Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([C:18]3[O:22][C:21]([C:23]#[N:24])=[CH:20][CH:19]=3)=[CH:7][CH:8]=2)[N:3]=1.[F:25][C:26]1[CH:27]=[C:28]([NH:41][C:42](=[O:55])[NH:43][C:44]2[CH:54]=[CH:53][C:47]([C:48]([N:50]([CH3:52])[CH3:51])=[O:49])=[CH:46][CH:45]=2)[CH:29]=[CH:30][C:31]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[C:23]([C:21]1[O:22][C:18]([C:6]2[CH:5]=[C:4]3[C:9]([C:10]([N:12]4[CH2:17][CH2:16][O:15][CH2:14][CH2:13]4)=[N:11][C:2]([C:31]4[CH:30]=[CH:29][C:28]([NH:41][C:42](=[O:55])[NH:43][C:44]5[CH:54]=[CH:53][C:47]([C:48]([N:50]([CH3:52])[CH3:51])=[O:49])=[CH:46][CH:45]=5)=[CH:27][C:26]=4[F:25])=[N:3]3)=[CH:8][CH:7]=2)=[CH:19][CH:20]=1)#[N:24]
Reactant: N#Cc1ccc(-c2ccc3c(N4CCOCC4)nc(Cl)nc3c2)o1
Reactant: CN(C)C(=O)c1ccc(NC(=O)Nc2ccc(B3OC(C)(C)C(C)(C)O3)c(F)c2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1ccc(NC(=O)Nc2ccc(-c3nc(N4CCOCC4)c4ccc(-c5ccc(C#N)o5)cc4n3)c(F)c2)cc1
Temperature: 95 °C
Reaction time: 2 h
Yield: 6.1 %

Procedure:
To a 50 mL round bottom flask, 5-(2-chloro-4-morpholino-quinazolin-7-yl)furan-2-carbonitrile (0.12 g, 0.00035 mol), 4-(3-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide (0.144 g, 0.00053 mol), cesium carbonate (0.228 g, 0.0007 mol), DMF (3 mL) and water (3 mL) were added. The reaction mixture was degassed with nitrogen for 5-10 min. To the same reaction flask, Pd(PPh3)2Cl2 (0.013 g, 0.0000175 mol) was added and again degassed with nitrogen for 5-10 min. The reaction mixture was stirred at 95° C. for 2 h. To the cooled reaction mixture, water was added and extracted with ethyl acetate. The organic layer was separated, washed with water, brine and dried over anhydrous sodium sulfate. The organic layer was evaporated under reduced pressure to afford the crude product. The crude product was purified by column chromatography using 60-120 silica gel and 2-5% MeOH in chloroform to obtain the title compound [0.013 g, 6%]. 1H NMR (400 MHz, DMSO-d6): δ 9.21 (s, 1H), 9.04 (s, 1H), 8.27 (d, J=2.0 Hz, 1H), 8.19-8.13 (m, 2H), 7.93 (dd, J′=1.6, J″=8.4 Hz, 1H), 7.82 (d, J=4.0 Hz, 1H), 7.64 (d, J=3.6 Hz, 2H), 7.61 (d, J=2.0 Hz, 1H), 7.54 (d, J=8.4 Hz, 2H), 7.28 (dd, J′=8.8 Hz, J″=2.0 Hz, 2H), 3.83 (s, 8H), 2.96 (s, 6H). LC-MS (ESI): Calculated mass: 605.2; Observed mass: 606.2 (RT: 1.17 min).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([CH:15]([CH2:18][CH:19]=[CH2:20])[CH2:16][OH:17])[CH:12]([CH3:14])[CH3:13].[Cl-].[NH4+]>C(Cl)Cl.C(N(CC)CC)C>[CH2:11]([CH:15]([CH2:18][CH:19]=[CH2:20])[CH:16]=[O:17])[CH:12]([CH3:14])[CH3:13]
Reactant: C=CCC(CO)CC(C)C
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: C=CCC(C=O)CC(C)C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Oxalyl chloride (5.45 g, 43 mmol) was dissolved in methylene chloride (50 mL), and the solution was cooled to −78° C. Then, dimethyl sulfoxide (6.1 mL) was added dropwise thereto. To the mixture, a methylene chloride (40 mL) solution of 2-isobutylpent-4-en-1-ol (4.9 g, 34 mmol) was subsequently added dropwise, and the mixture was stirred at this temperature for 1 hour. Triethylamine (24 mL) was added thereto, and the mixture was brought to room temperature. A saturated aqueous solution of ammonium chloride was added thereto. The organic layer was separated, washed with water and saturated saline, then dried, and then concentrated to obtain the compound of interest as an oil substance. This compound was used in the next reaction without being purified.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:21])[O:4][C:5]2[CH:18]=[C:17]([CH3:19])[C:16]([Cl:20])=[CH:15][C:6]=2[C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:14].[F:22][C:23]([F:34])([F:33])[C:24]1[CH:25]=[C:26]([N:30]=[C:31]=[O:32])[CH:27]=[CH:28][CH:29]=1>C1C=CC=CC=1>[Cl:20][C:16]1[C:17]([CH3:19])=[CH:18][C:5]2[O:4][C:3](=[O:21])[C:2]([NH:1][C:31]([NH:30][C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([C:23]([F:22])([F:33])[F:34])[CH:25]=3)=[O:32])=[C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[CH3:14])[C:6]=2[CH:15]=1
Reactant: Cc1cc2oc(=O)c(N)c(-c3ccccc3C)c2cc1Cl
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Solvent: c1ccccc1
Product: Cc1cc2oc(=O)c(NC(=O)Nc3cccc(C(F)(F)F)c3)c(-c3ccccc3C)c2cc1Cl

