Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[N:3]=1.[F:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1.[C:27](=O)([O-])[O-:28].[Na+].[Na+].C1(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C(C)=CC=CC=1.[Pd]>[F:19][C:20]1[CH:26]=[CH:25][C:23]([NH:24][C:27]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)[N:3]=2)=[O:28])=[CH:22][CH:21]=1.[F:18][C:15]([F:16])([F:17])[C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[O:8][C:4]1[CH:5]=[CH:6][CH:7]=[CH:2][N:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: FC(F)(F)c1cccc(Oc2cccc(Cl)n2)c1
Reactant: O=C([O-])[O-]
Agent: [Pd]
Agent: [Na+]
Agent: c1ccc(P(CCCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1C
Product: FC(F)(F)c1cccc(Oc2ccccn2)c1
Product: O=C(Nc1ccc(F)cc1)c1cccc(Oc2cccc(C(F)(F)F)c2)n1
Temperature: 200 °C
Reaction time: 16 h
Yield: 2.9 %
Yield: 92.1 %

Procedure:
6.84 g (25 mmol) of 2-chloro-6-[3-(trifluoromethyl)phenoxy]pyridine (content 99.5 percent prepared according to Example 1), 4.17 g (37.5 mmol) of 4-fluoroaniline, 2.92 g (27.5 mmol) of sodium carbonate, 0.27 g (0.25 mmol) of palladium/activated charcoal (10 percent Pd) and 0.32 g (0.75 mmol) of 1,4-bis(diphenylphosphino)butane (IV, n=4, R8=R9=R10=R11=phenyl) in 25 ml of xylene were placed in an autoclave at room temperature. The autoclave was flushed with inert gas, carbon monoxide was then introduced under a pressure of 5 bar and the temperature was raised to 200° C. The CO pressure was increased to 14.5 bar and the mixture was stirred for 16 hours at 200° C. After cooling to room temperature and depressurization, the reaction mixture was treated with 50 ml of xylene and 50 ml of water and filtered. The aqueous phase was extracted with 25 ml of xylene and the combined organic phases were washed with 30 ml of water. The composition of the dissolved products was determined by GC. 92.1 percent of the title compound (amide), 1.9 percent of educt and 6.0 percent of by-products (3.1 percent of secondary amine formed by direct substitution of Cl by the aniline, and 2.9 percent of 2-[3-(trifluoromethyl)phenoxy]pyridine formed by hydrogenolysis) were found. After distillation of the solvent, the crude product (8.63 g) was obtained in the form of a yellow solid. The crude product was purified by recrystallization from methylcyclohexane. the yield of the title compound product was 6.3 g (67 percent) of colorless crystals. The melting point of the product was 104° to 105° C. Other data concerning the title compound was:
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:11]=1[CH:12]=[N:13][OH:14]>CN(C=O)C>[Cl:1][O:14][N:13]=[CH:12][C:11]1[C:10]([Cl:9])=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:19]
Reactant: O=C1CCC(=O)N1Cl
Reactant: ON=Cc1c(Cl)cccc1Cl
Solvent: CN(C)C=O
Product: ClON=Cc1c(Cl)cccc1Cl
Temperature: 40 °C
Reaction time: 1 h
Yield: 75.3 %

Procedure:
N-Chlorosuccinimide (1162 g, 8.53 mol) in DMF (4.5 L) is added dropwise over a solution of 2,6-dichloro-benzaldehyde oxime (1621.78 g, 8.53 mol) in DMF (5.3 L) heated at 40° C. (addition is complete in about 6 hours). The mixture is stirred for 1 h at that temperature. The reaction is cooled at room temperature, poured onto H2O (30 L) at 0° C., and extracted with MTBE (36 L). The organic layer is washed with brine, dried over Na2SO4, filtered and evaporated to dryness (at 30° C.). The crude, as a solid-oil, is triturated in 1 L of hexane and the solid formed is filtered and dried under vacuum to obtain the desired compound (1440.9 g, 75% yield). MS (m/e): 224 (M+1)
