Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:3]=1.[CH3:18][C:19]1[CH:31]=[C:30]([CH2:32][NH:33][CH2:34][CH2:35][CH3:36])[CH:29]=[CH:28][C:20]=1[O:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].C(N(CC1C=CC(OCC(OCC)=O)=C(C)C=1)C1C=NC=C(C2C=CC(Cl)=CC=2)N=1)CCC>>[CH3:18][C:19]1[CH:31]=[C:30]([CH2:32][N:33]([CH2:34][CH2:35][CH3:36])[C:2]2[CH:7]=[N:6][CH:5]=[C:4]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)[N:3]=2)[CH:29]=[CH:28][C:20]=1[O:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCCNCc1ccc(OCC(=O)OCC)c(C)c1
Reactant: FC(F)(F)c1ccc(-c2cncc(Cl)n2)cc1
Agent: CCCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1cncc(-c2ccc(Cl)cc2)n1
Product: CCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1cncc(-c2ccc(C(F)(F)F)cc2)n1
Yield: 11.5 %

Procedure:
Using 2-chloro-6-(4-(trifluoromethyl)phenyl]pyrazine (0.303 g, 1 mmol) and ethyl {2-methyl-4-[(propylamino)methyl]phenoxy}acetate (0.4 g, 1.5 mmol) and the synthetic procedure described for Intermediate 77. Purification by Biotage™ chromatography (Si, 40 g) eluting 9:1–7:3 cyclohexane:EtOAc afforded the title compound as a pale yellow oil (56 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([O:11][CH2:12][CH3:13])[CH:5]=1.[N+:15]([O-])([OH:17])=[O:16]>C(OCC)C>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([N+:15]([O-:17])=[O:16])[C:7]([OH:10])=[C:6]([O:11][CH2:12][CH3:13])[CH:5]=1
Reactant: CCOc1cc(C(=O)OC)ccc1O
Reactant: O=[N+]([O-])O
Solvent: CCOCC
Product: CCOc1cc(C(=O)OC)cc([N+](=O)[O-])c1O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 3-ethoxy-4-hydroxy-benzoic acid methyl ester (5.3 g, 27.0 mmol, 1.0 equiv) in diethyl ether (60 mL) was added dropwise nitric acid 65% (3.71 mL, 5.24 g, 54.0 mmol, 2.0 equiv) over a period of 30 min. After the addition was completed the reaction mixture was stirred for 4 h at rt. The reaction product precipitated out of solution, was filtered off, washed with cold diethyl ether (3×20 mL) and dried yielding 4.61 g (%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 1.53 (t, J=7.0 Hz, 3H), 3.94 (s, 3H), 4.21 (q, J=7.0 Hz, 2H), 7.75 (d, J=1.8 Hz, 1H), 8.42 (d, J=1.8 Hz, 1H), 11.01 (s, 1H). 13C NMR (75 MHz, CDCl3): δ 14.56, 52.59, 65.77, 118.37, 118.54, 121.36, 133.59, 149.44, 149.83, 165.09. MS (ISN): 240.1 [M−H]−.
Reaction SMILES: [NH2:1][C@@H:2]([C:4]([OH:6])=[O:5])[CH3:3].C(N(CC)CC)C.[C:14]([O-])(=[O:28])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].S([O-])(OC(C)(C)S(OC1C=CC(O)=CC=1)(=O)=O)(=O)=O.Cl>O>[C:14]([NH:1][C@@H:2]([C:4]([OH:6])=[O:5])[CH3:3])(=[O:28])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: C[C@@H](N)C(=O)O
Reactant: CCCCCCCCCCCCCC(=O)[O-]
Agent: CC(C)(OS(=O)(=O)[O-])S(=O)(=O)Oc1ccc(O)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCCCCCCCCCCC(=O)N[C@H](C)C(=O)O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
D-alanine 1.78 g (0.02 mol) and triethylamine 2.8 ml (0.02 mol) were dissolved in 60 ml of water. Myristate of 4-hydroxyphenyldimethylsulfomethyl sulfate 9.52 g (0.02 mol) was added to the solution, and the mixture was stirred for 12 hours at room temperature. The solution reacted was adjusted to pH 2 or 3 with 1N-HCl and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate, and freed of solvent in vacuo. The oily residue obtained was purified by column chromatography (column: 2.5×15 cm) on 50 g of silica gel and N-myristoyl-D-alanine 3.6 g was obtained.
Reaction SMILES: O1CCOCC1.Br[C:8]1[CH:9]=[N:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:12][CH:13]=1.CN(C1CCCCC1)C1CCCCC1.[C:34]([O:38][CH3:39])(=[O:37])[CH:35]=[CH2:36]>C(OCC)(=O)C.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].F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C>[CH3:39][O:38][C:34](=[O:37])/[CH:35]=[CH:36]/[C:8]1[CH:9]=[N:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:12][CH:13]=1
Reactant: Brc1cnc(-c2ccccc2)nc1
Reactant: C=CC(=O)OC
Agent: [Pd]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: CN(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)/C=C/c1cnc(-c2ccccc2)nc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 56.1 %

