Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:9]2[CH:10]=[C:11](/[CH:14]=[CH:15]/[C:16](O)=[O:17])[CH:12]=[CH:13][C:8]=2[S:7][C:6]2[N:19]=[CH:20][CH:21]=[N:22][C:5]1=2.ClP(=O)(OCC)OCC.[NH3:32].C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][CH2:3][N:4]1[C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][C:16]([NH2:32])=[O:17])[CH:12]=[CH:13][C:8]=2[S:7][C:6]2[N:19]=[CH:20][CH:21]=[N:22][C:5]1=2
Reactant: COCN1c2cc(/C=C/C(=O)O)ccc2Sc2nccnc21
Reactant: N
Agent: CCOP(=O)(Cl)OCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCN1c2cc(C=CC(N)=O)ccc2Sc2nccnc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
950 mg of (E)-3-(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)propenoic acid was dissolved in a solvent mixture of tetrahydrofuran (10 ml) with N,N-dimethylformamide (10 ml) in a nitrogen atmosphere. Under ice-cooling, 0.48 ml of diethyl chlorophosphonate was dropped into the reaction mixture. After stirring at room temperature for 30 minutes, ammonia gas was blown into the system. Then the reaction mixture was distributed into an aqueous solution of sodium carbonate and ethyl acetate and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the crystals thus precipitated were recrystallized from diisopropyl ether/ethyl acetate to thereby give 400 mg of the title compound as yellow crystals.
Reaction SMILES: CCN(C(C)C)C(C)C.[NH2:10][C:11]1[C:16]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]3[C:31](=[O:32])[C:30]([C:33]4[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=4)=[CH:29][N:28]([CH2:40][CH3:41])[CH:27]=3)=[O:25])=[CH:19][CH:18]=2)=[CH:15][C:14](C2C=CC(OC)=C(OC)C=2)=[CH:13][N:12]=1.CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.NC1C=CC(C2C(N)=NC=C([Br:92])C=2)=CC=1>CN(C=O)C.O>[NH2:10][C:11]1[C:16]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]3[C:31](=[O:32])[C:30]([C:33]4[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=4)=[CH:29][N:28]([CH2:40][CH3:41])[CH:27]=3)=[O:25])=[CH:19][CH:18]=2)=[CH:15][C:14]([Br:92])=[CH:13][N:12]=1
Reactant: CCn1cc(C(=O)Nc2ccc(-c3cc(-c4ccc(OC)c(OC)c4)cnc3N)cc2)c(=O)c(-c2ccc(F)cc2)c1
Reactant: Nc1ccc(-c2cc(Br)cnc2N)cc1
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCn1cc(C(=O)Nc2ccc(-c3cc(Br)cnc3N)cc2)c(=O)c(-c2ccc(F)cc2)c1
Reaction time: 0.17 h
Yield: 242 %

Procedure:
DIPEA (120 μl) was added to a solution of the compound obtained in Step of Example 3 (80 mg) and COMU (192 mg) in DMF (1.5 ml) at room temperature, and the mixture was stirred for 10 minutes. The compound obtained in Step 1 of Example 1 (100 mg) was added at room temperature. The mixture was stirred for four hours, followed by the addition of water. The precipitated solid was collected by filtration to give 174 mg of the title compound.
Reaction SMILES: C1(C)C=CC=CC=1.[C:8]1([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl[CH2:21][CH2:22][CH:23]1[N:36]([CH3:37])[C:28]2=[N:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[N:27]2[C:26](=[O:38])[N:25]([CH3:39])[CH2:24]1.C(OC(=O)C)(=O)C>C(N(CC)CC)C>[OH2:38].[CH3:37][N:36]1[C:28]2=[N:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[N:27]2[C:26](=[O:38])[N:25]([CH3:39])[CH2:24][CH:23]1[CH2:22][CH2:21][N:17]1[CH2:18][CH2:19][N:14]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:15][CH2:16]1.[CH3:37][N:36]1[C:28]2=[N:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[N:27]2[C:26](=[O:38])[N:25]([CH3:39])[CH2:24][CH:23]1[CH2:22][CH2:21][N:17]1[CH2:18][CH2:19][N:14]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:15][CH2:16]1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CN1CC(CCCl)N(C)c2nc3ccccc3n2C1=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: CN1CC(CCN2CCN(c3ccccc3)CC2)N(C)c2nc3ccccc3n2C1=O
Product: O
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.9 %

