Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(OC1C=CC2[C@@H]3[C@H]([C@H]4[C@@](CC3)(C)[C@@H](C(=O)NCCC)CC4)CCC=2C=1)N.[S:30](=[O:59])(=[O:58])([O:32][C:33]1[CH:50]=[CH:49][C:48]2[C@@H:47]3[C@H:38]([C@H:39]4[C@@:43]([CH2:45][CH2:46]3)([CH3:44])[C:42]([C:51](=[O:57])[N:52]([CH3:56])[CH2:53][CH2:54][CH3:55])=[CH:41][CH2:40]4)[CH2:37][CH2:36][C:35]=2[CH:34]=1)[NH2:31]>>[S:30](=[O:58])(=[O:59])([O:32][C:33]1[CH:50]=[CH:49][C:48]2[C@@H:47]3[C@H:38]([C@H:39]4[C@@:43]([CH2:45][CH2:46]3)([CH3:44])[C@@H:42]([C:51](=[O:57])[N:52]([CH3:56])[CH2:53][CH2:54][CH3:55])[CH2:41][CH2:40]4)[CH2:37][CH2:36][C:35]=2[CH:34]=1)[NH2:31]
Reactant: CCCN(C)C(=O)C1=CC[C@H]2[C@@H]3CCc4cc(OS(N)(=O)=O)ccc4[C@H]3CC[C@]12C
Agent: CCCNC(=O)[C@H]1CC[C@H]2[C@@H]3CCc4cc(OS(N)(=O)=O)ccc4[C@H]3CC[C@]12C
Product: CCCN(C)C(=O)[C@H]1CC[C@H]2[C@@H]3CCc4cc(OS(N)(=O)=O)ccc4[C@H]3CC[C@]12C

Procedure:
In similar manners to those described for the synthesis of compound 7, compound 29m was prepared from compound 11m. TOF-MS m/z 435 (M+H)+; 1H NMR (270 MHz, DMSO-d6) δ 0.60-0.68 (m, 3H, CH3), 0.76-0.88 (m, 3H, CH2CH3), 2.70-3.70 (m, 5H, N(CH3)CH2), 6.95 (d, 1H, J=2.6 Hz, ArH), 7.00 (dd, 1H, J=2.6, 8.6 Hz, ArH), 7.32 (d, 1H, J=8.6 Hz, ArH), 7.83 (brs, 2H, NH2).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[N:19]=[N:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([CH:26]([C:31]4[CH:36]=[CH:35][C:34]([O:37][CH2:38][C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=5)=[CH:33][CH:32]=4)[C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:22][CH:21]=3)=[N:16]2)[CH2:10][CH2:9]1)=O)(C)(C)C>Cl.O1CCOCC1.O>[CH3:28][C:27]([CH3:30])([CH3:29])[CH:26]([C:31]1[CH:32]=[CH:33][C:34]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=2)=[CH:35][CH:36]=1)[C:23]1[CH:22]=[CH:21][C:20]([C:17]2[N:18]=[N:19][N:15]([CH2:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[N:16]=2)=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Cn2nnc(-c3ccc(C(c4ccc(OCc5ccccn5)cc4)C(C)(C)C)cc3)n2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)C(c1ccc(OCc2ccccn2)cc1)c1ccc(-c2nnn(CC3CCNCC3)n2)cc1

