Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][N:6]([C:8]2([C:11](=[NH:15])OCC)[CH2:10][CH2:9]2)[CH:7]=1.Cl.Cl.[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([N:26]2[CH2:31][CH2:30][CH2:29][C@@H:28]([C:32]([N:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)=[O:33])[CH2:27]2)=[N:23][C:24]=1N.C(O)(=O)C.C(N(CC)CC)C.[Cl-].[NH4+]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[N:5][N:6]([C:8]2([C:11]3[NH:15][C:24]4=[N:23][C:22]([N:26]5[CH2:31][CH2:30][CH2:29][C@@H:28]([C:32]([N:34]6[CH2:38][CH2:37][CH2:36][CH2:35]6)=[O:33])[CH2:27]5)=[CH:21][CH:20]=[C:19]4[N:18]=3)[CH2:9][CH2:10]2)[CH:7]=1
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Reactant: CCOC(=N)C1(n2cc(OC)cn2)CC1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: COc1cnn(C2(c3nc4ccc(N5CCC[C@@H](C(=O)N6CCCC6)C5)nc4[nH]3)CC2)c1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
To a solution of crude ethyl 1-(4-methoxy-1H-pyrazol-1-yl)cyclopropanecarbimidate (79.5 mg, 0.380 mmol) in ethanol (1.5 mL) was added (R)-(1-(5,6-diaminopyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone dihydrochloride (151 mg, 0.417 mmol) followed by glacial acetic acid (0.435 mL, 7.59 mmol). The mixture was degassed with nitrogen, and then triethylamine (0.318 mL, 2.28 mmol) was added. The reaction mixture was heated at 100° C. for 20 min and then at 85° C. for 18 h. The mixture was poured into a saturated aqueous solution of ammonium chloride (40 mL) and extracted with dichloromethane (50 mL×3). The combined organics were washed with a saturated aqueous solution of sodium bicarbonate. The aqueous layer was extracted with dichloromethane (40 mL×2). The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified via HPLC to afford the title compound. MS (ESI+) (M+H) 436.2; HPLC retention time 1.85 min (Method A).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[N:9]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[Cl:8][C:4]1[N:3]=[C:2]([N:12]2[CH2:11][CH2:10][N:9]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13]2)[CH:7]=[N:6][CH:5]=1
Reactant: Clc1cncc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(C)(C)OC(=O)N1CCN(c2cncc(Cl)n2)CC1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
2,6-dichloropyrazine (10.0 g, 67.1 mmol), tert-butyl piperazine-1-carboxylate (12.5 g, 67.1 mmol) and cesium carbonate (43.7 g, 134 mmol) were added to a round bottom flask and flushed with nitrogen. DMF (300 ml) was then added and the reaction was stirred at 100° C. for 3 hours. The reaction mixture was cooled to room temperature, then diluted with EtOAc (600 mL) and washed with brine (600 mL). The aqueous layer was washed with additional EtOAc (600 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to a crude residue that was purified by silica gel chromatography to afford tert-butyl 4-(6-chloropyrazin-2-yl)piperazine-1-carboxylate as an off-white solid. LRMS calculated for C13H19ClN4O2[M+H]+, 299.1; found 299.1.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[N:27](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[C:8]2[CH:47]=[CH:48][C:49]([N:51]([CH3:61])[C:52]([NH:54][CH:55]3[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]3)=[O:53])=[CH:50][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].Cl>C(Cl)Cl.CCOCC.CO>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[CH:15][CH:16]=2)[C:8]2[CH:47]=[CH:48][C:49]([N:51]([CH3:61])[C:52]([NH:54][CH:55]3[CH2:56][CH2:57][CH2:58][CH2:59][CH2:60]3)=[O:53])=[CH:50][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cc(N(C)C(=O)NC3CCCCC3)ccc2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: CO
Product: CCCCc1nc2cc(N(C)C(=O)NC3CCCCC3)ccc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared in analogous manner to Example 58b from 4'-[(2-n-butyl-5-(N-cyclohexylaminocarbonyl-methylamino)-benzimidazol-1-yl)-methyl]-2-(1-triphenylmethyl-tetrazol-5-yl)-biphenyl and hydrochloric acid in methylene chloride/ether/methanol.
