Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]1C1C=C(Cl)C=CC=1OCC=C)=O)(C)(C)C.CN1C(=O)CC(=O)N(C)C1=O>CO.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:16][NH:8]1
Reactant: C=CCOc1ccc(Cl)cc1C1c2ccccc2CN1C(=O)OC(C)(C)C
Agent: [Pd]
Agent: CN1C(=O)CC(=O)N(C)C1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Product: c1ccc2c(c1)CNC2

Procedure:
A mixture under N2 of (±)-1-(2-allyloxy-5-chloro-phenyl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (10.35 g, 26.8 mmol, 1.00 eq.), 1,3-dimethylbarbituric acid (8.38 g, 53.6 mmol, 2.00 eq.) and tetrakis(triphenylphosphine) palladium (0) (1.55 g, 1.34 mmol, 0.05 eq.) in MeOH (300 mL) was stirred at r.t. for 5 hours. The mixture was partitioned between AcOEt (250 mL) and water (250 mL). The layers were separated and the aq. phase was extracted with AcOEt (2×100 mL). The comb. org. phases were washed with sat. aq. NaCl soln. (1×250 mL), dried over MgSO4, and concentrated in vacuo. The residue was purified by flash master (column: 340 g, flow: 90 mL/min, Heptane to Heptane+50% AcOEt) to give the desired phenol 30.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[CH2:7][CH2:6]2.ClCCl.B(Br)(Br)Br>ClCCl>[CH3:12][C:8]1([CH3:13])[C:9]2[C:5](=[CH:4][C:3]([OH:2])=[CH:11][CH:10]=2)[CH2:6][CH2:7]1
Reactant: COc1ccc2c(c1)CCC2(C)C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC1(C)CCc2cc(O)ccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 101.4 %

Procedure:
To a stirred solution of 5-methoxy-1,1-dimethylindane (941 mg, 5.34 mmol) in anhydrous dichloromethane (20 ml) was added 1.0 M boron tribromide dichloromethane solution (10.7 ml, 10.7 mmol) via a syringe at −78° C. The mixture was warmed to ambient temperature and stirred for 1.5 hours. The mixture was quenched with water (15 ml) and extracted with dichloromethane. The combined solution was washed with brine, dried over sodium sulfate. After filtration to separate solvent and sodium sulfate, the solvent was removed under reduced pressure to give 878 mg of the crude 1,1-dimethylindan-5-ol as a gray solid.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[CH2:5]1[O:9][C:8]2[CH:10]=[C:11]([OH:14])[CH:12]=[CH:13][C:7]=2[O:6]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([O:14][CH2:3][CH:2]=[CH2:1])=[CH:10][C:8]=2[O:9]1
Reactant: Oc1ccc2c(c1)OCO2
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc2c(c1)OCO2
Yield: 96.2 %

Procedure:
Allyl bromide (1.75 g., 14 mmol) was added to a solution of sesamol (2.0 g, 14 mmol) that had been dissolved in 50 ml of dry acetone, followed by addition of powdered potassium carbonate (2.4 g, 17 mmol) and the resulting cloudy solution was refluxed for 18 h. The solution was cooled and the solvent removed in vacuo. The remaining suspension was extracted into ether and the organic layer was washed with water (1×25 ml ), brine solution (1×25 ml ), and dried over MgSO4. Concentration of solvent yielded 2.4 g (94%) of a pale yellow oil which was used in the next step with no further purification.
Reaction SMILES: [CH2:1]([N:8]1[C:15]2[CH:16]=[C:17](Br)[CH:18]=[CH:19][C:14]=2[O:13][C:10]2([CH2:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[Br:26][C:27]1[CH:28]=[CH:29][C:30]([Cl:35])=[C:31]([CH:34]=1)[CH:32]=[O:33]>C1COCC1>[CH2:1]([N:8]1[C:15]2[CH:16]=[C:17]([CH:32]([C:31]3[CH:34]=[C:27]([Br:26])[CH:28]=[CH:29][C:30]=3[Cl:35])[OH:33])[CH:18]=[CH:19][C:14]=2[O:13][C:10]2([CH2:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cc(Br)ccc1Cl
Reactant: Brc1ccc2c(c1)N(Cc1ccccc1)CC1(CC1)O2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC(c1ccc2c(c1)N(Cc1ccccc1)CC1(CC1)O2)c1cc(Br)ccc1Cl
Reaction time: 0.5 h
Yield: 49.4 %