Procedure:
Crude 2h (0.102 mmol) was dissolved in a pre-mixed solution of 4N HCl in dioxane (5.00 mL) and deionized water (250 μL) at 10° C. The resultant solution was warmed to room temperature and aged for approximately 1.3 h. After concentrating in vacuo, the residue was purified by flash chromatography on silica gel [100% EtOAc (120 mL) followed by 0%-100% EtOAc/(DCM:MeOH:ammonium hydroxide (95:5:1)] to afford compound Ie-2bx, Ie-2bx: m/z (ES) 497 (MH)+. 1HNMR (500 MHz, CDCl3): δ 8.59 (d, 1H, J=4.3 Hz), 8.05 (d, 2H, J=8.2 Hz), 7.70 (dt, 1H, J=7.6, 1.4 Hz), 7.53 (m, 3H), 7.36 (d, 2H, J=8.7 Hz), 7.21 (dd, 1H, J=6.9, 5.1 Hz), 6.92 (d, 2H, J=8.4 Hz), 5.19 (s, 2H), 4.51 (d, 2H, J=7.1 Hz), 3.75 (s, 1H), 3.10 (bd, 2H, J=12.4 Hz), 2.60 (dt, 2H, J=12.1, 2.0 Hz), 2.21 (m, 1H), 1.86 (bs, 1H), 1.60 (bd, 2H, J=12.3 Hz), 1.28 (m, 2H), 1.04 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([CH2:10][OH:11])=[CH:6][C:3]=1[C:4]#[N:5].C(OC([N:19]1[C:27]2[N:22]([C:23](=[O:29])[N:24]=[C:25](Cl)[CH:26]=2)[CH2:21][C@@H:20]1[CH3:30])=O)(C)(C)C>>[F:1][C:2]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:25]2[CH:26]=[C:27]3[NH:19][C@@H:20]([CH3:30])[CH2:21][N:22]3[C:23](=[O:29])[N:24]=2)=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: C[C@H]1Cn2c(cc(Cl)nc2=O)N1C(=O)OC(C)(C)C
Reactant: N#Cc1cc(CO)ccc1F
Product: C[C@H]1Cn2c(cc(OCc3ccc(F)c(C#N)c3)nc2=O)N1

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from 2-fluoro-5-(hydroxymethyl)benzonitrile and (S)-tert-butyl-7-chloro-2-methyl-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10]C)=[O:9])[CH:5]=C(C)[N:3]=1.[Se](=O)=[O:14].O1[CH2:21][CH2:20][O:19][CH2:18]C1>>[CH3:18][O:19][C:20]([C:21]1[CH:5]=[C:6]([C:8]([OH:10])=[O:9])[N:7]=[C:2]([Cl:1])[N:3]=1)=[O:14]
Reactant: C1COCCO1
Reactant: O=[Se]=O
Reactant: COC(=O)c1cc(C)nc(Cl)n1
Product: COC(=O)c1cc(C(=O)O)nc(Cl)n1
Temperature: 105 °C

Procedure:
To a stirred solution of methyl 2-chloro-6-methylpyrimidine-4-carboxylate (3.73 g, 20 mmol.) in dioxane (20 mL) is added selenium dioxide (3.55 g, 32 mmol) and the mixture is heated at 105° C. for 12 hours. The suspension is filtered through Celite and washed well with dioxane. The solvent is removed under reduced pressure to give 2-chloro-pyrimidine-4,6-dicarboxylic acid monomethyl ester; HPLC Retention time 0.65 minutes (condition C); MS 217.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[S:12][C:11]([CH2:13][CH3:14])=[N:10][C:9]=2[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#N)[CH:16]=2)[CH:5]=[CH:4][N:3]=1.S(=O)(=O)(O)[OH:24].[OH-:28].[Na+]>C(O)(=O)C>[NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[S:12][C:11]([CH2:13][CH3:14])=[N:10][C:9]=2[C:15]2[CH:16]=[C:17]([CH:18]=[CH:19][CH:20]=2)[C:21]([OH:24])=[O:28])[CH:5]=[CH:4][N:3]=1
Reactant: [OH-]
Reactant: O=S(=O)(O)O
Reactant: CCc1nc(-c2cccc(C#N)c2)c(-c2ccnc(N)c2)s1
Agent: [Na+]
Solvent: CC(=O)O
Product: CCc1nc(-c2cccc(C(=O)O)c2)c(-c2ccnc(N)c2)s1
Temperature: 110 °C
Reaction time: 6 h
Yield: 84 %

Procedure:
To a solution of 5-(2-amino-4-pyridyl)-4-(3-cyanophenyl)-2-ethyl-1,3-thiazole (0,50 g, 1.6 mmol) in acetic acid (5 mL) was added 50% sulfuric acid (2.0 mL), and the mixture was stirred for 6 hours at 110° C. The reaction mixture was basified with aqueous sodium hydroxide solution and washed with ethylacetate. The aqueous phase was neutralized with hydrochloric acid, and the deposited crystal was washed with water and ethyl ether to obtain a title compound (0.45 g, yield 84%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5](Cl)=[O:6].[CH3:12][C:13]1[C:18]2[NH:19][C:20](=[O:22])[O:21][C:17]=2[CH:16]=[CH:15][CH:14]=1.[Cl-].[Cl-].[Cl-].[Al+3]>>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5]([C:15]1[CH:14]=[C:13]([CH3:12])[C:18]2[NH:19][C:20](=[O:22])[O:21][C:17]=2[CH:16]=1)=[O:6]
Reactant: Cc1cccc2oc(=O)[nH]c12
Reactant: O=C(Cl)c1cc(F)cc(F)c1
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1cc(C(=O)c2cc(F)cc(F)c2)cc2oc(=O)[nH]c12
Temperature: 0 °C

