Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:14]1[CH:18]=[CH:17][S:16][CH:15]=1)[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.[NH2:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[CH:30]=[N:29][CH:28]=[CH:27]2>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH:30]1[C:31]2[C:26](=[CH:25][C:24]([NH:23][C:11](=[O:13])[CH2:10][CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:14]3[CH:18]=[CH:17][S:16][CH:15]=3)=[CH:33][CH:32]=2)[CH:27]=[CH:28][N:29]=1
Reactant: CC(C)(C)OC(=O)NC(CC(=O)O)c1ccsc1
Reactant: Nc1ccc2cnccc2c1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NC(CC(=O)Nc1ccc2cnccc2c1)c1ccsc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To 3-(tert-butyoxcarbonylamino)-3-(thiophen-3-yl)propanoic acid (E4) in pyridine was added EDC, DMAP, and 6-aminoisoquinoline. The solution was stirred for 10 hours at room temperature. The mixture was poured into NaHCO3(sat) and extracted with EtOAc, dried (Na2SO4), filtered, and evaporated. Column chromatography (SiO2, 5% MeOH/CH2Cl2) gave pure tert-butyl 3-(isoquinolin-6-ylamino)-3-oxo-1-(thiophen-3-yl)propylcarbamate (E5).
Reaction SMILES: [C:1]1([C:11]([N:13]2[CH2:17][CH:16]([C:18](=[O:20])[CH3:19])[CH:15]([CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)[CH2:14]2)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:35][Mg+].[Br-]>C1COCC1>[C:1]1([C:11]([N:13]2[CH2:17][CH:16]([C:18]([OH:20])([CH3:35])[CH3:19])[CH:15]([CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([C:28]4[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=4)[CH2:24][CH2:23]3)[CH2:14]2)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)C1CN(C(=O)c2cccc3ccccc23)CC1CN1CCC(c2ccc(F)cc2)CC1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(C)(O)C1CN(C(=O)c2cccc3ccccc23)CC1CN1CCC(c2ccc(F)cc2)CC1
Reaction time: 0.5 h

Procedure:
To a solution of 0.03 g (0.065 mmol) of 1-(1-naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-acetylpyrrolidine in 20 mL of THF at rt was added 0.19 mL (0.195 mmol) of MeMgBr (1M in THF) and the reaction mixture was stirred for 30 min. The reaction mixture was partitioned between CH2Cl2 and NaHCO3. The organic fraction was filtered through a thin pad of Celite and the filtrate was concentrated. The residue was purified by chromatography (silica, MeOH:CH2Cl2, 2:98) to give the title compound. 1H NMR (CDCl3) δ (key peaks) 7.88-7.89 (m, 3H), 7.45-7.57 (m, 4H), 7.13-7.19 (m, 2H), 6.94-6.99 (m, 2H), 1.31 and 1.08 (s, 3H), 1.25 and 0.91 (s, 3H); Mass Spectrum (ESI) m/e=475 (M+1).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.Br[CH2:14][CH2:15][N:16]1[CH:20]=[CH:19][C:18]([C:21]([O:23][CH3:24])=[O:22])=[C:17]1[CH2:25][C:26]([O:28][CH3:29])=[O:27].C(NC(C)C)(C)C.[Li]>O1CCCC1.O>[CH:25]1([C:26]([O:28][CH3:29])=[O:27])[CH2:14][CH2:15][N:16]2[CH:20]=[CH:19][C:18]([C:21]([O:23][CH3:24])=[O:22])=[C:17]12
Reactant: COC(=O)Cc1c(C(=O)OC)ccn1CCBr
Agent: [Li]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: O
Product: COC(=O)c1ccn2c1C(C(=O)OC)CC2
Temperature: 10 °C
Reaction time: 2 h

