Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH:12]2[CH2:14][CH2:13]2)[CH:3]=1.Cl[CH2:16][CH2:17][CH2:18][S:19](Cl)(=[O:21])=[O:20]>>[CH:12]1([C:4]2[CH:3]=[C:2]([N:1]3[CH2:16][CH2:17][CH2:18][S:19]3(=[O:21])=[O:20])[CH:11]=[CH:10][C:5]=2[C:6]([O:8][CH3:9])=[O:7])[CH2:14][CH2:13]1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: COC(=O)c1ccc(N)cc1C1CC1
Product: COC(=O)c1ccc(N2CCCS2(=O)=O)cc1C1CC1

Procedure:
To a mixture of methyl 2-bromo-4-nitrobenzoate (871 mg), bis(tricyclohexylphosphine)palladium(II)dichloride (136 mg), tripotassium phosphate (3.98 g) and cyclopropylboronic acid (863 mg) were added toluene (10 mL) and water (0.4 mL), and the mixture was stirred with heating under reflux for 8 hr. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The solvent was evaporated from the organic layer, and the obtained residue was purified by column chromatography (ethyl acetate:hexane) to give methyl 2-cyclopropyl-4-nitrobenzoate (285 mg). The obtained methyl 2-cyclopropyl-4-nitrobenzoate (285 mg) was dissolved in a solution of ethyl acetate and ethanol, and catalytic hydrogenation was performed using palladium carbon to give methyl 4-amino-2-cyclopropylbenzoate (189 mg). Using the obtained methyl 4-amino-2-cyclopropylbenzoate (189 mg) and 3-chloropropane-1-sulfonyl chloride (0.156 mL) and by the reaction and treatment in the same manner as in Preparation Example 17, the title compound (168 mg) was obtained.
Reaction SMILES: C([O:8][C:9]([CH:11]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:12]([NH:14][C@H:15]1[C@@H:18]([C:19]([O:21][CH3:22])=[O:20])[N:17]([S:23]([O-:26])(=[O:25])=[O:24])[C:16]1=[O:27])=[O:13])=[O:10])C1C=CC=CC=1.[Na+].C(=O)([O-])O.[Na+]>[Pd].C(O)C>[C:9]([CH:11]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:12]([NH:14][C@H:15]1[C@@H:18]([C:19]([O:21][CH3:22])=[O:20])[N:17]([S:23]([OH:26])(=[O:25])=[O:24])[C:16]1=[O:27])=[O:13])([OH:10])=[O:8]
Reactant: COC(=O)[C@@H]1[C@H](NC(=O)C(C(=O)OCc2ccccc2)c2ccccc2)C(=O)N1S(=O)(=O)[O-]
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COC(=O)[C@@H]1[C@H](NC(=O)C(C(=O)O)c2ccccc2)C(=O)N1S(=O)(=O)O
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To 6 ml of 80% ethanol are added 106 mg of sodium cis-3-(2-benzyloxycarbonyl-2-phenylacetamido)-4-methoxycarbonyl-2-oxoazetidine-1-sulfonate, 106 mg of 5% palladium-on-carbon and 16.8 mg of sodium hydrogen carbonate, and the mixture is vigorously stirred under hydrogen atmosphere for 3.5 hours at ambient temperature under atmosphere pressure. The reaction mixture is subjected to filtration, and the filtrate is concentrated under reduced pressure. The concentrate is purified by column chromatography on Amberlite XAD-II, followed by lyophilization to give cis-3-(2-carboxy-2-phenylacetamido)-4-methoxycarbonyl-1-sulfo-2-oxoazetidine.disodium salt as a mixture of diastereomers.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][CH2:18][CH:17](Br)[C:16]2=[O:21])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:22]#[N:23].[Na+].[I-].[Na+].O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][CH2:18][CH:17]([C:22]#[N:23])[C:16]2=[O:21])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C(Br)CCN1c1ccc(OCc2ccccc2)cc1
Reactant: [C-]#N
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC1CCN(c2ccc(OCc3ccccc3)cc2)C1=O
Temperature: 120 °C
Reaction time: 0.17 h
Yield: 13 %