Procedure:
1.45 g (8.21 mmol) 3,5-difluorobenzoic acid chloride, 1.22 g (8.21 mmol) 4-methyl-3H-benzoxazol-2-one and 4.40 g (33.0 mmol) aluminium trichloride were heated to 125° C. for 1.5 h with stirring. The mixture was mixed with ice water and the product precipitated as a solid was suction filtered and washed with water. After trituration of the precipitate with MeOH it was suction filtered, washed with MeOH and dried i. vac.
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[S:10][C:6]=2[C:5](I)=[CH:4][N:3]=1.[N:13]1[CH:18]=[C:17](B(O)O)[CH:16]=[N:15][CH:14]=1.[NH2:22][C:23]1[N:24]=[C:25]([CH3:28])[S:26][CH:27]=1>>[CH3:11][C:9]1[S:10][C:6]2[C:5]([C:17]3[CH:18]=[N:13][CH:14]=[N:15][CH:16]=3)=[CH:4][N:3]=[C:2]([NH:22][C:23]3[N:24]=[C:25]([CH3:28])[S:26][CH:27]=3)[C:7]=2[N:8]=1
Reactant: Cc1nc2c(Cl)ncc(I)c2s1
Reactant: OB(O)c1cncnc1
Reactant: Cc1nc(N)cs1
Product: Cc1nc(Nc2ncc(-c3cncnc3)c3sc(C)nc23)cs1

Procedure:
The title compound, MS: m/e=341.0 (M+H+), was prepared in accordance with the general method of example 2, step 1 and step 2 from 4-chloro-7-iodo-2-methyl-thiazolo[4,5-c]pyridine (Example B), 5-pyrimidineboronic acid and 4-amino-2-methylthiazole (Example C).
Reaction SMILES: [C:1]1([C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15]>C(O)(=O)C>[C:1]1([C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[NH:9][C:14](=[O:16])[CH3:15])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccccc1-c1ccccc1
Solvent: CC(=O)O
Product: CC(=O)Nc1ccccc1-c1ccccc1
Reaction time: 2 h
Yield: 99.5 %

Procedure:
2-Phenylaniline (5 g, 29.55 mmol) was dissolved in acetic acid (30 mL), acetic anhydride (3.62 g, 35.45 mmol) was added thereto under ice bath, and the mixture was stirred under ice bath for 2 hours. The solution was concentrated under reduced pressure. to the residue was added water (15 mL), and the mixture was stirred at room temperature for 3 hours. The precipitate was collected by filtration, washed with purified water, and dried under reduced pressure to obtain 2-phenyl-N-acetylaniline (6.21 g).
Reaction SMILES: [Cl:1][C:2]([Cl:13])([Cl:12])[CH2:3][O:4][C:5]([NH:7][CH2:8][C:9](Cl)=[O:10])=[O:6].[Pb](SC#N)[S:15][C:16]#[N:17]>C1(C)C=CC=CC=1>[Cl:1][C:2]([Cl:13])([Cl:12])[CH2:3][O:4][C:5]([NH:7][CH2:8][C:9]([N:17]=[C:16]=[S:15])=[O:10])=[O:6]
Reactant: N#CS[Pb]SC#N
Reactant: O=C(Cl)CNC(=O)OCC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(CNC(=O)OCC(Cl)(Cl)Cl)N=C=S
Temperature: 25 °C

Procedure:
A solution of 20 parts of the preceeding acetyl chloride and 30 parts of lead thiocyanate in 150 parts by volume of toluene is refluxed for about 4 hours, then cooled to ambient temperature and filtered. The solvent is removed from the filtrate and the remaining oil distilled using fractionating column under vacuum to give {[(2,2,2-trichloroethoxy)carbonyl]amino}acetyl isothiocyanate. This compound is represented by the following formula
Reaction SMILES: [Br:1][C:2]([CH3:7])([CH3:6])[C:3](Br)=[O:4].[CH2:8]([NH2:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CCOC(C)=O>[Br:1][C:2]([CH3:7])([CH3:6])[C:3]([NH:15][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:4]
Reactant: NCc1ccccc1
Reactant: CC(C)(Br)C(=O)Br
Solvent: CCOC(C)=O
Product: CC(C)(Br)C(=O)NCc1ccccc1
Yield: 91 %

