Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH:8]([C:10]([NH:12][C:13]2[CH:25]=[CH:24][C:16]3S[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[C:15]=3[CH:14]=2)=[O:11])[CH3:9])=[CH:3][CH:2]=1.[S:26](=[O:30])(=O)(O)[OH:27].OO.C([O-])(O)=O.[Na+]>C(O)(=O)C.O>[O:27]=[S:26]1(=[O:30])[C:20]2[CH:21]=[CH:22][CH:23]=[CH:18][C:19]=2[C:15]2[CH:14]=[C:13]([NH:12][C:10]([CH:8]([CH3:9])[CH2:7][C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)=[O:11])[CH:25]=[CH:24][C:16]1=2
Reactant: CC(Cc1ccncc1)C(=O)Nc1ccc2sc3ccccc3c2c1
Reactant: O=S(=O)(O)O
Agent: O=C([O-])O
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(Cc1ccncc1)C(=O)Nc1ccc2c(c1)-c1ccccc1S2(=O)=O
Temperature: 60 °C
Reaction time: 2 h

Procedure:
2-[(2-Pyrid-4-yl-1-methylethyl)carbonylamino]dibenzothiophene (Example 11; 0.39 g, 1.13 mmol) was dissolved in glacial acetic acid (10 ml) and concentrated sulphuric acid (0.5 ml) at 60° C. 30% aqueous hydrogen peroxide (1.3 ml) was added in one portion and the solution was stirred at 60° C. for two hours. The mixture was allowed to cool and then poured into water (50 ml). The mixture was made basic by the addition of solid NaHCO3 and extracted with DCM (2×50 ml). The combined organic layers were washed with brine (50 ml), dried and evaporated in vacuo to leave a pale yellow solid. NMR: 8.45 (d, 2H), 8.3 (d, 1H), 8.0 (d, 1H), 7.95 (d, 1H), 7.9 (d, 1H), 7.8 (t, 1H), 7.7 (dd, 1H), 7.65 (t, 1H), 7.25 (d, 2H), 3.0 (m, 2H), 2.7 (m, 1H), 1.15 (d, 3H); m/z 379.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][NH:10][C:11]1[N:20]=[C:19]([N:21]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[CH3:22])[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:31][CH3:32])[CH:17]=2)[N:12]=1)(C)(C)C.ClC1N=C(N(C2C=CC(OC)=CC=2)C)C2C(=CC=C(OC)C=2)N=1.C(OC(=O)NCCN)(C)(C)C.C(N(C(C)C)CC)(C)C>CCCCO>[NH2:7][CH2:8][CH2:9][NH:10][C:11]1[N:20]=[C:19]([N:21]([C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[CH3:22])[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:31][CH3:32])[CH:17]=2)[N:12]=1
Reactant: COc1ccc(N(C)c2nc(NCCNC(=O)OC(C)(C)C)nc3ccc(OC)cc23)cc1
Agent: CC(C)(C)OC(=O)NCCN
Agent: COc1ccc(N(C)c2nc(Cl)nc3ccc(OC)cc23)cc1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(N(C)c2nc(NCCN)nc3ccc(OC)cc23)cc1
Temperature: 130 °C
Reaction time: 48 h
Yield: 70 %

Procedure:
(2-{6-Methoxy-4-[(4-methoxy-phenyl)-methyl-amino]-quinazolin-2-ylamino}-ethyl)-carbamic acid tert-butyl ester: A mixture of (2-chloro-6-methoxy-quinazoline-4-yl)-(4-methoxy-phenyl)-methyl-amine (0.6 g, 1.81 mmol), (2-amino-ethyl)-carbamic acid tert-butyl ester (0.4 g, 2.54 mmol) and diisopropylethylamine (0.76 mL, 4.4 mmol) in 3 mL of n-BuOH was stirred at 130° C. for 2 days. The solvent was evaporated under reduced pressure. The title compound (0.56 g; 70%) was isolated by preparative TLC (CH2Cl2/MeOH=5/3 as eluent). 1H NMR (DMSO-d6) δ 7.3-7.28 (d, 1H), 7.2 (d, 2H), 7.11-7.08 (d, 1H), 7.02-7.00 (d, 2H), 6.2 (s, 1H), 3.7 (s, 3H), 3.46 (s, 3H), 3.42 (t, 2H), 3.23 (s, 3H), 3.17 (t, 2H), 1.37 (s, 9H); LC-MS (ESI+; 454 ([M+H]+).
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][S:8](Cl)(=[O:10])=[O:9])(=O)C.[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([S:8]([CH2:7][CH2:6][CH2:5][OH:4])(=[O:9])=[O:10])[CH2:15][CH2:14]1
Reactant: CN1CCNCC1
Reactant: CC(=O)OCCCS(=O)(=O)Cl
Product: CN1CCN(S(=O)(=O)CCCO)CC1

