Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[C:18]([O:22][C:23]([NH:25][C@@H:26]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1)[C:27]([OH:29])=O)=[O:24])([CH3:21])([CH3:20])[CH3:19].Cl.Cl.[NH2:39][CH2:40][C:41]([N:43]1[CH2:48][CH2:47][N:46]([C:49]2[CH:54]=[CH:53][C:52]([Cl:55])=[CH:51][CH:50]=2)[CH2:45][CH2:44]1)=[O:42].C(N(C(C)C)CC)(C)C>CN(C)C=O.C(=O)([O-])O.[Na+]>[C:18]([O:22][C:23]([NH:25][C@@H:26]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1)[C:27]([NH:39][CH2:40][C:41]([N:43]1[CH2:44][CH2:45][N:46]([C:49]2[CH:54]=[CH:53][C:52]([Cl:55])=[CH:51][CH:50]=2)[CH2:47][CH2:48]1)=[O:42])=[O:29])=[O:24])([CH3:19])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccn1)C(=O)O
Reactant: NCC(=O)N1CCN(c2ccc(Cl)cc2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccn1)C(=O)NCC(=O)N1CCN(c2ccc(Cl)cc2)CC1
Yield: 96.9 %

Procedure:
Diphenylphosphoryl azide (25 g) was added to a solution of (2S)-2-(tert-butoxycarbonylamino)-3-(2-pyridyl)propanoic acid (23 g) in N,N-dimethylformamide (230 ml) at 5° C. To the mixture was added a solid of 2-amino-1-[4-(4-chlorophenyl)-1-piperazinyl]-ethan-1-one dihydrochloride (28.2 g) at 5° C. with stirring and then diisopropylethylamine (47 ml) was added dropwise at 7-10° C. The mixture was stirred at 7-10° C. for 30 minutes and at room temperature for 2 hours. The mixture was diluted with saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The aqueous layer was extracted with two 500-ml portions of ethyl acetate, and the combined organic layers were extracted with 1N hydrochloric acid (150 ml×2). The combined aqueous layers were basified (pH 9) with sodium hydrogencarbonate and extracted with ethyl acetate. The organic layer was washed thoroughly with aqueous sodium hydrogencarbonate solution and brine, dried over magnesium sulfate and concentrated in vacuo to give the title compound (42 g).
Reaction SMILES: [CH3:1][C:2]([O:13][Si:14]([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:15][CH3:16])([CH3:12])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[N:5]1.[H][H]>[Pd].C(O)C>[CH3:1][C:2]([O:13][Si:14]([CH2:17][CH3:18])([CH2:15][CH3:16])[CH2:19][CH3:20])([CH3:12])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([NH2:9])=[N:5]1
Reactant: [H][H]
Reactant: CC[Si](CC)(CC)OC(C)(C)Cn1ccc([N+](=O)[O-])n1
Agent: [Pd]
Solvent: CCO
Product: CC[Si](CC)(CC)OC(C)(C)Cn1ccc(N)n1

Procedure:
In a Parr shaker bottle was placed 1-(2-methyl-2-triethylsilanyloxy-propyl)-3-nitro-1H-pyrazole (197 mg, 0.65 mmol), 10% palladium on activated carbon (25 mg) and ethanol (10 mL). The bottle was then placed on the Parr shaker at 50 psi of hydrogen pressure for 1 h. The reaction was then filtered through a pad of celite and washed with ethanol, concentration in vacuo afforded 1-(2-methyl-2-triethylsilanyloxy-propyl)-1H-pyrazol-3-ylamine (191 mg, 100% (wet with some ethanol)) as a clear colorless oil: ES-HRMS m/e calcd for C13H27N3OSi (M+H)+ 270.1996, observed 270.1995; 1H NMR (300 MHz, CDCl3) δ ppm 0.56 (q, J=7.9 Hz, 6H, 3×SiCH2), 0.92 (t, J=7.9 Hz, 9H, 3×CH3), 1.21 (s, 6H, 2×CH3), 2.63 (br.s., 2H, NH2), 3.83 (s, 2H, NCH2), 5.59 (d, J=2.4 Hz, 1H, Ar), 7.22 (d, J=2.4 Hz, 1H, Ar).
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([NH2:19])=[NH:18])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CN(C)/[CH:22]=[CH:23]/[C:24]([C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=1)=O.C(=O)([O-])[O-].[K+].[K+]>CN1CCCN(C)C1=O.O>[N:1]1([S:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17]3[N:19]=[C:24]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:33])([F:34])[F:35])=[CH:28][CH:27]=4)[CH:23]=[CH:22][N:18]=3)=[CH:14][CH:15]=2)(=[O:8])=[O:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: N=C(N)Nc1ccc(S(=O)(=O)N2CCOCC2)cc1
Reactant: CN(C)/C=C/C(=O)c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCN(C)C1=O
Product: O=S(=O)(c1ccc(Nc2nccc(-c3ccc(C(F)(F)F)cc3)n2)cc1)N1CCOCC1
Temperature: 107.5 °C
Reaction time: 18 h
Yield: 75.4 %