Procedure:
Prepared in 91% yield (10.7 g, 42 mmol) from the reaction of 2-bromo-2-methylpropanoyl bromide (10.6 g, 46 mmol) with benzylamine (5.1 mL, 46 mmol) via general procedure A. Rf=0.84 (3:1, hexanes:EtOAc); mp 73.4-75.5° C.; 1H NMR (400 MHz, CDCl3): δ 7.41-7.23 (m, 1H), 7.03 (br s, 1H), 4.46 (d, J=5.8 Hz, 1H), and 1.99 (s, 1H); 13C NMR (125 MHz, CDCl3): δ 172.0, 137.8, 128.8, 127.6, 127.6, 62.8, 44.4, and 32.6; IR (neat) 3291 (br), 3065, 301, 3008, 2938, 2919, 1642 (s), 1533 cm-1; HRMS (ESI) calculated 256.0332 C11H15BrNO [M+H]+, observed 256.0329.
Reaction SMILES: [SH:1][C:2]1[N:3]([CH3:31])[C:4]([C:7]2[CH:12]=[CH:11][N:10]3[C:13]([C:16]4[CH:17]=[C:18]([NH:22][C:23]([NH:25][CH2:26][C:27]([F:30])([F:29])[F:28])=[O:24])[CH:19]=[CH:20][CH:21]=4)=[CH:14][N:15]=[C:9]3[CH:8]=2)=[N:5][N:6]=1.[OH-:32].[K+].I[CH3:35]>CCO>[CH:23]([OH:24])=[O:32].[CH3:31][N:3]1[C:2]([S:1][CH3:35])=[N:6][N:5]=[C:4]1[C:7]1[CH:12]=[CH:11][N:10]2[C:13]([C:16]3[CH:17]=[C:18]([NH:22][C:23]([NH:25][CH2:26][C:27]([F:30])([F:28])[F:29])=[O:24])[CH:19]=[CH:20][CH:21]=3)=[CH:14][N:15]=[C:9]2[CH:8]=1
Reactant: CI
Reactant: [OH-]
Reactant: Cn1c(S)nnc1-c1ccn2c(-c3cccc(NC(=O)NCC(F)(F)F)c3)cnc2c1
Agent: [K+]
Solvent: CCO
Product: CSc1nnc(-c2ccn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)n1C
Product: O=CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.3 %

Procedure:
To a solution of 1-{3-[7-(5-Mercapto-4-methyl-4H-[1,2,4]triazol-3-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea (72 mg, 0.16 mmol) in EtOH (3 ml) was added KOH (10 mg, 0.18 mmol) and iodomethane (20 μl, 0.16 mmol) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was placed in an ice bath and the precipitate formed filtered off. The precipitate was purified by reverse phase HPLC to afford the title compound (18 mg). MS: [M+H]+=462.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][CH2:12][CH:13]=[O:14])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.N1CCC[C@H]1C(O)=O.Cl[N:24]1[C:28](=[O:29])[CH2:27][CH2:26][C:25]1=[O:30].C(Cl)(Cl)[Cl:32]>>[Cl:32][CH:12]([CH2:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]=[CH:2][CH:3]=[CH:4]2)[CH:13]([N:24]1[C:28](=[O:29])[CH2:27][CH2:26][C:25]1=[O:30])[OH:14]
Reactant: O=CCCc1ccc2ncccc2c1
Reactant: O=C1CCC(=O)N1Cl
Reactant: ClC(Cl)Cl
Agent: O=C(O)[C@@H]1CCCN1
Product: O=C1CCC(=O)N1C(O)C(Cl)Cc1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.5 %