Procedure:
Under nitrogen, n-butyllithium (1.3M in hexane, 75 mL, 98 mmol) was added slowly at -5°-0° C., with stirring, to a solution of di(isopropyl)amine (13.8 mL, 10.0 g, 98 mmol) in tetrahydrofuran (dry, 50 mL). The resulting solution was transferred to an addition funnel and added, under nitrogen at 0°-5° C., to a stirred slurry of methyl N-(2-bromoethyl)-3-methoxycarbonyl-2-pyrroleacetate (20.0 g, 66 mmol) in tetrahydrofuran (dry, 100 mL). There was a slight temperature rise, and complete dissolution occurred after addition of about two-thirds of the lithium di(isopropyl)amine solution. The resulting solution was stirred for 2 hours while warming to 10° C., then diluted with water (100 mL) with slight heat evolution. The solvents were stripped by atmospheric distillation: 240 mL collected, with a pot temperature of 80° C., to afford a solution of dimethyl 2,3-dihydro-1H-pyrrolo[1,2-a]pyrrole-1,7-dicarboxylate. The diester may be isolated at this point by quenching with water, extraction into an organic solvent such as ethyl acetate, and evaporation of the solvent; and purified by conventional methods. However, it is also convenient to saponify the diester to the dicarboxylic acid without isolation from the solution.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([C:9](=O)[CH3:10])[CH:6]=[CH:5][N:4]=1.[C:12]([OH:21])(=[O:20])[C:13]1[C:14](=[CH:16][CH:17]=[CH:18][CH:19]=1)[NH2:15].CC1C=CC(S(O)(=O)=O)=CC=1.[BH4-].[Na+]>C1(C)C=CC=CC=1>[CH3:1][NH:2][C:3]1[N:8]=[C:7]([CH:9]([NH:15][C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=2[C:12]([OH:21])=[O:20])[CH3:10])[CH:6]=[CH:5][N:4]=1
Reactant: Nc1ccccc1C(=O)O
Reactant: CNc1nccc(C(C)=O)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CNc1nccc(C(C)Nc2ccccc2C(=O)O)n1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
To a solution of 1-(2-methylamino-pyrimidin-4-yl)-ethanone (Step A, 1.0 g, 6.61 mmol) in dry toluene (40 mL) was added anthranilic acid (635 mg, 4.63 mmol) and TsOH (25 mg, 0.132 mmol). The resulting mixture was heated at 90° C. for 20 h, then cooled to RT. NaBH4 (500 mg, 13.23 mmol) was added and the reaction was stirred for 5 h. The reaction was quenched with MeOH and evaporated in vacuo. The crude solid was purified by chromatography on silica gel. Elution with CH2Cl2:MeOH mixture (95:5) gave final compound. MS m/z: 273.3 (M+H). Calc'd. for C14H17N4O2-273.3.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C(Cl)Cl.[CH3:14][OH:15]>[Ti](Cl)(Cl)(Cl)Cl.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:14](=[O:15])[CH2:5][C:4]1[CH:8]=[CH:9][CH:10]=[CH:2][CH:3]=1
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: CO
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: O=C(Cc1ccccc1)c1c[nH]c2ccc(Br)cc12

Procedure:
To 5-bromoindole (160 g), 1-phenylacetyl-1H-1,2,3-benzotriazole (193.62 g) and methylene chloride (2120 ml) were added, the mixture was stirred under ice cooling while adding a solution of titanium(IV) chloride (179 ml) in a methylene chloride solution (450 ml) and the mixture was stirred at room temperature for 1.5 hours. To the reaction solution, methanol (220 ml) and water (1126 ml) were added, the mixture was stirred at room temperature for 21 hours and in an ice water bath for 3 hours, then the precipitated crystals were obtained by filtration to afford the above-identified compound (163.0 g).
Reaction SMILES: [CH2:1]([N:8]([CH3:34])[C:9]([C:11]1[N:15]=[C:14]([C@H:16]([CH2:25][CH2:26][CH2:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])[O:13][N:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([N:8]([CH3:34])[C:9]([C:11]1[N:15]=[C:14]([C@H:16]([CH2:25][CH2:26][CH2:27][CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]2)[CH2:17][C:18]([OH:20])=[O:19])[O:13][N:12]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(Cc1ccccc1)C(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(Cc1ccccc1)C(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 86.8 %