Procedure:
Dioxane (1.3 mL) was added to a mixture of 5-bromo-2-phenylpyrimidine (310 mg, 1.32 mmol, prepared as described in Org. Lett. 2002, 4, 513), tri-t-butylphosphonium tetrafluoroborate (11 mg, 0.038 mmol), and tris(dibenzylideneacetone)dipalladium(0) (18 mg, 0.020 mmol). N-Methyldicyclohexylamine (0.31 mL, 1.45 mmol) and methyl acrylate (0.24 mL, 2.67 mmol) were added and the mixture was stirred for 72 h at room temperature. The mixture was diluted with ethyl acetate, filtered through a small plug of silica gel which was washed with additional ethyl acetate, and the combined filtrates were concentrated. The residue was triturated with 5:1 hexane/ethyl acetate and the solid was filtered and dried in vacuo to provide 178 mg (56%) of the title compound as an off-white solid. MS 241 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:7](=O)[CH2:6][O:5][C:4]2[CH:9]=[CH:10][CH:11]=[C:12]([O:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:3]1=2>C1COCC1.CO>[CH3:1][N:2]1[CH2:7][CH2:6][O:5][C:4]2[CH:9]=[CH:10][CH:11]=[C:12]([O:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:3]1=2
Reactant: CCOC(=O)COc1cccc2c1N(C)C(=O)CO2
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)COc1cccc2c1N(C)CCO2
Temperature: 27 °C
Reaction time: 6 h
Yield: 76 %

Procedure:
A solution of ethyl 2-((4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-5-yl)oxy)acetate (100 mg, 0.377 mmol) in anhydrous THF (3 mL) was cooled to 0° C. and BH3-Me2S (0.1 mL) added. The solution was stirred at 27° C. for 6 h, diluted with methanol and concentrated. The residue was partitioned between ethyl acetate (30 mL) and water (20 mL), the organic layer washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by preparative TLC. (72 mg, yield 76%) MS (ESI+) e/z: 252.2 [M+1]+. 1H NMR (CDCl3, 400 MHz), δ ppm: 6.87-6.76 (m, 1H), 6.62-6.52 (m, 1H), 6.40-6.28 (m, 1H), 4.70 (s, 2H), 4.34-4.22 (m, 2H), 4.18-4.06 (m, 2H), 3.21-3.07 (m, 2H), 2.99-2.85 (m, 3H), 1.33-1.25 (m, 3H).
Reaction SMILES: CC1NC(C)=C(C(OCC[Cl:26])=O)C(C2C=CC=C([N+]([O-])=O)C=2)C=1C(OC)=O.[CH3:28][CH:29]([NH:44][CH3:45])[CH2:30][CH:31]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1(C)C=CC=CC=1.C(OCC)C>[ClH:26].[CH3:28][CH:29]([NH:44][CH3:45])[CH2:30][CH:31]([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCl)C1c1cccc([N+](=O)[O-])c1
Agent: CNC(C)CC(c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Cl
Reaction time: 25 h