Procedure:
A mixture of N-[4-(morpholin-4-ylsulfonyl)phenyl]guanidine (85 mg, 0.3 mmol), (2E)-3-(dimethylamino)-1-[4-(trifluoromethyl)phenyl]prop-2-en-1-one (43 mg, 0.18 mmol), and potassium carbonate (83 mg, 0.6 mmol) in 1 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) is stirred at 105 to 110° C. for 18 hrs. It is then cooled to room temperature, and diluted with water (15 ml). The resulting suspension is filtered, and the precipitate is washed with dilute citric acid and water, and then dissolved in ethyl acetate. The organic solution is passed through a pad of silica gel, and the filtrate is evaporated. The residue is triturated with a mixture of methylene chloride and hexanes to give 63 mg of a yellow solid; mp 240-241° C.; MS (ESI) m/z 465.2 (M+H); HRMS: calcd for C21H19F3N4O3S, 464.1130; found (ESI_FT), 465.11835.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]([CH3:13])([C:10]([OH:12])=[O:11])[C:7](O)=[O:8].[CH3:14][S:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1>C1COCC1>[CH3:14][S:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:7](=[O:8])[C:6]([CH3:13])([CH3:5])[C:10]([OH:12])=[O:11])=[CH:18][CH:17]=1
Reactant: CSc1ccc(N)cc1
Reactant: CC(C)(C(=O)O)C(=O)O
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CSc1ccc(NC(=O)C(C)(C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Thionyl chloride (8.15 g, 5 ml, 0.069 mol) was added to a stirred solution of 2,2-dimethylmalonic acid (7.26 g, 0.055 mol) in dry THF (55 ml). The mixture was heated under reflux for 3 hr. The reaction mixture was cooled to room temperature and 4-methylthioaniline (15.3 g, 0.11 mol) in THF (30 ml) was then added dropwise over 30 mins to the solution. The mixture was stirred at room temperature for 2 hr. The reaction mixture was then concentrated in vacuo and then treated with hydrochloric acid (2N, 100 ml). The product was extracted with ethyl acetate (2×100 ml). The organic extracts were combined, then washed with water (100 ml) and saturated sodium hydrogen carbonate solution (5×80 ml). The organic layer was then acidified with hydrochloric acid (5N, 250 ml) and the resultant white crystalline precipitate was collected by filtration to afford N-(4-methylthiophenyl)-2,2-dimethylmalonamic acid. mp 130-132° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:12](Cl)(=[O:14])=[O:13])[CH:8]=2)[O:3]1.[NH2:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[CH3:1][C:2]1([CH3:16])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:12]([NH:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])(=[O:14])=[O:13])[CH:8]=2)[O:3]1
Reactant: CC(C)(C)OC(=O)CN
Reactant: CC1(C)CCc2cc(S(=O)(=O)Cl)ccc2O1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CNS(=O)(=O)c1ccc2c(c1)CCC(C)(C)O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To the solution of 2,2-dimethylchroman-6-sulfonyl chloride (3.165 g, 10.92 mmol) in DCM (50 mL) at −30° C. was added tert-butyl 2-aminoacetate (2.308 mL, 16.39 mmol), Hunig'sBase (3.82 mL, 21.85 mmol), and catalytic amount of DMAP. The mixture was stirred at 25° C. overnight while the reddish orange color of the reaction mixture turned bright yellow. The crude reaction mixture was diluted with EtOAc, washed with dilute aqueous hydrochloric acid solution, then aqueous NaHCO3 solution and brine. The organic layer was dried over MgSO4 and removed on a rotavapor to give a creamy powder. The crude material was purified by silica chromatography (15-30% EtOAc/Hexanes) to yield 3.6 grams of an off white powder (88%). 1H NMR (500 MHz, CDCl3) δ 7.58 (d, J=2.1 Hz, 1H), 7.55 (dd, J=8.6, 2.3 Hz, 1H), 6.81 (t, J=10.6 Hz, 1H), 4.90 (s, 1H), 3.64 (d, J=5.1 Hz, 2H), 2.81 (t, J=6.7 Hz, 2H), 1.81 (t, J=6.7 Hz, 2H), 1.35 (s, 9H), 1.34 (s, 6H). LRMS [ESI, (M−H)−] m/z calcd for C17H24NO5S 354.14, found 354.2.
Reaction SMILES: [C:1]([C@@H:3]([NH:5][C:6](=[O:12])OC(C)(C)C)[CH3:4])#[N:2].[CH2:13]([O:20][C:21]1[CH:22]=[C:23]([CH:34]=[CH:35][CH:36]=1)[O:24][C:25]1[CH:33]=[CH:32][C:28](C(O)=O)=[CH:27][CH:26]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([O:20][C:21]1[CH:22]=[C:23]([CH:34]=[CH:35][CH:36]=1)[O:24][C:25]1[CH:26]=[CH:27][C:28]([C:6]([NH:5][C@H:3]([C:1]#[N:2])[CH3:4])=[O:12])=[CH:32][CH:33]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: C[C@@H](C#N)NC(=O)OC(C)(C)C
Reactant: O=C(O)c1ccc(Oc2cccc(OCc3ccccc3)c2)cc1
Product: C[C@@H](C#N)NC(=O)c1ccc(Oc2cccc(OCc3ccccc3)c2)cc1
Yield: 38.5 %