Reaction SMILES: [Cl-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N:9]=[N:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][C:12]=2[OH:21])[CH:4]=1.[C:22]1([CH3:33])[CH:27]=[CH:26][C:25]([S:28]([O:31]C)(=[O:30])=[O:29])=[CH:24][CH:23]=1>>[C:22]1([CH3:33])[CH:23]=[CH:24][C:25]([S:28]([O-:31])(=[O:29])=[O:30])=[CH:26][CH:27]=1.[OH:21][C:12]1[CH:13]=[CH:14][C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11]=1[N:10]=[N:9][C:5]1[CH:4]=[N+:3]([CH3:22])[CH:8]=[CH:7][CH:6]=1
Reactant: Oc1ccc2ccccc2c1N=Nc1cccnc1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Agent: [Cl-]
Agent: [Na+]
Product: C[n+]1cccc(N=Nc2c(O)ccc3ccccc23)c1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Reaction time: 0.75 h

Procedure:
A mixture of 50.3 pounds of sodium chloride and 3.7 pounds (6.75 moles) of 1-(3-pyridylazo)-2-naphthol is blended in a Patterson-Kelly liquid-solid blender and 2.89 pounds (7.05 moles) of methyl p-toluenesulfonate added thereto over a period of about 45 minutes. The temperature of the reaction is maintained at about 40°-50° C for an additional period of about one hour. The product is of acceptable purity.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:32]([N:39]1[CH2:42][CH2:41][C@H:40]1[CH2:43][OH:44])([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33].[Br:45][C:46]1[CH:47]=[C:48](O)[CH:49]=[N:50][C:51]=1[Cl:52]>C1COCC1>[Br:45][C:46]1[CH:47]=[C:48]([O:44][CH2:43][C@@H:40]2[CH2:41][CH2:42][N:39]2[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH:49]=[N:50][C:51]=1[Cl:52]
Reactant: Oc1cnc(Cl)c(Br)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cnc(Cl)c(Br)c1
Temperature: 25 °C

Procedure:
To a solution of diethyl azodicarboxylate (1.52 mL, 9.6 mmol) in THF (56 mL) was added triphenylphosphine (2.52 g, 9.6 mmol) at 0° C., and the reaction mixture was stirred for half an hour. 1-BOC-2-(S)-azetidinemethanol (1.44 g, 7.7 mmol) and 5-bromo-6-chloropyridine-3-ol (1.4 g, 6.4 mmol; prepared according to V. Koch and S. Schnatterer, Synthesis 1990, 499-501)) were then added. The reaction mixture was slowly warmed up to room temperature overnight. Solvent was removed, and the residue was chromatographed on a silica gel column, eluting with chloroform:methanol 100:1 to afford the title compound. MS (DCI/NH3) m/z 377, 379 (M+H)+.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:7][C:6]([C:8]([NH2:10])=[NH:9])=[CH:5][C:4]=1[C:11]1[S:12][CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:15]=1.[CH3:22]N.O>CO>[NH:9]=[C:8]([NH:10][CH3:22])[C:6]1[S:7][C:3]([S:2][CH3:1])=[C:4]([C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:15]=2)[CH:5]=1
Reactant: CSc1sc(C(=N)N)cc1-c1nc(-c2ccccc2)cs1
Reactant: CN
Solvent: O
Solvent: CO
Product: CNC(=N)c1cc(-c2nc(-c3ccccc3)cs2)c(SC)s1
Yield: 72 %

Procedure:
5-Methylthio-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carboxamidine (20 mg, 0.06 mmol) as prepared in Example 10 step (b) was dissolved in MeOH, and to this solution methylamine (0.6 mL, 2M solution in tetrahydrofuran) was added. This solution was refluxed for 6 h, at which time the solvents were removed under vacuum to give a solid. This solid was dissolved in a small amount of MeOH. H2O was added dropwise to the methanolic solution until a precipitate was formed. This solid was isolated, washed with a small amount of water and dried under vacuum to give 15 mg (72%) of {imino[5-methylthio-4-(4-phenyl(1,3-thiazol-2-yl))(2-thienyl)]methyl}methylamine. 1H-NMR (DMSO-d6; 300 MHz) δ 2.77 (s, 3H), 3.00 (s, 3H), 7.36-7.42 (m, 1H), 7.47-7.52 (m, 2H), 8.07-8.10 (m, 2H), 8.23 (s, 1H), 8.55 (s, 1H). Mass spectrum (ESI, m/z): Calcd. for C16H15N3S3, 346.5 (M+H), found 346.2.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9]([C@H:11]1[CH2:16][CH2:15][C@@H:14]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:12]1)=O.O>C(OCC)C>[C:21]([O:20][C:18]([NH:17][C@H:14]1[CH2:13][CH2:12][C@@H:11]([CH2:9][OH:8])[CH2:16][CH2:15]1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: COC(=O)[C@H]1CC[C@@H](NC(=O)OC(C)(C)C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](CO)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Under argon atmosphere, a suspension of 1.29 g of lithium aluminum hydride in 40 mL of anhydrous ethyl ether was treated dropwise with a solution of 5.80 g of cis-4-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid methyl ester in 20 mL of anhydrous ethyl ether with cooling in ice, and stirred for 3 hours while allowing to gradually warm to room temperature. The reaction solution was cooled to 0° C., combined a small amount of water to decompose an excessive lithium aluminum hydride. The insolubles were filtered off through Celite, and the filtrate was concentrated, and then the residue was washed with n-hexane to obtain 3.60 g of the desirable compound as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[Cl:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]I>>[Cl:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N:16]1[C:17](=[O:20])[CH2:18][CH2:19][N:13]([C:11](=[O:12])/[CH:10]=[CH:9]/[C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:14][CH2:15]1
Reactant: ClCCCCCI
Reactant: O=C1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCN1
Product: O=C(/C=C/c1ccc(Cl)c(Cl)c1)N1CCC(=O)N(CCCCCCl)CC1

Procedure:
In analogy to the procedure described in example 5A, 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-[1,4]diazepan-5-one (intermediate 1A]) and 1-chloro-5-iodopentane gave the title compound as yellow oil. MS: 416.9 (MH+, 3Cl).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[NH3:24]>C1COCC1.CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH2:24])=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Reactant: N
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a suspension of 4.565 g (20 mmol) 4-benzyloxybenzoic acid in 25 ml THF and 0.3 ml N,N-dimethylformamide was added dropwise at 0° C. a solution of 2.6 ml oxalyl chloride in 5 ml THF. Stirring was continued for 3 hours at room temperature, then the suspension was added slowly to a stirred ice-cold solution of concentrated aqueous ammonia. The organic solvent was evaporated, 100 ml water added and the precipitate isolated and dried in vacuo at 50° C. Yield: 4.29 g (94%) white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[NH:15][N:14]=[N:13][N:12]=2)=[O:9])[CH:5]=[N:4][CH:3]=1.[CH3:16][CH:17]1[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]1>C1C=CC=CC=1>[CH3:16][CH:17]1[CH2:22][CH2:21][CH2:20][N:19]([C:2]2[N:7]=[C:6]([C:8]([NH:10][C:11]3[NH:15][N:14]=[N:13][N:12]=3)=[O:9])[CH:5]=[N:4][CH:3]=2)[CH2:18]1