Procedure:
A solution of 3.94 g of methyl 2-chloroethyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate and 4.78 g of 1,N-dimethyl-3,3-diphenylpropylamine in 12 ml of toluene was refluxed under stirring for 25 hours. Upon completion of the reaction the mixture was diluted with diethyl ether and the 1,N-dimethyl-3,3-diphenylpropylamine hydrochloride formed was collected by filtration. The filtrate was then evaporated, and the crude product thus obtained was purified by repeated chromatography on silica gel, using first chloroform, then chloroform:ethyl acetate (85:15 by volume) and lastly ethyl acetate as eluent. The purified product was dissolved in methanol and ethanolic hydrogen chloride was added. The solution was filtered and evaporated to dryness. Repeated washings with warm diethyl ether:acetone (98:2 by volume) afforded 2.98 g of the title compound, m.p. 113°-120° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].CO[CH:12](OC)[N:13]([CH2:16][CH3:17])[CH2:14][CH3:15]>O1CCOCC1>[CH2:14]([N:13]([CH2:16][CH3:17])[CH:12]=[CH:2][C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)=[O:3])[CH3:15]
Reactant: CC(=O)c1cccnc1
Reactant: CCN(CC)C(OC)OC
Solvent: C1COCCO1
Product: CCN(C=CC(=O)c1cccnc1)CC

Procedure:
A mixture of 0.10 mole of 3-acetylpyridine and 0.10 mole of N,N-diethylformamide dimethylacetal in 100 ml of dioxane was refluxed for 10 hours. The solvent was removed, giving 3-diethylamino-1-(3-pyridinyl)-2-propen-1-one.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[I:7][C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=O.[CH2:17]1[O:29][C:28]2[CH:27]=[C:26]3[C:21]([C:22]([NH:30][CH2:31][CH2:32][N:33]([CH3:35])[CH3:34])=[CH:23][CH:24]=[N:25]3)=[CH:20][C:19]=2[O:18]1.C(N(CC)CC)C>C(Cl)Cl.C(Cl)(Cl)Cl>[CH2:17]1[O:29][C:28]2[CH:27]=[C:26]3[C:21]([C:22]([N:30]([CH2:31][CH2:32][N:33]([CH3:35])[CH3:34])[C:10](=[O:12])[C:9]4[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=4[I:7])=[CH:23][CH:24]=[N:25]3)=[CH:20][C:19]=2[O:18]1
Reactant: CN(C)CCNc1ccnc2cc3c(cc12)OCO3
Reactant: O=C(O)c1ccccc1I
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CN(C)CCN(C(=O)c1ccccc1I)c1ccnc2cc3c(cc12)OCO3
Yield: 84 %

