Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([Br:9])=[C:4](Cl)[N:3]=1.[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([O:21][CH3:22])=[C:16](B(O)O)[CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(COC)OC>[Br:9][C:5]1[C:6]([Cl:8])=[N:7][C:2]([NH2:1])=[N:3][C:4]=1[C:14]1[CH:13]=[C:12]([Cl:11])[CH:17]=[CH:16][C:15]=1[O:21][CH3:22]
Reactant: COc1ccc(Cl)cc1B(O)O
Reactant: Nc1nc(Cl)c(Br)c(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(Cl)cc1-c1nc(N)nc(Cl)c1Br
Temperature: 25 °C
Reaction time: 72 h
Yield: 22.9 %

Procedure:
To a mixture of 2-amino-4,6-dichloro-5-bromo-pyrimidine (1.22 g, 5.0 mmol), 5-chloro-2-methoxy-phenyl boronic acid (1.03 g, 5.5 mmol), palladium (II) acetate (0.17 g, 0.75 mmol) and triphenylphosphine (0.393 g, 1.5 mmol) was added a solution of sodium carbonate (3.18 g, 30 mmol) in water (20 ml) followed by glyme (100 ml). The mixture was stirred under an argon atmosphere at room temperature for 72 hours. Filtration and concentration of the filtrate yielded a residue which was purified by flash chromatography on silica gel eluting with ethyl acetate-hexane (1:3) to provide 5-bromo-4-chloro-6-(5-chloro-2-methoxy-phenyl)-pyrimidin-2ylamine (0.40 g, 23% yield) as a beige powder.
Reaction SMILES: N1C2C(=CC=CC=2)C=CC=1.[CH2:11]([N:18]1[C@H:21]([C:22]#[CH:23])[C@@H:20]([C@H:24]([O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[CH3:25])[C:19]1=[O:34])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.B1C2CCCC1CCC2.[OH-:44].[Na+].[O-]O>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].C1COCC1.C(OCC)C.O>[CH2:11]([N:18]1[C@H:21]([CH2:22][CH2:23][OH:44])[C@@H:20]([C@H:24]([O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:28])[CH3:29])[CH3:25])[C:19]1=[O:34])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C#C[C@@H]1[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N1Cc1ccccc1
Reactant: [OH-]
Agent: [Pd]
Agent: B1C2CCCC1CCC2
Agent: CC(=O)[O-]
Solvent: c1ccc2ncccc2c1
Solvent: O
Solvent: CCOCC
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N(Cc2ccccc2)[C@@H]1CCO
Temperature: 25 °C
Reaction time: 12 h
Yield: 64.2 %

Procedure:
There were added 0.015 ml of quinoline and 1.5 ml of petroleum ether to 103 mg (0.30 mmol) of 1-benzyl-4(S)-ethynyl-3(S)-[1(R)-t-butyldimethysilyloxyethyl]-2-azetidinone, to which 1.5 mg of Lindlar catalyst was added. The mixture was vigorously stirred at room temperature for 12 hours under hydrogen atmosphere. The reaction solution was filtered and the filtrate was concentrated, to which 2 ml of petroleum ether and 3 mg of Lindlar catalyst were added and the reaction was continued for 36 hours under hydrogen atmosphere. The reaction solution was subjected to silica-gel (10 g) column-chromatography (eluent; benzene:methylene chloride=1:1) to give a partially reduced product including the starting material, which was employed in the following reaction without further purification. The partially reduced product including the starting material was dissolved in 2 ml of THF, to which 1.1 ml (0.63 mmol) of a THF solution of 9-BBN (0.6 M) was added while cooling with an ice bath. After the mixture was stirred in the ice bath for 1 hour, 0.5 ml (0.3 mmol) of a THF solution of 9-BBN (0.6 M) was added to the mixture and was stirred for 2 hours in the ice bath and then for 1 hour at room temperature. There were added 0.56 ml (2.3 mmol) of 4 N sodium hydroxide and 0.4 ml of 31% aqueous solution of hydroperoxide to the obtained reaction mixture on the ice bath and the resultant was stirred at room temperature for 1 hour. The reaction solution was diluted with diethyl ether, added with water and extracted three times with diethyl ether. The extract was washed with an aqueous solution of dilute sodium thiosulfate and then with a saturated aqueous solution of sodium chloride, dried with anhydrous magnesium sulfate and concentrated. The obtained residue was purified by 10 g of silica-gel column-chromatography (eluent; diethyl ether:hexane=3:1→5:1) to give 70 mg of 1-benzyl-3(S)-[1(R)-t-butyldimethylsilyloxyethyl]-4(R)-(2-hydroxyethyl)-2-azetidinone.