Procedure:
A mixture of 3-amino-6-chloro-7-methyl-4-(2-methylphenyl)-2H-benzopyran-2- one (297 mg), 3-trifluoromethylphenylisocyanate (374 mg) and benzene (4 ml) was refluxed for 2 hours and then distilled to remove the solvent. The residue was crystallized from ethyl ether. The resulting crystals were recrystallized from ethanol to obtain colorless needles of N-[6-chloro-7-methyl-4-(2-methylphenyl)-2-oxo- 2H-1-benzopyran-3-yl]-N'-(3-trifluoromethylphenyl) urea.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([N:10]1[C@H:15]2[CH2:16][CH2:17][C@@H:11]1[CH:12]([C:19]([O:21][CH3:22])=[O:20])[C:13](=O)[CH2:14]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl-].[NH4+].C(=O)([O-])O.[Na+].FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(N(CC)CC)C.CN(C1C=CN=CC=1)C.CO>[CH2:3]([N:10]1[C@H:15]2[CH2:16][CH2:17][C@@H:11]1[C:12]([C:19]([O:21][CH3:22])=[O:20])=[CH:13][CH2:14]2)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)C1C(=O)C[C@@H]2CC[C@H]1N2Cc1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CO
Product: COC(=O)C1=CC[C@@H]2CC[C@H]1N2Cc1ccccc1
Reaction time: 2 h
Yield: 81.2 %