Procedure:
Oxalyl chloride (1.05 g, 8.1 mmol) was added to a solution of o-iodobenzoic acid (0.57 g, 2.3 mmol) in methylene chloride (20 mL) under nitrogen, and the stirred mixture refluxed for 4 h. The mixture was then concentrated to dryness under vacuum. The acid chloride was redissolved in methylene chloride (20 mL) and added to a solution of compound 7 and triethylamine (2.0 g, 20.0 mmol) in methylene chloride (20 mL). The reaction was stirred at reflux under nitrogen for 2 h. The mixture was then cooled and washed with a saturated solution of sodium bicarbonate (3×75 mL), and extracted into dilute HCl (3×75 mL), and the combined aqueous extracts were washed with chloroform (75 mL), made basic using 30% NaOH, then extracted with chloroform (3×75 mL). The combined organic extracts were washed with brine (100 mL), dried (anhydrous MgSO4), and concentrated in vacuo, to give 795 mg, in 84% yield; IR (CHCl3) 1653; 1H NMR (CDCl3) δ 2.23 (s, 6H), 2.60 (m, 2H), 3.52 (m, 1H), 4.57 (m, 1H), 6.13 (d, 1H, J=0.7), 6.16 (d, 1H, J=0.7), 6.78 (m, 3H), 7.32 (m, 2H), 7.36 (s, 1H), 7.64 (d, 1H, J=7.6), 8.48 (d, 1H, J=4.8); 13C NMR (CDCl3) δ 45.6, 46.8, 56.5, 93.9, 98.4, 102.3, 106.5, 120.2, 122.8, 126.5, 127.2, 128.3, 130.2, 139.5, 141.5, 145.6, 148.2, 149.2, 151.2, 170.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:20]=[CH:19][C:11]([C:12]([O:14]C(C)(C)C)=[O:13])=[CH:10][N:9]=1.C(O)(C(F)(F)F)=O.C1(C)C=CC=CC=1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:20]=[CH:19][C:11]([C:12]([OH:14])=[O:13])=[CH:10][N:9]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2F)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C(O)c1ccc(-c2ccccc2F)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.7 %

Procedure:
To tert-butyl 6-(2-fluorophenyl)nicotinate (479 mg, 1.75 mmol) in DCM (12 mL) at 0° C. was added TFA (2.5 mL). After stirring at rt overnight, toluene was added (10 mL) and the solvent removed to give a white solid (375 mg, 98%), 6-(2-fluorophenyl)nicotinic acid. LC/MS (M+H)=218.0 observed, 218.06 expected.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[C:5]([F:16])=[CH:4][N:3]=1.[OH:17][CH:18]([CH2:28][OH:29])[CH2:19][O:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1>>[OH:17][CH:18]([CH2:28][OH:29])[CH2:19][O:20][C:21]1[CH:27]=[CH:26][C:24]([NH:25][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=3)[C:5]([F:16])=[CH:4][N:3]=2)=[CH:23][CH:22]=1
Reactant: Nc1ccc(OCC(O)CO)cc1
Reactant: Oc1cccc(Nc2nc(Cl)ncc2F)c1
Product: OCC(O)COc1ccc(Nc2ncc(F)c(Nc3cccc(O)c3)n2)cc1

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N-(3-hydroxyphenyl)-4-pyrimidineamine and 4-(2,3-dihydroxypropoxy)aniline were reacted to produce N2-[4-(2,3-dihydroxypropoxy)phenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.38 (s, 1H), 9.18 (s, 1H), 8.98 (s, 1H), 8.12 (d, 1H, J=3.5 Hz), 7.58 (d, 2H, J=8.8 Hz), 7.22 (d, 1H, J=2.3 Hz), 7.12 (dd, 2H, J=2.3 and 8.8 Hz), 6.79 (d, 2H, J=8.8 Hz), 6.45 (d, 1H, J=8.8 Hz), 4.91 (d, 1H, J=5.3 Hz), 4.65 (t, 1H, J=5.8 Hz), 3.92-3.89 (m, 1H), 3.79-3.74 (m, 2H), 3.44 (t, 2H, J=5.3 Hz); LCMS: ret. time: 12.79 min.; purity: 89%; MS (m/e): 387 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH2:14][C:11]2([O:13][CH2:12]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:17][C:18](=[CH2:21])[CH2:19][NH2:20].CCN(C(C)C)C(C)C>C(O)C>[CH2:1]([N:8]1[CH2:15][CH2:14][C:11]([CH2:12][NH:20][CH2:19][C:18]([CH3:21])=[CH2:17])([OH:13])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(C)CN
Reactant: c1ccc(CN2CCC3(CC2)CO3)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: C=C(C)CNCC1(O)CCN(Cc2ccccc2)CC1
Temperature: 70 °C