Reaction SMILES: [N:1]12[CH2:7][C:5]([C:8]([O:10]C)=O)([CH2:6]1)[CH2:4][CH2:3][CH2:2]2.O.[OH-].[Li+].C[Li].[CH3:17]COCC.Cl.C(=O)([O-])[O-].[K+].[K+]>CO.O>[C:8]([C:5]12[CH2:6][N:1]([CH2:7]1)[CH2:2][CH2:3][CH2:4]2)(=[O:10])[CH3:17]
Reactant: CCOCC
Reactant: COC(=O)C12CCCN(C1)C2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(=O)C12CCCN(C1)C2
Temperature: 25 °C
Reaction time: 20 h
Yield: 35.9 %

Procedure:
A solution of methyl 1-azabicyclo[3.1.1]hept-5-ylcarboxylate (D4, 1.12 g, 0.0072 mole) in methanol (5 ml) was treated with a solution of lithium hydroxide monohydrate (308 mg, 0.0073 mole) in water (20 ml) and the resulting solution stirred at room temperature for 20 h, then concentrated in vacuo to leave a white solid which was dried thoroughly. A stirred suspension of this product in dry THF (120 ml) under nitrogen was treated at room temperature with 1M methyllithium in ether (8.0 ml, 0.0080 mole) and then heated under reflux for 3.5 h. The mixture was allowed to cool, then poured into excess well stirred cold 1M hydrochloric acid. The resulting solution was basified to saturation point with potassium carbonate and extracted with ethyl acetate (1×100 ml), followed by chloroform (2×60 ml). The combined extracts were dried (Na2SO4) and concentrated in vacuo to give the title compound (D 16) as a yellow oil (360 mg, 36%). This material was used without further purification.
Reaction SMILES: Br[C:2]1[C:12]([F:13])=[CH:11][C:5]2[S:6](=[O:10])(=[O:9])[CH2:7][CH2:8][C:4]=2[CH:3]=1.[NH2:14][C@H:15]1[CH2:20][CH2:19][CH2:18][N:17]([CH:21]2[CH2:26][CH2:25][N:24]([C:27]3[N:32]=[CH:31][C:30]([CH2:33][CH3:34])=[CH:29][N:28]=3)[CH2:23][CH2:22]2)[C:16]1=[O:35].CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:33]([C:30]1[CH:29]=[N:28][C:27]([N:24]2[CH2:23][CH2:22][CH:21]([N:17]3[CH2:18][CH2:19][CH2:20][C@H:15]([NH:14][C:2]4[C:12]([F:13])=[CH:11][C:5]5[S:6](=[O:10])(=[O:9])[CH2:7][CH2:8][C:4]=5[CH:3]=4)[C:16]3=[O:35])[CH2:26][CH2:25]2)=[N:32][CH:31]=1)[CH3:34]
Reactant: O=S1(=O)CCc2cc(Br)c(F)cc21
Reactant: CCc1cnc(N2CCC(N3CCC[C@H](N)C3=O)CC2)nc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CCc1cnc(N2CCC(N3CCC[C@H](Nc4cc5c(cc4F)S(=O)(=O)CC5)C3=O)CC2)nc1
Temperature: 90 °C
Reaction time: 4 h
Yield: 31.9 %

Procedure:
A flask was charged with 5-bromo-6-fluoro-2,3-dihydrobenzo[b]thiophene 1,1-dioxide (0.070 g, 0.26 mmol), (S)-3-amino-1′-(5-ethylpyrimidin-2-yl)-[1,4′-bipiperidin]-2-one (Steps A-C, 0.05 g, 0.16 mmol), Pd2 dba3 (0.0075 g, 0.0082 mmol), Binap-rac (0.0010 g, 0.0016 mmol), sodium t-butoxide (0.033 g, 0.35 mmol), and degassed toluene (3 mL). The reaction was stirred at 90° C. for 4 hours. The organic solvent was removed under reduced pressure. The residue was purified using silica gel column chromatography with 50-100% ethyl acetate, followed by preparative TLC using 2% methanol in ethyl acetate to provide (S)-1′-(5-ethylpyrimidin-2-yl)-3-((6-fluoro-1,1-dioxido-2,3-dihydrobenzo[b]thiophen-5-yl)amino)-[1,4′-bipiperidin]-2-one (0.025 g, 0.051 mmol, 31% yield) as off white solid. Mass spectrum (apci) m/z=488.3 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.CCO.