Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH:3]([CH3:7])[C:4]([OH:6])=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.OC(C(F)(F)F)=O.[F:48][C:49]1[CH:75]=[C:74]([F:76])[CH:73]=[CH:72][C:50]=1[O:51][CH:52]1[CH2:57][CH2:56][N:55]([C:58]2[N:59]=[C:60]3[CH2:71][CH2:70][NH:69][CH2:68][C:61]3=[N:62][C:63]=2[NH:64][CH:65]([CH3:67])[CH3:66])[CH2:54][CH2:53]1>CC(N(C)C)=O>[F:48][C:49]1[CH:75]=[C:74]([F:76])[CH:73]=[CH:72][C:50]=1[O:51][CH:52]1[CH2:53][CH2:54][N:55]([C:58]2[N:59]=[C:60]3[CH2:71][CH2:70][N:69]([C:4](=[O:6])[CH:3]([O:2][CH3:1])[CH3:7])[CH2:68][C:61]3=[N:62][C:63]=2[NH:64][CH:65]([CH3:67])[CH3:66])[CH2:56][CH2:57]1
Reactant: COC(C)C(=O)O
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCNC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC(C)C(=O)N1CCc2nc(N3CCC(Oc4ccc(F)cc4F)CC3)c(NC(C)C)nc2C1
Temperature: 60 °C
Reaction time: 0.75 h

Procedure:
To a solution of 2-methoxypropanoic acid (10.8 μL, 0.113 mmol) in DMA (0.4 mL) at room temperature was added DIPEA (45.5 μL, 0.261 mmol) and HATU (42.9 mg, 0.113 mmol). To this was added a solution of 2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (45.0 mg, 0.087 mmol) in DMA (0.47 mL). The resulting reaction mixture was stirred at 60° C. for 45 min. The reaction mixture was allowed to cool to room temperature and was purified directly by HPLC Method B, with the exception that a Waters SunFire™ C18, 5 μm, ID 30×75 mm column was used, using a 50% to 80% ACN gradient to give the title compound, as a TFA salt, as a pale yellow solid (11.2 mg, 21.4%). 1H NMR (400 MHz, methanol-d4) δ ppm 1.36 (m, 9H), 1.98 (m, 2H), 2.14 (m, 2H), 2.83 (m, 2H), 3.16 (m, 2H), 3.35 (s, 3H), 3.49 (m, 2H), 3.90 (m, 1H), 3.93 (t, J=5.8 Hz, 1H), 4.12 (m, 1H), 4.35 (m, 1H), 4.52 (m, 1H), 4.59-4.79 (m, 2H), 6.88 (m, 1H), 6.99 (ddd, J=11.4, 8.6, 3.0 Hz, 1H), 7.18 (td, J=9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+ 490.5.
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[CH:9]=[C:10]([CH2:14][CH2:15][CH2:16][OH:17])[CH:11]=[CH:12][CH:13]=1.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.Cl>C(Cl)(Cl)Cl.O>[Cl:7][C:8]1[CH:9]=[C:10]([CH2:14][CH2:15][CH2:16][O:17][S:24]([C:21]2[CH:22]=[CH:23][C:18]([CH3:28])=[CH:19][CH:20]=2)(=[O:26])=[O:25])[CH:11]=[CH:12][CH:13]=1
Reactant: OCCCc1cccc(Cl)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)OCCCc2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
86 ml of pyridine are added dropwise to 90 g of 3-(3-chlorophenyl)propan-1-ol and 124 g of p-toluenesulfonic acid chloride in 300 ml of chloroform at 0° C. When the addition is complete, the mixture is stirred at room temperature for 3 hours, and the solution is poured into a mixture of 400 ml of water and 120 ml of concentrated hydrochloric acid. The organic phase is separated off, washed 3 times with water, dried over sodium sulfate and concentrated to a viscous oil in vacuo.