Procedure:
Under a nitrogen atmosphere, NaBH4 (69.6 mg, 1.84 mmol) was added to a methanol (10 ml) solution of the methyl (1R,5S)-8-benzyl-3-oxo-8-azabicyclo[3.2.1]octane-2-carboxylate ((−)-2b) (264 mg, 0.92 mmol) obtained in Example 19, in an ice bath, and the reaction mixture was stirred for 2 hours. After completion of the reaction, a saturated aqueous ammonium chloride solution was added to the reaction mixture and the excess solvent was evapolated under reduced pressure. The residue was adjusted to pH 8.0-8.5 with a saturated aqueous sodium hydrogencarbonate solution and extracted with chloroform. The extract was dried over Na2SO4, filtered and then concentrated in vacuo. Then, the residue was dissolved in chloroform (10 ml) under a nitrogen atmosphere, and triethylamine (267 μl, 1.91 mmol) and DMAP as a catalyst were added thereto. In an ice bath, trifluoroacetic anhydride (203 μl, 1.44 mmol) was added thereto and the resulting mixture was stirred at room temperature for 44 hours. After completion of the reaction, the reaction mixture was adjusted to pH 8.0-8.5 with a saturated aqueous sodium hydrogencarbonate solution and extracted with chloroform. The extract was dried over Na2SO4, filtered and then concentrated in vacuo, and the thus obtained crude product was purified by a silica gel column chromatography (AcOEt:hexane=1:5) to obtain 192.2 mg of the title compound methyl (1R,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-2-ene-2-carboxylate. The yield from the above two steps was 81 mol %.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=2)=[C:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[S:6]1(=[O:33])=[O:32])([CH3:4])([CH3:3])[CH3:2].[Li+].[I-]>N1C=CC=CC=1>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=2)=[C:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[S:6]1(=[O:32])=[O:33])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(OCCCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)cc1
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: CC(C)(C)N1C(=O)C(NCCCOc2ccc(C(=O)O)cc2)=C(c2ccccc2)S1(=O)=O
Yield: 3.4 %

Procedure:
Methyl 4-{3-[(2-tert-butyl-1,1-dioxido-3-oxo-5-phenyl-2,3-dihydroisothiazol-4-yl)amino]propoxy}benzoate (0.90 g, 0.19 mmol) and LiI (0.382 g, 2.86 mmol) was dissolved in dry pyridine (1 mL) and heated at reflux for 4 h and then left at rt over night. The reaction mixture was purified by flash chromatography using first Hexane and EtOAc and then EtOAc and MeOH as eluant giving the title compound (0.003 g, 3.4%). 1H NMR (CD3CN): 7.98 (d, 2H), 7.56-7.48 (m, 5H), 6.90 (d, 2H), 6.02 (t, 1H), 3.90 (t, 2H), 3.12-3.08 (m, 21, 1.82-1.76 (t, 2H), 1.17 (s, 9H); Mass Spectrum: M+H+ 459.
Reaction SMILES: C([O:5][C:6](=[O:28])[CH2:7][CH:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10](CC2C=CC(OC)=CC=2)[C:9]1=[O:27])(C)(C)C>C(O)(C(F)(F)F)=O>[O:27]=[C:9]1[CH:8]([CH2:7][C:6]([OH:28])=[O:5])[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10]1
Reactant: COc1ccc(CN2C(=O)C(CC(=O)OC(C)(C)C)Cc3ccccc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CC1Cc2ccccc2NC1=O
Yield: 93 %

Procedure:
The [1-(4-methoxy-benzyl)-2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl]-acetic acid tert-butyl ester (3.35 mmol) obtained in the previous step is dissolved in 7 mL of TFA and heated to reflux for 1.5 hours. After removal of the excess TFA under reduced pressure, acid-base extraction gives the crude (2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl)-acetic acid as a yellow solid. Yield: 93%.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:6]([C:8]1[CH:9]=[C:10]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:24][CH:23]=2)[C:11](=[O:21])[N:12]2[C:17]=1[C:16]1[S:18][CH:19]=[CH:20][C:15]=1[CH:14]=[CH:13]2)=[O:7].[CH2:42](I)[CH3:43]>>[CH3:1][O:2][CH2:3][CH2:4][N:5]([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:6]([C:8]1[CH:9]=[C:10]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:24][CH:23]=2)[C:11](=[O:21])[N:12]2[C:17]=1[C:16]1[S:18][C:19]([CH2:42][CH3:43])=[CH:20][C:15]=1[CH:14]=[CH:13]2)=[O:7]
Reactant: COCCN(C(=O)c1cc(-c2ccc(OCc3ccccc3)cc2)c(=O)n2ccc3ccsc3c12)c1ccccc1
Reactant: CCI
Product: CCc1cc2ccn3c(=O)c(-c4ccc(OCc5ccccc5)cc4)cc(C(=O)N(CCOC)c4ccccc4)c3c2s1