Procedure:
A solution of tert-butyl (3R)-3-(3-{[benzyl(methyl)amino]carbonyl}-1,2,4-oxadiazol-5-yl)-6-cyclohexylhexanoate (Preparation 33) (296 mg, 0.63 mmol) in dichloromethane (4 ml) was treated with trifluoroacetic acid (1 ml) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 17 hours. The solvent was removed under reduced pressure and the residue azeotroped from toluene to afford the title compound (226 mg).
Reaction SMILES: [CH3:1][C@@:2]([S:23]([CH3:26])(=[O:25])=[O:24])([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([B:14]2[O:18][C:17]([CH3:20])([CH3:19])[C:16]([CH3:22])([CH3:21])[O:15]2)=[CH:10][CH:9]=1)[C:3]([OH:5])=O.[O:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]1[O:33][NH2:34].BrC1C=CC(CCC(C)(S(C)(=O)=O)C(NOC2CCCCO2)=O)=CC=1>>[CH3:1][C@@:2]([S:23]([CH3:26])(=[O:24])=[O:25])([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([B:14]2[O:15][C:16]([CH3:21])([CH3:22])[C:17]([CH3:20])([CH3:19])[O:18]2)=[CH:10][CH:9]=1)[C:3]([NH:34][O:33][CH:28]1[CH2:29][CH2:30][CH2:31][CH2:32][O:27]1)=[O:5]
Reactant: NOC1CCCCO1
Reactant: CC1(C)OB(c2ccc(CC[C@](C)(C(=O)O)S(C)(=O)=O)cc2)OC1(C)C
Agent: CC(CCc1ccc(Br)cc1)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Product: CC1(C)OB(c2ccc(CC[C@](C)(C(=O)NOC3CCCCO3)S(C)(=O)=O)cc2)OC1(C)C
Yield: 77.5 %

Procedure:
The title compound (7.2 g, 77%) was prepared from (2R)-2-methyl-2-(methylsulfonyl)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]butanoic acid (7.4 g, 19.3 mmol) and O-tetrahydro-2H-pyran-2-yl-hydroxylamine (3.3 g, 28 mmol) by a procedure analogous to that described for (+/−)-4-(4-bromophenyl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide as in Preparation 3 step C. LCMS m/z 480.8 (M−1).
Reaction SMILES: [CH2:1]([OH:4])[CH:2]=[CH2:3].Cl[C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1.[OH-].[K+]>COCCOCCOCCOCCOC>[F:13][C:12]([F:15])([F:14])[C:9]1[CH:10]=[CH:11][C:6]([O:4][CH:1]=[CH:2][CH3:3])=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1ccc(Cl)cc1
Reactant: C=CCO
Agent: COCCOCCOCCOCCOC
Agent: [K+]
Agent: [OH-]
Product: CC=COc1ccc(C(F)(F)F)cc1
Temperature: 100 °C
Yield: 67.7 %

Procedure:
A mixture of 4.0 kg of allyl alcohol and 6.2 kg of 4-chlorobenzotrifluoride was added over 6 hours to a stirred mixture of 6.8 kg of 85% potassium hydroxide and 17.4 g of tetraglyme at 80° C. The temperature was then raised to 100° C. for 2.5 hours, after which time the reaction mixture was cooled and distilled, and the residue was triturated with toluene and re-distilled to give 4.7 kg of propenyl 4-trifluoromethylphenyl ether.
Reaction SMILES: C1(/C=C/C2C=CC=CC=2)C=CC=CC=1.[CH3:15][CH2:16][C@@H:17]1[CH:22]2[CH2:23][C@H:24]([C@@H:25]([O:38]C(C3C=CC(Cl)=CC=3)=O)[C:26]3C=CN=[C:32]4[C:27]=3[CH:28]=[C:29](OC)[CH:30]=[CH:31]4)N(CC2)C1.CC[OH:50]>>[C:27]1([C@@H:26]([OH:50])[C@@H:25]([C:24]2[CH:15]=[CH:16][CH:17]=[CH:22][CH:23]=2)[OH:38])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CCO
Reactant: CC[C@H]1CN2CCC1C[C@@H]2[C@@H](OC(=O)c1ccc(Cl)cc1)c1ccnc2ccc(OC)cc12
Agent: C(=C/c1ccccc1)\c1ccccc1
Product: O[C@H](c1ccccc1)[C@H](O)c1ccccc1
Yield: 92 %

Procedure:
Catalytic asymmetric dihydroxylation reaction of trans-stilbene by using LDH-osmate of the formula IIa The reaction was performed by using an identical process as in Example 9 except the cinchona alkaloid is DHQD-CLB. (R,R)-(+)-1,2-diphenyl-1,2-ethandiol of more than 98.0% of enantiomeric excess was obtained (yield 92%) [∝]D+91.32 (c 1.0, EtOH): e.e.=98.2%
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)(=O)=O)[N:3]=1.[CH3:19][N:20]([CH3:24])[CH2:21][CH2:22][NH2:23]>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([NH:23][CH2:22][CH2:21][N:20]([CH3:24])[CH3:19])[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: CN(C)CCN
Solvent: COCCOC
Product: CN(C)CCNc1nc(N)nc(-c2ccco2)c1C#N