Procedure:
To a stirred solution of 4-benzyl-6-bromo-spiro[3H-1,4-benzoxazine-2,1′-cyclopropane] (1.12 g, 3.4 mmol) in THF (10 mL) was added 1.6 M solution of n-BuLi in hexanes (2.12 mL, 3.4 mmol) at −78° C. The reaction mixture was stirred for 30 min, and then transferred to a stirred solution of 5-bromo-2-chlorobenzaldehyde (745 mg, 3.4 mmol) in THF (10 mL) at −78° C. After stirring for 1 h, the reaction was quenched by the addition of saturated ammonium chloride solution and extracted with ethyl acetate. The ethyl acetate layer was washed with water, brine, dried over sodium sulphate, and concentrated. The resulting residue was purified by silica gel column chromatography to furnish (4-benzylspiro[3H-1,4-benzoxazine-2,1′-cyclopropane]-6-yl)-(5-bromo-2-chloro-phenyl)methanol (790 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[C:3]=1[Cl:9].[NH:10]1[C:18]2[C:13](=[CH:14][C:15]([CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[CH:27]=[C:28]([NH:32][C:33](=[O:37])[CH:34]([CH3:36])[CH3:35])[CH:29]=[CH:30][CH:31]=4)[CH2:22][CH2:21]3)=[CH:16][CH:17]=2)[CH:12]=[CH:11]1>>[Cl:9][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]1[C:18]2[C:13](=[CH:14][C:15]([CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[CH:27]=[C:28]([NH:32][C:33](=[O:37])[CH:34]([CH3:35])[CH3:36])[CH:29]=[CH:30][CH:31]=4)[CH2:22][CH2:21]3)=[CH:16][CH:17]=2)[CH:12]=[CH:11]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc4[nH]ccc4c3)CC2)c1
Reactant: Clc1cccc(I)c1Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc4c(ccn4-c4cccc(Cl)c4Cl)c3)CC2)c1

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 1,2-dichloro-3-iodobenzene and N-{3-[1-(1H-indol-5-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide: 1H NMR (400 MHz, CDCl3) δ 7.68-6.94 (m, 12H), 6.68 (d, 1H, J=2.8 Hz), 3.69 (s, 2H), 3.15-3.02 (m, 2H), 2.54-2.42 (m, 2H), 2.18-2.02 (m, 2H), 1.88-1.76 (m, 4H), 1.25 (d, 6H, J=6.8 Hz); ESMS m/e: 520.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([O:16][CH2:17][CH:18]([F:20])[F:19])[CH2:13][C@H:12]1[C:21]([OH:23])=[O:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:25]>CO.CCOCC>[F:19][CH:18]([F:20])[CH2:17][O:16][C@@H:14]1[CH2:15][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[C@H:12]([C:21]([O:23][CH3:25])=[O:22])[CH2:13]1
Reactant: O=C(O)[C@@H]1C[C@H](OCC(F)F)CN1C(=O)OCc1ccccc1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CCOCC
Product: COC(=O)[C@@H]1C[C@H](OCC(F)F)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2S,4S)-1-(benzyloxycarbonyl)-4-(2,2-difluoroethoxy)pyrrolidine-2-carboxylic acid (2.0 g, 6.07 mmol) in MeOH and ether (80 ml) (1:1) was added TMS-diazomethane (4.56 mL, 9.11 mmol) (2.0M solution in ether) dropwise at 0° C. The reaction mixture was stirred at RT for 1 h and concentrated. The residue was used in the next step.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([C:19]([NH:21][CH:22]([C:30]([OH:32])=[O:31])[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:20])=[CH:16][CH:17]=2)[C:12]([NH:33][C:34]([NH2:36])=[NH:35])=[N:11][CH:10]=1.Cl.NC(N)=N.[C:42](OC(=O)C(CC1C=CC=CC=1)NC(C1C=C2C(C(Cl)=CN=C2Cl)=CC=1)=O)([CH3:45])([CH3:44])[CH3:43].O>CS(C)=O>[C:42]([O:31][C:30](=[O:32])[CH:22]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[NH:21][C:19]([C:15]1[CH:14]=[C:13]2[C:18]([C:9]([Cl:8])=[CH:10][N:11]=[C:12]2[NH:33][C:34]([NH2:36])=[NH:35])=[CH:17][CH:16]=1)=[O:20])([CH3:45])([CH3:44])[CH3:43]
Reactant: CC(C)(C)OC(=O)C(Cc1ccccc1)NC(=O)c1ccc2c(Cl)cnc(Cl)c2c1
Reactant: N=C(N)Nc1ncc(Cl)c2ccc(C(=O)NC(Cc3ccccc3)C(=O)O)cc12
Agent: Cl
Agent: N=C(N)N
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)C(Cc1ccccc1)NC(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 46.8 %

