetonitrile (50 mL) and water (5 mL) was stirred under a N2 atmosphere for 3 days. This was treated with Na2SO4 and then with 1-(3-flurobenzyl)-1H-indazol-5-ylamine (3.24 gm, 0.90 equiv) and NaHCO3 (1 gm) and left stirring for 18 hr at RT. The reaction was filtered and the filter cake was washed with DCM (100 mL). The filtrate was concentrated and silica gel chromatography (elution with 30% EtOAc in hexane) of the residue gave the title compound as a tan solid (3.78 gm, 65% yield): 1H NMR (CDCl3) δ 3.03 (t, J=5.9 Hz, 1H), 4.98 (d, J=5.7 Hz, 2H), 5.55 (s, 2H), 6.76 (d, J=2.7 Hz, 1H), 6.83 (d, J=9.0 Hz, 1H), 6.98-6.90 (m, 3H), 7.43 (d, J=2.5 Hz, 1H), 7.51 (dd, J=2.1, 8.8 Hz, 1H), 7.96 (s, 1H), 8.03 (s, 1H), 8.22 (s, 1H), 9.91 (s, 1H); MS: (M+H+); HPLC Ret Time: 2.38 min (YMC C18 S5, 3.0×50 mm, 4 min gradient, 4 mL/min.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([Br:9])=[CH:4][C:3]=1[F:10].[Cl:11][C:12]1[N:17]=[CH:16][C:15]([C:18](N(C)OC)=[O:19])=[CH:14][CH:13]=1.[Cl-].[NH4+]>C1COCC1.[Li]CCCC.CCCCCC>[Br:9][C:5]1[C:6]([F:8])=[CH:7][C:2]([C:18]([C:15]2[CH:16]=[N:17][C:12]([Cl:11])=[CH:13][CH:14]=2)=[O:19])=[C:3]([F:10])[CH:4]=1
Reactant: Fc1cc(Br)c(F)cc1Br
Reactant: CON(C)C(=O)c1ccc(Cl)nc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(c1ccc(Cl)nc1)c1cc(F)c(Br)cc1F
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 35.9 %

Procedure:
A mixture of 1,4-dibromo-2,5-difluorobenzene (1.36 g) in anhydrous THF (20 ml) and 1.6M n-BuLi in hexane (3.43 ml) was stirred at −78° C. under nitrogen for 20 min. The reaction mixture was added to 6-chloro-N-methyl-N-(methyloxy)-3-pyridinecarboxamide (0.921 g) in THF (20 ml) and stirred at −78° C. The mixture was then stirred at −70° C. for 30 min allowed to warm to room temperature then cooled again to −70° C. and treated with 10% aqueous ammonium chloride. The reaction mixture was warmed to room temperature and partitioned between ethyl acetate and 10% aqueous ammonium chloride. The organic layer was separated using a hydrophobic filter tube and the solvent was removed under vacuum. The residue was purified using a silica SPE cartridge eluting with petroleum ether/ethyl acetate (9:1 to 1:3) to give impure title compound (0.548 g).
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][C:6]([O-:7])=[CH:5][CH:4]=1)[CH3:2].[Na+:10].Cl[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]Cl>>[CH2:1]([C:3]1[CH:9]=[CH:8][C:6]([O:7][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:7][C:6]2[CH:8]=[CH:9][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=2)=[CH:5][CH:4]=1)[CH3:2].[OH-:7].[Na+:10]
Reactant: ClCCCCCCCCCCCCCl
Reactant: CCc1ccc([O-])cc1
Agent: [Na+]
Product: CCc1ccc(OCCCCCCCCCCCCOc2ccc(CC)cc2)cc1
Product: [OH-]

Procedure:
1,12-bis (4-ethylphenoxy) dodecane is prepared from sodium 4-ethylphenoxide and 1,12-dichlorododecane, according to the method of Example 1, and sulfonated to the disulfonic acid derivative and neutralized with sodium hydroxide according to the method of Example 2, to afford the disodium sulfonate derivative.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[F:9][C:10]([F:27])([F:26])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[N:22]3[N:23]=[CH:24][CH:25]=[C:21]3[N:20]=[CH:19][CH:18]=2)[CH:12]=1>C(Cl)(Cl)Cl>[Br:1][C:25]1[CH:24]=[N:23][N:22]2[C:17]([C:13]3[CH:12]=[C:11]([C:10]([F:26])([F:9])[F:27])[CH:16]=[CH:15][CH:14]=3)=[CH:18][CH:19]=[N:20][C:21]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: FC(F)(F)c1cccc(-c2ccnc3ccnn23)c1
Solvent: ClC(Cl)Cl
Product: FC(F)(F)c1cccc(-c2ccnc3c(Br)cnn23)c1

Procedure:
A 3.75 g. portion of N-bromosuccinimide is added to a solution of 5.26 g. of 7-(α,α,α-trifluoro-m-tolyl)pyrazolo[1,5-a]pyrimidine in 50 ml. of chloroform producing an exothermic reaction. The mixture is refluxed on a steam bath for 15 minutes and then treated as described in Example 14, giving the desired product, m.p. 138°-140° C.
Reaction SMILES: C(OC1C=CC(C=O)=CC=1)CCC.Br[C:15]1[CH2:19][CH2:18][O:17][N:16]=1.[OH:20][C:21]1[CH:22]=[N:23][CH:24]=[N:25][CH:26]=1>>[N:23]1[CH:22]=[C:21]([O:20][C:15]2[CH2:19][CH2:18][O:17][N:16]=2)[CH:26]=[N:25][CH:24]=1
Reactant: BrC1=NOCC1
Reactant: Oc1cncnc1
Agent: CCCCOc1ccc(C=O)cc1
Product: c1ncc(OC2=NOCC2)cn1