Reaction SMILES: [CH2:1]([N:3]([CH2:8][CH3:9])[CH2:4][CH2:5][CH2:6][OH:7])[CH3:2].[H-].[Na+].[H][H].C[O:15][C:16]([C:18]1[C:27]2[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=2[CH:21]=[CH:20][C:19]=1[NH:28][S:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1F)(=[O:31])=[O:30])=[O:17].[I-].[Na+]>CN(C=O)C>[CH2:1]([N:3]([CH2:8][CH3:9])[CH2:4][CH2:5][CH2:6][O:7][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[S:29]([NH:28][C:19]1[CH:20]=[CH:21][C:22]2[CH2:23][CH2:24][CH2:25][CH2:26][C:27]=2[C:18]=1[C:16]([OH:17])=[O:15])(=[O:30])=[O:31])[CH3:2]
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccccc2F)ccc2c1CCCC2
Reactant: [H][H]
Reactant: CCN(CC)CCCO
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC)CCCOc1ccccc1S(=O)(=O)Nc1ccc2c(c1C(=O)O)CCCC2
Temperature: 72.5 °C
Reaction time: 72 h
Yield: 27.9 %

Procedure:
A solution of 3-diethylamino-1-propanol (217 mg, 1.65 mmol) in 1 mL dry DMF was added dropwise to 60% sodium hydride dispersion (55 mg, 1.38 mmol). The mixture was stirred until hydrogen evolution ceased. To this mixture was added a solution of 2-([(2-fluorophenyl)sulfonyl]amino)-5,6,7,8-tetrahydro-1-napthalenecarboxylic acid methyl ester (100 mg, 0.28 mmol) in 1 mL of DMF. The mixture was stirred at 70 to 75° C. for three days, concentrated, and dissolved in 2 mL of pyridine. The mixture was treated with 3 equivalents of sodium iodide, heated in a microwave reactor at 150° C. for 25 minutes, and concentrated. The concentrate was purified by C18 reverse-phase HPLC using acetonitrile/water/0.1% TFA to provide the desired product (36 mg, 57.1%). MS (APCI): m/e 461.3 (M+H)+; 1H NMR (400 MHz, CD3OD) δ 7.74 (dd, 1H), 7.54 (dt, 1H), 7.27 (d, 1H) 7.12 (d, 1H), 6.98-7.04 (m, 2H), 4.27 (t, 2H), 3.43-3.51 (m, 2H), 3.25-3.36 (m, 6H), 3.65-3.81 (m, 4H), 3.35 (m, 2H), 1.70 (m, 4H), 1.37 (t, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]#[C:10][C:11]2[CH:12]=[N:13][CH:14]=[C:15]([CH:18]=2)[C:16]#[N:17])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:19][S:20](Cl)(=[O:22])=[O:21]>N1C=CC=CC=1.O1CCCC1.O>[C:16]([C:15]1[CH:18]=[C:11]([C:10]#[C:9][C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([NH:1][S:20]([CH3:19])(=[O:22])=[O:21])[CH:3]=2)[CH:12]=[N:13][CH:14]=1)#[N:17]
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1cncc(C#Cc2ccc(F)c(N)c2)c1
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)Nc1cc(C#Cc2cncc(C#N)c2)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.8 %

Procedure:
Dissolve 5-(3-amino-4-fluorophenylethynyl)-nicotinonitrile, (prepared as described in EXAMPLE 160), (0.2 g, 0.8 mmol) in anhydrous pyridine. Add a solution of methanesulfonyl chloride (0.1 g, 0.88 mmol) in tetrahydrofuran to the reaction and stir overnight at room temperature. Concentrate and dissolve the crude reaction in ethyl acetate and water. Wash the organic layer with water, an aqueous saturated solution of sodium chloride, dry (potassium carbonate), filter, concentrate and purify (silica gel chromatography, eluting with 95:5 to 80:20 dichloromethane:ethyl acetate), to give the title compound as a tan solid (50 mg, 20%).