Procedure:
300 mg (0.87 mmol) of (RS)-1-(4-benzyloxy-phenyl)-3-bromo-pyrrolidin-2-one is dissolved in 5 ml N,N-dimethylformamide. 64 mg (1.3 mmol) sodium cyanide and 13 mg (0.09 mmol) sodium iodide are added and the suspension stirred for 10 min. at 120° C. The reaction mixture is treated with water and extracted with ethyl acetate to yield 33 mg (13%) of a colorless solid. MS: m/e=293.3 (M+H)+.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1>C(OCC)(=O)C.C(O)C.[Pd]>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=[N+]([O-])c1ccc(-n2ccnc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1ccc(-n2ccnc2)cc1
Yield: 80 %

Procedure:
A solution of 4-(1H-imidazol-1-yl)-nitrobenzene (20 g; ~0.11 mol) in a mixture of 500 ml ethyl acetate and 500 ml ethanol was hydrogenated in a Parr hydrogenation apparatus at 28.12 kPa (40 psi) and 25° C. by using 0.5 g 5% Pd-C as a catalyst. The reaction mixture was filtered and evaporated in vacuo to give the title compound (14 g) as crystals. M.p. 142°-144° C.
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7](C=C[C:10]4[C@:15]3([CH3:16])[CH:14]=[CH:13][C:12](=[O:20])[CH:11]=4)[C@@H:6]1[CH2:5][CH2:4][C:3]2=[O:21].[O:22]1[CH2:27][CH2:26][O:25]CC1>[Os](=O)(=O)(=O)=O.N1C=CC=CC=1>[OH:22][C@H:27]1[C:14]2[C@:15]([CH3:16])([CH:10]=[CH:11][C:12](=[O:20])[CH:13]=2)[C@@H:17]2[C@H:7]([C@H:6]3[C@@:2]([CH2:19][CH2:18]2)([CH3:1])[C:3](=[O:21])[CH2:4][CH2:5]3)[C@H:26]1[OH:25]
Reactant: C[C@]12C=CC(=O)C=C1C=C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: C1COCCO1
Agent: O=[Os](=O)(=O)=O
Solvent: c1ccncc1
Product: C[C@]12C=CC(=O)C=C1[C@H](O)[C@H](O)[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To 0.83 g. of 1,4,6-androstatriene-3,17-dione in 15 ml. of dioxane and 0.83 ml. of pyridine add 0.75 g. of osmium tetroxide. Stir the reaction mixture under an atmosphere of nitrogen at room temperature in the absence of light for two days. Isolate the resultant product in a manner similar to that described in Example 1B. Purify by chromatographing on thin layer plates developing with ethyl acetate-chloroform-methanol (4.5:4.5:1). Combine like fractions, elute with ethyl acetate, and evaporate the eluate to a residue comprising 6β,7β-dihydroxy-1,4-androstadiene-3,17-dione. Yield=445 mg. (48% theory). Further purify by recrystallization from methanol; [α]D26° +66.7° (acetone); λmaxmethanol 244 nm (γ=15,300); n.m.r. (dmso-d6 /D2O) δ0.89 (C13 -CH3); 1.37 (C10 -CH3); 3.25(7α-H; d,d J10,3Hz); 4.24 (6α-H; d,J 3.5Hz); 6.11 (C4 -H; d,J 2Hz); 6.11 (C2 -H; d,d J10,2Hz); 7.18 (C1H; d,J 10Hz).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13]Cl)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>C(O)C.CO>[N:15]1([CH2:13][CH2:12][N:9]2[CH2:10][CH2:11][N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7][CH2:8]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: C1CCNCC1
Reactant: CCOC(=O)N1CCN(CCCl)CC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: CCO
Product: CCOC(=O)N1CCN(CCN2CCCCC2)CC1