Procedure:
3-(pyrimidin-5-yloxy)-4,5-dihydroisoxazole I-139a and I-139b was prepared in 3 steps from 4-butoxybenzaldehyde using Method 8 followed by cycloaddition using Method 1. The resulting bromo-4,5-dihydroisoxazole was reacted with 5-hydroxypyrimidine using Method 5. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC Method disclosed herein. [M+H]+=314.9 m/z. Activity: A
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].C[O-].[Na+].C[CH2:22][O:23]C(C)=O>CS(C)=O.CO>[CH3:22][O:23][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Cl
Reactant: CCOC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Product: COc1c([N+](=O)[O-])cc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Chloro-1,3-dinitro-5-trifluoromethyl-benzene (5.43 g, 20.1 mmol) was dissolved in 10 mL anhydrous DMSO. Sodium methoxide (5.85 mL of a 25% w/w solution in methanol) was added by syringe. The yellow solution immediately turned pink-orange, with heat evolved. The reaction was left stirring overnight at room temperature, then EtOAc (300 mL) was added and the mixture was washed once with dilute HCl aqueous solution, thrice with water and once with brine. The organic solution was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified through a short plug of silica gel and 4.65 g of 2-methoxy-1,3-dinitro-5-trifluoromethylbenzene was isolated as a yellow solid.
Reaction SMILES: [C:1]([NH:4][C@@H:5]([CH2:10][SH:11])[C:6](OC)=[O:7])(=[O:3])[CH3:2].[OH-].[NH4+:13]>C1(C)C=CC=CC=1.ClCCl.CO>[C:1]([NH:4][C@@H:5]([CH2:10][SH:11])[C:6]([NH2:13])=[O:7])(=[O:3])[CH3:2]
Reactant: [NH4+]
Reactant: COC(=O)[C@H](CS)NC(C)=O
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(=O)N[C@@H](CS)C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
45a (53.4 g, 0.30 mol) was diluted with 250 mL of toluene and 200 mL of ammonium hydroxide. The mixture was stirred at room temperature overnight then concentrated. The resulting residue was suspended in 250 mL of acetonitrile/H2O (9.3:1) and stirred at room temperature until the insoluble material formed a viscous paste. The solvent was decanted then concentrated to give a viscous liquid. The crude product was taken up in dichloromethane/methanol (8.5:1) and passed through a silica gel column eluting with dichloromethane/methanol (8.5:1). Fractions containing the least polar UV-active component were combined and concentrated to give 25 g (52%) of (R)-2-acetamido-3-mercaptopropanamide as white solid. 1HNMR (DMSO-d6) δ 8.0 (d, 1H), 7.41 (s, 1H), 7.13 (s, 1H), 4.33 (m, 1H), 2.76 (m, 1H), 2.65 (m, 1H), 2.22 (m, 1H), 1.88 (s, 3H).
Reaction SMILES: C(OC(C1C=CC(C([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22][CH2:21][C:19]3=[O:20])[CH2:14][CH2:13]2)=O)=CC=1)=N)C.[NH3:31].[CH3:32][OH:33]>>[C:32]([C:15]1([N:18]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22][CH2:21][C:19]2=[O:20])[CH2:16][CH2:17][NH:12][CH2:13][CH2:14]1)(=[O:33])[NH2:31]
Reactant: CO
Reactant: CCOC(=N)c1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Reactant: N
Product: NC(=O)C1(N2C(=O)CCc3ccccc32)CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-{1-[4-(1-Ethoxy-1-iminomethyl)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril (1 g) is dissolved in methanol (10 ml) and thereto is added aqueous ammonia (10 ml) and the mixture is stirred at room temperature overnight. The solvent is concentrated and water is added to the residue. The mixture is extracted with chloroform, dried with sodium carbonate, concentrated and then purified by silica gel column chromatography (solvent: chloroform:methanol=10:1) and recrystallized from ethanol/n-hexane to give 1-[1-(4-carbamoyl-4-piperidinyl]-3,4-dihydrocarbostyril (0.2 g) as white powder, m.p.: 101°-104° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][N:18]=1>C(Cl)Cl>[Cl:16][C:17]1[N:18]=[CH:19][C:20]([C:21]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:22])=[CH:24][CH:25]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1N
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(Cl)nc1
Temperature: 25 °C

Procedure:
To a solution of t-butyl (2-aminophenyl)carbamate A1 (10 g, 48.0 mmol) in CH2Cl2 (200 mL) was added 6-chloronicotinoyl chloride (8.5 g, 48.0 mmol). The reaction mixture was concentrated after 2 hours of stirring at room temperature and purified by flash chromatography (10-75% EtOAc/hexanes) to give the Boc-protected nicotinamide B1 confirmed by MS (ESI+): cal'd [M+Na]+ 370.1, obs'd 370.1.