Reaction SMILES: C(O)(=O)C.C[Si]([N:9]=[N+:10]=[N-:11])(C)C.[C:12]1(=[O:17])[CH2:16][CH2:15][CH:14]=[CH:13]1.C(N(CC)CC)C>ClCCl>[N:9]([CH:14]1[CH2:15][CH2:16][C:12](=[O:17])[CH2:13]1)=[N+:10]=[N-:11]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: O=C1C=CCC1
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: ClCCl
Product: [N-]=[N+]=NC1CCC(=O)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 52.3 %

Procedure:
To a solution of acetic acid (20 g, 0.33 mol) in dichloromethane (375 mL) was added trimethylsilyl azide (38 g, 0.33 mol), and the mixture was stirred at room temperature for 20 minutes. Then cyclopent-2-enone (9 g, 0.11 mol) was added to the reaction mixture followed by triethylamine (2.22 g, 0.022 mol), and the mixture was stirred at room temperature for 48 hours. The resulting mixture was quenched with aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The organic layer was washed with brine three times and purified by column chromatography (Hexanes/ethyl acetate=1:3) to give 7.2 g of 3-Azido-cyclopentanone as a colorless liquid (TLC showed two spots), which was used for next step directly. 1H NMR (400 MHz, CDCl3): δ: 4.31-4.26 (m, 1H), 2.46-2.08 (m, 6H).
Reaction SMILES: C[O-].[Na+].[Cl:4][C:5]1[CH:6]=[CH:7][C:8]2[NH:14][C:13](=[O:15])[CH2:12][N:11]=[C:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9]=2[CH:22]=1.CN(C)C=O.Br[CH2:29][C:30]([O:32][CH3:33])=[O:31]>C1(C)C=CC=CC=1>[CH3:33][O:32][C:30](=[O:31])[CH2:29][N:14]1[C:8]2[CH:7]=[CH:6][C:5]([Cl:4])=[CH:22][C:9]=2[C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:11][CH2:12][C:13]1=[O:15]
Reactant: O=C1CN=C(c2ccccc2)c2cc(Cl)ccc2N1
Reactant: COC(=O)CBr
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COC(=O)CN1C(=O)CN=C(c2ccccc2)c2cc(Cl)ccc21
Reaction time: 8 h
Yield: 42 %

Procedure:
Sodium methoxide (5.95 g., 0.11 mole) is added to a solution of 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (27 g., 0.1 mole) in 200 ml. of dimethylformamide and the mixture is stirred and heated on a steambath for about 20 minutes. To this mixture is added a solution of methyl bromoacetate (16.7 g., 0.11 mole) in 165 ml. of toluene during 1 hour while stirring and heating are continued. The mixture is heated for an additional 2 hours, allowed to stand overnight at room temperature (about 25° C.) and evaporated to dryness in vacuo. The residue is stirred with 500 ml. of water until a suspension results. The suspension is filtered and the solid thus obtained is crystallized first from ether and then from ethanol to give 14.5 g. (42% yield) of 7-chloro-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-1-acetic acid methyl ester of melting point 137°-138° C.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]([N:8]([O:10][CH3:11])[CH3:9])=[O:7])=[CH:4][C:3]=1[OH:14].N1C=CN=C1.[CH3:20][C:21]([Si:24](Cl)([CH3:26])[CH3:25])([CH3:23])[CH3:22]>CN(C=O)C>[Si:24]([O:14][C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][C:2]=1[F:1])[C:6]([N:8]([O:10][CH3:11])[CH3:9])=[O:7])([C:21]([CH3:23])([CH3:22])[CH3:20])([CH3:26])[CH3:25]
Reactant: CON(C)C(=O)c1ccc(F)c(O)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1ccc(F)c(O[Si](C)(C)C(C)(C)C)c1
Reaction time: 48 h
Yield: 66.8 %

Procedure:
To a solution of 4-fluoro-3-hydroxy-N-methoxy-N-methylbenzamide (1.90 g, 9.55 mmol) in DMF (8 mL) was added imidazole (740 mg, 10.8 mmol) and TBDMSCl (1.62 g, 10.8 mmol) at room temperature. The reaction mixture was stirred for 48 h and quenched with saturated NaHCO3. The solution was extracted with ether (3×) and the combined ether portions were washed with LiCl (10%), dried over Na2SO4, filtered and concentrated. The resulting colorless oil was purified by ISCO chromatography (120 g column) using hexanes/EtOAc (0-100% over 30 min) to give 3-(tert-butyldimethylsilyloxy)-4-fluoro-N-methoxy-N-methylbenzamide (RT=10-12 minutes) as a colorless oil (2.00 g, 67% yield). LCMS: RT=2.06 min [M+H] 314.22 (Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); NMR: 400 MHz 1H (CDCl3) 7.26 ppm, 2H, m; 7.02 ppm, 1H, m; 3.50 ppm, 3H, s; 3.31 ppm, 3H, s; 0.97 ppm, 9H, s, 0.16 ppm, 6H, s.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-].[K+].C(Cl)(Cl)Cl.Cl.[CH2:19]([OH:21])C>C1(C)C=CC=CC=1>[OH:11][C:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[C:4]([CH:19]=[O:21])=[CH:3][CH:2]=1
Reactant: CCO
Reactant: Oc1cccc2c1CCCC2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: O=Cc1ccc(O)c2c1CCCC2
Reaction time: 0.25 h

Procedure:
5,6,7,8-Tetrahydro-naphthalen-1-ol (108, 20 g, 135 mmol) was stirred in 100 mL of ethanol, and potassium hydroxide (7.57 g, 135 mmol) as an aqueous solution was added. The mixture was stirred for 15 minutes and went clear. Solvents were removed and dried. PEG (MW 380-420, 53 mL) was added, followed by chloroform (32.3 mL, 405 mmol) and toluene (34 mL). An aqueous potassium hydroxide solution (50% by weight, 54.4 mL) was introduced dropwise with stirring over 15 minutes. The stirring was continued for another 30 minutes. 1M HCl was added to acidify the reaction mixture and it was extracted with EtOAc three times. The combined organic layers were washed with water and brine The combined organic layers were dried over MgSO4, filtered, concentrated, and purified by flash chromatography (0-40% EtOAc/hexane) to give 4-hydroxy-5,6,7,8-tetrahydro-naphthalene-1-carbaldehyde (109, 4.7 g).
Reaction SMILES: [C:1]([NH:6][C:7]1[CH:8]=[C:9]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:5])[CH2:2][CH2:3][CH3:4].[H-].[Na+].[CH2:23](I)[CH2:24][CH2:25][CH3:26].Cl>CN(C)C=O.C(OCC)(=O)C>[CH2:23]([CH2:4][CH2:3][CH2:2][C:1]([NH:6][C:7]1[CH:8]=[C:9]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:5])[CH2:24][CH2:25][CH3:26]
Reactant: CCCCI
Reactant: CCCC(=O)Nc1cc(C(=O)OCC)ccc1[N+](=O)[O-]
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCCC(=O)Nc1cc(C(=O)OCC)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 116 %

Procedure:
A solution of 1.86 g of ethyl 3-butyrylamino-4-nitrobenzoate in 10 ml of N,N-dimethylformamide was added dropwise to a slurry of 0.428 g of 60% sodium hydride and 10 ml of N,N-dimethylformamide at room temperature, and the mixture was stirred at room temperature for 30 minutes. Subsequently, a solution of 1.97 g of n-butyl iodide in 10 ml of N,N-dimethylformamide was added dropwise thereto, and the mixture was heated at 50° C. for 13 hours. The reaction solution was poured into a mixed solution of 70 g of dilute hydrochloric acid and 70 g of ethyl acetate for extraction. The resulting organic layer was washed twice with water, dried, and then concentrated under reduced pressure to obtain 2.59 g of crude ethyl 3-(N-n-butylbutyrylamino)-4-nitrobenzoate. Then, 0.81 g of 1-n-butyl-6-ethoxycarbonyl-2-n-propylbenzimidazole (94) were formed in the same manner as in Example 24.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C([O:20][C:21](=[O:37])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]2[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][C:30]=2[CH3:36])[CH:23]=1)(C)(C)C>ClCCCl.C(O)(C)(C)C>[ClH:1].[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][N:3]=[C:2]2[NH:35][C:32]1[CH:33]=[CH:34][C:29]([O:28][C:24]2[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=2)[C:21]([OH:37])=[O:20])=[C:30]([CH3:36])[CH:31]=1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: Cc1cc(N)ccc1Oc1cccc(C(=O)OC(C)(C)C)c1