Reactant: O=C(Nc1nnn[nH]1)c1cncc(Cl)n1
Reactant: CC1CCCNC1
Solvent: c1ccccc1
Product: CC1CCCN(c2cncc(C(=O)Nc3nnn[nH]3)n2)C1

Procedure:
To a suspension of 1.13 g of 6-chloro-N-(1H-5-tetrazolyl)pyrazine-2-carboxamide in 20 ml of benzene, 2.94 ml of 3-methylpiperidine was added, and the mixture was refluxed for 6 hours. The reation mixture was evaporated, ethanol was added to the residue, and then the ethanol solution was adjusted with ethanolic hydrogen chloride to pH 3. The precipitate was collected by filtration, and recrystalized from a mixture of dimethylsulfoxide and methanol affording 0.81 g of the desired compound as pale yellow columns, m.p. 236.5°-238.5 ° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[CH2:10][CH2:11][C:12](=O)[CH3:13].C(N(CC)CC)C.Cl.[CH3:23][O:24][NH2:25]>CO.O>[CH3:23][O:24][N:25]=[C:12]([CH2:11][CH2:10][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][C:4]=1[Cl:9])[CH3:13]
Reactant: CC(=O)CCc1c(Cl)cc(Cl)cc1Cl
Reactant: CON
Agent: Cl
Solvent: CO
Solvent: O
Solvent: CCN(CC)CC
Product: CON=C(C)CCc1c(Cl)cc(Cl)cc1Cl
Temperature: 60 °C
Yield: 97.8 %

Procedure:
To a stirred solution of 4-(2,4,6-trichloro-phenyl)-butan-2-one (0.9 g, 3.57 mmol) in methanol (5 ml), was added triethylamine (0.73 ml, 5.3 mmol) and O-methyl-hydroxylamine hydrochloride (0.447 g, 5.3 mmol). The reaction mixture was heated at a temperature of 60° C. for 3 hours. When the TLC confirmed the completion of the reaction, the reaction mass was allowed to attain ambient temperature. After the reaction mixture was diluted with water and methanol was evaporated off, the aqueous layer was extracted with ethyl acetate (3×30 ml). The combined ethyl acetate layers were washed with water followed by brine solution and dried over sodium sulfate before complete evaporation of the solvents to give 4-(2,4,6-trichloro-phenyl)-butan-2-one O-methyl-oxime (0.980 g) crude, which was taken up for reduction without any further purification.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[CH3:5][O:6][CH:7]([O:11][CH2:12][CH2:13][O:14][CH2:15][CH3:16])[C:8]([OH:10])=[O:9].[AlH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1>O.C(O)C>[CH3:5][O:6][CH:7]([O:11][CH2:12][CH2:13][O:14][CH2:15][CH3:16])[C:8]([O-:10])=[O:9].[C:1]([O-:4])(=[O:3])[CH3:2].[AlH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1
Reactant: CCOCCOC(OC)C(=O)O
Reactant: CC(=O)O
Agent: C1CC[AlH]OC1
Solvent: O
Solvent: CCO
Product: CC(=O)[O-]
Product: CCOCCOC(OC)C(=O)[O-]
Reaction time: 2 h

Procedure:
Acetic acid (28.6 mL) and methoxy(ethoxyethoxy) acetic acid (76.7 mL) was dissolved in 500 mL of water and Vista Captal B boehmite (20 g) was slowly added and the solution was allowed to reflux for 72 hours. The solution was filtered and the filtrate was evaporated under reduced pressure resulting in a white/clear gel. The gel was dissolved in ethanol and the product was collected as a white powder upon the addition of diethyl ether. Yield: 25.4 g. The TGA of the product showed a 28.5% ceramic yield (weight loss of 71.5%). The alumoxane was heated from 25° C. to 200° C. at the rate of 1.5° C.min−1, soaked for 2 h. at 200° C. followed by a temperature ramp up to 1000° C. at the rate of 5° C.min−1, soaked for 2 h.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[CH:4]=1.C(=O)([O-])[OH:13].[Na+].O>CC(C)=O>[CH3:11][O:10][C:5]1[CH:4]=[C:3]([CH2:2][OH:13])[CH:8]=[C:7]([CH3:9])[CH:6]=1