Procedure:
N-[(4-Chloro-1-guanidino-7-isoquinolinyl)carbonyl]-DL-phenylalanine trifluoroacetate ##STR68## NaH (78 mg, 60% dispersion in mineral oil, 1.95 mmol) was added to a solution of guanidine hydrochloride (188 mg, 1.97 mmol) in DMSO (6 mL) at 50° C. and the solution was stirred for 15 min. N-[(1,4-Dichloro-7-isoquinolinyl)carbonyl]-DL-phenylalanine t-butyl ester (350 mg, 0.79 mmol) was added and the mixture heated at 80° C. overnight. The cooled mixture was poured into water (50 mL) and extracted with EtOAc (2×25 mL). The combined organics were washed with brine, dried (Na2SO4) and evaporated in vacuo. The residue was crystallised with CH2Cl2 -i-Pr2O to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)carbonyl]-DL-phenylalanine t-butyl ester (172 mg, 0.37 mmol) as a cream coloured solid.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].C([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][O:19][P:20]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])=[CH:13][C:12]=1[O:38][CH3:39])(=O)C>CO>[P:20]([O:19][CH2:18][CH2:17][C:14]1[CH:15]=[CH:16][C:11]([OH:10])=[C:12]([O:38][CH3:39])[CH:13]=1)([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:21]
Reactant: COc1cc(CCOP(=O)(OCc2ccccc2)OCc2ccccc2)ccc1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COc1cc(CCOP(=O)(OCc2ccccc2)OCc2ccccc2)ccc1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
K2CO3 (126 mg, 0.910 mmol) was added to a stirred solution of 4-(2-{[bis(benzyloxy)phosphoryl]oxy}ethyl)-2-methoxyphenyl acetate (214 mg, 0.455 mmol) in MeOH (30 mL) at 25° C. The reaction was stirred at 25° C. for 1 h. The reaction mixture was concentrated in vacuo and the resulting residue was partitioned between water (20 mL) and EtOAc (20 mL). The aqueous layer was separated and extracted with EtOAc (2×20 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo to afford dibenzyl 2-(4-hydroxy-3-methoxyphenyl)ethyl phosphate, as an oil. LCMS calc.=429.2; found=429.1 (M±Na)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH2:16](Cl)[O:17][CH3:18]>C1COCC1.O>[CH3:16][O:17][CH2:18][O:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1cccc(O)c1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)Cc1cccc(OCOC)c1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A solution of Ethyl 2-(3-hydroxyphenyl)acetate (11 g, 61 mmol) in THF (100 mL) was added NaH (2.93 g, 73.3 mmol) and MOM-Cl) 5.94 g, 73.3 mmol) at 0° C. The reaction mixture was stirred for 16 hrs at 0° C. then warmed to room temperature. The reaction mixture was diluted with H2O (200 mL) and extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using EtOAc:hexanes (1:10) as eluant.
Reaction SMILES: Br[C:2]1[C:3]([CH3:11])=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH2:24])[N:19]=2)[CH:13]=1.C([O-])([O-])=O.[Cs+].[Cs+].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>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:11][C:3]1[C:2]([NH:24][C:20]2[N:19]=[C:18]([C:14]3[CH:13]=[N:12][CH:17]=[CH:16][CH:15]=3)[CH:23]=[CH:22][N:21]=2)=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[CH:5][N:4]=1
Reactant: Nc1nccc(-c2cccnc2)n1
Reactant: Cc1ncc([N+](=O)[O-])cc1Br
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1ncc([N+](=O)[O-])cc1Nc1nccc(-c2cccnc2)n1
Temperature: 90 °C
Yield: 50.3 %