Procedure:
To a 50 mL of toluene containing 3.0 g (0.03 mol) of triethylamine and 2.94 g (0.0183 mol) of N-phenylpiperazine was added 3.5 g (0.012 mol) of 2-(2-chloroethyl)-3,4-dihydro-1,4-dimethyl-1H-[1,3,5]triazepino[3,2-a]benzimidazol-5(2H)-one. The reaction mixture was heated to reflux for 7 days. (Note: 3.19 g (0.02 mol) of N-phenylpiperazine was added after ~2 days followed by 1.60 g (0.1 mol) after ~2 additional days during the week). After cooling to room temperature, the entire reaction mixture was treated with ~5 mL of acetic anhydride and stirred at room temperature for 2 hr. The reaction mixture was washed with 2×50 mL of 1N NaOH, dried over Na2SO4, filtered and concentrated by rotary evaporation. The residue was subjected to preparative HPLC using isopropyl alcohol as the eluent and silica gel as the stationary phase. Like fractions were combined and concentrated by rotary evaporation to give 2.7 g (53%) of a glass.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:23][C@H:22]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][C@H:20]([C:32](O)=[O:33])[CH2:19]3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl:35][C:36]1[CH:46]=[CH:45][CH:44]=[CH:43][C:37]=1[CH2:38][NH:39][CH:40]1[CH2:42][CH2:41]1.C(N(C(C)C)C(C)C)C.CCCP(=O)=O>CC(N(C)C)=O.C(OCC)(=O)C>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:19][C@@H:20]([C:32](=[O:33])[N:39]([CH2:38][C:37]4[CH:43]=[CH:44][CH:45]=[CH:46][C:36]=4[Cl:35])[CH:40]4[CH2:42][CH2:41]4)[CH2:21][C@@H:22]([NH:24][C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])[CH2:23]3)=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: Clc1ccccc1CNC1CC1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](C(=O)O)CN(C(=O)OCC2c3ccccc3-c3ccccc32)C1
Agent: CCCP(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H](C(=O)N(Cc2ccccc2Cl)C2CC2)CN(C(=O)OCC2c3ccccc3-c3ccccc32)C1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a stirred, ice-cooled mixture of (3S*,5R*)-5-tert-butoxycarbonylamino-piperidine-1,3-dicarboxylic acid 1-(9H-fluoren-9-ylmethyl) ester (233.3 mg, 0.5 mmol), (2-chlorobenzyl)-cyclopropylamine (99.9 mg, 0.55 mmol) and N-ethyldiisopropylamine (685 μL, 4 mmol) in dimethylacetamide (2.5 mL), propylphosphonic anhydride solution (˜50% in DMF, 480 μL, ˜0.75 mmol) is added. The reaction mixture is stirred for 14 h at RT, diluted with ethyl acetate and washed twice with an aqueous NaHCO3 solution. The combined organic layers are dried (Na2SO4) and evaporated in vacuo, and the residue is purified by preparative HPLC (C18 column, 10-100% CH3CN+0.1% TFA/H2O+0.1% TFA, 20 min, flow 20 mL/min). The combined pure fractions are treated with Na2CO3, CH3CN is removed in vacuo, and the residual aqueous phase is extracted three times with CH2Cl2. The combined organic layers are dried (Na2SO4) and evaporated to afford the title compound as a white amorphous solid. MS: 630.7 [M+H]+; tR (HPLC, Nucleosil C18; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 8 min, then 100% CH3CN+0.1% TFA for 2 min, flow 1.5 ml/min): 8.24 min.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])/[C:3](/[NH:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1)=[CH:4]\[C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:23](/[C:25](=[CH:31]/[C:32]1[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][CH:33]=1)/[C:26]([O:28][CH2:29][CH3:30])=[O:27])#[N:24].N12CCCN=C1CCCCC2>O1CCOCC1>[NH2:24][C:23]1[N:10]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([F:18])([F:19])[F:20])[CH:16]=2)[C:3]([C:2]([F:1])([F:21])[F:22])=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:31]([C:32]2[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][CH:33]=2)[C:25]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)/C=C(/Nc1cncc(C(F)(F)F)c1)C(F)(F)F
Reactant: CCOC(=O)/C(C#N)=C\c1ccc(C#N)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: CCOC(=O)C1=C(N)N(c2cncc(C(F)(F)F)c2)C(C(F)(F)F)=C(C(=O)OCC)C1c1ccc(C#N)cc1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
Under Argon, the compound of Example 29A (180 mg, 0.40 mmol) and the compound of Example 28A (90.36 mg, 0.40 mmol) are dissolved in dioxane (5 ml). 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) (6.08 mg, 0.04 mmol) is added, and the resulting solution is stirred at 85° C. overnight. The crude mixture is cooled to room temperature and purified directly by preparative HPLC.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:40])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=O)=[CH:33][N:32]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1.[NH2:41][C:42]([CH3:46])([CH3:45])[CH2:43][OH:44].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(Cl)Cl>[Cl:1][C:2]1[C:3]([F:40])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([NH:41][C:42]([CH3:46])([CH3:45])[CH2:43][OH:44])=[O:37])=[CH:33][N:32]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(C(=O)O)cn2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reactant: CC(C)(N)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(C(=O)NC(C)(C)CO)cn2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Yield: 22.8 %