Reactant: O=C([O-])O
Reactant: COc1cc(C)cc(CBr)c1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COc1cc(C)cc(CO)c1
Yield: 80.6 %

Procedure:
To a solution of 1-(bromomethyl)-3-methoxy-5-methylbenzene (2.14 g) in acetone (80 mL) were added sodium hydrogen carbonate (1.05 g) and water (50 mL), and the mixture was heated under reflux for 18 hr. The reaction mixture was extracted with ethyl acetate, and the extract was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.22 g) as a yellow oil.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:49][CH:50]2[CH2:54][CH2:53][CH2:52][CH2:51]2)[C:40]([NH:42][C:43]2[CH:47]=[CH:46][N:45](C)[N:44]=2)=[O:41])[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].[CH2:55]([S:57](N1C=CC(N)=N1)(=[O:59])=[O:58])[CH3:56].N1C(C)=CC=CC=1C>C(Cl)Cl.C(OCC)(=O)C>[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:49][CH:50]2[CH2:51][CH2:52][CH2:53][CH2:54]2)[C:40]([NH:42][C:43]2[CH:47]=[CH:46][N:45]([S:57]([CH2:55][CH3:56])(=[O:59])=[O:58])[N:44]=2)=[O:41])[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:36])=[O:37]
Reactant: CCS(=O)(=O)n1ccc(N)n1
Reactant: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1cccc(C)n1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCS(=O)(=O)n1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 45.9 %

Procedure:
Triphenylphosphine (216 mg, 0.83 mmol) was dissolved in methylene chloride (8 mL) and cooled to 0° C. To this solution was added N-bromosuccinimide (166 mg, 0.94 mmol) and was stirred at 0° C. until it was completely dissolved and became light purple in color. The 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 182 mg, 0.55 mmol) was then added and it was stirred at 0° C. for 15 min and then warmed to 25° C. and stirred for 30 min. The mixture was chilled to 0° C. and 1-ethanesulfonyl-1H-pyrazol-3-ylamine (88 mg, 0.50 mmol) was added followed by 2,6-lutidine (192 μL, 1.65 mmol). The mixture was continued to stir at 0° C. for 30 min and then at 25° C. for 3 h. The reaction was diluted with ethyl acetate (50 mL), washed with water (3×20 mL) and saturated aqueous brine solution (2×20 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 10% ethyl acetate/hexanes to 70% ethyl acetate/hexanes) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(1-ethanesulfonyl-1H-pyrazol-3-yl)-propionamide (112 mg, 46%) as a white foam: ESI-LRMS m/e calcd for C20H26ClN3O5S2 [M+] 487.1. found 488.2 [M+H+], 396.1 [M−SO2CH2CH3+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.04-1.18 (m, 2H, CH2), 1.22 (t, J=7.3 Hz, 1H, CH3), 1.40-1.89 (m, 8H, 4×CH2), 2.12-2.23 (m, 1H, CH), 3.29 (s, 3H, SO2CH3), 3.38 (q, J=7.3 Hz, 2H, SO2CH2), 3.67 (t, J=7.5 Hz, 1H, CH), 6.99 (d, J=2.7 Hz, 1H, Ar), 7.45 (d, Jo=8.1, 1H, Ar), 7.56 (d, Jm=1.3 Hz, 1H, Ar), 7.89 (d, J=2.7 Hz, 1H, Ar), 8.06 (d, Jo=8.1 Hz, 1H, Ar), 8.74 (s, 1H, NH).