Procedure:
General procedure D was used to deprotect 0.65 mmol of 4 and immediately coupled to 0.975 mmol of 40. After flash chromatography 0.96 g (0.25 mmol) of the title product was recovered. 1H NMR (300 MHz, CDCl3) δ 7.76 (d, J=8.8, 2H), 7.49-7.21 (m, 6H), 7.00 (d, J=8.7, 2H), 6.80 (d, J=8.3, 1H), 6.65 (d, J=12.0, 3H), 5.22-5.08 (m, 1H), 5.03 (s, 2H), 1.65 (d, J=7.2, 3H).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:13][C:14](=[O:19])[NH:15][CH2:16][CH2:17][NH2:18])([CH3:12])([CH3:11])[CH3:10].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].ClCCl>ClCCCl>[C:9]([O:13][C:14](=[O:19])[NH:15][CH2:16][CH2:17][NH:18][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:12])([CH3:10])[CH3:11]
Reactant: O=Cc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCCNCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.4 %

Procedure:
Benzaldehyde (3.3 ml, 32.4 mmol) was added to a stirred solution of tert-butyl-N-(2-aminoethyl)carbamate (5.19 g, 32.4 mmol) in 1,2-dichloroethane (50 ml). After stirring for 1 h sodium triacetoxyborohydride (10.3 g, 48.6 mmol) was added in two portions and the reaction mixture stirred at room temperature for a further 3 h. Dichloromethane (300 ml) was added and the mixture washed with 1N sodium hydroxide. The organic layer was dried (Na2SO4) and evaporated in vacuo. The residue was chromatographed on silica gel eluting with 50–100% ethyl acetate in hexane then 1–5% methanol in ethyl acetate to afford the title compound (4.9 g, 60%). Mass spectrum (AP+): Found 251 (MH+). C14H22N2O2 requires 250.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[C:17](=[O:18])[CH:16]=[CH:15][N:14]([CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[N:13]=3)=[CH:10][CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]([F:35])([F:34])[F:33].CC(C)([O-])C.[Na+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])O.[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].C1(C)C=CC=CC=1>[C:1]1([N:7]2[C:11]([C:12]3[C:17](=[O:18])[CH:16]=[CH:15][N:14]([CH:19]4[CH2:24][CH2:23][N:22]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[C:32]([F:35])([F:34])[F:33])[CH2:21][CH2:20]4)[N:13]=3)=[CH:10][CH:9]=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: FC(F)(F)c1ccccc1Br
Reactant: O=c1ccn(C2CCNCC2)nc1-c1ccnn1-c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: O=c1ccn(C2CCN(c3ccccc3C(F)(F)F)CC2)nc1-c1ccnn1-c1ccccc1
Yield: 11.3 %