Reaction SMILES: [C:1](=[O:3])=O.[CH:4]1([NH2:10])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.C(N(CC)CC)C.P(Cl)(Cl)(Cl)=O>ClCCl>[CH:4]1([N:10]=[C:1]=[O:3])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: NC1CCCCC1
Reactant: O=C=O
Solvent: CCN(CC)CC
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=C=NC1CCCCC1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
Carbon dioxide was added subsurface to a dichloromethane (20 mL) solution containing cyclohexylamine (0.02 mol, 1.98 g), triethylamine (0.06 mol, 6.0 g) at -10° C. (ice and salt bath) for 30 min at a pressure of 0 psig. The reaction mixture was transferred via cannula all at once under carbon dioxide to the precooled solution of phosphorus oxychloride (0.02 mol, 3.2 g) in 20 mL dichloromethane. After stirring ca. 30 min at -10° C. a white ppt formed. The ppt was filtered off and the filtrate concentrated in vacuo. The residue was extracted with 3×20 mL diethyl ether. The ether layers (light yellow) were 20 concentrated and the residue was distilled under vacuum collecting product, cyclohexyl isocyanate, at 31°-33° C. (1.45 g, 58%) of 97% purity as judged by GC. IR (neat) 2261 cm-1. 1H NMR (CDCl3) δ 3.44-3.39 (m, 1H), 1.90-1.85 (m, 2H), 1.72-1.68 (m, 2H), 1.50-1.41 (m, 2H), 1.33-1.20 (m, 3H) ppm.
Reaction SMILES: [C:1]1([NH:7][C:8]([CH2:10][Br:11])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:12][C:13]([NH2:15])=[Se:14]>CC(C)=O>[BrH:11].[C:1]1([NH:7][C:8]([CH2:10][NH:15][C:13](=[NH:12])[SeH:14])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(CBr)Nc1ccccc1
Reactant: NC(N)=[Se]
Solvent: CC(C)=O
Product: Br
Product: N=C([SeH])NCC(=O)Nc1ccccc1

Procedure:
6.4 g of phenylcarbamoylmethyl bromide and 3.7 g of selenourea were boiled in 100 ml of acetone under reflux for one four. Then, the mixture was cooled, thereby to form a precipitate. The precipitate was filtered off to obtain phenylcarbamoylmethyl selenoisourea hydrobromide ##STR14## Then, 30 ml of an aqueous solution containing 3.4 g (10 mmol) of the above-obtained phenylcarbamoylmethyl selenoisourea hydrobromide was prepared. To the thus obtained solution was dropwise added 20 ml of an aqueous potassium carbonate solution containing 1.66 g (12 mmol) of potassium carbonate at -10° C. To the obtained solution was dropwise added 3.51 g (10 mmol) of triethylphosphine gold chloride dissolved in ethanol containing a few drops of methylene chloride at -10° C. and then, the mixture was stirred for one hour at -10° C. to precipitate crystals. The crystals were filtered off, washed with water-ethanol and water, successively, and dried. Thus, there was obtained 2.9 g (5.5 mmol) of [(phenylcarbamoyl) methyl]seleno (triethylphosphine) gold.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[F:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH2:13]Br.C([O-])C.[Na+]>C(O)C>[F:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH2:13][O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1