Procedure:
A mixture of 6-benzyl-1-oxa-6-azaspiro[2.5]octane (2 g) and 2-methylprop-2-en-1-amine HCl (2 g) and Hunig's Base (3.44 mL) in ethanol (30 mL) was heated at 70° C. for 18 hours. The mixture was cooled to room temperature and the solvent evaporated under reduced pressure. The residue was partitioned between DCM and brine, the aqueous layer was re-extracted with fresh DCM and the combined organics dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure to afford the subtitled compound. Yield 2.70 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9]COC)=[C:7]([CH2:13][CH2:14][CH2:15][CH3:16])[C:6]([O:17][CH3:18])=[C:5]([O:19]COC)[C:4]=1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]1[C:33]([O:34]COC)=[C:32]([O:38][CH3:39])[C:31]([CH2:40][CH2:41][O:42]COC)=[C:30]([O:46]COC)[C:29]=1[O:50][CH3:51].Cl.C(=O)([O-])O.[Na+].O=O>O1CCCC1.C(O)(C)C.CO.C1C=CC=CC=1.O1CCCC1.C(O)(C)C>[CH3:1][O:2][C:3]1[C:8](=[O:9])[C:7]([CH2:13][CH2:14][CH2:15][CH3:16])=[C:6]([O:17][CH3:18])[C:5](=[O:19])[C:4]=1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]1[C:33](=[O:34])[C:32]([O:38][CH3:39])=[C:31]([CH2:40][CH2:41][OH:42])[C:30](=[O:46])[C:29]=1[O:50][CH3:51]
Reactant: CCCCc1c(OC)c(OCOC)c(CCCCCc2c(OC)c(OCOC)c(CCOCOC)c(OC)c2OCOC)c(OC)c1OCOC
Agent: Cl
Agent: O=C([O-])O
Agent: O=O
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: c1ccccc1
Product: CCCCC1=C(OC)C(=O)C(CCCCCC2=C(OC)C(=O)C(CCO)=C(OC)C2=O)=C(OC)C1=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
520 Milligrams of 1-[2,5-dimethoxy-4-butyl-3,6-bis(methoxymethoxy)phenyl]-5-[2,5-dimethoxy-3,6-bis(methoxymethoxy)-4-(2-methoxymethyloxyethyl)phenyl]pentane was dissolved in 5 ml of tetrahydrofuran with 5 ml of isopropanol, to this solution was added 1 milliliter of tetrahydrofuran-isopropanol (1:1) solution of 20%-hydrogen chloride, and the whole mixture was stirred at room temperature for 12 hours. After concentrated the reaction mixture, the residue obtained was treated by an azeotrotic distillation with benzene, then dissolved in 8 ml of methanol, further a small amount of sodium hydrogen carbonate was added thereto, and oxygen gas was blown into the solution for 2 hours. This solution was concentrated, and 50 ml of dichloromethane was added to the residue and the solution was washed with water and with a saturated sodium chloride aqueous solution, and concentrated. Then this product was purified by means column chromatography (diameter 2 cm×length 10 cm, adsorbent: "Silica gel 60" manufacture by E. Merck A. G., developing solvent: 30% ethyl acetate-n-hexane) to obtain 231 mg of 1-(2,5-dimethoxy-6-butyl-1,4-benzoquinone-3-yl)-5-[2,5-dimethoxy-6-(2-hydroxyethyl)-1,4-benzoquinon- 3-yl]pentane. Amorphous powdery substance.
Reaction SMILES: CN(C)C=O.[Cl:6][C:7]1[C:12]2[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:14]([CH:16](Cl)[CH3:17])[O:15][C:11]=2[C:10]([N:24]2[C:29](=[O:30])[CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[N:26]([CH3:35])[C:25]2=[O:36])=[C:9]([F:37])[CH:8]=1.[C-:38]#[N:39].[K+].C(=O)([O-])[O-].[K+].[K+]>O>[Cl:6][C:7]1[C:12]2[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:14]([CH:16]([C:38]#[N:39])[CH3:17])[O:15][C:11]=2[C:10]([N:24]2[C:29](=[O:30])[CH:28]=[C:27]([C:31]([F:33])([F:32])[F:34])[N:26]([CH3:35])[C:25]2=[O:36])=[C:9]([F:37])[CH:8]=1
Reactant: [C-]#N
Reactant: CCOC(=O)c1c(C(C)Cl)oc2c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc(Cl)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C(C)C#N)oc2c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc(Cl)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.3 %