Procedure:
To a mixture of 3-bromo-2-methyl-5-nitro-pyridine (380 mg, 1.75 mmol) and 4-pyridin-3-yl-pyrimidin-2-ylamine (250 mg, 1.45 mmol) in dry toluene (20 mL) were added Cs2CO3 (710 mg, 2.18 mmol), Pd2(dba)3 (26 mg, 0.028 mmol) and Xantphos (50 mg, 0.086 mmol). The mixture was evacuated and purged with N2 (3 cycles), heated to 90° C. under N2 for 16 h. After completion (monitored by TLC), the reaction mixture was cooled to rt, diluted with EtOAc and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (SiO2) using CH2Cl2-MeOH (98:2) to afford product (225 mg, 50%). 1H NMR (200 MHz, CDCl3): δ 2.76 (s, 3H), 7.23 (m, 1H), 7.38 (d, J=6.0 Hz, 1H), 7.51 (m, 1H), 8.51 (m, 1H), 8.63 (d, J=6.0 Hz, 1H), 8.77 (m, 1H), 9.04 (d, J=2.0 Hz, 1H), 9.28 (d, J=2.0 Hz, 1H), 9.77 (d, J=2.0 Hz, 1H); Mass [M+H]+: 309.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:38])[C@@H:15]([C:23]1[CH:28]=[CH:27][C:26]([S:29]([CH:32]2[CH2:34][CH2:33]2)(=[O:31])=[O:30])=[C:25]([CH:35]2[CH2:37][CH2:36]2)[CH:24]=1)[CH2:16][C@H:17]1[CH2:21][CH2:20][C:19](=[O:22])[CH2:18]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:39][C:40]([CH3:45])([CH2:43]O)[CH2:41][OH:42].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:38])[C@@H:15]([C:23]1[CH:28]=[CH:27][C:26]([S:29]([CH:32]2[CH2:34][CH2:33]2)(=[O:31])=[O:30])=[C:25]([CH:35]2[CH2:37][CH2:36]2)[CH:24]=1)[CH2:16][C@H:17]1[CH2:21][CH2:20][C:19]2([O:42][CH2:41][C:40]([CH3:45])([CH3:43])[CH2:39][O:22]2)[CH2:18]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CC[C@H](C[C@@H](C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)c2ccc(S(=O)(=O)C3CC3)c(C3CC3)c2)C1
Reactant: CC(C)(CO)CO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC1(C)COC2(CC[C@H](C[C@@H](C(=O)N3C(=O)OC[C@H]3Cc3ccccc3)c3ccc(S(=O)(=O)C4CC4)c(C4CC4)c3)C2)OC1
Temperature: 25 °C
Yield: 99.9 %

Procedure:
A mixture of (4R)-4-benzyl-3-{(2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(1R)-3-oxocyclopentyl]propanoyl}-1,3-oxazolidin-2-one (25.7 g), 2,2-dimethylpropane-1,3-diol (50 g), pyridinium paratoluenesulfonate (1.32 g), and toluene (205 mL) was stirred under heating and reflux for 6 hours. After leaving it to be cooled at room temperature, saturated aqueous sodium bicarbonate (100 mL) was added thereto and the aqueous layer was extracted with ethyl acetate (100 mL×2). The organic layer was combined, sequentially washed with 1 M aqueous sodium hydroxide solution (50 mL), saturated aqueous ammonium chloride solution (50 mL), and saturated brine (50 mL), and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain (4R)-4-benzyl-3-{(2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(2R)-8,8-dimethyl-6,10-dioxaspiro[4.5]dec-2-yl]propanoyl}-1,3-oxazolidin-2-one (29.8 g) as a colorless amorphous substance.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH2:7][CH2:8][C:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=1)[C:3]([O:5]C)=O.[NH2:22][CH2:23][C:24]([OH:26])=[O:25].C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH3:21][C:2]1([CH3:1])[CH2:7][CH2:8][CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:22]([CH2:23][C:24]([OH:26])=[O:25])[C:3]1=[O:5]
Reactant: NCC(=O)O
Reactant: COC(=O)C(C)(C)CCC(=O)c1cccc(C(F)(F)F)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC1(C)CCC(c2cccc(C(F)(F)F)c2)N(CC(=O)O)C1=O
Temperature: 140 °C