Procedure:
To a solution of rac-6-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-nicotinic acid methyl ester prepared in Example 138 (0.2 g, 0.33 mmol) in tetrahydrofuran (3 mL) was added an aqueous solution (1 N) of NaOH (1 mL, 1 mmol) and methanol (1 mL). The reaction mixture was stirred at room temperature for 20 h, and the “pH” of the solution was adjusted to 5-6 by aqueous HCl solution. The mixture was extracted ethyl acetate twice. The combined organic extracts were washed with water, brine, dried over MgSO4, and concentrated to give rac-6-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-nicotinic acid as a white foam (0.12 g). In a manner similar to the method described in Examples 1e, rac-6-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-nicotinic acid (0.12 g, 0.2 mmol) was reacted with 2-amino-2-methyl-1-propanol (Aldrich) (0.1 g, 1.1 mmol), HATU (0.2 g, 0.5 mmol) and iPr2NEt (0.3 g, 2.3 mmol) in CH2Cl2 at room temperature for 20 h to give rac-6-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-N-(2-hydroxy-1,1-dimethyl-ethyl)-nicotinamide as a white solid (30 mg, 22%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.O.[OH-].[Na+].[I:18]I>C(Cl)(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([OH:8])[C:5]([I:18])=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1
Reactant: Nc1nc(O)cc(-c2ccccc2)n1
Reactant: II
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: Nc1nc(O)c(I)c(-c2ccccc2)n1
Yield: 78 %

Procedure:
Following the procedure of Example 16 but substituting 21.4 g. (0.113 M) of 2-amino-6-phenyl-4-pyrimidinol, 200 ml. water, 500 ml. chloroform, 5.6 g. sodium hydroxide and 28.8 g. I2, a yield of 29.0 g. (78%) of 2-amino-5-iodo-6-phenyl-4-pyrimidinol is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[C:10](=[O:11])[CH2:9][NH:8][S:7]1(=[O:13])=[O:12].[CH3:20][O:21][C:22]1[C:31]2[C:26](=[CH:27][C:28]([CH2:32]O)=[CH:29][CH:30]=2)[N:25]=[CH:24][CH:23]=1.C(P(CCCC)CCCC)CCC.CN(C(/N=N/C(N(C)C)=O)=O)C>C1COCC1.[Ni]>[CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[C:10](=[O:11])[CH2:9][N:8]([CH2:32][C:28]2[CH:27]=[C:26]3[C:31]([C:22]([O:21][CH3:20])=[CH:23][CH:24]=[N:25]3)=[CH:30][CH:29]=2)[S:7]1(=[O:13])=[O:12]
Reactant: COc1ccc(CN2C(=O)CNS2(=O)=O)c(OC)c1
Reactant: COc1ccnc2cc(CO)ccc12
Agent: [Ni]
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)/N=N/C(=O)N(C)C
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)CN(Cc3ccc4c(OC)ccnc4c3)S2(=O)=O)c(OC)c1
Reaction time: 18 h