[N:28]1([CH2:34][C:35]2[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=2)[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(OCC)C>[Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:39]([C:38]3[CH:37]=[CH:36][C:35]([CH2:34][N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[CH:42][CH:41]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=Cc1ccc(CN2CCOCC2)cc1
Reactant: Nc1ncc(Cl)c(N2CCN(Cc3cccnc3)CC2)c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: Clc1cnc2[nH]c(-c3ccc(CN4CCOCC4)cc3)nc2c1N1CCN(Cc2cccnc2)CC1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
To a mixture of 5-chloro-3-nitro-4-(4-pyridin-3-ylmethyl-piperazin-1-yl)-pyridin-2-ylamine (0.031 g, 0.09 mmol) and EtOH (3.0 ml) was added 4-morpholin-4-ylmethyl-benzaldehyde (0.025 g, 0.12 mmol) followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.36 ml, 0.36 mmol). The reaction mixture was stirred at 80° C. for 20 h, then allowed to cool to room temperature and concentrated in vacuo. The resulting residue was absorbed on silica, and the free-running powder was placed on a 10 g isolute silica column. Elution with a gradient of methanol (2 to 13%) in ethyl acetate/dichloromethane (v:v; 4:1) afforded a yellow solid. The title compound was obtained as a pale yellow solid after trituration with diethyl ether (0.014 g, 30%); 1H-NMR (500 MHz, DMSO-d6) 2.38 (br s, 4H) and 3.59 (t, J=4.5 Hz, 4H) (morpholine N(CH2)2 and morpholine O(CH2)2), 2.62 (br s, 4H, piperazine N(CH2)2), 3.53 (s, 2H) and 3.61 (s, 2H) (NCH2-pyridyl and C6H4CH2N), 3.71 (br s, 4H, piperazine N(CH2)2), 7.39 (dd, J=5.30, 8.2 Hz, pyridine 5-H), 7.47 (d, J=8.2 Hz, 2H) and 8.12 (d, J=8.7 Hz, 2H) (3,5-C6H4— and 2,6-C6H4—), 7.78 (d, J=6.9 Hz, 1H, pyridine 4-H), 8.14 (s, 1H, imidazo[4,5-b]pyridine 5-H), 8.50 (dd, J=1.50, 4.6 Hz, 1H, pyridine 6-H), 8.56 (d, J=1.5 Hz, 1H, pyridine 2-H), 13.42 (br s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[C:7]1([Li])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(OCC)C>[OH:1][CH2:5][CH2:4][CH2:3][C:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6]
Reactant: [Li]c1ccccc1
Reactant: O=C1CCCO1
Solvent: CCOCC
Product: O=C(CCCO)c1ccccc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 97.4 %

Procedure:
To a solution of dihydrofuran-2-one (5.71 g, 66 mmol) in diethyl ether (70 mL) at −78° C. was slowly added phenyl lithium (24 mL, 40 mmol, 1.67 M solution in cyclohexane/diethyl ether). After stirring at −78° C. for 2 hours, the reaction mixture was quenched by the addition of 10% NH4Cl (35 mL). The mixture was warmed to room temperature and the layers separated. The aqueous layer was extracted with diethyl ether (2×40 mL). The combined organics were washed with water (2×40 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (2:3 hexanes/ethyl acetate) to provide the product (6.4 g, 97%) as pale yellow oil.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][CH:4]([OH:7])[CH:3]1[OH:8].[Cl:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[C:13](Cl)=[CH:12][C:11]=1[Cl:20].C(N(CC)CC)C>C(O)(C)(C)C>[Cl:9][C:10]1[C:11]([Cl:20])=[CH:12][C:13]([NH:1][CH:2]2[CH2:6][CH2:5][CH:4]([OH:7])[CH:3]2[OH:8])=[C:14]([N+:16]([O-:18])=[O:17])[CH:15]=1
Reactant: NC1CCC(O)C1O
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)cc1Cl
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cc(Cl)c(Cl)cc1NC1CCC(O)C1O

Procedure:
(±)-(1R*, 2S*, 3R*)-3-Amino-1,2-cyclopentanediol (7.10 g, 50.0 mmol), 1,2,4-trichloro-5-nitrobenzene (11.67 g, 50.0 mmol as 97%, Aldrich), triethylamine (10 mL) and t-butanol (50 mL) were refluxed under nitrogen for 7 hours. Volatiles were removed in vacuo and the black residue chromatographed on silica gel. Title compound was eluted with methanol:chloroform/1:24 as an orange solid (6.45 g, 42%). Crystallization of such a sample from ethanol-water gave title compound as yellow needles, m.p. 137°-140° C.; 1H-NMR (DMSO-d6)δ: 8.26 and 7.49 (both s, 1 each, 2 aromatic CH), 8.06 (d, J=7.0 Hz, 1, NH), 5.04 (d, J=6.1 Hz, 1, OH), 4.65 (d, J=4.1 Hz, 1, OH), 4.0-3.7 (m, 3, 2 OCH and NCH), 2.2-2.21, 2.0-1.8, 1.7 -1.3 (all m, 4, 4 CH).
Reaction SMILES: [NH2:1][S:2]([C:5]1[N:6]([CH3:14])[CH:7]=[CH:8][C:9]=1[C:10]([O:12][CH3:13])=[O:11])(=[O:4])=[O:3].[CH3:15][O:16][C:17]1[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([NH:24][C:25](=O)[O:26]C2C=CC=CC=2)[N:18]=1.C1CCN2C(=NCCC2)CC1.Cl>C(#N)C.O>[CH3:15][O:16][C:17]1[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([NH:24][C:25]([NH:1][S:2]([C:5]2[N:6]([CH3:14])[CH:7]=[CH:8][C:9]=2[C:10]([O:12][CH3:13])=[O:11])(=[O:4])=[O:3])=[O:26])[N:18]=1
Reactant: COC(=O)c1ccn(C)c1S(N)(=O)=O
Reactant: COc1nc(C)nc(NC(=O)Oc2ccccc2)n1
Agent: Cl
Solvent: O
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1ccn(C)c1S(=O)(=O)NC(=O)Nc1nc(C)nc(OC)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.5 %

Procedure:
Methyl 2-(aminosulfonyl)-1-methyl-1H-pyrrole-3-carboxylate (0.10 g, 0.46 mmol) and 0.13 g (0.50 mmol) of phenyl (4-methoxy-6-methyl-1,3,5-triazin-2-yl)carbamate were combined in 2 mL of acetonitrile and 0.075 mL of DBU was added and the resulting amber solution was stirred at ambient temperature for 30 min. The reaction mixture was diluted with 15 mL of water and acidified with 0.5 mL 1N HCl and the resulting precipitate was collected by filtration and rinsed successively with water and ether, then dried to afford 0.13 g of the title compound as a white solid, m.p. 189°-190° C. (dec). 1H NMR (Me2SO-d6, 200 MHz.) δ: 12.5 (NH), 11.1 (NH), 7.22 (d,1H), 6.60 (d,1H), 4.01 (s,3H), 3.98 (s,3H), 3.71 (s,3H), 2.49 (s,3H).