Procedure:
A mixture of 3-(1-phenyl-1H-pyrazol-5-yl)-1-piperidin-4-ylpyridazin-4(1H)-one (25.7 mg), 2-bromobenzotrifluoride (27 mg), Pd2(dba)3 (1.8 mg), sodium tert-butoxide (8.8 mg), X-phos (1.9 mg) and toluene (1.0 mL) was heated using a microwave reactor (Synthos3000) at 120° C. for 10 min. To the reaction mixture was added 5% sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate (the extract was separated by an organic layer-separation filter). The extract was distilled by blowing air at 60° C., and the residue was dissolved in DMSO. The solution was purified by preparative HPLC (column: Hydrosphere, solvent: 10 mM NH4HCO3/MeCN). The obtained eluate containing the title compound was concentrated by blowing air at 60° C. to give the title compound (4.2 mg).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:4]([CH3:22])[C:5](=[O:21])[C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:10][C:9]([O:19][CH3:20])=[CH:8][CH:7]=2.[C:23]1([CH2:29][CH2:30][CH2:31][CH2:32][C:33](O)=[O:34])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.C(=O)(O)[O-].[Na+]>CN(C)C=O.O>[CH3:20][O:19][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[C:5](=[O:21])[N:4]([CH3:22])[C:3]([CH2:2][NH:1][C:33](=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[C:12]2[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1ccc2c(=O)n(C)c(CN)c(-c3ccccc3)c2c1
Reactant: O=C(O)CCCCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(=O)n(C)c(CNC(=O)CCCCc3ccccc3)c(-c3ccccc3)c2c1
Yield: 82352.9 %

Procedure:
A solution of 41 (50 mg, 0.170 mmol), 5-phenylvaleric acid (33 mg, 0.187 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (36 mg, 0.187 mmol), 1-hydroxy-7-azabenzotriazole (25 mg, 0.187 mmol) in N,N-dimethylformamide was stirred at room temperature for 18 h. The contents of the reaction flask were poured into water and sat. sodium bicarbonate. Extracted with methylene chloride (3×). The combined organic extracts were washed with 5% potassium bisulfate, dried with sodium sulfate (anh.) and filtered. Concentration of the filtrate in vacuo followed by trituration with ether gave 42 as a white solid (62 mg, 140 mmol, 82.1%).
Reaction SMILES: [BH4-].[CH3:2][O:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([C:13]2[NH:22][C:16]3=[N:17][CH:18]=[C:19]([NH2:21])[CH:20]=[C:15]3[CH:14]=2)[CH:10]=[CH:11][CH:12]=1.[CH:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CO>[CH2:23]([NH:21][C:19]1[CH:20]=[C:15]2[CH:14]=[C:13]([C:9]3[CH:10]=[CH:11][CH:12]=[C:7]([O:6][CH2:5][CH2:4][O:3][CH3:2])[CH:8]=3)[NH:22][C:16]2=[N:17][CH:18]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=Cc1ccccc1
Reactant: COCCOc1cccc(-c2cc3cc(N)cnc3[nH]2)c1
Agent: [BH4-]
Solvent: CO
Product: COCCOc1cccc(-c2cc3cc(NCc4ccccc4)cnc3[nH]2)c1
Reaction time: 16 h
Yield: 6.5 %

Procedure:
Polymer supported borohydride (706 mg, 1.8 mmol) was added to a mixture of 2-[3-(2-methoxy-ethoxy)-phenyl]-1H-pyrrolo[2,3-b]pyridin-5-ylamine (50 mg, 0.18 mmol) and benzaldehyde (18mg, 0.18 mmol) in methanol (3 mL). The mixture was stirred for 16 hours, filtered, concentrated in vacuo and purified by preparative HPLC to afford benzyl-{2-[3-(2-methoxy-ethoxy)-phenyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-amine (4.4 mg, 7%)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:12][CH:13]([CH2:21][CH3:22])[C:14]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:15]>>[CH2:17]([O:16][C:14](=[O:15])[CH:13]([NH:12][C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH2:21][CH3:22])[CH:18]([CH3:19])[CH3:20]
Reactant: CCC(N)C(=O)OCC(C)C
Reactant: O=C(O)Cc1ccc(F)cc1
Product: CCC(NC(=O)Cc1ccc(F)cc1)C(=O)OCC(C)C