Reactant: Oc1ccc(I)cc1
Reactant: Fc1cccc(CBr)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Fc1cccc(COc2ccc(I)cc2)c1

Procedure:
A solution of 3.0 g (15.9 mmol) of 4-iodophenol and 3.49 g (15.9 mmol) of 3-fluorobenzyl bromide in 30 ml ethanol is treated dropwise at RT with 20 ml of a 1 molar solution of sodium ethanolate in ethanol. The reaction mixture is refluxed for 4 h and the precipitated sodium bromide is filtered off. The filtrate is evaporated to dryness, treated with 100 ml of water, acidified by addition of citric acid and extracted three times with dichloromethane. After drying and evaporation, the residue is subjected to chromatography on silica gel (hexane/ethyl acetate 9:1). This yields 4.23 g (81%) of a colorless solid. mp=48° C.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl[C:11]1[C:30]([C:31]2[NH:32][CH:33]=[CH:34][N:35]=2)=[CH:29][C:14]([C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=2)=[O:16])=[CH:13][N:12]=1.Cl.[CH3:37][C:38]1([OH:42])[CH2:41][NH:40][CH2:39]1>CC(O)C>[OH:42][C:38]1([CH3:37])[CH2:41][N:40]([C:11]2[C:30]([C:31]3[NH:32][CH:33]=[CH:34][N:35]=3)=[CH:29][C:14]([C:15]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][C:25]([F:27])([F:26])[F:28])=[CH:22][CH:23]=3)=[O:16])=[CH:13][N:12]=2)[CH2:39]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(-c2ncc[nH]2)c1
Reactant: CC1(O)CNC1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(O)CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2-c2ncc[nH]2)C1
Temperature: 140 °C

Procedure:
DIPEA (0.139 mL, 0.794 mmol) was added to a mixture of 6-chloro-5-(1H-imidazol-2-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 69.1, 76 mg, 0.199 mmol) and 3-methylazetidin-3-ol HCl (27 mg, 0.218 mmol) in iPrOH (1 mL) and the RM was stirred at 140° C. 4.5 h. The solvent was evaporated off under reduced pressure and the residue was treated with water, extracted with EtOAc and the combined extracts were washed with water and brine, dried over MgSO4/charcoal and the solvent was evaporated off under reduced pressure. The residue was purified by flash chromatography (Silica gel column, 15 g, EtOAc/EtOH from 95:5 to 9:1) and crystallized from n-hexane/EtOAc to give the title product as white crystals. UPLC-MS (Condition 3) tR=0.7 min, m/z=434.2 [M+H]+; 1H-NMR (600 MHz, DMSO-d6) δ ppm 1.32 (s, 3H) 3.54-3.67 (m, 4H) 5.47 (s, 1H) 7.05 (s, 1H) 7.26 (s, 1H) 7.35 (d, J=8.66 Hz, 2H) 7.87 (d, J=9.03 Hz, 2H) 8.15 (d, J=2.07 Hz, 1H) 8.76 (d, J=2.07 Hz, 1H) 10.25 (s, 1H) 12.39 (br. s, 1H).
Reaction SMILES: [NH:1]([C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[C@H:2]([C:6]([NH:8][C@H:9]([C:13]([N:15]([CH3:31])[C@H:16]([C:20]([N:22]1[CH2:30][CH2:29][CH2:28][C@H:23]1[C:24]([O:26]C)=[O:25])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:7])[CH:3]([CH3:5])[CH3:4].O>CO>[NH:1]([C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[C@H:2]([C:6]([NH:8][C@H:9]([C:13]([N:15]([CH3:31])[C@H:16]([C:20]([N:22]1[CH2:30][CH2:29][CH2:28][C@H:23]1[C:24]([OH:26])=[O:25])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[CH:10]([CH3:11])[CH3:12])=[O:7])[CH:3]([CH3:4])[CH3:5]