Procedure:
745 mg (2.60 mmol) of the title B compound in Example 9, 2-(2,4-dimethoxybenzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one, 328 mg (1.73 mmol) of the title E compound, (4-methoxyquinoline-7-yl)-methanol and 448 mg (526 mg., 2.60 mmol) of tributylphosphine are stirred in 5 mL of THF. 448 mg (2.60 mmols) of TMAD is added and the mixture is stirred for 18 h. A spatula tip of Raney nickel is added, the mixture is stirred for 10 min, and then filtered through Celite. The filtrate is evaporated to dryness and chromatographed on a Biotage 40M column with 98:2 EtOAc/EtOH to afford 2-(2,4-dimethoxy-benzyl)-5-(4-methoxy-quinolin-7-ylmethyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one: mp=128-132° C.; 1H-NMR (CDCl3) δ 3.79 (2H, s), 3.81 (3H, s), 3.85 (3H, s), 4.06 (3H, s), 4.51 (2H, s), 4.82 (2H, s), 6.46 (2H, m), 6.78 (1H, d, J=5.2) 7.30 (1H, m), 7.53 (1H, dd, J=8.5, 1.5), 7.96 (1H, s), 8.22 (1H, d J=8.5), 8.77 (1H, d, J=5.2); [M+1]+=458.
Reaction SMILES: [O:1]=[C:2]1[C:10](=[C:11]2[C:19]3[C:14](=[CH:15][C:16]([CH2:20][CH2:21][CH2:22]OS(C)(=O)=O)=[CH:17][CH:18]=3)[CH2:13][O:12]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.O>CN(C=O)C>[N:28]1([CH2:22][CH2:21][CH2:20][C:16]2[CH:15]=[C:14]3[C:19](=[CH:18][CH:17]=2)[C:11](=[C:10]2[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[NH:3][C:2]2=[O:1])[O:12][CH2:13]3)[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1
Reactant: C1COCCN1
Reactant: CS(=O)(=O)OCCCc1ccc2c(c1)COC2=C1C(=O)Nc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C1Nc2ccccc2C1=C1OCc2cc(CCCN3CCOCC3)ccc21
Temperature: 90 °C
Yield: 98.3 %

Procedure:
A mixture of methanesulfonic acid 3-[1-(2-oxo-1,2-dihydro-indol-3-ylidene)-1,3-dihydro-isobenzofuran-5-yl]-propyl ester (400 mg, 1.04 mmol) and morpholine (1.5 ml, 17.2 mmol) in DMF (5 ml) was heated at 90° C. for 1.5 hours. The mixture was cooled, and poured into water (125 ml) with stirring. The solid was filtered, washed with water and dried under vacuum to give 3-[5-(3-morpholin-4-yl-propyl)-3H-isobenzofuran-1-ylidene]-1,3-dihydro-indol-2-one as a yellow solid (385 mg, 98%).
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH:19]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[C:20]([NH2:22])=[O:21])[CH2:14][CH2:13]2)=[CH:4]1.[F:29][C:30]1[CH:31]=[C:32]([CH:38]=[CH:39][CH:40]=1)/[CH:33]=[CH:34]/[C:35](O)=[O:36]>>[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH:19]([CH:23]3[CH2:24][CH2:25][N:26]([C:35](=[O:36])/[CH:34]=[CH:33]/[C:32]4[CH:38]=[CH:39][CH:40]=[C:30]([F:29])[CH:31]=4)[CH2:27][CH2:28]3)[C:20]([NH2:22])=[O:21])[CH2:14][CH2:13]2)=[CH:4]1
Reactant: O=C(O)/C=C/c1cccc(F)c1
Reactant: NC(=O)C(NC1CCC(c2c[nH]c3ccccc23)CC1)C1CCNCC1
Agent: Cl
Product: NC(=O)C(NC1CCC(c2c[nH]c3ccccc23)CC1)C1CCN(C(=O)/C=C/c2cccc(F)c2)CC1

Procedure:
The title compound was prepared from the product of Example 1, step J (0.50 mmol), trans-3-fluorocinnamic acid, by the method of Example 1, step K, giving the title compound as a white solid that was mostly the more polar cyclohexyl diastereomer by LCMS. Mass spectrum (LCMS, ESI pos.) calcd. for C30H35FN4O2: 503 (M+H). Found: 503
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[S:12][CH3:13])[CH2:6][C:7]#[N:8].C[O:15][N:16]=O>>[OH:15][N:16]=[C:6]([C:7]#[N:8])[C:5]1[CH:9]=[CH:10][C:11]([S:12][CH3:13])=[C:3]([S:2][CH3:1])[CH:4]=1
Reactant: CSc1ccc(CC#N)cc1SC
Reactant: CON=O
Product: CSc1ccc(C(C#N)=NO)cc1SC
Yield: 58.1 %