Procedure:
By reaction of 1-(ethoxycarbonyl-4-(2-chloroethyl)-piperazine (11.05 grams; 0.05 moles), piperidine (4.3 grams; 0.05 moles) and potassium carbonate (7.0 grams; 0.05 moles) in 150 cc of ethanol by boiling until disappearance of the reactants by TLC (methanol), a product is obtained which is identical to the product described in Example 13 as shown by boiling point, melting point, mixed melting point of the dihydrochloride; Rf and IR.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH3:11].[Br:12][CH2:13][CH2:14][CH2:15]Br>C(#N)C>[Br:12][CH2:13][CH2:14][CH2:15][O:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: COc1cc(C#N)ccc1O
Reactant: BrCCCBr
Solvent: CC#N
Product: COc1cc(C#N)ccc1OCCCBr
Reaction time: 8 h

Procedure:
A mixture of 4-hydroxy-3-methoxybenzonitrile (7.5 g, 50 mmol), K2 CO3 (12.5 g), and 1,3dibromopropane (15 g, 75 mmol) in acetonitrile (100 ml) was heated at reflux for 3 hours and left standing at room temperature overnight. The solvent of the reaction was removed on a rotary evaporator, and the crude solid was extracted into methylene chloride (500 ml). The insolubles were filtered off. The dichloromethane solution was concentrated and the material was purified on a flash chromatography column (SiO2, 105 g; eluted with 2:3 dichloromethane:hexane, and then with dichloromethane). The desired product thus purified weighed 7.74 g (52%). Recrystallization twice from ethanol gave analytically pure 4-(3-bromopropoxy)-3-methoxybenzonitrile, m.p.=99°-101° C.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)=O)=[CH:8][CH:7]=1)[CH:2]([CH3:4])[CH3:3].NN.[OH-].[K+].O>C(O)CO>[CH2:1]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][C:14]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)=[CH:10][N:11]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CNc1ccc(C(=O)c2c[nH]c3ncccc23)cn1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: CC(C)CNc1ccc(Cc2c[nH]c3ncccc23)cn1
Temperature: 180 °C

Procedure:
To (6-Isobutylamino-pyridin-3-yl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone (P-0025, 60.0 mg, 0.20 mmol, prepared as described in Example 5) in 1,2-ethanediol (5.0 mL) was added hydrazine (1.0 mL, 0.032 mol) and potassium hydroxide (200.0 mg, 3.56 mmol). The reaction mixture was heated to 180° C. overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified by silica gel column chromatography eluting with 10% methanol in dichloromethane to give compound (P-0028, 10 mg, 16.7%). MS (ESI) [M+H+]+=281.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[N:11][N:12]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[CH:13]=2)O1.Br[C:22]1[N:27]=[C:26]([NH2:28])[CH:25]=[CH:24][CH:23]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:16]1[CH:17]=[CH:18][CH:19]=[C:14]([N:12]2[CH:13]=[C:9]([C:22]3[N:27]=[C:26]([NH2:28])[CH:25]=[CH:24][CH:23]=3)[CH:10]=[N:11]2)[CH:15]=1
Reactant: Nc1cccc(Br)n1
Reactant: CC1(C)OB(c2cnn(-c3cccnc3)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: Nc1cccc(-c2cnn(-c3cccnc3)c2)n1
Temperature: 75 °C