Procedure:
To a solution of 3-quinolin-6-ylpropanal (Step 6, 2.3 g, 0.012 mol) in chloroform (5 mL) cooled at 0° C. was added L-proline (0.4 g, 0.004 mol). To the mixture was then added N-chlorosuccinimide (1.74 g, 0.0130 mol) at 0° C. The reaction was warmed to r.t. and stirred overnight. The reaction was thick slurry. Solid was filtered and was washed with chloroform to give the pure product (2 g, 50.5%). 1H-NMR (300 MHz, CDCl3): 8.90 (dd, J=4.0, 2.0 Hz, 1H), 8.13 (d, J=8.0 Hz, 1H), 8.05 (d, J=8.4 Hz, 1H), 7.73 (s, 1H), 7.65 (dd, J=8.0, 2.0 Hz, 1H), 7.40 (dd, J=8.4, 4.0 Hz, 1H), 5.46 (d, J=9.4 Hz, 1H), 4.95 (ddd, J=9.4, 8.0, 3.1 Hz, 1H), 3.73 (dd, J=14.3, 3.1 Hz, 1H), 3.19 (dd, J=14.3, 8.0 Hz, 1H), 2.75 (s, 4H).
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.N([CH:21]([CH3:23])C)C(C)C.[CH3:24][Si:25]([C:28]#[CH:29])([CH3:27])[CH3:26]>[Cu]I.C1COCC1>[CH3:24][Si:25]([C:28]#[C:29][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:23]#[C:21][Si:25]([CH3:27])([CH3:26])[CH3:24])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1)([CH3:27])[CH3:26]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)NC(C)C
Reactant: O=C(c1ccc(Br)cc1)c1ccc(Br)cc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1ccc(C(=O)c2ccc(C#C[Si](C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 40 h
Yield: 96 %

Procedure:
To a flask containing a mixture of 4,4'-dibromobenzophenone (5.0 g, 14.7 mmol), PdCl2 (PPh3)2 (0.42 mg, 0.60 mmol), and CuI (60 mg, 0.30 mmol) was added THF (100 mL), iPr2NH (20 mL) and trimethylsilylacetylene (4.6 mL, 32.5 mmol) under a nitrogen atmosphere. The mixture was stirred at room temperature for 40 hours. The solvent was removed under vacuum, and the residue was extracted with CH2Cl2 /H2O. The organic layer was collected, dried over MgSO4, filtered through Al2O3, and pumped dry. The residue was recrystallized from CH2Cl2 /hexane at -30° C. to afford pale brown crystalline 4,4'-bis(trimethylsilylethynyl)benzophenone in 96% yield (5.29 g). 1H NMR (300 MHz, C6D6, 25° C., TMS): δ=0.25 (s, 18 H, CH3), 7.53 (d, J=8.6 Hz, 4 H, C6H4), 7.69 (d, 4 H, C6H4). To a mixture of 4,4'-bis(trimethylsilylethynyl)benzophenone (1.0 g, 2.67 mmol) and KOH (0.30 g, 5.36 mmol) was added 50 mL of MeOH and the solution was stirred at room temperature for 3 hours. The solution was then extracted with Et2O. The Et2O solution was pumped dry and the residue was chromatographed using EtOAc/hexane (1:50 to 1:5) as eluent to afford 4,4'-diethynylbenzophenone in 68% yield (0.42 g).
Reaction SMILES: C(OC([O:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O:21]CC=C)=[O:20])=[C:14]([CH2:17]O)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9])=O)C=C.[OH:27][CH2:28][C:29]1[S:33][C:32]2=[CH:34][N:35]=[CH:36][N:31]2[CH:30]=1>>[OH:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O-:21])=[O:20])=[C:14]([CH2:17][N:35]3[CH:34]=[C:32]4[S:33][C:29]([CH2:28][OH:27])=[CH:30][N+:31]4=[CH:36]3)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9]
Reactant: OCc1cn2cncc2s1
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CO)[C@H](C)[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(Cn3cc4sc(CO)c[n+]4c3)[C@H](C)[C@H]12
Yield: 3.1 %