Procedure:
To a stirred solution of methyl 2,2-dimethyl-5-oxo-5-[3-(trifluoromethyl)phenyl]pentanoate from Step A (45.0 mg, 0.149 mmol) and glycine (99.0 mg, 1.32 mmol) in MeOH (2 mL) and acetic acid (0.045 mL) was added sodium cyanoborohydride (50.0 mg, 0.794 mmol). The reaction mixture was heated to reflux for 18 h. To the resulting mixture was added xylenes (3 mL) and heated to 140° C. for 4 h. The solvent was removed in vacuo and the crude solid dissolved in DMSO (1 mL). The crude product was purified by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. Lyophilization provided the title compound. MS: m/z=330 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][N:11]([C:13]([CH3:18])([CH3:17])[C:14](O)=[O:15])[CH:12]=2)=[CH:4][C:3]=1[O:19][CH:20]([C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[C:24]([F:29])[C:23]=1[Cl:30])[CH3:21].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[CH3:45][N:46]([CH3:51])[CH2:47][CH2:48][CH2:49][NH2:50]>CN(C=O)C>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][N:11]([C:13]([CH3:18])([CH3:17])[C:14]([NH:50][CH2:49][CH2:48][CH2:47][N:46]([CH3:51])[CH3:45])=[O:15])[CH:12]=2)=[CH:4][C:3]=1[O:19][CH:20]([C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[C:24]([F:29])[C:23]=1[Cl:30])[CH3:21]
Reactant: CC(Oc1cc(-c2cnn(C(C)(C)C(=O)O)c2)cnc1N)c1c(Cl)ccc(F)c1Cl
Reactant: CN(C)CCCN
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(Oc1cc(-c2cnn(C(C)(C)C(=O)NCCCN(C)C)c2)cnc1N)c1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.4 %

Procedure:
To a solution of 2-(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-pyrazol-1-yl)-2-methyl-propionic acid (1.00 g, 2.20 mmol) in DMF (5.5 mL) were added HOBT (300 mg, 2.20 mmol), EDC (633 mg, 3.30 mmol), and N,N-dimethyl-propane-1,3-diamine (225 mg, 2.20 mmol). The reaction was stirred overnight at room temperature. The reaction was then purified by reversed phase C-18 prep HPLC eluting with acetonitrile/water with 0.1% acetic acid to afford 2-(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-pyrazol-1-yl)-N-(3-dimethylamino-propyl)-isobutyramide (170 mg, 14% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][N:9](C(OC(C)(C)C)=O)[CH:8](C(OC)=O)[C:7]2=[O:23].[ClH:24].O>O1CCOCC1>[ClH:24].[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][NH:9][CH2:8][C:7]2=[O:23]
Reactant: COC(=O)C1C(=O)c2cccc(Br)c2CN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: O=C1CNCc2c(Br)cccc21
Temperature: 25 °C

Procedure:
To a flask containing 2-tert-butyl 3-methyl 8-bromo-4-oxo-3,4-dihydroisoquinoline-2,3(1H)-dicarboxylate (24-1) (3.44 g, 8.95 mmol) (mixed with impurities) was added was added Dioxane (20 ml), then 5N HCl in H2O (20 ml, 100 mmol). The reaction mixture was then heated to 90 C in the hood overnight. Followed by LC/MS. The next morning another 20 mL of 5N HCl was added and the reaction mixture was heated to 110 C for 3 hours, then was concentrated. The resulting residue was triturated with DCM (hot, then cooled to room temperature) & filtered to yield 8-bromo-2,3-dihydroisoquinolin-4(1H)-one hydrochloride (24-2). HRMS [M+H]: calculated; 225.9862, observed; 225.9860.
Reaction SMILES: [Na].F[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([OH:13])=[N:8][CH:9]=[N:10]2)=[CH:5][C:4]=1[N+:14]([O-:16])=[O:15].Cl.[CH3:18][OH:19]>>[CH3:18][O:19][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([OH:13])=[N:8][CH:9]=[N:10]2)=[CH:5][C:4]=1[N+:14]([O-:16])=[O:15]
Reactant: CO
Reactant: O=[N+]([O-])c1cc2c(O)ncnc2cc1F
Agent: Cl
Agent: [Na]
Product: COc1cc2ncnc(O)c2cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 92 %

Procedure:
Sodium (92 mg, 4 mmol) was dissolved in methanol (4 mL) under nitrogen at 0° C. 7-Fluoro-6-nitroquinazolin-4-ol (418 mg, 2 mmol) was added. The mixture was refluxed for 3 h and cooled to room temperature and treated with 2N HCl to adjust its pH to 3-4. After the mixture was concentrated, the residue was diluted with ethyl acetate and washed with water twice. The organic layer was concentrated to give 405 mg (92%) of 7-methoxy-6-nitroquinazolin-4-ol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[NH:18][C:17](=O)[C:16]2[C:11](=[CH:12][C:13]([CH3:20])=[CH:14][CH:15]=2)[N:10]=1.C(N(C(C)C)CC)(C)C.P(Cl)(Cl)([Cl:32])=O>C1(C)C=CC=CC=1>[Cl:32][C:17]1[C:16]2[C:11](=[CH:12][C:13]([CH3:20])=[CH:14][CH:15]=2)[N:10]=[C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[N:18]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccccc1-c1nc2cc(C)ccc2c(=O)[nH]1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1nc(Cl)c2ccc(C)cc2n1
Temperature: 80 °C