Procedure:
20 ml of N,N-dimethylformamide was added to 0.8 g (1.6 mmol) of 3-[4-chloro-2-(1-chloroethyl)-3-ethoxycarbonyl-6-fluorobenzofuran-7-yl]-1-methyl-6-trifluoromethyluracil, 0.16 g (2.5 mmol) of potassium cyanide and 0.40 g (2.9 mmol) of potassium carbonate, followed by stirring at room temperature for 3 hours. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed sequentially with water and a saturated sodium chloride aqueous solution and then, dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. Then, the obtained residue was purified by silica gel column chromatography to obtain 0.58 g (yield: 74%) of the desired product as a yellow glassy substance. Refractive index: 1.5348 (20° C.).
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].Br[C:6]1[C:7]([CH3:20])=[N:8][N:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]3[NH:17][CH:18]=[CH:19][C:12]=23)[CH:10]=1.C(N(CC)CC)C.CN(C=O)C>C(OCC)(=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>[CH3:20][C:7]1[C:6](/[CH:3]=[CH:2]/[C:1]#[N:4])=[CH:10][N:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]3[NH:17][CH:18]=[CH:19][C:12]=23)[N:8]=1
Reactant: Cc1nn(-c2ccnc3[nH]ccc23)cc1Br
Reactant: C=CC#N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nn(-c2ccnc3[nH]ccc23)cc1/C=C/C#N
Yield: 191.3 %

Procedure:
A solution of 2-propenenitrile (0.043 mL, 0.00065 mol), bis(triphenylphosphine)palladium(II) chloride (0.0091 g, 0.000013 mol), 4-(4-bromo-3-methyl-1H-pyrazol-1-yl)-1H-pyrrolo[2,3-b]pyridine (0.036 g, 0.00013 mol), and triethylamine (TEA) (0.15 mL, 0.0011 mol) in DMF (0.15 mL, 0.0019 mol) was microwaved at 120° C. for 2 h. The solution was then diluted with ethyl acetate and washed with water (×2) and brine successively. The organic phase was dried and concentrated in vacuo to give 62 mg of the product as an orange solid. The orange solid was purified by prep-LCMS to give 12 mg of an off-white solid as a trifluoroacetic acid (TFA) salt which was triturated with MTBE (1 mL) to provide the purified product as a pale green solid. (dried at 60° C. for 4 h, 9 mg, 28% yield).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH:3]([N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13]1)[C:4]1[CH:5]=[N:6][C:7]([NH:10][NH2:11])=[CH:8][CH:9]=1.[CH:27]([C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][C:33]([C:39]([O:41]C)=[O:40])=[CH:34][CH:35]=2)[N:30]=1)=O.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1.C(=O)(O)[O-].[Na+].[Li+].[OH-]>CCO.C1COCC1.CCOCC.C(OCC)(=O)C>[C:20]([O:19][C:18]([NH:17][C@H:14]1[CH2:15][CH2:16][N:12]([CH:3]([C:4]2[CH:9]=[CH:8][C:7]3[N:6]([C:27]([C:29]4[CH:38]=[CH:37][C:36]5[C:31](=[CH:32][C:33]([C:39]([OH:41])=[O:40])=[CH:34][CH:35]=5)[N:30]=4)=[N:11][N:10]=3)[CH:5]=2)[C:2]([F:25])([F:1])[F:26])[CH2:13]1)=[O:24])([CH3:22])([CH3:23])[CH3:21]
Reactant: COC(=O)c1ccc2ccc(C=O)nc2c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(C(c2ccc(NN)nc2)C(F)(F)F)C1
Agent: O=C([O-])O
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N[C@H]1CCN(C(c2ccc3nnc(-c4ccc5ccc(C(=O)O)cc5n4)n3c2)C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.5 %