Procedure:
According to the method described under 1.1., 34.8 g (0.166 mol) of 3,4-bis(methylthio)benzyl cyanide are reacted with 0.166 mol methylnitrite. After the isolation 23.0 g (58%) α-hydroxyimino-3,4-bis(methylthio)benzyl cyanide are obtained as a brown substance with a melting point of 131-133° C. Elemental analysis: C10H10N2OS2 (238.33)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[CH:14][C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][NH:8]1.Br[CH2:27][C:28](Br)=[O:29].[NH2:31][C@@H:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[CH:14][C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][N:8]1[CH2:27][C:28]([NH:31][C@@H:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33]1)=[O:29]
Reactant: COc1cc2c(c(OC)c1)C(Cc1ccc(OC)c(OC)c1)NCC2
Reactant: N[C@H]1CCc2ccccc21
Reactant: O=C(Br)CBr
Product: COc1cc2c(c(OC)c1)C(Cc1ccc(OC)c(OC)c1)N(CC(=O)N[C@H]1CCc3ccccc31)CC2

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-6,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with (1S)-1-amino-indane
Reaction SMILES: C(=O)(SC)O[O:3][CH:4]([O:8][C:9](=[O:13])[CH:10]([CH3:12])[CH3:11])[CH:5]([CH3:7])[CH3:6].[OH:17][N:18]1[C:22](=[O:23])[C@H:21]([O:24][C:25](=[O:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:20]([O:33][C:34](=[O:41])[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:19]1=[O:42].[C:43](OO)(=[O:45])C.C(O)(=O)C>ClCCCl>[CH3:12][CH:10]([CH3:11])[C:9]([O:8][C@@H:4]([O:3][C:43]([O:17][N:18]1[C:22](=[O:23])[C@H:21]([O:24][C:25](=[O:32])[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C@@H:20]([O:33][C:34](=[O:41])[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:19]1=[O:42])=[O:45])[CH:5]([CH3:6])[CH3:7])=[O:13]
Reactant: CSC(=O)OOC(OC(=O)C(C)C)C(C)C
Reactant: O=C(O[C@H]1C(=O)N(O)C(=O)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Reactant: CC(=O)OO
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)C(=O)O[C@@H](OC(=O)ON1C(=O)[C@H](OC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)C1=O)C(C)C
Temperature: 15 °C
Yield: 25 %

Procedure:
A 3 L three necked round bottom flask fitted with a mechanical stirrer, Teflon coated temperature probe and an addition funnel was charged with compound (11) (234 g, 1 mol), compound (30) (330 g, 0.95 mol), and 1,2-dichloroethane (2200 mL). The reaction mixture was cooled under a nitrogen atmosphere in an ice water bath to 15° C. To the stirred reaction mixture was added a 39% solution of peracetic acid in dilute acetic acid (500 mL, 2.94 mol) over 2 h, maintaining the temperature between 15° C. and 22° C. This temperature was maintained for an additional 12 h during which time a white precipitate was formed. The reaction mixture was further cooled to 3-4° C., the product collected by filtration, and washed with hexane (2×1 L). The product was dried in vacuo, yielding the title compound (28) (128 g, 0.24 mol, 25% yield). The diastereomeric purity of the product was determined to be >99% d.e. by HPLC using a chiral column. 1H NMR (CDCl3, 400 MHz): δ 1.0 (d, 6H), 1.2 (dd, 6H), 2.1 (m, 1H), 2.65 (m, 1H), 6.0 (br. s, 2H), 6.6 (d, 1H), 7.45 (app. t, 4H), 7.65 (app. t, 2H), 8.05 (d, 4H).
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[N:11]([CH:12]([CH3:14])[CH3:13])[C:10]([CH2:15][O:16][CH3:17])=[N:9][CH:8]=1)=O.C(=O)(O)O.[C:23]1([NH:29][C:30]([NH2:32])=[NH:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C[O-].[Na+]>CC(N(C)C)=O>[NH:29]([C:30]1[N:32]=[C:5]([C:7]2[N:11]([CH:12]([CH3:14])[CH3:13])[C:10]([CH2:15][O:16][CH3:17])=[N:9][CH:8]=2)[CH:4]=[CH:3][N:31]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COCc1ncc(C(=O)C=CN(C)C)n1C(C)C
Reactant: N=C(N)Nc1ccccc1
Agent: C[O-]
Agent: O=C(O)O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COCc1ncc(-c2ccnc(Nc3ccccc3)n2)n1C(C)C
Temperature: 110 °C