Reaction SMILES: CS([C:5]1[N:9]=[C:8]([CH:10]2[CH2:15][CH:14]3[CH2:16][CH:11]2[CH2:12][CH2:13]3)[S:7][N:6]=1)(=O)=O.[CH2:17]([OH:22])[C:18]#[C:19][CH2:20]C.[H-].[Na+]>CN(C)C=O.[Cl-].[Na+].O>[CH:11]12[CH2:16][CH:14]([CH2:13][CH2:12]1)[CH2:15][CH:10]2[C:8]1[S:7][N:6]=[C:5]([O:22][CH2:17][C:18]#[C:19][CH3:20])[N:9]=1
Reactant: CS(=O)(=O)c1nsc(C2CC3CCC2C3)n1
Reactant: CCC#CCO
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC#CCOc1nsc(C2CC3CCC2C3)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
300 mg of 3-methylsulfonyl-5-(2-norbornyl)-1,2,4-thiadiazole and 107 mg of 2-pentyn-1-ol were dissolved in 2.5 g of N,N-dimethylformamide, 60 mg of sodium hydride (60% in oil) was added thereto under ice-cooling, and the reaction mixture was stirred for 30 minutes under ice-cooling and for 1 hour under room temperature. Then, the reaction mixture was added to saturated brine, and extracted with t-butyl methyl ether. The organic layer was concentrated under reduced pressure, and the residue obtained was subjected to silica gel column chromatography to give 5-(2-norbornyl)-3-(2-butynyloxy)-1,2,4-thiadiazole. 150 mg of the exo-isomer having low polarity (hereinafter referred to as the present invention compound (9-1)) and 50 mg of the endo-isomer having high polarity (hereinafter referred to as the present invention compound (9-2)) were obtained by using hexane-ethyl acetate system as a carrier solvent.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@:9]2([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH2:28][C:29]4[CH:34]=[CH:33][C:32]([O:35][C:36]5[CH:41]=[CH:40][C:39]([C:42](=O)[CH3:43])=[CH:38][CH:37]=5)=[CH:31][CH:30]=4)[CH:22]=3)[O:20][C@@:6]1([CH2:45][O:46][C:47](=[O:49])[CH3:48])[CH2:7][O:8]2)(=[O:3])[CH3:2].N1C=CC=CC=1.Cl.[CH2:57]([O:59][NH2:60])[CH3:58]>C(O)C.C(OCC)(=O)C>[C:1]([O:4][C@H:5]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@:9]2([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH2:28][C:29]4[CH:34]=[CH:33][C:32]([O:35][C:36]5[CH:41]=[CH:40][C:39]([C:42](=[N:60][O:59][CH2:57][CH3:58])[CH3:43])=[CH:38][CH:37]=5)=[CH:31][CH:30]=4)[CH:22]=3)[O:20][C@@:6]1([CH2:45][O:46][C:47](=[O:49])[CH3:48])[CH2:7][O:8]2)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(Oc5ccc(C(C)=O)cc5)cc4)c3)(O1)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]2OC(C)=O
Reactant: CCON
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCON=C(C)c1ccc(Oc2ccc(Cc3cc([C@]45OC[C@](COC(C)=O)(O4)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]5OC(C)=O)ccc3Cl)cc2)cc1