Procedure:
By lithiation of 8-(4-benzyloxy-phenyl)-7-oxo-7H-thieno[2,3-a]quinolizine-10-carboxylic acid (2-methoxy-ethyl)-phenyl-amide and reaction with ethyl iodide.
Reaction SMILES: [C:1]([C:3]#[C:4][C:5]([C:8]1[CH:9]=[CH:10][C:11]([O:16][CH3:17])=[C:12]([CH:15]=1)[CH:13]=O)([CH3:7])[CH3:6])#[N:2].[NH2:18][C@H:19]1[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:20]1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(OC(N1CCC[C@H](NCC2C=C(C(C#N)C)C=CC=2OC)[C@@H]1C1C=CC=CC=1)=O)(C)(C)C>>[C:28]([O:27][C:25]([N:21]1[CH2:22][CH2:23][CH2:24][C@H:19]([NH:18][CH2:13][C:12]2[CH:15]=[C:8]([C:5]([CH3:7])([CH3:6])[C:4]#[C:3][C:1]#[N:2])[CH:9]=[CH:10][C:11]=2[O:16][CH3:17])[C@@H:20]1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:26])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)[C@@H]1c1ccccc1
Reactant: COc1ccc(C(C)(C)C#CC#N)cc1C=O
Agent: COc1ccc(C(C)C#N)cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Product: COc1ccc(C(C)(C)C#CC#N)cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1

Procedure:
This compound was prepared from Compound 64 and Compound 17 in the same manner of Compound 18.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH3:17])=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH:14]=O)=[CH:5][CH:4]=1.[C:18]([O:22][C:23](=[O:41])[N:24]([CH2:31][C:32](=[O:40])[NH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1)[CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)([CH3:21])([CH3:20])[CH3:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C.ClCCl>[C:18]([O:22][C:23](=[O:41])[N:24]([CH:25]1[CH2:26][CH2:27][N:28]([CH2:14][CH2:13][N:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[C:7]([CH3:17])=[CH:8][C:9]2=[O:16])[CH2:29][CH2:30]1)[CH2:31][C:32](=[O:40])[NH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: COc1ccc2c(C)cc(=O)n(CC=O)c2c1
Reactant: CC(C)(C)OC(=O)N(CC(=O)Nc1ccccn1)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(C)cc(=O)n(CCN3CCC(N(CC(=O)Nc4ccccn4)C(=O)OC(C)(C)C)CC3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.8 %

Procedure:
To 3 mL of dichloromethane solution containing 85 mg of (7-methoxy-4-methyl-2-oxoquinolin-1(2H)-yl)acetaldehyde, 0.12 g of tert-butyl(2-oxo-2-(pyridin-2-ylamino)ethyl)(piperidin-4-yl)carbamate and 21 μl of acetic acid were added and stirred at room temperature for 1 hour. To the reaction mixture, 0.12 g of sodium triacetoxyborohydride was added and stirred at the same temperature for 30 min. Chloroform and aqueous saturated sodium hydrogen carbonate solution were added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed sequentially with water and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; chloroform : methanol=9:1] to give 0.12 g of tert-butyl(1-(2-(7-methoxy-4-methyl-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)(2-oxo-2-(pyridin-2-ylamino)ethyl)carbamate as a white foam.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C@H:10]1[NH:15][C:14](=[O:16])[C@@H:13]([C@@H:17]([CH3:20])[CH2:18][CH3:19])[N:12]([CH:21]([C:32]2[CH:33]=[N:34][C:35]([CH3:39])=[CH:36][C:37]=2[CH3:38])[C:22]([NH:24][C:25]2C=CC=CC=2O)=[O:23])[C:11]1=[O:40].N1CCOCC1>>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C@H:10]1[NH:15][C:14](=[O:16])[C@@H:13]([C@@H:17]([CH3:20])[CH2:18][CH3:19])[N:12]([C@H:21]([C:32]2[CH:33]=[N:34][C:35]([CH3:39])=[CH:36][C:37]=2[CH3:38])[C:22]([NH:24][CH3:25])=[O:23])[C:11]1=[O:40]
Reactant: CC[C@H](C)[C@@H]1C(=O)N[C@H](C2Cc3ccccc3C2)C(=O)N1C(C(=O)Nc1ccccc1O)c1cnc(C)cc1C
Solvent: C1COCCN1
Product: CC[C@H](C)[C@@H]1C(=O)N[C@H](C2Cc3ccccc3C2)C(=O)N1[C@@H](C(=O)NC)c1cnc(C)cc1C