Procedure:
Following General Procedure I above and using 4-fluorophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure J above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure. NMR data was as follows:
Reaction SMILES: [N:1]1([C:7]([NH:9][CH:10]([CH2:14][S:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:17])=[O:16])[C:11]([OH:13])=O)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:25][CH:26]1[C:29](=[O:30])[NH:28][CH:27]1[O:31][C:32](=[O:34])[CH3:33].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>ClCCl>[N:1]1([C:7]([NH:9][CH:10]([CH2:14][S:15]([CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)(=[O:16])=[O:17])[C:11]([NH:25][CH:26]2[C:29](=[O:30])[NH:28][CH:27]2[O:31][C:32](=[O:34])[CH3:33])=[O:13])=[O:8])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: CC(=O)OC1NC(=O)C1N
Reactant: O=C(O)C(CS(=O)(=O)Cc1ccccc1)NC(=O)N1CCOCC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(=O)OC1NC(=O)C1NC(=O)C(CS(=O)(=O)Cc1ccccc1)NC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 12.5 %

Procedure:
2-[(Morpholine-4-carbonyl)-amino]-3-phenylmethanesulfonyl-propionic acid (100 mg, 0.28 mmol), acetic acid 3-amino-4-oxo-azetidin-2-yl ester (52 mg, 0.36 mmol), EDC (100 mg, 0.52 mmol), and HOBt (100 mg, 0.64 mmol) were combined. Dichloromethane (2 mL) was added and then 4-methylmorpholine (0.2 mL). The mixture was stirred at ambient temperature for 2 h. After dilution with ethyl acetate (100 mL) the solution was washed with 1N aqu. HCl (30 mL), sat. aqu. NaHCO3 (30 mL) and brine (30 mL), dried with MgSO4 and evaporated under vacuum. The residue was subjected to flash chromatography on silica gel (ethyl acetate) to give acetic acid 3-{2-[(morpholine-4-carbonyl)-amino]-3-phenylmethanesulfonyl-propionylamino}-4-oxo-azetidin-2-yl ester (17 mg, 0.035 mmol). 1H NMR: (DMSO) 9.18 (s, 1H), 8.72 (d, J=6.4 Hz, 1H), 7.41–7.30 (m, 5H), 7.08 (m, 1H), 5.76 (s, 1H), 4.80–4.61 (m, 2H), 4.49 (s, 2H), 3.63–3.22 (m, 10H), 2.08 (s, 3H). MS: (M+H)+ 483.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:27]([F:30])([F:29])[F:28])=[C:10]([CH2:14][O:15][CH:16]3[CH2:19][N:18]([C:20]([NH:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17]3)[CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[S:31]1[CH:35]=[CH:34][CH:33]=[C:32]1B(O)O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)(O)[O-].[Na+]>O1CCCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[S:31]1[CH:35]=[CH:34][CH:33]=[C:32]1[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:27]([F:29])([F:30])[F:28])=[C:10]([CH2:14][O:15][CH:16]3[CH2:19][N:18]([C:20]([NH:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:17]3)[CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)NC(=O)N1CC(OCc2cccc(-c3ccc(I)cc3)c2C(F)(F)F)C1
Reactant: OB(O)c1cccs1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)N1CC(OCc2cccc(-c3ccc(-c4cccs4)cc3)c2C(F)(F)F)C1
Temperature: 65 °C
Yield: 72.4 %