Procedure:
Using 3-acetoxypropane-1-sulfonyl chloride and 1-methylpiperazine, the same reaction as in Reference Example 44 and 46 was conducted to produce the title compound. m.p. 90°-93° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:21]3=[N:22][CH:23]=[CH:24][C:25]([C:26]([F:29])([F:28])[F:27])=[C:20]3[NH:19][C:18]2=[O:30])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.I[CH2:32][CH3:33].C([O-])(O)=O.[Na+]>>[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][C:14]([N:17]2[C:21]3=[N:22][CH:23]=[CH:24][C:25]([C:26]([F:29])([F:28])[F:27])=[C:20]3[N:19]([CH2:32][CH3:33])[C:18]2=[O:30])=[CH:15][CH:16]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCI
Reactant: O=c1[nH]c2c(C(F)(F)F)ccnc2n1-c1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Product: CCn1c(=O)n(-c2ccc(OCc3ccccc3)cc2)c2nccc(C(F)(F)F)c21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of NaH (40.9 mg), 3-[4-(benzyloxy)phenyl]-7-(trifluoromethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (197 mg) in DMF(dry) (3 mL) was added iodoethane (0.082 mL), and the mixture was stirred at room temperature for 3 h. To the mixture was added sat. NaHCO3 aq. and the mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated in vacuo to give the title compound (197 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH2:11][CH2:12][Cl:13]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:10][CH2:11][CH2:12][Cl:13])=[CH:4][CH:3]=1
Reactant: ClCCCBr
Reactant: Sc1ccc(Cl)cc1
Product: ClCCCSc1ccc(Cl)cc1

Procedure:
Prepared by Procedure R and Scheme Z using 4-chlorobenzenethiol and 1-bromo-3-chloropropane.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C:11]([OH:28])([CH:18]([CH3:27])[CH:19](OS(C)(=O)=O)[CH2:20][CH3:21])[CH2:12][N:13]1[CH:17]=[N:16][CH:15]=[N:14]1>CN(C)C=O>[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C@@:11]1([CH2:12][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)[C@@H:18]([CH3:27])[C@H:19]([CH2:20][CH3:21])[O:28]1
Reactant: CCC(OS(C)(=O)=O)C(C)C(O)(Cn1cncn1)c1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC[C@@H]1O[C@@](Cn2cncn2)(c2ccc(F)cc2F)[C@H]1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 22.2 %

Procedure:
960 mg (0.24 mmole) of sodium hydride (as a 60% w/w dispersion in mineral oil) were added, whilst ice-cooling, to a solution of 77.9 mg (0.2 mmole) of 2-(2,4-difluorophenyl)-4-methanesulfonyloxy-3-methyl-1-(1H-1,2,4-triazol-1-yl)-2-hexanol in 4.9 ml of dimethylformamide. The resulting mixture was then stirred at room temperature for 3 hours. At the end of this time, the reaction mixture was poured into 20 ml of ice-water and extracted with 40 ml of ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated by evaporation under reduced pressure. The residue was purified by preparative thin layer chromatography, using a 2:1 by volume mixture of hexane and ethyl acetate as the developing solvent, to afford 13.0 mg (yield 22.2%) of the title compound as an oil.
Reaction SMILES: [OH:1][CH:2]([C@@H:14]([NH:19][C:20](=[O:34])[O:21][CH2:22][C:23]1([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:26][CH2:25][CH2:24]1)[CH2:15][CH2:16][CH2:17][CH3:18])[C:3](=[O:13])[NH:4][C@@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:6].[Br-].[K+].C(=O)(O)[O-].[Na+]>ClCCl>[O:13]=[C:3]([NH:4][C@@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:6])[C:2]([C@@H:14]([NH:19][C:20](=[O:34])[O:21][CH2:22][C:23]1([CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:24][CH2:25][CH2:26]1)[CH2:15][CH2:16][CH2:17][CH3:18])=[O:1]
Reactant: CCCC[C@H](NC(=O)OCC1(Cc2ccccc2)CCC1)C(O)C(=O)N[C@H](C)c1ccccc1
Agent: O=C([O-])O
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Product: CCCC[C@H](NC(=O)OCC1(Cc2ccccc2)CCC1)C(=O)C(=O)N[C@H](C)c1ccccc1
Reaction time: 0.5 h
Yield: 54 %