Procedure:
Similarly prepared from intermediate 4 and morpholine:
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][OH:7])[N:3]=[CH:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH:18]1([NH:21][C:22]([C:24]2[CH:25]=[CH:26][C:27]([CH3:43])=[C:28]([NH:30][C:31]([C:33]3[CH:34]=[N:35][C:36](S(C)(=O)=O)=[N:37][CH:38]=3)=[O:32])[CH:29]=2)=[O:23])[CH2:20][CH2:19]1>C1COCC1>[CH:18]1([NH:21][C:22]([C:24]2[CH:25]=[CH:26][C:27]([CH3:43])=[C:28]([NH:30][C:31]([C:33]3[CH:34]=[N:35][C:36]([O:7][CH2:6][C:4]4[N:3]=[CH:2][S:1][CH:5]=4)=[N:37][CH:38]=3)=[O:32])[CH:29]=2)=[O:23])[CH2:20][CH2:19]1
Reactant: OCc1cscn1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cnc(S(C)(=O)=O)nc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cnc(OCc2cscn2)nc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 22.3 %

Procedure:
To a solution of thiazole-4-methanol (79 mg) in THF (1 mL) at 0° C. under argon was added 1M lithium bis(trimethylsilyl)amide in THF (0.35 mL). After 30 minutes N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-(methylsulfonyl)pyrimidine-5-carboxamide (127 mg, 0.34 mmol) in THF (3 mL) was added and the reaction warmed to room temperature and stiired for 5 hours. The reaction mixture was partitioned between ethyl acetate and water, the organic phases washed with brine, dried (Na2SO4) and concentrated. The residue was purified by flash chromatography on a 12 g silica cartridge eluting with a gradient of 0 to 5% Methanol/DCM to give the title compound as a solid (31 mg, 23%); NMR Spectrum: (DMSOd6) 0.56 (m, 2H), 0.69 (m, 2H), 2.29 (s, 3H), 2.85 (m, 1H), 5.63 (s, 2H), 7.36, (d, 1H) 7.67 (dd, 1H), 7.83 (dd, 2H), 8.49 (d, 1H), 9.14 (m, 2H), 10.14 (s, 1H); Mass Spectrum: M+H+ 410.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2([C:19]([NH2:21])=[O:20])[CH2:18][CH2:17]2)[C:5]([Cl:22])=[CH:4][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[NH2:29][C:30]1[CH:31]=[N:32][N:33]([CH:35]2[CH2:38][N:37]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:36]2)[CH:34]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1>[C:19]([C:16]1([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][CH2:8][C:6]2[C:5]([Cl:22])=[CH:4][N:3]=[C:2]([NH:29][C:30]3[CH:31]=[N:32][N:33]([CH:35]4[CH2:38][N:37]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:36]4)[CH:34]=3)[N:7]=2)[CH2:18][CH2:17]1)(=[O:20])[NH2:21]
Reactant: NC(=O)C1(c2ccccc2CCc2nc(Cl)ncc2Cl)CC1
Reactant: CC(C)(C)OC(=O)N1CC(n2cc(N)cn2)C1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC(n2cc(Nc3ncc(Cl)c(CCc4ccccc4C4(C(N)=O)CC4)n3)cn2)C1