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile and 2-dimethylaminoethylamine in DME. ES-MS m/e (%): 273 (M+H+, 100), 228 ([M—Me2NH]+, 80).
Reaction SMILES: FC1C=C(C=CC=1)C([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19]2[N:24]=[CH:25][N:26]=[CH:27][C:18]3=2)[CH:9]=1)=O.O1CCOCC1.[OH-].[Na+].CCOC(C)=O>CC(O)C.C(Cl)(Cl)Cl>[CH3:14][C:11]1[CH:12]=[CH:13][C:8]([NH2:7])=[CH:9][C:10]=1[C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19]1[N:24]=[CH:25][N:26]=[CH:27][C:18]2=1
Reactant: Cc1ccc(NC(=O)c2cccc(F)c2)cc1-c1ccc2[nH]c3ncncc3c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: Cc1ccc(N)cc1-c1ccc2[nH]c3ncncc3c2c1
Temperature: 100 °C
Yield: 93.8 %

Procedure:
To 3-fluoro-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-6-yl)phenyl]benzamide (205 mg, 0.517 mmol) was added 1,4-dioxane (3.1 mL) and aqueous sodium hydroxide (3.8M, 2.72 mL, 10.0 mmol) followed by solid sodium hydroxide (1.67 g, 41.7 mmol). The reaction was heated to 100° C. until LCMS indicated complete hydrolysis, typically 16-24 hours. The reaction was cooled to ambient temperature and partitioned between water and EtOAc, which resulted in the formation of solids. These solids were dissolved through successive extractions with EtOAc and 3:1 CHCl3:IPA. The organic phases were separately washed with water and saturated aqueous NaCl, then dried (MgSO4), the dried solutions were combined and evaporated to dryness to leave the crude product (133 mg, 93.8%). 1H NMR (300 MHz, DMSO): δ 12.33 (bs, 1H), 9.46 (s, 1H), 8.91 (s, 1H), 8.16 (s, 1H), 7.57 (d, 1H), 7.44 (dd, 1H), 6.94 (d, 1H), 6.4-6.6 (m, 2H), 5.00 bs, 2H), 2.08 (s, 3H). MS (EI) m/z=275 (M+H).
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[CH2:9](NC(=O)[C@H]([C@H](CC)C)N)C1C=CC=CC=1.C(N(CC)CC)C.ClCC(NC1C=CC(Cl)=CC=1Cl)=O>C1COCC1>[NH2:1][C@H:2]([C:3]([OH:5])=[O:4])[C@H:6]([CH2:7][CH3:8])[CH3:9]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: CC[C@H](C)[C@H](N)C(=O)NCc1ccccc1
Agent: O=C(CCl)Nc1ccc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC[C@H](C)[C@H](N)C(=O)O
Yield: 127.1 %

Procedure:
Using the procedure described in Example 5, treatment of a solution of L-proline-L-isoleucine benzylamide (58 mg, 0.18 mmol), with triethylamine (130 uL, 0.93 mmol, 5.0 eq), and N-chloroacetyl-2,4-dichloroaniline (53 mg, 0.22 mmol, 1.2 eq) in THF (7 mL), provided a crude product. A portion of the product was purified by preparative TLC to provide 30 mg (32%) of L-isoleucine, N-[1-(2,4-dichlorophenylcarbamoylmethyl)-L-proline] benzylamide.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](N(OC)C)=[O:13])[C:9]([N:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][O:26][CH3:27])[CH2:20][CH2:19]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH3:28][Mg]Br>O1CCCC1>[Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:13])[CH3:28])[C:9]([N:18]2[CH2:19][CH2:20][N:21]([CH2:24][CH2:25][O:26][CH3:27])[CH2:22][CH2:23]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: C[Mg]Br
Reactant: COCCN1CCN(c2c(C(=O)N(C)OC)cc(Cl)c3cccnc23)CC1
Solvent: C1CCOC1
Product: COCCN1CCN(c2c(C(C)=O)cc(Cl)c3cccnc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
To a mixture of 5-chloro-N-methoxy-8-[4-(2-methoxyethyl)piperazin-1-yl]-N-methylquinoline-7-carboxamide (63 mg, 0.16 mmol) in tetrahydrofuran (0.2 mL) was added 1.40 M methylmagnesium bromide in tetrahydrofuran (0.69 mL, 0.96 mmol). The reaction was stirred at room temperature overnight, quenched with saturated ammonium chloride, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, and then concentrated to dryness under reduced pressure. The resultant residue was purified on silica gel, eluting with 0 to 10% MeOH in dichloromethane, to give the desired product (22 mg, 39%). LCMS calculated for C18H23ClN3O2(M+H)+: m/z=348.1; found: 348.1.
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[CH3:16][C:17]1[CH:18]=[C:19]([CH:28]([NH2:30])[CH3:29])[CH:20]=[N:21][C:22]=1[N:23]1[CH:27]=[CH:26][CH:25]=[N:24]1>>[Cl:14][C:13]1[C:3]2[CH2:2][N:30]([CH:28]([C:19]3[CH:20]=[N:21][C:22]([N:23]4[CH:27]=[CH:26][CH:25]=[N:24]4)=[C:17]([CH3:16])[CH:18]=3)[CH3:29])[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: Cc1cc(C(C)N)cnc1-n1cccn1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Agent: Cl
Product: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)cnc1-n1cccn1
Yield: 35 %