Solvent: CC(C)(C)O
Solvent: ClCCCl
Product: COc1cc2ncnc(Nc3ccc(Oc4cccc(C(=O)O)c4)c(C)c3)c2cc1OC
Product: Cl
Temperature: 90 °C
Yield: 92.7 %

Procedure:
To a suspension of 4-chloro-6,7-dimethoxy-quinazoline (3.0 g, 13.35 mmol) in 1,2-dichloroethane (40 mL) and tert-butyl alcohol (40 mL) was added 3-(4-amino-2-methyl-phenoxy)-benzoic acid tert-butyl ester (3.99 g, 13.35 mmol). The reaction was heated at 90° C. for 90 minutes. The reaction was then cooled to room temperature and hydrogen chloride gas was bubbled through the solution for 40 minutes. A small amount of hot methanol was added to solublize the gummed solids. Solids then crashed out upon cooling. The solids were filtered and rinsed with cold ethyl acetate. The solids were further dried at 50° C. in a vacuum oven, yielding light yellow solids as the mono hydrochloride salt (5.79 g, 93%). 1H NMR (400 MHz, DMSO-d6) δ 11.39(bs, 1H), 8.82(s, 1H), 8.29(s, 1H), 7.64(d, J=7.06 Hz, 1H), 7.63(s, 1H), 7.55(d, J=8.72 Hz, 1H), 7.50(t, J=15.78, 7.89 Hz, 1H), 7.33(s, 1H), 7.30(s, 1H), 7.08(d, J=8.72 Hz, 1H), 3.98(s, 3H), 3.96(s, 3H), 2.17(s, 3H), LRMS (M+): 732.3, (M−): 430.3.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=C(C=C)[C:5]([CH2:21][O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)=[C:6]2[C:10]=1[N:9]([S:11]([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:8]=[CH:7]2.O.CC[C@H]1[C@H]2C[C@H]([C@H](OC3C4C(=CC=CC=4)C(O[C@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C([O:53]C)C=C4)N(CC2)C1.[C:90]([OH:94])(C)([CH3:92])[CH3:91]>>[CH3:1][C:2]1[CH:3]=[C:91]([CH:90]([OH:94])[CH2:92][OH:53])[C:5]([CH2:21][O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)=[C:6]2[C:10]=1[N:9]([S:11]([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:8]=[CH:7]2
Reactant: C=Cc1cc(C)c2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1COC1CCCCO1
Reactant: CC(C)(C)O
Reactant: CC[C@@H]1CN2CC[C@@H]1C[C@@H]2[C@H](Oc1nnc(O[C@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(COC4CCCCO4)c(C(O)CO)cc(C)c32)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a suspension of (±)-7-methyl-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-tosyl-5-vinyl-1H-indole (1.8 g, 4.2 mmol) in tert-BuOH (70 mL)/H2O (70 mL) was added AD-mix-alpha (5 g, 4.2 mmol), and then the mixture was stirred at room temperature for 24 h. The reaction was quenched by aq. Na2S2O3, and the whole mixture was stirred for 0.25 h. The mixture was diluted with CH2Cl2 and partitioned. The organic phase was washed with H2O and brine, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by SiO2 column chromatography (CH2Cl2/MeOH=94/6) to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ 7.84 (d, J=3.79 Hz, 1H), 7.62 (d, J=8.34 Hz, 2H), 7.40 (d, J=8.34 Hz, 2H), 7.18 (s, 1H), 6.95-6.98 (m, 1H), 5.14 (dd, J=3.92, 6.95 Hz, 1H), 4.69-5.03 (m, 3H), 4.52-4.68 (m, 2H), 3.74-3.92 (m, 1H), 3.44-3.55 (m, 1H), 2.46 (s, 3H), 2.34 (s, 3H), 1.34-1.74 (m, 6H).