Procedure:
A suspension of 1-(2-(2-(2,5-dichloropyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxamide A14 (0.100 g, 0.297 mmol), Cs2CO3 (0.291 g, 0.892 mmol) and tert-butyl 3-(4-amino-1H-pyrazol-1-yl)azetidine-1-carboxylate (0.142 g, 0.595 mmol) in dioxane (3 mL) was sonicated for 10 minutes. Xantphos (6.9 mg, 12 μmol) and Pd(II) acetate (1.3 mg, 5.9 μmol) were added to the suspension and the mixture was irradiated in the microwave for 20 minutes at 120° C. The resulting mixture was adsorbed onto silica gel and purified by column chromatography (Biotage Isolera, 24 g SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C. then 0-40% MeOH in EtOAc) to give the title compound A18 as a yellow oil (110 mg, 69%). LCMS-A: rt 6.349 min; m/z 538.3 [M+H]+.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([N:12]([CH2:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:22]=[N:23][C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:33]4[N:38]=[CH:37][C:36](/[CH:39]=[CH:40]/[C:41]([OH:43])=[O:42])=[CH:35][C:34]=4[CH3:44])[CH2:29][CH2:28]3)=[N:25][CH:26]=2)[CH:18]=[CH:19][CH:20]=1)[CH3:13])=[O:11])=O)(C)(C)C.C(Cl)(Cl)[Cl:46].[ClH:49].O1CCOCC1>O1CCOCC1>[ClH:46].[ClH:49].[NH2:8][CH2:9][C:10]([N:12]([CH2:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:22]=[N:23][C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:33]4[N:38]=[CH:37][C:36](/[CH:39]=[CH:40]/[C:41]([OH:43])=[O:42])=[CH:35][C:34]=4[CH3:44])[CH2:29][CH2:28]3)=[N:25][CH:26]=2)[CH:18]=[CH:19][CH:20]=1)[CH3:13])=[O:11]
Reactant: ClC(Cl)Cl
Reactant: Cc1cc(/C=C/C(=O)O)cnc1N1CCN(c2ncc(-c3cccc(CN(C)C(=O)CNC(=O)OC(C)(C)C)c3)cn2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(/C=C/C(=O)O)cnc1N1CCN(c2ncc(-c3cccc(CN(C)C(=O)CN)c3)cn2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(2E)-3-[6-(4-{5-[3-({[N-(tert-Butoxycarbonyl)glycyl](methyl)amino}methyl)phenyl]pyrimidin-2-yl}piperazin-1-yl)-5-methylpyridin-3-yl]acrylic acid (147 mg) was dissolved in dioxane (3 ml), and CHCl3 (1 ml) and 4 M hydrogen chloride/dioxane (1 ml) was added thereto, followed by stirring at room temperature overnight. The precipitated solid was collected by filtration to obtain (2E)-3-(6-{-4-[5-(3-{[glycyl(methyl)amino]methyl}phenyl)pyrimidin-2-yl]piperazin-1-yl}-5-methylpyridin-3-yl)acrylic acid dihydrochloride (130 mg).
Reaction SMILES: [CH3:1][C:2]1[CH2:3][C:4]2[CH:5]=[CH:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[C:9]=2[C:10]=1[Li].[CH3:16][Si:17]([CH3:20])(Cl)[Cl:18]>O1CCCC1.C(OCC)C>[CH3:1][C:2]1[CH2:3][C:4]2[CH:5]=[CH:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[C:9]=2[C:10]=1[Si:17]([CH3:20])([CH3:16])[Cl:18]
Reactant: C[Si](C)(Cl)Cl
Reactant: [Li]C1=C(C)Cc2ccc3ccccc3c21
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1=C([Si](C)(C)Cl)c2c(ccc3ccccc23)C1
Temperature: 0 °C
Yield: 100 %