Reactant: COC(=O)[C@@H]1CCCN1C(=O)[C@H](C(C)C)N(C)C(=O)[C@@H](NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)C(C)C
Solvent: O
Solvent: CO
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H](C(=O)N(C)[C@H](C(=O)N1CCC[C@H]1C(=O)O)C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
31.96 g (57 mmol) of Z-Val-Val-MeVal-Pro-OMe were dissolved in 250 ml of methanol. 102.6 ml of a 1N LIOH solution was added and the mixture stirred overnight at room temperature. After addition of 500 ml of water, the aqueous phase was washed three times with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and evaporated to dryness yielding 30.62 g of the desired product as a white solid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[C:11](=[CH:12][N:13]=[C:14]([Cl:17])[CH:15]=2)[N:10]=[CH:9][CH:8]=1)(=O)=O.[CH3:20][C:21]1[N:26]=[C:25]([NH2:27])[CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:22]=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.COCCOC>[C:16]([C:24]1[C:25]([NH2:27])=[N:26][C:21]([CH3:20])=[CH:22][C:23]=1[C:7]1[C:16]2[C:11](=[CH:12][N:13]=[C:14]([Cl:17])[CH:15]=2)[N:10]=[CH:9][CH:8]=1)([CH3:11])([CH3:7])[CH3:15]
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(N)n1
Reactant: O=S(=O)(Oc1ccnc2cnc(Cl)cc12)C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: COCCOC
Product: Cc1cc(-c2ccnc3cnc(Cl)cc23)c(C(C)(C)C)c(N)n1
Yield: 17 %

Procedure:
A solution of 6-chloro-1,7-naphthyridin-4-yl trifluoromethanesulfonate (1.0 equiv.), 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (1.0 equiv.) and Pd(dppf)Cl2—CH2Cl2 (0.1 equiv.) in 3:1 DME/2M Na2CO3 was heated in a microwave at 100° C. for 15 minutes. Upon cooling, the solution was partitioned between EtOAc and Na2CO3(sat.) washed further with NaCl(sat.), dried over MgSO4, concentrated and purified by silica gel chromatography (2-4% MeOH/CH2Cl2 w/0.1% DIEA eluant) to yield tert-butyl 4-(6-chloro-1,7-naphthyridin-4-yl)-6-methylpyridin-2-amine (17%). LC/MS=271.0 (M+H), LC=1.81 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:24])=[C:6]([C:8]([NH:17][S@:18]([C:20]([CH3:23])([CH3:22])[CH3:21])=[O:19])([CH:14]([F:16])[F:15])[CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:7]=1>CCO.CCCCCCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:24])=[C:6]([C@:8]([NH:17][S@:18]([C:20]([CH3:22])([CH3:21])[CH3:23])=[O:19])([CH:14]([F:16])[F:15])[CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:7]=1.[F:15][CH:14]([F:16])[CH2:8][CH2:9][C:10]([O-:12])=[O:11]
Reactant: COC(=O)CC(N[S@@](=O)C(C)(C)C)(c1cc(Br)ccc1F)C(F)F
Solvent: CCCCCCC
Solvent: CCO
Product: COC(=O)C[C@](N[S@@](=O)C(C)(C)C)(c1cc(Br)ccc1F)C(F)F
Product: O=C([O-])CCC(F)F
Yield: 43.4 %
Yield: 40.8 %

Procedure:
Chiral separation of methyl 3-(5-bromo-2-fluorophenyl)-3-((S)-1,1-dimethylethylsulfinamido)-4,4-difluorobutanoate (3.8 g, 8.83 mmol) by preparative chiral HPLC on Reprosil Chiral NR column with eluent 5% EtOH/n-heptane to give (S)-methyl 3-(5-bromo-2-fluorophenyl)-3-((S)-1,1-dimethylethylsulfinamido)-4,4-difluorobutanoate (1.55 g, 3.6 mmol, 40.8% yield) as a colourless oil and (R)-methyl 3-(5-bromo-2-fluorophenyl)-3-(S)-1,1-dimethylethylsulfinamido)-4,4-difluorobutanoate (1.65 g, 3.83 mmol, 43.4% yield) as a colorless oil.