Procedure:
5-(3-Dimethylaminoprop-2-en-1-oyl)-1-isopropyl-2-methoxymethylimidazole (Method 50; 1.26 g, 5 mmol), phenylguanidine hydrogen carbonate (1.09 g, 5.5 mmol) and sodium methoxide (594 mg, 11 mmol) were suspended in anhydrous DMA (10 ml) and the mixture heated at 110° C. for 3 hours. The volatiles were evaporated in vacuo the residues was suspended in water (50 ml). The solution was extracted DCM (3×50 ml). The combined extracts were washed with water (50 ml) and then brine (50 ml), dried and the volatiles removed by evaporation. The residue was purified by flash silica chromatography eluting with DCM:MeOH (100:0 increasing in polarity to 97:3) to give the title compound as brown oil. NMR: 1.43 (d, 6H), 3.30 (s, 3H), 4.56 (s, 2H), 5.54 (m, 1H), 6.96 (t, 1H), 7.05 (d, 1H), 7.24 (t,2H), 7.44 (s, 1H), 7.65 (d, 2H), 8.41 (d, 1H), 9.42 (s, 1H); m/z 324.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[CH:6][C:5]([C:8]([OH:10])=O)=[N:4]1)[CH3:2].CN(C)C=O.C(Cl)(=O)C(Cl)=O.[NH2:22][C:23]1[CH:24]=[C:25]([CH:42]=[CH:43][C:44]=1[F:45])[O:26][C:27]1[CH:28]=[CH:29][C:30]2[N:31]([CH:33]=[C:34]([NH:36][C:37]([CH:39]3[CH2:41][CH2:40]3)=[O:38])[N:35]=2)[N:32]=1>CN(C)C(=O)C.O1CCCC1>[CH:39]1([C:37]([NH:36][C:34]2[N:35]=[C:30]3[CH:29]=[CH:28][C:27]([O:26][C:25]4[CH:42]=[CH:43][C:44]([F:45])=[C:23]([NH:22][C:8]([C:5]5[CH:6]=[CH:7][N:3]([CH2:1][CH3:2])[N:4]=5)=[O:10])[CH:24]=4)=[N:32][N:31]3[CH:33]=2)=[O:38])[CH2:40][CH2:41]1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Reactant: CCn1ccc(C(=O)O)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCn1ccc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2F)n1
Yield: 40.5 %

Procedure:
Using 1-ethyl-1H-pyrazole-3-carboxylic acid (128 mg, 0.92 mmol), tetrahydrofuran (2.0 mL), N,N-dimethylformamide (20 μL, 0.26 mmol), oxalyl chloride (80 μL, 0.92 mmol), N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.61 mmol) and N,N-dimethylacetamide (4.0 mL), and in the same manner as in Example 238, the title compound (111 mg, 40%) was obtained as a white powder.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[O:22][C:23]([C@@H:26]3[CH2:32][CH2:31][C@@H:30]4[CH2:33][N:27]3[C:28](=[O:39])[N:29]4[O:34][S:35]([OH:38])(=[O:37])=[O:36])=[N:24][N:25]=2)[CH2:17][CH2:16]1)=O)(C)(C)C.C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl.CCOCC>[S:35]([OH:38])([O:34][N:29]1[C:28](=[O:39])[N:27]2[CH2:33][C@H:30]1[CH2:31][CH2:32][C@H:26]2[C:23]1[O:22][C:21]([N:18]2[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]2)=[N:25][N:24]=1)(=[O:36])=[O:37]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nnc([C@@H]3CC[C@@H]4CN3C(=O)N4OS(=O)(=O)O)o2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1N2C[C@@H](CC[C@H]2c2nnc(N3CCNCC3)o2)N1OS(=O)(=O)O
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 35.6 %

Procedure:
TFA (0.30 mL) was added to a 0° C. mixture of tetrabutylammonium tert-butyl 4-(5-((2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octan-2-yl)-1,3,4-oxadiazol-2-yl)piperazine-1-carboxylate (21 mg, 0.03 mmol) in dry DCM (0.80 mL). The reaction mixture was stirred at 0° C. for 2-3 hrs then diluted with ether (−15 mL). The precipitate was collected via centrifugation, washed with ether (3×) and dried under high vacuum to afford (2S,5R)-7-oxo-2-(5-(piperazin-1-yl)-1,3,4-oxadiazol-2-yl)-1,6-diazabicyclo[3.2.1]octan-6-yl hydrogen sulfate (4 mg, 35%) as a light yellow solid after prep-HPLC purification using ammonium formate buffer. ESI-MS (EI+, m/z): 375.2. 1H NMR (300 MHz, D2O) δ 4.65 (d, J=6.6 Hz, 1H), 4.19 (br s, 1H), 3.80-3.65 (m, 2H), 3.38-3.28 (m, 2H), 3.20-3.16 (m, 1H), 2.99-2.95 (m, 1H), 2.32-1.88 (m, 4H).