Procedure:
Under argon, 3.17 g (11.7 mmol) of 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]pyridine, 2.02 g (11.7 mmol) of 6-bromopyridine-2-amine and 945 mg (817 μmol) of tetrakis(triphenylphosphine)palladium were added to a mixture, degassed by means of argon, of 23.3 ml of 2 M sodium carbonate solution in water and 63.3 ml of acetonitrile. The reaction mixture was heated to 75° C. for 18 hours, diluted with acetonitrile after cooling, dried over MgSO4, filtered and concentrated. The crude product thus obtained was purified by chromatography (acetonitrile/acetone).
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([C:22]([N:24]3[CH2:29][CH2:28][C:27]([F:31])([F:30])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[CH3:32][S:33]([NH:36][C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1)(=[O:35])=[O:34].N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:5]2[CH2:6][CH2:7][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([C:40]3[CH:39]=[CH:38][C:37]([NH:36][S:33]([CH3:32])(=[O:34])=[O:35])=[CH:42][CH:41]=3)[C:17]([C:22]([N:24]3[CH2:25][CH2:26][C:27]([F:30])([F:31])[CH2:28][CH2:29]3)=[O:23])=[CH:16]4)=[O:12])[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCC2)CC1
Reactant: CS(=O)(=O)Nc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(-n2c(C(=O)N3CCC(F)(F)CC3)cc3cc(C(=O)N4CCN(C5CCC5)CC4)ccc32)cc1
Yield: 19 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 41), 4-(methanesulfonylamino)phenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless foam (19%).
Reaction SMILES: C([O:5][C:6](=[O:43])[CH2:7][O:8]/[N:9]=[C:10](/[C:30]1[N:31]=[C:32]([NH:35]C(OC(C)(C)C)=O)[S:33][CH:34]=1)\[C:11]([NH:13][C@H:14]1[C@@H:17]([CH2:18][N:19]2[CH2:23][CH2:22][O:21][C:20]2=[O:24])[N:16]([S:25]([OH:28])(=[O:27])=[O:26])[C:15]1=[O:29])=[O:12])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:35][C:32]1[S:33][CH:34]=[C:30](/[C:10](=[N:9]/[O:8][CH2:7][C:6]([OH:43])=[O:5])/[C:11](=[O:12])[NH:13][C@H:14]2[C@@H:17]([CH2:18][N:19]3[CH2:23][CH2:22][O:21][C:20]3=[O:24])[N:16]([S:25]([OH:28])(=[O:26])=[O:27])[C:15]2=[O:29])[N:31]=1
Reactant: CC(C)(C)OC(=O)CO/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1CN1CCOC1=O)c1csc(NC(=O)OC(C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1nc(/C(=N/OCC(=O)O)C(=O)N[C@@H]2C(=O)N(S(=O)(=O)O)[C@@H]2CN2CCOC2=O)cs1
Yield: 24.4 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (3S,4R)-3-((Z)-2-((2-(tert-butoxy)-2-oxoethoxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-oxo-4-((2-oxooxazolidin-3-yl)methyl)azetidine-1-sulfonic acid (135 mg, 0.208 mmol), DCM (1.04 mL) and TFA (801 μl, 10.4 mmol). The crude residue purified by reverse phase prep HPLC (XSelect CSH, 19×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 24 mL/min), affording the title compound (25 mg, 23%) as a white powder. LCMS: Rt=0.25 min, m/z=493.0 (M+1) Method 2m_acidic; 1H NMR (500 MHz, DMSO-d6) δ 9.41 (d, J=9.1 Hz, 1H) 6.86 (s, 1H) 5.24 (dd, J=9.0, 5.8 Hz, 1H) 4.62 (s, 2H) 4.20-4.11 (m, 3H) 3.72-3.63 (m, 2H) 3.40-3.31 (m, 2H assumed; obscured by water).
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Cl[CH2:12][C:13]1[CH:18]=[C:17]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH3:25])[CH:16]=[CH:15][N:14]=1.[OH-].[Na+]>C(O)C>[CH3:25][O:24][CH2:23][CH2:22][CH2:21][CH2:20][O:19][C:17]1[CH:16]=[CH:15][N:14]=[C:13]([CH2:12][S:1][C:2]2[NH:6][C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=3[N:3]=2)[CH:18]=1
Reactant: Sc1nc2ccccc2[nH]1
Reactant: COCCCCOc1ccnc(CCl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COCCCCOc1ccnc(CSc2nc3ccccc3[nH]2)c1
Yield: 70.7 %