Reaction SMILES: O1CCCC1.[C:6]1([CH3:22])[CH:11]=[CH:10][C:9]([NH:12][C:13](=[S:21])[CH2:14][CH2:15][C:16]([CH3:20])([CH3:19])[CH:17]=[CH2:18])=[CH:8][CH:7]=1.II.C1CCN2C(=NCCC2)CC1>O>[CH3:20][C:16]1([CH3:19])[C:17](=[CH2:18])[S:21][C:13](=[N:12][C:9]2[CH:8]=[CH:7][C:6]([CH3:22])=[CH:11][CH:10]=2)[CH2:14][CH2:15]1
Reactant: C=CC(C)(C)CCC(=S)Nc1ccc(C)cc1
Agent: II
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: C=C1SC(=Nc2ccc(C)cc2)CCC1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.5 %

Procedure:
In a tetrahydrofuran (25 ml) solution of 4,4-dimethyl-5-hexenethioic acid p-tolylamide (1.2 g), a tetrahydrofuran (10 ml) solution of iodine (1.5 g) was added dropwise at 0° C., followed by raising the temperature to room temperature and further stirring overnight. After cooling to 0° C., a tetrahydrofuran (3 ml) solution of DBU (1.8 g) was added dropwise. After raising the temperature to room temperature and further stirring overnight, water was added and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 0.53 g of the target compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(Cl)(O[C:19](=[O:25])OC(Cl)(Cl)Cl)Cl.[NH2:27][C@@H:28]1[CH2:32][CH2:31][C@@H:30]([C:33]([N:35]2[CH2:42][CH2:41][C@:40]3([CH3:46])[C:43]([CH3:45])([CH3:44])[C@H:36]2[CH2:37][C:38]2[C:50]([OH:51])=[CH:49][CH:48]=[CH:47][C:39]=23)=[O:34])[CH2:29]1>ClCCl>[OH:51][C:50]1[C:38]2[CH2:37][C@@H:36]3[C:43]([CH3:44])([CH3:45])[C@:40]([CH3:46])([C:39]=2[CH:47]=[CH:48][CH:49]=1)[CH2:41][CH2:42][N:35]3[C:33]([C@@H:30]1[CH2:31][CH2:32][C@@H:28]([NH:27][C:19]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:25])[CH2:29]1)=[O:34]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC1(C)[C@H]2Cc3c(O)cccc3[C@]1(C)CCN2C(=O)[C@@H]1CC[C@@H](N)C1
Reactant: Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)[C@H]2Cc3c(O)cccc3[C@]1(C)CCN2C(=O)[C@@H]1CC[C@@H](NC(=O)Nc2ccccc2)C1
Reaction time: 0.5 h

Procedure:
Aniline (19 μL) and triethylamine (100 μL) dissolved in dichloromethane (0.5 mL) are added to a solution of triphosgene (19 mg) in dichloromethane (0.5 mL) chilled in an ice bath. After stirring the solution for 30 min, [(1R,3R)-3-amino-cyclopentyl]-[(2R,6S)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-methanone (80 mg) and triethylamine (30 μL) dissolved in dichloromethane (1 mL) are added. The resulting solution is stirred in the cooling bath for 15 min and then at room temperature for 2 h. The solution is concentrated under reduced pressure and the residue is purified by HPLC on reversed phase (MeCN/H2O/F3CCO2H) to give the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:17]=[C:16]([N:18]2[CH2:23][CH2:22][CH2:21][CH:20]([CH2:24][NH:25]C(=O)OCC3C=CC=CC=3)[CH2:19]2)[C:15]2[C:10](=[CH:11][C:12]([CH3:36])=[CH:13][CH:14]=2)[N:9]=1.N#N>[Pd].CCO.CCOC(C)=O>[NH2:25][CH2:24][CH:20]1[CH2:21][CH2:22][CH2:23][N:18]([C:16]2[C:15]3[C:10](=[CH:11][C:12]([CH3:36])=[CH:13][CH:14]=3)[N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[OH:1])[N:17]=2)[CH2:19]1