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([S:11]([NH:14][C@H:15]([C:37]([N:39]3[CH2:44][CH2:43][N:42]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[CH2:41][CH2:40]3)=[O:38])[CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][S:24]([C:27]4[C:28]5[CH:29]=[CH:30][N:31]=[CH:32][C:33]=5[CH:34]=[CH:35][CH:36]=4)(=[O:26])=[O:25])=[CH:19][CH:18]=3)(=[O:13])=[O:12])[C:5]=2[CH:4]=[CH:3][N:2]=1.[H-].[Na+].[CH3:53]I.O>CN(C)C=O>[CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([S:11]([N:14]([CH3:53])[C@H:15]([C:37]([N:39]3[CH2:40][CH2:41][N:42]([C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)[CH2:43][CH2:44]3)=[O:38])[CH2:16][C:17]3[CH:18]=[CH:19][C:20]([O:23][S:24]([C:27]4[C:28]5[CH:29]=[CH:30][N:31]=[CH:32][C:33]=5[CH:34]=[CH:35][CH:36]=4)(=[O:25])=[O:26])=[CH:21][CH:22]=3)(=[O:12])=[O:13])[C:5]=2[CH:4]=[CH:3][N:2]=1
Reactant: CI
Reactant: O=C([C@H](Cc1ccc(OS(=O)(=O)c2cccc3cnccc23)cc1)NS(=O)(=O)c1cccc2cnccc12)N1CCN(c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN([C@@H](Cc1ccc(OS(=O)(=O)c2cccc3cnccc23)cc1)C(=O)N1CCN(c2ccccc2)CC1)S(=O)(=O)c1cccc2cnccc12
Reaction time: 1.5 h

Procedure:
2.27 g of the amorphous compound obtained in Example 108 was dissolved in 30 ml of dimethylformamide, to the solution were sequentially added 160 mg of 60% sodium hydride and 0.3 ml of methyl iodide with ice cooling, and the mixture was stirred for 90 minutes with ice cooling. After adding 80 ml of water, the reaction mixture was extracted with 100 ml of ethyl acetate, and the extract was washed with 80 ml of saturated sodium chloride aqueous solution, dried over magnesium sulfate and concentrated under a reduced pressure. The resulting residue was applied to a silica gel column and eluted with chloroform/methanol (60:1), to obtain 1.8 g of the title compound in a yellow amorphous form.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH2:9]([Mg]Br)[CH:10]([CH3:12])[CH3:11].CCOCC>O1CCCC1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Ni]Cl.[Fe]>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([CH2:9][CH:10]([CH3:12])[CH3:11])=[N:3][CH:4]=1
Reactant: CC(C)C[Mg]Br
Reactant: Brc1ccc(Br)nc1
Agent: Cl[Ni]Cl
Agent: [Fe]
Agent: [CH]1[CH][CH][C](P(c2ccccc2)c2ccccc2)[CH]1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)Cc1ccc(Br)cn1
Temperature: -10 °C
Reaction time: 3.5 h

Procedure:
To a solution of 2,5-dibromopyridine (4.5 g, 19 mmol) in tetrahydrofuran (50 ml) was added [1,1′-bis (diphenylphosphino)ferrocene]dichloronickel (II) (103 mg, 0.19 mmol) and the resulting mixture was cooled to −10° C. A 2M solution of isobutylmagnesium bromide in ether (12.4 ml, 24.7 mmol) was added slowly and the mixture was stirred at −10 to 10° C. for 3.5 hours. After quenching with saturated aqueous ammonium chloride solution, the mixture was partitioned between ether and water and the product from the organic phase was chromatographed on silica gel eluting with 10% ether in pentane to afford the 5-Bromo-2-(2-methylpropyl)pyridine compound as a volatile oil.