Procedure:
A mixture comprising 2.55 g (0.017 mol) of 2-mercaptobenzimidazole, 5.09 g (0.022 mol) of 2-chloromethyl-4-(4-methoxybutoxy)pyridine, 0.84 g (0.020 mol) of 95% sodium hydroxide and 60 ml of ethanol was stirred at 40° C. for 1.5 hours. After the completion of the reaction, the reaction mixture was distilled to remove the solvent. The obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane) to obtain 4.13 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10](=[O:15])[C:9]=2[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl.O>[CH3:14][C:11]1([CH3:13])[O:12][C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:1]([S:35]([CH3:34])(=[O:37])=[O:36])[S:35]([CH3:34])(=[O:37])=[O:36])=[CH:3][CH:4]=2)=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)=[CH:18][CH:17]=2)[C:10]1=[O:15]
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)OC(c2ccc(N)cc2)=C(c2ccc(OCc3ccc4ccccc4n3)cc2)C1=O
Solvent: ClCCl
Solvent: O
Product: CC1(C)OC(c2ccc(N(S(C)(=O)=O)S(C)(=O)=O)cc2)=C(c2ccc(OCc3ccc4ccccc4n3)cc2)C1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 56.2 %

Procedure:
To a stirred solution of 5-(4-aminophenyl)-2,2-dimethyl-4-(4-(quinolin-2-ylmethoxy)phenyl) furan-3(2H)-one (60 mg, 0.13 mmol) in DCM (5 mL) were added methane sulfonyl chloride (0.012 g, 0.15 mmol) and TEA (0.04 mL, 0.27 mmol) at 0° C. under N2 atmosphere. The reaction mixture was stirred at RT for 10 min. The reaction mixture diluted with water and extracted with DCM (2×10 mL). The combined organic layers were washed with water (2×5 mL), brine and dried over anhydrous Na2SO4. After filtration and evaporation, the crude material was purified by silica gel column chromatography to afford N-(4-(5,5-dimethyl-4-oxo-3-(4-(quinolin-2-ylmethoxy)phenyl)-4,5-dihydrofuran-2-yl)phenyl)-N-(methylsulfonyl)methane sulfonamide (25 mg, 30%), as a white color solid. 1H NMR (500 MHz, CDCl3): δ 8.22 (d, J=8.5 Hz, 1H), 8.10 (d, J=7.9 Hz, 1H), 7.76 (d, J=8.4 Hz, 1H), 7.80 (d, J=8.2 Hz, 2H), 7.74 (t, J=8.2 Hz, 1H), 7.70 (d, J=8.5 Hz, 1H), 7.56 (d, J=7.5 Hz, 1H), 7.28 (d, J=7.4 Hz, 2H), 7.12 (d, J=7.5 Hz, 2H), 7.08 (d, J=7.6 Hz, 2H), 5.42 (s, 2H), 3.42 (s, 6H), 1.58 (s, 6H). MS: [M+Na]: m/z=615.1, [M+H]: m/z=593.1. HPLC: 98.9% (RT-2.52 min), Column: Acquity BEH-C-18, 50×2.1 mm, 1.7 um. Mobile Phase: 0.025% TFA in Water (A), ACN (B), Flow rate: 0.5 ml/min (Gradient).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:6][C@H:5]([N:7]2[C:11]3=[N:12][CH:13]=[CH:14][N:15]=[C:10]3[N:9]([CH:16]3[CH2:18][CH2:17]3)[C:8]2=[O:19])[CH2:4]1.Cl[C:21]1[N:25]([CH3:26])[C:24]2[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=2[N:22]=1.C(NC(C)C)(C)C>CS(C)=O>[CH:16]1([N:9]2[C:10]3=[N:15][CH:14]=[CH:13][N:12]=[C:11]3[N:7]([C@H:5]3[CH2:6][C@H:3]([NH:2][C:21]4[N:25]([CH3:26])[C:24]5[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=5[N:22]=4)[CH2:4]3)[C:8]2=[O:19])[CH2:17][CH2:18]1
Reactant: Cn1c(Cl)nc2ccccc21
Reactant: N[C@H]1C[C@H](n2c(=O)n(C3CC3)c3nccnc32)C1
Agent: Cl
Solvent: CC(C)NC(C)C
Solvent: CS(C)=O
Product: Cn1c(N[C@H]2C[C@H](n3c(=O)n(C4CC4)c4nccnc43)C2)nc2ccccc21
Temperature: 120 °C
Reaction time: 48 h