Reactant: Cc1ccc2c(N3CCCC(CNC(=O)OCc4ccccc4)C3)nc(-c3ccccc3O)nc2c1
Agent: [Pd]
Agent: N#N
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1ccc2c(N3CCCC(CN)C3)nc(-c3ccccc3O)nc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of benzyl (1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate (1.75 g, 3.63 mmol) and EtOH/EtOAc (50 mL/20 mL) was heated to obtain a homogeneous solution. After cooling to room temperature, Pd/C (175 mg, 10% wt Pd on carbon) was added and the flask was sealed with a septum. The same flask was 3 times charged with N2 and evacuated under vacuum. The mixture was then stirred under an H2 atmosphere at ambient pressure for 1 h. The product was collected by filtration through a plug of Celite, eluting with MeOH. The filtrate was concentrated to a yellow solid (1.26 g) to give 2-(4-(3-(aminomethyl)piperidin-1-yl)-7-methylquinazolin-2-yl)phenol. LC/MS: m/z 349.3 (M+H)+ at 1.80 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [NH:1]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C@H:2]([C:26](O)=O)[CH2:3][C:4](=[O:25])[NH:5][C:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:51][C:52]1[CH:53]=[C:54]([C:59]2[CH:64]=[CH:63][C:62]([C:65]#[N:66])=[C:61]([F:67])[CH:60]=2)[CH:55]=[CH:56][C:57]=1[NH2:58]>C(#N)C>[C:65]([C:62]1[CH:63]=[CH:64][C:59]([C:54]2[CH:55]=[CH:56][C:57]3[NH:58][C:26]([C@@H:2]([NH:1][C:29](=[O:30])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:3][C:4](=[O:25])[NH:5][C:6]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)=[N:51][C:52]=3[CH:53]=2)=[CH:60][C:61]=1[F:67])#[N:66]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Reactant: N#Cc1ccc(-c2ccc(N)c(N)c2)cc1F
Agent: CC(C)COC(=O)Cl
Solvent: CC#N
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)c1nc2cc(-c3ccc(C#N)c(F)c3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.9 %

Procedure:
To a solution of Boc-Asn(Trt)-OH (100.4 mg, 0.2116 mmol) in acetonitrile (2.0 mL) cooled in an ice water bath was added 4-methylmorpholine (0.059 mL, 0.53 mmol) and isobutyl chloroformate (0.027 mL, 0.21 mmol). After stirring for 60 minutes, 3′,4′-diamino-3-fluoro-[1,1-biphenyl]-4-carbonitrile (Preparation 81, 42.7 mg, 0.188 mmol) was added and the mixture allowed to warm to room temperature. After stirring for 18 hours the reaction mixture was concentrated in vacuo and redissolved in acetic acid. After stirring at room temperature for 6.5 hours, the mixture was concentrated in vacuo, redissolved in ethyl acetate, washed with water, 0.5M HCl, and brine. The organic layer was dried over anhydrous magnesium sulphate, filtered, and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with a 0-100% ethyl acetate/hexanes gradient to afford the title compound (75 mg, 60%).