Temperature: 80 °C
Yield: 72.5 %

Procedure:
To a solution of (1R,2S,3S,4R,5S)-1-(acetoxymethyl)-5-(3-(4-(4-acetylphenoxy)benzyl)-4-chlorophenyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triyl triacetate (300.0 mg, 0.43 mmol) in ethanol (5 mL) under nitrogen atmosphere, was added pyridine (0.17 mL, 2.15 mmol) and O-ethylhydroxylamine hydrochloride (84.0 mg, 0.86 mmol). The reaction mixture was heated at 80° C. for 4 h. After completion of the reaction as confirmed by TLC, the crude compound was diluted with ethyl acetate (2×20 mL). The organic layer was separated, washed with 5% HCl (10 mL), water (10 mL), dried over Na2SO4 and concentrated in vacuo to afford crude product which was purified by column chromatography (silica gel, 1:4 EtOAc:Pet Ether) to afford the title compound (230.0 mg, 72%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.Cl.Cl.[CH3:12][CH:13]1[CH:18]([NH2:19])[CH:17]2[CH2:20][CH2:21][N:14]1[CH2:15][CH2:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>CC#N.CCOC(C)=O>[Br:1][C:2]1[S:6][C:5]([C:7]([NH:19][CH:18]2[CH:17]3[CH2:20][CH2:21][N:14]([CH2:15][CH2:16]3)[CH:13]2[CH3:12])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Br)s1
Reactant: CC1C(N)C2CCN1CC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC1C(NC(=O)c2ccc(Br)s2)C2CCN1CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.6 %

Procedure:
5-Bromothiophene-2-carboxylic acid (1.63 g, 7.88 mmol, 1 eq), the product from Step 158d (1.68 g, 7.88 mmol, 1 eq) and HATU (2.97 g, 7.81 mmol, 1 eq) are suspended in 60 mL CH3CN. The mixture is cooled in an ice bath and DIEA (8.2 mL, 47.28 mmol, 6 eq) is added dropwise. The mixture is allowed to warm to room temperature and stirred overnight. EtOAc and satd NaHCO3 are added. The aqueous layer is extracted with EtOAc. The combined organic layers are washed with 1N NaOH, dried over MgSO4, filtered and concentrated. The residue is purified by silica gel chromatography using a Biotage Flash 40S column (90:9:1 CHCl3/MeOH/NH4OH) to provide 1.26 g (49%) of 5-bromo-N-(2-methyl-1-azabicyclo[2.2.2]oct-3-yl)-thiophene-2-carboxamide as a trans/cis mixture of isomers. The p-toluenesulfonic acid salt of the product is made and recrystallized from IPA/ether to give the product as light yellow solid. MS (ESI) for C13H17BrN2OS m/z 328.9/330.9 (M+H)+. Reverse phase HPLC (ZORBAX Eclipse XDB-C8, 4.6 mm×15 cm, 80:12:8 H2O/CH3CN/IPA) revealed a 95:5 trans/cis mixture of isomers.