Procedure:
A glass microwave reaction vessel was charged with 1-(trans-3-aminocyclobutyl)-3-cyclopropyl-1H-imidazo[4,5-b]pyrazin-2(3H)-one hydrochloride (Intermediate 79, 0.1138 g, 0.404 mmol), 2-chloro-1-methyl-1H-benzo[d]imidazole (0.081 g, 0.485 mmol), and diisopropylamine (0.211 ml, 1.212 mmol, Sigma-Aldrich Chemical Company, Inc.) in DMSO (0.577 ml) and heated to 120° C. to stir for 2 days. The crude product was purified by reverse-phase preparative HPLC using a Phenomenex Gemini column, micron, C18, 110 Å, 100×50 mm, 0.1% TFA in CH3CNiH2O, gradient 10% to 100% over min. Fractions containing product were collected and concentrated. Residue taken up in DCM and loaded onto a Silicycle Si-carbonate cartridge to remove any salts to give the title compound (103 mg, 0.027 mmol, 6.79 yield). LCMS showed product peak at 1.57 min (m+1=376.0). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.97-1.03 (m, 2 H) 1.04-1.11 (m, 2 H) 2.47 (d, J=3.33 Hz, 1 H) 2.98 (tt, f=7.04, 3.72 Hz, 1 H) 3.27 (dt, J=13.30, 8.12 Hz, 2 H) 3.56 (s, 3 H) 4.53-4.66 (m, 1 H) 5.24 (quin, J=8.31 Hz, 1 H) 6.89-6.99 (m, 2 H) 7.02 (d, J=6.46 Hz, 1 H) 7.13-7.19 (m, 1 H) 7.19-7.25 (m, 1 H) 7.96-8.00 (m, 1 H) 8.00-8.04 (m, 1 H)
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:16]([NH:17][CH:18]=[O:19])[C:15](=[O:20])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2].C(OC(=O)C)(=O)C>N1C=CC=CC=1>[C:1]([O:4][CH2:5][C:6]1[C@H:11]([C:12]([OH:14])=[O:13])[N:10]2[C:15](=[O:20])[C@@H:16]([NH:17][CH:18]=[O:19])[C@H:9]2[S:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC=O)[C@H]2SC1
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OCC1=CS[C@@H]2[C@H](NC=O)C(=O)N2[C@H]1C(=O)O
Reaction time: 1 h

Procedure:
3-Acetoxymethyl-7β-formamidoceph-3-em-4-carboxylic acid (3.0 g., 1 mmol.) was suspended in dry pyridine (12 ml) at room temperature. Acetic anhydride (1.2 ml.) was added to the stirred suspension and the reaction allowed to proceed for 1 hr. On cooling with ice, the pyridinium salt crystallised and this was filtered off. Treatment of the solid with dilute hydrochloric acid and extraction with ethyl acetate gave the free acid which was obtained as a gum after washing the organic phase with water, drying, and evaporation. The gum (0.61 g 20.3%) could not be crystallised. The spectroscopic properties of the product are consistent with the structure of the compound named in the title νmax (film) 3300 (NH), 1770 (β-lactam), 1730 (OCOCH3), 1675 cm-1 (HCON--) τ (D2O/NaHCO3) 1.82 (singlet, HCO--), 3.52 (singlet, =CH--S), 4.51 and 4.71 (double doublet, J=4 Hz, 6H and 7H protons), 5.22 (collapsed quartet), 5.82 (singlet, CHCO2H) and 7.89 (singlet, CH3COO--).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@:8]2([CH3:16])[C@@H:13]([F:14])[CH2:12][O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1.[CH:18]1([CH2:21][O:22][C:23]2[CH:24]=[CH:25][C:26]([C:29](O)=[O:30])=[N:27][CH:28]=2)[CH2:20][CH2:19]1>>[NH2:15][C:10]1[O:11][CH2:12][C@H:13]([F:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:29]([C:26]3[CH:25]=[CH:24][C:23]([O:22][CH2:21][CH:18]4[CH2:20][CH2:19]4)=[CH:28][N:27]=3)=[O:30])[CH:3]=[CH:4][C:5]=2[F:17])([CH3:16])[N:9]=1
Reactant: O=C(O)c1ccc(OCC2CC2)cn1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OC[C@@H]1F
Product: C[C@]1(c2cc(NC(=O)c3ccc(OCC4CC4)cn3)ccc2F)N=C(N)OC[C@@H]1F