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:7]1([CH3:13])[CH:12]=[CH:11]C=[CH:9][CH:8]=1.Cl[CH2:15]Cl>C1COCC1.C1(C)C=C(C)C=C(C)C=1>[CH2:2]([C:1]12[CH2:13][CH:7]([CH2:12][CH2:11]1)[CH:8]=[CH:9]2)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:15]
Reactant: Cc1ccccc1
Reactant: C=CCCCC
Reactant: ClCCl
Solvent: C1CCOC1
Solvent: Cc1cc(C)cc(C)c1
Product: CCCCCCC12C=CC(CC1)C2
Temperature: 80 °C

Procedure:
HxNB, (10.0 g, 0.056 mol), 1-hexene (4.71 g, 0.056 mol) and toluene (56.7 g) were combined in a 250 mL serum bottle and heated to 80° C. in an oil bath to form a solution. To this solution were added Pd1446, (4.10E-4 g, 2.80E-7 mol) and DANFABA, (2.20E-4 g, 2.80E-7 mol), each in the form of a concentrated solution in dichloromethane. After addition, the resulting mixture was maintained at 80° C. for 40 minutes. The homopolymer was precipitated by adding methanol drop wise into the vigorously stirred reaction mixture. The precipitated copolymer was collected by filtration and dried in an oven at 60° C. under vacuum. After drying, 5.8 g was obtained (58%). The molecular weight of the copolymer, determined by GPC in THF solvent (polystyrene standard) provided Mw=121,541 and Mn=59,213. The refractive indices of this polymer were measured by prism coupling method and determined to be 1.5146 in TE mode and 1.5129 in TM mode at a wavelength of 633 nm. The Tg (based on thermomechanical analysis (TMA) measurement) of this polymer was 208° C. The dried homopolymer was dissolved in sufficient mesitylene to result in a 10 wt % homopolymer solution.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]2[CH:12]=[CH:11][NH:10][C:6]=2[N:7]=[CH:8][N:9]=1.[H][H].[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C)C=O.O>[C:15]1([S:21]([N:10]2[C:6]3[N:7]=[CH:8][N:9]=[C:4]([Cl:3])[C:5]=3[CH:12]=[CH:11]2)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: [H][H]
Reactant: Clc1ncnc2[nH]ccc12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)n1ccc2c(Cl)ncnc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
In a flame-dried flask under nitrogen, 780 mg of 60% sodium hydride (19.5 mmol) in mineral oil was added to 30 mL of dimethylformamide (DMF) and the resulting mixture cooled to 0° C. A solution of 2.0 g (13.0 mmol) of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine in 10 mL of DMF was added slowly over a 5 minute period. The reaction was stirred for 10 min at which time generation of hydrogen (H2) ceased. Benzenesulfonylchloride (1.7 mL/13.0 mmol) was added, the reaction warmed to room temperature and stirred for 1 hour. Water was added, and the resulting precipitate was filtered and dried in vacuo to obtain 3.4 grams (89%) of the title compound as a crystalline solid, mp 163-167° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:25][CH:24]=1)[C:3]([N:5]([CH2:14][CH:15]([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[N:8]=1)=[O:4].[CH2:34]([NH:41][C:42]([NH:44][N:45]([CH2:50][CH:51]=[CH2:52])[CH2:46][C:47](O)=[O:48])=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O.CN(C=O)C>[CH2:34]([NH:41][C:42]([NH:44][N:45]([CH2:50][CH:51]=[CH2:52])[CH2:46][C:47]([NH:1][C@@H:2]([CH2:22][C:23]1[CH:24]=[CH:25][C:26]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[CH:27][CH:28]=1)[C:3]([N:5]([CH2:14][CH:15]([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[N:8]=1)=[O:4])=[O:48])=[O:43])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CCOC(CN(Cc1cccc(F)n1)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1)OCC
Reactant: C=CCN(CC(=O)O)NC(=O)NCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=CCN(CC(=O)N[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)N(Cc1cccc(F)n1)CC(OCC)OCC)NC(=O)NCc1ccccc1
Yield: 90.4 %

Procedure:
To a mixed solution of (2S)-2-amino-3-(4-(tert-butoxy)phenyl)-N-(2,2-diethoxyethyl)-N-((6-fluoropyridin-2-yl)methyl)propanamide (881 mg, 1.91 mmol) described in Production Example 2-2 and DMF (10.0 mL) were added 2-(((benzylcarbamoyl)amino)(prop-2-en-1-yl)amino)acetic acid (503 mg, 1.91 mmol) described in International Publication No. 2009148192, triethylamine (532 μL, 3.82 mmol) and HATU (871 mg, 2.29 mmol) at room temperature. The resultant mixture was stirred at room temperature for 35 minutes. Water was added to the reaction mixture, and the resultant solution was extracted with ethyl acetate. An organic layer was washed with water and saturated brine, was then dried over anhydrous magnesium sulfate, and was then filtrated. The solvent was evaporated under a reduced pressure, the resultant residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=20:1) to give the title compound (1.22 g, yield: 91%).