Procedure:
The title compound is prepared in 35% yield (230 mg, pale brown oil) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (500 mg, 1.8 mmol, Step-1 of Intermediate-1) and 1-(5-methyl-6-(1H-pyrazol-1-yl)pyridin-3-yl)ethanamine hydrochloride (430 mg, 1.8 mmol, Amine-68, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(OCC)(=O)C>[NH:11]([C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: Nc1ccccc1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cccnc1Nc1ccccc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
A mixture of 11.21 g (70 mmol) of 2-chloro-3-nitropyridine and 19.56 g (210 mmol) of aniline was heated under stirring at 100° C. for 1 h. The reaction liquid was cooled to room temperature and dissolved in ethyl acetate. The solution was washed with an aqueous citric acid solution and then with water. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure and the residue was recrystallized from ethyl acetate/n-hexane to obtain 13.7 g of the title compound.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:15])[O:13][CH3:14])=[CH:7][CH:6]=1)=[O:4].CC(C1C=CC(N)=CC=1)=O.[OH-].[Na+].COC(Cl)=O>CCOC(C)=O.O.O1CCOCC1>[CH3:14][O:13][C:12](=[O:15])[NH:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH3:2])=[CH:6][CH:7]=1
Reactant: COC(=O)Nc1ccc(C(=O)CBr)cc1
Agent: CC(=O)c1ccc(N)cc1
Agent: COC(=O)Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)Nc1ccc(C(C)=O)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 53 %

Procedure:
methyl 4-(2-bromoacetyl)phenylcarbamate: 4-Aminoacetophenone was suspended in a 1:1 mixture of dioxane and water (150 mL), and NaOH (4.4 g, 0.11 mol) was added. The mixture was stirred until the NaOH dissolved, then cooled to 0° C. prior to dropwise addition of methylchloroformate (8.5 mL, 0.11 mol). The resulting mixture was stirred at 0° C. for an additional 10 min then at rt for 2 h, followed by standing overnight. The solvent was removed by evaporation and the residual solids were partitioned between EtOAc and water. The layers were separated and the aqueous was reextracted 2× with EtOAc. The combined organic extracts were dried over MgSO4, filtered and evaporated to yield a tan powder. The crude product was suspended in EtOAc, washed 3× with 1N HCl to remove unreacted aniline, then washed with brine, dried over MgSO4, filtered and evaporated to provide methyl-4-acetylphenylcarbamate as an orange/tan solid (11.2 g, 53%). A portion of this material (3 g, 15.53 mmol) was suspended in CHCl3 (60 mL) and bromine (0.960 mL, 18.63 mmol) was added in small portions. About halfway through the addition, most of the starting material had dissolved in the dark orange reaction mixture. At this point, the mixture quickly decolorized with the formation of a tan precipitate. The remaining bromine was added over ˜5 min, then the mixture was stirred at rt. After ˜30 min, the solid product was collected by filtration and washed with CHCl3 and air-dried overnight to provide the bromoketone (3.25 g, 77%) which was used without further purification. 1HNMR (500 MHz, DMSO-d6) δ: 10.14 (1 H, s), 7.95 (2 H, d, J=8.8 Hz), 7.59 (2 H, d, J=8.8 Hz), 4.83 (2 H, s), 3.57-3.83 (3 H, m).
Reaction SMILES: IC1C=CC(C(Cl)=O)=CC=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][CH:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[C:28]([F:33])[CH:27]=1.[I:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]([N:43]=[C:44]=[S:45])=[O:42])=[CH:37][CH:36]=1>C1(C)C=CC=CC=1.C(O)C>[I:34][C:35]1[CH:36]=[CH:37][C:38]([C:41]([N:43]=[C:44]=[S:45])=[O:42])=[CH:39][CH:40]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][CH:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:44]([NH:43][C:41](=[O:42])[C:38]2[CH:39]=[CH:40][C:35]([I:34])=[CH:36][CH:37]=2)=[S:45])=[C:28]([F:33])[CH:27]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Agent: O=C(Cl)c1ccc(I)cc1
Agent: O=C(N=C=S)c1ccc(I)cc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(I)cc4)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
4-Iodo-1-benzenecarbonyl isothiocyanate was prepared using commercially available 4-iodo-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 4-iodo-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (92 mg, yield 96%).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:17][SH:18].C(=O)([O-])[O-].CS(O[CH:28]1[CH2:33][CH2:32][CH:31]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:30][CH2:29]1)(=O)=O>CN(C)C=O>[C:37]([O:36][C:35]([NH:34][CH:31]1[CH2:32][CH2:33][CH:28]([S:18][CH2:17][C:3]2[N:4]=[C:5]([C:7]3[CH:8]=[CH:9][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:15][CH:16]=3)[O:6][C:2]=2[CH3:1])[CH2:29][CH2:30]1)=[O:41])([CH3:40])([CH3:38])[CH3:39]
Reactant: COC(=O)c1ccc(-c2nc(CS)c(C)o2)cc1
Reactant: CC(C)(C)OC(=O)NC1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2nc(CSC3CCC(NC(=O)OC(C)(C)C)CC3)c(C)o2)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 15 %