Procedure:
The thus-obtained white solid (2-methylbenzo[e]indenyllithium, 0.94 g, 5.1 mmols) was dissolved in dry tetrahydrofuran/diethyl ether (40 ml, 1/1 v/v). On the other hand, dimethyldichlorosilane (2.60 g, 20.2 mmols) was dissolved in dry tetrahydrofuran/diethyl ether (20 ml, 1/1 v/v), and the resulting solution was dropwise added to the previously-prepared 2-methylbenzo[e]indenyllithium solution at −5° C., over 1 hour. After the addition, this was immediately warmed up to 0° C. with stirring, and further stirred at room temperature for 2 hours. The solvent was removed from the pale yellow suspension under reduced pressure to obtain a yellow paste. The paste was extracted with dry diethyl ether (10 ml×3), and the resulting solution was filtered through a cannula. The filtrate was collected, the solvent was removed under reduced pressure, and this was dried under reduced pressure until it had a constant weight. The thus-obtained viscous yellow oil is 2-methylbenzo[e]indenyldimethylchorosilane (1.35 g, yield 100%).
Reaction SMILES: C([Li])CCC.[CH2:6]([C@H:13]1[CH2:17][O:16][C:15](=[O:18])[NH:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:19](Cl)(=[O:29])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>C1COCC1>[O:29]=[C:19]([N:14]1[C@@H:13]([CH2:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:17][O:16][C:15]1=[O:18])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: CCCCCCCCCC(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
n-Butyl lithium (160 mL, 398 mmol, 2.5M in hexanes) is added to a solution of (S)-4-benzyl-2-oxazolidinone 51 (64 g, 362 mmol) in THF (750 mL) at -78° C. under argon and stirred for 15 min. Decanoyl chloride 59 (69 g, 362 mmol) is added to the solution dropwise and stirred for 40 min, then warmed to 0° C. for 2 hours. The reaction is quenched with NH4Cl and extracted with EtOAc. The organic layer is washed with 1N HCl, aqueous NaHCO3, aqueous NaCl, and dried over MgSO4. The crude product is recrystallized from hexane to give 60.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:12][C@@H:11]2[CH2:13][C@H:8]1[C:9](=[O:14])[S:10]2)=[O:6])[CH:2]=[CH2:3].Cl.[CH3:16][NH:17][CH3:18].C(N(C(C)C)CC)(C)C.Cl>C(#N)C.C(OCC)(=O)C>[CH3:16][N:17]([CH3:18])[C:9]([C@@H:8]1[CH2:13][C@H:11]([SH:10])[CH2:12][N:7]1[C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])=[O:14]
Reactant: C=CCOC(=O)N1C[C@@H]2C[C@H]1C(=O)S2
Reactant: CNC
Agent: Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)N1C[C@@H](S)C[C@H]1C(=O)N(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (1S,4S)-5-allyloxycarbonyl-2 -thia-5-azabicyclo[2.2.1]heptan-3-one (39.2 mg) in acetonitrile (1 ml) were added dimethylamine hydrochloride (16.5 mg) and diisopropylethylamine (35.7 mg). The mixture was stirred for 3 hours at room temperature. After the reaction was over, 1N-hydrochloric acid (0.092 ml) was added thereto, and the mixture was diluted with ethyl acetate (2 ml) and dried over magnesium sulfate. Distillation of the solent, followed by purifying the residue by silica gel chromatography, gave oily (2S,4S) -N,N-dimethyl-1-allyloxycarbonyl-4-mercapto-2-pyrrolidinecarboxamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-])=O)=[C:6]2[C:11]=1[CH:10]=[N:9][CH:8]=[CH:7]2>C(O)(=O)C.[Zn]>[Cl:1][C:2]1[C:11]2[CH:10]=[N:9][CH:8]=[CH:7][C:6]=2[C:5]([NH2:12])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c2cnccc12
Agent: [Zn]
Solvent: CC(=O)O
Product: Nc1ccc(Cl)c2cnccc12
Temperature: 25 °C

Procedure:
To a solution of 8-chloro-5-nitroisoquinoline (1 mmol) in acetic acid, zinc dust (10 mmol) was added. Reaction mixture was refluxed for 5 hours. Reaction mixture was cooled to room temperature and filtered through celite bed. Filtrate was concentrated under vacuum to afford the desired compound.