Reaction SMILES: O=[C:2]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4][NH:3]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:17].ClCCl.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[S:17]=[C:2]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4][NH:3]1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCNC(=S)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 5-oxo-1,4-diazepane-1-carboxylate, P4S10 (0.2 eq.), HMDO (2 eq.) and dichloromethane were combined and stirred magnetically at room temperature for 1 hour. The reaction mixture was then cooled to 0° C. and aqueous K2CO3 solution (1.26 mL of 5.3 M/mmol P4S10 taken) was added. A volume of acetone equal to one half of the reaction solvent was added to obtain a stirrable mixture, and the reaction mixture was stirred vigorously for 30 minutes at 0° C. Volatiles were evaporated, water and ethyl acetate were added, layers were separated and the organic phase was washed with water and brine. The organic extract was dried over Na2SO4 and evaporated, to afford the title compound. 1H NMR (300 MHz, CDCl3) δ 8.7 (bs, 1H), 3.68-3.60 (m, 4H), 3.42-3.38 (m, 2H), 3.15-3.09 (m, 2H), 1.43 (s, 9H); MS (ES) C10H18N2O2S requires 230. Found: 231 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:26]/[O:27][C:28]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)/[C:8]([NH:10][CH:11]2[C:24](=[O:25])[N:13]3[C:14]([C:21]([OH:23])=[O:22])=[C:15](/[CH:18]=[CH:19]\[CH3:20])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.C([O-])([O-])=O.[K+].[K+].[C:53]([O:56][CH:57](Br)[CH3:58])(=[O:55])[CH3:54].C([O-])(O)=O.[Na+]>CN(C=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:26]/[O:27][C:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)/[C:8]([NH:10][CH:11]2[C:24](=[O:25])[N:13]3[C:14]([C:21]([O:23][CH:57]([O:56][C:53](=[O:55])[CH3:54])[CH3:58])=[O:22])=[C:15](/[CH:18]=[CH:19]\[CH3:20])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(=O)OC(C)Br
Reactant: C/C=C\C1=C(C(=O)O)N2C(=O)C(NC(=O)/C(=N\OC(c3ccccc3)(c3ccccc3)c3ccccc3)c3csc(N)n3)[C@H]2SC1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C/C=C\C1=C(C(=O)OC(C)OC(C)=O)N2C(=O)C(NC(=O)/C(=N\OC(c3ccccc3)(c3ccccc3)c3ccccc3)c3csc(N)n3)[C@H]2SC1
Temperature: 5 °C
Reaction time: 1.08 h
Yield: 96.5 %

Procedure:
To a cooled solution of the product of Procedure 7 (34.4 g, 52.8 mmol) and well-milled K2CO3 (7.24 g, 52.8 mmol) in dry DMF (344 ml) was added 1-acetoxyethyl bromide (17.64 g, 105.6 mmol) at 0° C. under argon and the mixture was stirred at about 5° C. for 65 min. The reaction mixture was poured into ice-water (1720 ml) with stirring adjusted to pH 7 with aq. NaHCO3 solution, and stirred for 30 min. The resulting precipitate was collected, washed with water (100 ml) and dried to give 37.61 g of the desired product (97%, purity 80%) as an amorphous powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]([O:15]CC)=O)=[N:10][N:9]=2)=[CH:4][CH:3]=1.[C-]#N.[Na+].Cl.[OH:22][CH:23]1[CH2:26][NH:25][CH2:24]1.C(N(CC)CC)C>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][C:11]([C:13]([N:25]3[CH2:26][CH:23]([OH:22])[CH2:24]3)=[O:15])=[N:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1nnc(-c2ccc(Cl)cc2)o1
Reactant: OC1CNC1
Agent: Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(c1nnc(-c2ccc(Cl)cc2)o1)N1CC(O)C1
Reaction time: 2.5 h
Yield: 90 %

Procedure:
To a suspension of ethyl 5-(4-chlorophenyl)-1,3,4-oxadiazole-2-carboxylate—for preparation, see e.g. WO 97/05131—(0.53 g, 2.10 mmol) in dry methanol (10 mL) was added sodium cyanide (20 mg, 0.42 mmol). A solution of 3-hydroxyazetidine hydrochloride (0.38 g, 2.78 mmol) and triethylamine (0.39 mL, 2.78 mmol) in methanol (10 mL) was added at ambient temperature. The mixture was stirred for 2.5 h. Water (30 mL) was added and the mixture was extracted with dichloromethane. The organic layers were combined and evaporated to a white solid, which was treated with toluene (5 mL) and then filtered. The product was washed with toluene (5 mL) and then dried in vacuo. There was obtained 0.52 g (90%) of 2B as a solid. 1H NMR (400 MHz, CD3OD): δ 4.00 (dd, 1H), 4.46 (dd, 2H), 4.70 (m, 1H), 4.93 (dd, 1H), 7.62 (d, 2H), 8.11 (d, 2H), MS (APCI+) m/z 280 [M+H]+.