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A8.2) and 5-cyclopropylmethoxy-pyridine-2-carboxylic acid following procedure I yielded the title compound as a white foam. MS (ISP): m/z=417.3 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]4[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=4)[CH:17]=3)=[C:11]([CH3:28])[N:10]=2)=[CH:5][N:4]=[C:3]1SC.[CH:31]([NH2:34])([CH3:33])[CH3:32]>>[CH:31]([NH:34][C:3]1[N:2]([CH3:1])[C:7](=[O:8])[C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]4[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=4)[CH:17]=3)=[C:11]([CH3:28])[N:10]=2)=[CH:5][N:4]=1)([CH3:33])[CH3:32]
Reactant: CC(C)N
Reactant: CSc1ncc(-c2ccc(Oc3ccnc(-c4cnn(C)c4)c3)c(C)n2)c(=O)n1C
Product: Cc1nc(-c2cnc(NC(C)C)n(C)c2=O)ccc1Oc1ccnc(-c2cnn(C)c2)c1
Temperature: 25 °C
Yield: 61.8 %

Procedure:
A mixture of Example C3 (0.14 g, 0.33 mmol) and isopropyl amine (3 mL, 35.0 mmol) was heated at 100° C. for 2 days in a sealed tube. The mixture was cooled to RT, the solid removed via filtration and the filtrate concentrated to dryness and purified via silica gel chromatography to obtain 2-(isopropylamino)-3-methyl-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-4(3H)-one (88 mg, 59%). 1H NMR (400 MHz, DMSO-d6): δ 8.68 (s, 1H), 8.36 (d, J=5.7 Hz, 1H), 8.28 (d, J=8.7 Hz, 1H), 8.25 (s, 1H), 7.96 (d, J=0.7 Hz, 1H), 7.52 (d, J=8.6 Hz, 1H), 7.23 (d, J=2.4 Hz, 1H), 7.05 (d, J=7.6 Hz, 1H), 6.60 (dd, J=5.7, 2.4 Hz, 1H), 4.33 (m, 1H), 3.85 (s, 3H), 3.37 (s, 3H), 2.35 (s, 3H), 1.23 (d, J=6.6 Hz, 6H); MS (ESI) m/z: 432.2 (M+H+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=[CH2:21])[CH:15]=1)=O)(C)(C)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C(N(CC)C(C)C)(C)C>ClCCl>[CH:20]([C:16]1[CH:15]=[C:14]([CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13][NH:8]2)[CH:19]=[CH:18][CH:17]=1)=[CH2:21]
Reactant: C=Cc1cccc(C2CCCCN2C(=O)OC(C)(C)C)c1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=Cc1cccc(C2CCCCN2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 2-(3-vinyl-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (650 mg, 2.26 mmol) in dichloromethane (15 mL) was cooled to 0° C., before adding trimethylsilyl trifluoromethanesulfonate (569 μL, 3.39 mmol). The reaction mixture was stirred at 0° C. for 1 h before adding N,N-diisopropylethylamine (1.6 mL, 5.24 mmol) to afford the 2-(3-vinyl-phenyl)-piperidine as a yellow solid. The solid was redissolved, along with 28f (900 mg, 1.98 mmol) in acetonitrile (20 mL). The solution was cooled to 0° C., before adding 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (1.05 g, 2.77 mmol) and N,N-diisopropylethylamine (1.4 mL, 7.92 mmol). The stirred reaction mixture was allowed to slowly warm to RT. After 2 h, the solvent was evaporated and the remaining residue dissolved in ethyl acetate (30 mL) and washed with water (3×30 mL). The organics were dried over anhydrous sodium sulfate, filtered and concentrated. The resultant residue was purified by silica gel chromatography using a stepwise gradient of iso-hexanes/ethyl acetate 1:0 to 0:1 to afford the title compound (1.25 g, 100%) as a yellow solid.