Reaction SMILES: [N+:1]([C:4]1[S:8][C:7]([S:9]([N:12]2[CH2:17][CH2:16][NH:15][C@@H:14]([CH2:18][N:19]3[CH:24]4[CH2:25][CH:26]([OH:28])[CH2:27][CH:20]3[CH2:21][O:22][CH2:23]4)[CH2:13]2)(=[O:11])=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+:29]([C:32]1[S:36][C:35]([S:37]([N:40]2[CH2:45][CH2:44][NH:43][C@@H:42]([CH2:46][N:47]3[CH:52]4[CH2:53][C:54](=[O:56])[CH2:55][CH:48]3[CH2:49][O:50][CH2:51]4)[CH2:41]2)(=[O:39])=[O:38])=[CH:34][CH:33]=1)([O-:31])=[O:30].CCN(C(C)C)C(C)C.Cl[C:67]1[N:72]=[CH:71][C:70]([C:73]([OH:82])([C:78]([F:81])([F:80])[F:79])[C:74]([F:77])([F:76])[F:75])=[CH:69][N:68]=1>O1CCOCC1>[N+:1]([C:4]1[S:8][C:7]([S:9]([N:12]2[CH2:17][CH2:16][N:15]([C:67]3[N:68]=[CH:69][C:70]([C:73]([OH:82])([C:74]([F:75])([F:76])[F:77])[C:78]([F:80])([F:81])[F:79])=[CH:71][N:72]=3)[C@@H:14]([CH2:18][N:19]3[CH:20]4[CH2:27][CH:26]([OH:28])[CH2:25][CH:24]3[CH2:23][O:22][CH2:21]4)[CH2:13]2)(=[O:11])=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+:29]([C:32]1[S:36][C:35]([S:37]([N:40]2[CH2:45][CH2:44][N:43]([C:67]3[N:68]=[CH:69][C:70]([C:73]([OH:82])([C:74]([F:75])([F:76])[F:77])[C:78]([F:80])([F:81])[F:79])=[CH:71][N:72]=3)[C@@H:42]([CH2:46][N:47]3[CH:48]4[CH2:55][C:54](=[O:56])[CH2:53][CH:52]3[CH2:51][O:50][CH2:49]4)[CH2:41]2)(=[O:39])=[O:38])=[CH:34][CH:33]=1)([O-:31])=[O:30]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)N2CCN[C@@H](CN3C4COCC3CC(O)C4)C2)s1
Reactant: OC(c1cnc(Cl)nc1)(C(F)(F)F)C(F)(F)F
Reactant: O=C1CC2COCC(C1)N2C[C@H]1CN(S(=O)(=O)c2ccc([N+](=O)[O-])s2)CCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: O=C1CC2COCC(C1)N2C[C@H]1CN(S(=O)(=O)c2ccc([N+](=O)[O-])s2)CCN1c1ncc(C(O)(C(F)(F)F)C(F)(F)F)cn1
Product: O=[N+]([O-])c1ccc(S(=O)(=O)N2CCN(c3ncc(C(O)(C(F)(F)F)C(F)(F)F)cn3)[C@@H](CN3C4COCC3CC(O)C4)C2)s1
Temperature: 100 °C

Procedure:
A 20-mL vial was charged with 9-(((2S)-4-((5-nitro-2-thiophenyl)sulfonyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-ol (endo) and 9-(((2S)-4-((5-nitro-2-thiophenyl)sulfonyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-one (0.53 g, 1.9 mmol), Hünig's base (0.67 mL, 3.8 mmol), 2-(2-chloropyrimidin-5-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol (0.53 g, 1.88 mmol, Intermediate D) and dioxane (10 mL). The vial was, sealed and heated at 100° C. overnight. The crude reaction was concentrated onto silica gel and purified via column chromatography (40 g silica gel, 0 to 100% EtOAc in hexanes) to give 9-(((2S)-4-((5-nitro-2-thiophenyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-ol (endo) and 9-(((2S)-4-((5-nitro-2-thiophenyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-one (0.46 g) as a 1:1 mixture.