Procedure:
The same procedure as in Example 1 was repeated except that 103 mg of allyl (1S,5R,6S)-6-[(1R)-1-allyloxycarbonyloxyethyl]-2-hydroxymethyl-1-methyl-1-carbapen-2-em-3-carboxylate and 87 mg of 2-hydroxymethylimidazo[5,1-b]thiazole were used, thereby obtaining 3.3 mg of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH:8]=[N:9][CH:10]=[CH:11][C:5]2=[N:4][C:3]=1[N:12]1[CH2:17][CH2:16][CH:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])[CH2:14][CH2:13]1.Cl.[F:28][C:29]1([F:34])[CH2:32][CH:31]([NH2:33])[CH2:30]1.[F-].[K+].CCN(C(C)C)C(C)C>CS(C)=O.O>[F:28][C:29]1([F:34])[CH2:32][CH:31]([NH:33][C:2]2[N:7]=[C:6]3[CH:8]=[N:9][CH:10]=[CH:11][C:5]3=[N:4][C:3]=2[N:12]2[CH2:17][CH2:16][CH:15]([O:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])[CH2:14][CH2:13]2)[CH2:30]1
Reactant: NC1CC(F)(F)C1
Reactant: Fc1ccc(OC2CCN(c3nc4ccncc4nc3Cl)CC2)c(F)c1
Agent: Cl
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Fc1ccc(OC2CCN(c3nc4ccncc4nc3NC3CC(F)(F)C3)CC2)c(F)c1
Temperature: 23 °C
Reaction time: 120 h
Yield: 94.5 %

Procedure:
Combined 3-chloro-2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)pyrido[3,4-b]pyrazine (0.46 g, 1.221 mmol), 3,3-difluorocyclobutanamine hydrochloride (0.526 g, 3.66 mmol), and potassium fluoride (0.092 g, 1.587 mmol) in DMSO (5 mL) and added DIPEA (1.063 mL, 6.10 mmol) at 23° C. The reaction was stirred at 23° C. for 5 days and diluted with water (20 mL) to furnish a yellow-orange suspension. The resulting solid was filtered, rinsed with water, and dried in vacuo to give the title compound (516.4 mg, 95%) as a yellow-orange solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.87-1.98 (m, 2H), 2.07-2.18 (m, 2H), 2.77-2.91 (m, 2H), 2.96-3.07 (m, 2H), 3.23-3.32 (m, 2H), 3.69-3.78 (m, 2H), 4.35-4.45 (m, 1H), 4.63 (tt, J=7.9, 3.8 Hz, 1H), 7.00-7.07 (m, 1H), 7.24-7.40 (m, 3H), 7.48 (d, J=5.4 Hz, 1H), 8.33 (d, J=5.4 Hz, 1H), 8.82 (s, 1H); ESI-MS m/z [M+H]+ 447.9.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1.Br[CH2:14][CH2:15][CH2:16][O:17][CH3:18].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[CH3:18][O:17][CH2:16][CH2:15][CH2:14][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: O=C1CCCc2ccc(O)cc21
Reactant: COCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COCCCOc1ccc2c(c1)C(=O)CCC2
Temperature: 80 °C
Reaction time: 23 h

Procedure:
To a solution of 7-hydroxy-1-tetralone (4.05 g) in acetonitrile (75 mL) were added 1-bromo-3-methoxypropane (4.59 g), potassium iodide (415 mg) and potassium carbonate (5.18 g), and the mixture was heated to stir at 80° C. for 23 hours. To the reaction mixture was added water under ice-cooling, and then the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was triturated with n-hexane to give 7-(3-methoxypropoxy)-3,4-dihydronaphthalen-1(2H)-one [REx(12-1)] (4.70) as a colorless powder.
Reaction SMILES: C([O:8][C:9]([C@:11]12[CH2:41][CH2:40][C@@H:39]([C:42]([CH3:44])=[CH2:43])[C@@H:12]1[C@@H:13]1[C@@:26]([CH3:29])([CH2:27][CH2:28]2)[C@@:25]2([CH3:30])[CH:16]([C@:17]3([CH3:38])[C@@H:22]([CH2:23][CH2:24]2)[C:21]([CH3:32])([CH3:31])[C:20](/[CH:33]=[CH:34]/[C:35]([OH:37])=[O:36])=[CH:19][CH2:18]3)[CH2:15][CH2:14]1)=[O:10])C1C=CC=CC=1.[H][H]>CO.C(OCC)(=O)C.[Pd]>[C:35]([CH2:34][CH2:33][C:20]1[C:21]([CH3:32])([CH3:31])[C@H:22]2[C@:17]([CH3:38])([CH2:18][CH:19]=1)[CH:16]1[C@:25]([CH3:30])([C@@:26]3([CH3:29])[C@H:13]([CH2:14][CH2:15]1)[C@H:12]1[C@H:39]([C:42]([CH3:44])=[CH2:43])[CH2:40][CH2:41][C@:11]1([C:9]([OH:10])=[O:8])[CH2:28][CH2:27]3)[CH2:24][CH2:23]2)([OH:37])=[O:36]
Reactant: [H][H]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)OCc3ccccc3)CC[C@]3(C)[C@H](CCC4[C@@]5(C)CC=C(/C=C/C(=O)O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CCC4[C@@]5(C)CC=C(CCC(=O)O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 5 h
Yield: 9.4 %