Procedure:
A solution of tert-butyl (3S)-1-(2,2,2-trifluoro-1-(6-hydrazinylpyridin-3-yl)ethyl)pyrrolidin-3-ylcarbamate (Example 1, Step D; 0.46 g, 1.03 mmol) and methyl 2-formylquinoline-7-carboxylate (0.22 g, 1.03 mmol) in EtOH (10 mL) was stirred at ambient temperature for 1 hour. The solvent was removed under reduced pressure. The residue was dissolved in DCM (10 mL) and iodo benzene diacetate (0.40 g, 1.24 mmol) was added. The mixture was stirred at ambient temperature for 1 hour. Ethyl acetate (20 mL) and saturated sodium bicarbonate (10 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue obtained was dissolved in THF (5 mL) and 2 N LiOH (5.15 mL, 10.30 mmol) was added. The mixture was stirred at ambient temperature for 6 hours. Ether (20 mL) was added. The aqueous layer was separated and acidified with saturated potassium hydrogen sulfate to about pH 3. The resulting solid was collected by filtration to give 2-(6-(1-((S)-3-(tert-butoxycarbonylamino)pyrrolidin-1-yl)-2,2,2-trifluoroethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinoline-7-carboxylic acid (0.45 g, 78.5%) as a solid.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH:9]([O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[CH2:8][CH2:7][N:6]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=O.[Li+].[BH4-]>C1COCC1.CO>[C:21]([O:20][C:18]([N:6]1[CH2:7][CH2:8][CH:9]([O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[CH:5]1[CH2:3][OH:2])=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: COC(=O)C1C(O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(O[Si](C)(C)C(C)(C)C)C1CO
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
A solution containing 39 (12 g, 33 mmol) in THF (50 mL) was cooled to 0° C. LiBH4 in THF (2M, 20 mL) was added in a dropwise fashion. After 1 h, the solution was warmed to ambient temperature. After 2 h, the solution was diluted with MeOH, then 120, and concentrated. The residue was extracted with EtOAc, washed with 1M HCl, saturated aqueous NaHCO3, brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford 9.5 g (87%) of 40 as a colorless oil.3 3Herdeis, C.; Hubmann, H. P.; Lotter, H. Tetrahedron: Asymmetry, 1994, 5, 119.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH3:13])=[CH:11][NH:10][C:9]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:4]([F:19])[CH:3]=1.[H-].[Na+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C>[CH2:22]([N:10]1[CH:11]=[C:12]([CH3:13])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[F:19])=[C:9]1[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)c1[nH]cc(C)c1-c1ccc(Cl)cc1F
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(-c2ccc(Cl)cc2F)c(C)cn1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 87.9 %

Procedure:
A solution of ethyl 3-(4-chloro-2-fluorophenyl)-4-methyl-1H-pyrrole-2-carboxylate (5.7 g, 20.2 mmol) in dry DMF (25 mL) was added dropwise to a cooled suspension of 60% NaH in mineral oil (0.89 g, 22.3 mmol) in dry DMF (25 mL). The mixture was stirred at 0° C. for 20 min, then benzylbromide (2.54 mL, 21.3 mmol) was added dropwise. The mixture was stirred for 10 min at 0° C., the cooling was removed and stirring was continued for 2 h at room temperature. The reaction was quenched by addition of saturated aqueous NH4Cl/ice (1:1, 150 mL) and the product was extracted with EtOAc (150 mL). The combined organic layers were dried on Na2SO4 and evaporated. The residual crude product purified using column chromatography (silica, heptane/EtOAc 2:1) to give the desired product (6.6 g, 88%) as an orange oil.