Procedure:
To a mechanically stirred suspension of 2-(2-methoxyphenyl)-7-methyl-3H-quinazolin-4-one (100 g, 0.37 mol) in 1 L toluene was added diisopropyl ethylamine (100 mL), followed by phosphorus oxychloride (69 g, 0.45 mol). The reaction was then heated to 80° C. for 4 h. The reaction mixture was distilled under reduced pressure to remove toluene, and the resulting residue was dissolved in 2.2 L CH2Cl2. Ice water was added, and the pH was adjusted to 8-9 with saturated aqueous sodium bicarbonate solution while maintaining the temperature below 20° C. The resulting organic layer was separated and the aqueous solution extracted with CH2Cl2, then the combined the organic layers were dried over sodium sulfate and distilled under reduced pressure. The crude product was dissolved 2:1 CH2Cl2/hexane, and the solution was passed through silica gel (2.5 kg, 60-120 mesh), followed by washing the silica bed with 2:1 CH2Cl2/hexane until the product eluted. The pure fractions were collected and combined, and the solvent was removed under reduced pressure. Hexane (500 mL) was added, and the mixture was stirred and filtered to give 4-chloro-2-(2-methoxy-phenyl)-7-methyl-quinazoline as a white to off-white solid (77 g, 72%). mp 161-164° C. 1H NMR (CDCl3) δ 2.6 (s, 3H), 3.9 (s, 3H), 6.9-7.2 (m, 2H), 7.4-7.6 (m, 2H), 7.7-8 (d, 2H), 8.2 (d,1H); 13C NMR (CDCl3) δ 22.23, 56.06, 112.2, 120.26, 120.69, 125.34, 127.94, 130.45, 131.08, 131.08. M/z (obs., [m+H]+)=285.
Reaction SMILES: [BH4-].[Na+].[I-].[OH:4][CH2:5][CH2:6][N+:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[C:15]([O:22][CH:23]([CH3:25])[CH3:24])[CH:14]=2)=[CH:9][CH:8]=1>CO.O>[N+:19]([C:16]1[CH:17]=[CH:18][C:13]([C:10]2[CH2:11][CH2:12][N:7]([CH2:6][CH2:5][OH:4])[CH2:8][CH:9]=2)=[CH:14][C:15]=1[O:22][CH:23]([CH3:25])[CH3:24])([O-:21])=[O:20]
Reactant: CC(C)Oc1cc(-c2cc[n+](CCO)cc2)ccc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [I-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)Oc1cc(C2=CCN(CCO)CC2)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
A mixture of 100 mg of 4-[4-nitro-3-(propan-2-yloxy)phenyl]pyridine (see method 1) and 0.075 ml of 2-iodoethanol in 1.7 ml of acetonitrile is heated at 85° C. (bath) for 1 h. 75 μl of 2-iodoethanol are then added and the heating is continued for 15 h at 91° C. The mixture is then concentrated under vacuum, so as to obtain a solid which is taken up with 10 ml of ethyl ether. The resulting heterogeneous mixture is filtered and the solid is rinsed with ethyl ether and dried under reduced pressure, so as to obtain 147 mg of 1-(2-hydroxyethyl)-4-[4-nitro-3-(propan-2-yloxy)phenyl]pyridinium iodide in the form of a solid. 44 g of sodium borohydride are added, at a temperature of about 0° C. (ice/water bath) to a solution of 0.142 g of 1-(2-hydroxyethyl)-4-[4-nitro-3-(propan-2-yloxy)phenyl]pyridinium iodide in 2.6 ml of methanol. After 30 minutes, a few drops of water are added and the mixture is left to return to ambient temperature. The mixture is concentrated to dryness under reduced pressure and then diluted with 150 ml of ethyl acetate. The organic phase is washed successively with 120 ml of a saturated sodium hydrogen carbonate solution and then 70 ml of a saturated sodium chloride solution. The organic phase is dried over anhydrous magnesium sulfate, filtered and then concentrated to dryness under reduced pressure, so as to obtain 90 mg of 2-{4-[4-nitro-3-(propan-2-yloxy)phenyl]-3,6-dihydropyridin-1(2H)-yl}ethanol.