Procedure:
A mixture of (E)-3-((1R,3aS,5aR,5bR,7aR,11aS,13aR,13bR)-3a-(benzyloxycarbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)acrylic acid (20 mg, 0.033 mmol) and 10% Pd/C (25 mg, 0.023 mmol) in MeOH (0.5 mL) and ethyl acetate (1 mL) was connected to a balloon of hydrogen and stirred at room temperature for 5 hours. The reaction mixture was filtered to remove Pd/C and the filtrates were concentrated under reduced pressure. The residue was dissolved in DMF and purified by prep HPLC to provide the desired product (1.59 mg, 9%). LCMS: m/e 509.6 (M−H)−, 2.36 min (method 6). 1H NMR (400 MHz, <DMSOmix>) δ 5.21 (d, J=5.0 Hz, 1H), 4.70 (br. s., 1H), 4.57 (br. s., 1H), 3.05-0.98 (m, 27H), 1.67 (s., 3H), 0.96 (s., 6H), 0.93 (s., 3H), 0.89 (s., 3H), 0.79 (s., 3H).
Reaction SMILES: [C:1]1([CH2:7][C:8]2([CH2:13][CH2:14][OH:15])[CH2:12][CH2:11][NH:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C.O.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:37]=[C:38]([O:42][CH3:43])[C:39]=1[O:40][CH3:41])[C:34](Cl)=[O:35]>C(OCC)(=O)C>[CH3:43][O:42][C:38]1[CH:37]=[C:33]([CH:32]=[C:31]([O:30][CH3:29])[C:39]=1[O:40][CH3:41])[C:34]([N:10]1[CH2:11][CH2:12][C:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([CH2:13][CH2:14][OH:15])[CH2:9]1)=[O:35]
Reactant: OCCC1(Cc2ccccc2)CCNC1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)N2CCC(CCO)(Cc3ccccc3)C2)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 18 h

Procedure:
Combine 3-(phenylmethyl)-3-(2-hydroxyethyl)pyrrolidine (3.94 mmol) and sodium carbonate (0.21 g, 2.00 mmol) in 1/1 ethyl acetate/water (50 mL). Cool the reaction mixture to 0° C. with an ice bath. Add 3,4,5-trimethoxybenzoyl chloride (0.83 g, 3.58 mmol). Warm to ambient temperature. After 18 hours, separate the layers and extract the aqueous layer three times with ethyl acetate. Dry the combined organic layers over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph the residue on silica gel eluting with ethyl acetate to give the title compound: Rf=0.09 (silica gel, ethyl acetate).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:21])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12]P(OCC)(OCC)=O.C1OCCOCCOCCOCCOC1.[C:37]([N:44]1[CH2:49][CH2:48][C:47](=O)[CH2:46][CH2:45]1)([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38]>C1COCC1.O>[C:40]([O:39][C:37]([N:44]1[CH2:49][CH2:48][C:47](=[CH:12][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]([O:4][CH3:3])=[O:21])[CH2:46][CH2:45]1)=[O:38])([CH3:43])([CH3:41])[CH3:42]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCOP(=O)(Cc1ccccc1C(=O)OC)OCC
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccccc1C=C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 13.5 %

Procedure:
Sodium hydride (526 mg; 12.05 mmol; 1.2 eq.) was added to a cold (0° C.) solution of 2-(diethoxy-phosphorylmethyl)-benzoic acid methyl ester (3.45 g; 12.05 mmol; 1.2 eq.) and 15-crown-5 (60 μL; 0.30 mmol; 0.03 eq.) in THF (10 mL) and the reaction mixture was stirred at room temperature for 30 min whereupon a solution of 1-boc-piperidin-4-one (2 g; 10.04 mmol; 1 eq.) in THF (10 mL) was added dropwise over 10 min at 0° C. The reaction mixture was stirred at room temperature for 2 days then diluted with water and extracted with EA (2×). The combined organic phase was washed with 1M (NaOH) then brine, dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography (heptanes/EA, 95/5 to 50/50) afforded the title compound (450 mg, 14%) as a white solid. UPLC/MS: (MS+) 332.3 ([M+H]+).