Procedure:
Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed A mixture of methyl 4-[5-methyl-4-(sulfanylmethyl)-1,3-oxazol-2-yl]benzoate (3 g, 11.39 mmol, 1.00 equiv), cescium carbonate (5.13 g, 15.70 mmol, 1.39 equiv) and tert-butyl N-[4-(methanesulfonyloxy)cyclohexyl]carbamate (3.22 g, 10.98 mmol, 1.20 equiv) in N,N-dimethylformamide (30 mL) was stirred at 50° C. for 3 h. The reaction was quenched by the addition of 50 mL of water and the resulting solution was extracted with 3×60 mL of ethyl acetate. The organic combined layers was washed with 2×200 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on\a silica gel column eluted with ethyl acetate/petroleum ether (1:15-1:5). The collected fractions were combined and concentrated under vacuum to give 760 mg (14%) of methyl 4-(4-[[(4-[[(tert-butoxy)carbonyl]amino]cyclohexyl)sulfanyl]methyl]-5-methyl-1,3-oxazol-2-yl)benzoate as a yellow solid. LC-MS: (ES, m/z): 461 [M+H]+, 405, 361, 271, 230, 115.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:16]=[C:15]([Sn](CCCC)(CCCC)CCCC)[CH:14]=[C:6]([C:7]([N:9]([CH3:13])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1.[CH3:31][C:32](=[CH2:36])[C:33](Cl)=[O:34].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C(Cl)(Cl)Cl.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]>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:16]=[C:15]([C:33](=[O:34])[C:32]([CH3:36])=[CH2:31])[CH:14]=[C:6]([C:7]([N:9]([CH3:13])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C(=O)OC)cc(C(=O)N(C)CCC)c1
Reactant: C=C(C)C(=O)Cl
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClC(Cl)Cl
Product: C=C(C)C(=O)c1cc(C(=O)OC)cc(C(=O)N(C)CCC)c1
Temperature: 60 °C

Procedure:
Dissolve N-methyl-N-propyl-5-tributylstannanyl-isophthalamic acid methyl ester (885 mg, 168 mmol), 2-methyl-acryloyl chloride (172 mg, 1.64 mmol), tris(dibenzylideneacetone)dipalladium (46 mg, 0.05 mmol) and tricyclohexylphosphine (46 mg, 0.16 mmol)) in chloroform (15.5 mL) in a previously degassed vessel. Flush the mixture with nitrogen gas and heat the sealed mixture overnight at 60° C. Cool to room temperature and filter though a filtering agent. Concentrate the filtrate and purify (silica gel chromatography, eluting with 0:100 to 20:80 ethyl acetate:hexanes) to give the title compound.