Procedure:
To a solution of aryl iodide (191) (100 mg, 0.19 mmol), 2-thiopheneboronic acid (48 mg, 0.38 mmol), palladium acetate (4 mg, 0.019 mmol) and triphenylphosphine (10 mg, 0.38 mmol) in tetrahydrofuran (10 mL) was added sodium bicarbonate (10 mL, saturated aqueous). The reaction mixture was heated to reflux (65° C.) for 4 h, cooled, filtered and partitioned between water (20 mL) and ethyl acetate (20 mL). The organic phase was separated and washed with brine (20 mL), dried (Na2SO4), filtered and the solvent removed under reduced pressure to afford the crude product, as a brown oil. Purification by silica gel chromatography (20% ethyl acetate/iso-hexane eluant) gave the title compound (193) as a brown solid (67.2 mg, 73% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:32][C:33]([O:35][CH3:36])=[O:34].Cl>CN(C=O)C>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH2:32][C:33]([O:35][CH3:36])=[O:34])([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(NC(=O)OCc1ccccc1)C(=O)OCC
Reactant: COC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC(=O)OC)(NC(=O)OCc1ccccc1)C(=O)OCC
Temperature: 50 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
A suspension of diethyl 2-benzyloxycarbonylaminomalonate (3.0 g), potassium carbonate (1.6 g), potassium iodide (0.19 g), and methyl 2-bromoacetate (1.9 g) in DMF (50 mL) was stirred at 50° C. for 1 hour. The reaction mixture was cooled, and then poured into diluted hydrochloric acid, the mixture was extracted with ethyl acetate, and the extract was washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography, in which elution was performed with n-hexane/ethyl acetate (4:1) for purification, and then crystallized from ethyl acetate/n-hexane to obtain the title compound (3.52 g, yield: 95%) as colorless oil.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[CH:5]=[CH:4][N:3]=1.[CH:14]1(C(O)=O)[CH2:16][CH2:15]1.S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+].[NH4+].[OH-]>OS(O)(=O)=O.O.[N+]([O-])([O-])=O.[Ag+]>[CH2:11]([O:10][C:8](=[O:9])[C:7]1[C:6]([CH3:13])=[CH:5][C:4]([CH:14]2[CH2:16][CH2:15]2)=[N:3][C:2]=1[CH3:1])[CH3:12]
Reactant: O=C(O)C1CC1
Reactant: CCOC(=O)c1c(C)ccnc1C
Agent: [Ag+]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Solvent: O
Product: CCOC(=O)c1c(C)cc(C2CC2)nc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 18 %

Procedure:
To a solution of ethyl 2,4-dimethylpyridine-3-carboxylate (0.59 g, 3.29 mmol) and cyclopropane carboxylic acid (1.2 ml (15.1 mmol) in 10% aqueous H2SO4 (3 ml) was added AgNO3 (154 mg, 0.91 mmol) followed by a solution of ammonium persulfate (1:541 g, 6.75 mmol) in water (6 ml) and the mixture stirred at room temperature overnight. The reaction was neutralized to pH 10 with saturated aqueous NH4OH (5 ml) and extracted with EtOAc (3×20 ml). The combined organic extracts were dried (Na2SO4), concentrated and purified by column chromatography on silica gel (Hexanes/EtOAc, 96:4 then 1:1 then 0:100) to afford desired 6-cyclopropyl-2,4-dimethyl-nicotinic acid ethyl ester (133 mg, 18%) as a clear oil along with recovered starting ethyl 2,4-dimethylpyridine-3-carboxylate (0.31 g). 1H NMR (CDCl3) δ 0.93-0.97 (m, 4H), 1.38 (t, 3H, J=6 Hz), 1.92-2.02 (m, 1H), 2.28 (s, 3H), 2.47 (s, 3H), 4.39 (q, 2H, J=6 Hz), 6.73 (s, 1H).
Reaction SMILES: S(Br)([Br:3])=O.[C:5]([OH:15])(=O)[C:6]1[NH:13][C:11](=[O:12])[NH:10][C:8](=[O:9])[CH:7]=1>O>[C:5]([Br:3])(=[O:15])[C:6]1[NH:13][C:11](=[O:12])[NH:10][C:8](=[O:9])[CH:7]=1
Reactant: O=C(O)c1cc(=O)[nH]c(=O)[nH]1
Reactant: O=S(Br)Br
Solvent: O
Product: O=C(Br)c1cc(=O)[nH]c(=O)[nH]1
Temperature: 30 °C

Procedure:
In a dry 2-necked, round bottomed flask, equipped with a magnetic stirrer and fixed with a separatory funnel, containing 10.07 ml (130 mmol) of thionyl bromide, and a water condenser, is placed 15.61 g (100 mmol) of orotic acid. Addition of the thionyl bromide is completed with heating to about 30° C. over the course of about 130 minutes. When addition of the thionyl bromide is complete the mixture is heated and stirred for an additional hour. The water condenser is then replaced with a distillation side arm condenser and the crude mixture is distilled. The crude distillate in the receiving flask is then fractionally distilled to obtain the acyl bromide, orotoyl bromide. This acyl bromide, 10.95 g (50 mmol), is put into a dry separatory funnel and combined with 100 mL of dry DCM for use in the next step of the reaction.