Reaction SMILES: CCN(CC)CC.[C:8]([O:12][C:13](=[O:29])[N:14]=[C:15]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])N1C=CC=N1)([CH3:11])([CH3:10])[CH3:9].[NH2:30][CH2:31][C:32]1([C:35]2[O:39][C:38]([CH:40]3[CH2:46][CH2:45][C@@H:44]4[CH2:47][N:41]3[C:42](=[O:56])[N:43]4[O:48][CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[N:37][N:36]=2)[CH2:34][CH2:33]1>CO>[C:25]([O:24][C:22]([N:21]=[C:15]([NH:14][C:13]([O:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:29])[NH:30][CH2:31][C:32]1([C:35]2[O:39][C:38]([CH:40]3[CH2:46][CH2:45][C@@H:44]4[CH2:47][N:41]3[C:42](=[O:56])[N:43]4[O:48][CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[N:37][N:36]=2)[CH2:33][CH2:34]1)=[O:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)n1cccn1
Reactant: NCC1(c2nnc(C3CC[C@@H]4CN3C(=O)N4OCc3ccccc3)o2)CC1
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N=C(NCC1(c2nnc(C3CC[C@@H]4CN3C(=O)N4OCc3ccccc3)o2)CC1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.5 %

Procedure:
Et3N (5 g, 0.05 mol) and tert-butyl(((tert-butoxycarbonyl)amino)(1H-pyrazol-1-yl)methylene)carbamate (5.5 g, 17.5 mmol) were added to a solution of (5R)-2-(5-(1-(aminomethyl)cyclopropyl)-1,3,4-oxadiazol-2-yl)-6-(benzyloxy)-1,6-diaza-bicyclo[3.2.1]octan-7-one (7 g, 0.017 mol) in CH3OH (500 mL). The mixture was stirred at rt for 4 hrs and then concentrated. The residue was purified by silica gel column chromatography (gradient elution 50 to 66% EtOAc/petroleum ether) to afford (5R)-2-(5-(1-(2,3-bis-(tert-butoxycarbonyl)-guanidinomethyl)cyclopropyl)-1,3,4-oxadiazol-2-yl)-6-(benzyloxy)-1,6-diaza-bicyclo[3.2.1]octan-7-one (9 g, 86%) as a white solid. ESI-MS (EI+, m/z): 612.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.S(O[CH2:22][CH:23]1[CH2:26][CH2:25][CH2:24]1)(C1C=CC(C)=CC=1)(=O)=O.O>CN(C=O)C.[K]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:22][CH:23]2[CH2:26][CH2:25][CH2:24]2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: Cc1ccc(S(=O)(=O)OCC2CCC2)cc1
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cc(Cl)ccc1OCC1CCC1
Temperature: 50 °C
Reaction time: 16 h
Yield: 117.1 %

Procedure:
5-Chlorosalicylaldehyde (7.7 g, 49.4 mmol) was dissolved in DMF (20 ml) with potassium carbonte (7.5 g, 54.1 mmol) and the cyclobutanemethanol tosylate (1 3 g, 54.1 mmol). The mixture was stirred at 50° C. under argon for 16 hours. Poured into water (500 ml). extracted with ethyl acetate (4×100 ml)and the combined organic fractions washed with 1M sodium hydroxide solution (100 ml), water (100 ml), saturated brine (100 ml) dried (MgSO4) and concentrated in vacuo to give 5-chloro-2-(cyclobutylmethoxy)benzaldehyde as a brown oil (13 g) which was used without further purification.
Reaction SMILES: Cl.[NH2:2][C:3]1([C:8]([N:10]2[C@@H:14]([CH3:15])[CH2:13][CH2:12][C@H:11]2[CH3:16])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4]1.[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[N:25]1[C:32]2[C@@H:31]3[CH2:33][C@@H:30]3[CH2:29][C:28]=2[C:27]([C:34](O)=[O:35])=[N:26]1>>[CH3:16][C@H:11]1[CH2:12][CH2:13][C@@H:14]([CH3:15])[N:10]1[C:8]([C:3]1([NH:2][C:34]([C:27]2[C:28]3[CH2:29][C@H:30]4[CH2:33][C@H:31]4[C:32]=3[N:25]([C:19]3[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:18]=3[F:17])[N:26]=2)=[O:35])[CH2:7][CH2:6][CH2:5][CH2:4]1)=[O:9]
Reactant: O=C(O)c1nn(-c2ccc(F)cc2F)c2c1C[C@H]1C[C@@H]21
Reactant: C[C@@H]1CC[C@H](C)N1C(=O)C1(N)CCCC1
Agent: Cl
Product: C[C@@H]1CC[C@H](C)N1C(=O)C1(NC(=O)c2nn(-c3ccc(F)cc3F)c3c2C[C@H]2C[C@@H]32)CCCC1

Procedure:
The title compound was prepared in a manner similar to that described in Method G using (1-aminocyclopentyl)((2R,5S)-2,5-dimethylpyrrolidin-1-yl)methanone hydrochloride and (1aR,5aR)-2-(2,4-Difluoro-phenyl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid. LCMS m/z=469.5 [M+H]+; 1H NMR (400 MHz, CD3CN) δ ppm 0.39-0.43 (m, 1H), 0.89-1.27 (m, 8H), 1.57-1.69 (m, 7H), 1.96-2.11 (m, 1H), 2.13-2.18 (m, 3H), 2.23-2.30 (m, 1H), 2.52-2.70 (m, 1H), 2.80 (d, J=17.2 Hz, 1H), 2.91 (dd, J=16.6, 6.6 Hz, 1H), 3.93-4.39 (m, 2H), 7.13-7.25 (m, 3H), 7.72 (td, J=8.8, 5.9 Hz, 1H).
Reaction SMILES: CO[CH:3]1[N:7]([C:8]([O:10][CH3:11])=[O:9])[C@H:6]([C:12]([O:14][CH3:15])=[O:13])[CH2:5][CH2:4]1.C[Si]([C:20]#[C:21][CH3:22])(C)C.[Sn](Cl)(Cl)(Cl)Cl.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[CH:20]([C@@H:3]1[N:7]([C:8]([O:10][CH3:11])=[O:9])[C@H:6]([C:12]([O:14][CH3:15])=[O:13])[CH2:5][CH2:4]1)=[CH:21][CH3:22]
Reactant: COC(=O)[C@@H]1CCC(OC)N1C(=O)OC
Reactant: CC#C[Si](C)(C)C
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC=C[C@H]1CC[C@@H](C(=O)OC)N1C(=O)OC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a cold −45° C. solution of dimethyl (2S)-5-methoxypyrrolidine-1,2-dicarboxylate (10 g, 46.08 mmol, Example 1B) and trimethylsilylpropyne (14.24 ml, 92.16 mmol, 2.0 equiv) in methylene chloride (180 mL) was added a solution of tin (IV) chloride (1 Min methylene chloride, 60.0 mL, 60.0 mmol, 1.3 equiv) dropwise via an addition funnel over 30 minutes. To the dark yellow solution was added solid aluminum chloride (8.58 g, 64.52 mmol, 1.4 equiv) in one portion. The resulting mixture was allowed to warm to room temperature and stirred at room temperature for 48 hours. The reaction mixture was carefully quenched by saturated aqueous NH4OH (100 mL) with ice cooling. A white precipitate formed and was removed by filtration. The crude product was obtained after concentration. The residue was chromatographed on a Biotage flash 40 M eluting with 70% hexane/30% ethyl acetate to afford the titled compound. MS (DCI/NH3) m/e 226 (M+H)+.