Procedure:
To a solution of 240 mg (0.51 mmol) of (1-benzylcyclobutyl)methyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate in 2 mL of dichloromethane at 0° C. was added 1 mg of 2,2,6,6-tetramethyl-1-piperidinyloxy free radical and 5 mg of potassium bromide. A solution of 30 mg of sodium bicarbonate in 2.5 mL of household bleach was added and the reaction stirred for 30 min. The reaction was extracted with ethyl acetate and and washed 0.5 N hydrochloric acid. The organic phase was washed with saturated sodium bicarbonate, washed with brine, dried over magnesium sulfate, and concentrated under vacuum. The product was purified by silica chromatography eluting with 2.5:7.5 acetone:hexanes to afford 128 mg (53%) of (1-benzylcyclobutyl)methyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate. M.P.=96-98° C. Elemental analysis: Theory; C=72.39%, H=7.81%, N=6.03%. Found; C=72.14%, H=7.81%, N=5.99%. 1H NMR (300 MHz, 80° C., DMSO-d6) δ 8.83 (d, J=8 Hz, 1H), 7.19-7.38 (m, 11H), 5.02 (qnt, J=7 Hz, 1H), 4.85 (m, 1H), 3.83 (s, 2H), 2.79 (s, 1H), 1.67-1.89 (m, 7H), 1.51-1.60 (m, 1H), 1.47 (d, J=7 Hz, 3H), 1.25-1.40 (m, 4H), 0.86 (t, J=7 Hz, 3H). ES-LCMS m/z 487 (M+Na). HRMS C28H36N2O4 m/z 487.2573 (M+Na)Cal; 487.2552 (M+Na)Obs.
Reaction SMILES: Cl.[CH2:2]=[C:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[CH3:9][O:10][C:11]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:12]=1[C:13](Cl)=[O:14]>ClCCl>[CH3:9][O:10][C:11]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:12]=1[C:13]([N:6]1[CH2:7][CH2:8][C:3](=[CH2:2])[CH2:4][CH2:5]1)=[O:14]
Reactant: COc1ccc(C(=O)Cl)c(OC)c1
Reactant: C=C1CCNCC1
Agent: Cl
Solvent: ClCCl
Product: C=C1CCN(C(=O)c2ccc(OC)cc2OC)CC1
Reaction time: 16 h

Procedure:
To a stirring solution of 4-methylene-piperidine hydrochloride (1.00 g, 8.12 mmol, JOC 66,2487-2492,2001) in 10 mL anhydrous dichloromethane at room temperature is added 2,4-dimethoxybenzoyl chloride (1.63 g, 8.12 mmol) and TEA (4 g, 40 mmol). The reaction mixture is allowed to stir for 16 hours. Dichloromethane is removed in vacuo, and the resultant residue is purified through silica gel chromatography (95% DCM, 5% MeOH) to give (2,4-dimethoxy-phenyl)-(4-methylene-piperidin-1-yl)-methanone. Yield: 1.62 g, 6.23 mmol. m/z (MS) M+1 261.01.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[N+:12]([C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][C:21]=1[CH3:22])[NH2:18])([O-:14])=[O:13]>>[N+:12]([C:15]1[CH:16]=[C:17]([NH:18][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])[CH:19]=[CH:20][C:21]=1[CH3:22])([O-:14])=[O:13]
Reactant: O=C(O)Cc1ccccc1Br
Reactant: Cc1ccc(N)cc1[N+](=O)[O-]
Product: Cc1ccc(Nc2ccccc2CC(=O)O)cc1[N+](=O)[O-]

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 3-nitro-4-methylaniline to yield 2-[(3-nitro-4-methylphenyl)amino]phenylacetic acid.
Reaction SMILES: [NH:1]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:2][C:3]([NH:5][C@H:6]([C:8]([NH:10][CH2:11][C:12]([OH:14])=O)=[O:9])[CH3:7])=[O:4].C1C=CC2N(O)N=NC=2C=1.O.Cl.[NH2:34][C@@H:35]([C:37]([NH:39][CH2:40][C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42])=[O:38])[CH3:36]>CN(C=O)C.C(Cl)CCl>[NH:1]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:2][C:3]([NH:5][C@H:6]([C:8]([NH:10][CH2:11][C:12]([NH:34][C@@H:35]([C:37]([NH:39][CH2:40][C:41]([O:43][CH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)=[O:42])=[O:38])[CH3:36])=[O:14])=[O:9])[CH3:7])=[O:4]
Reactant: C[C@H](NC(=O)CNC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Reactant: C[C@@H](N)C(=O)NCC(=O)OCc1ccccc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)CNC(=O)OC(C)(C)C)C(=O)NCC(=O)N[C@H](C)C(=O)NCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 70 %

Procedure:
To a solution of Boc-Gly-Ala-Gly prepared as in Example 34B (11.0 g, 36.5 mmol) in anhydrous DMF (270 ml), was added HOBT.circle-solid.H2O (5.46 g, 40.4 mmol), EDC.circle-solid.HCl (7.74 g, 40.4 mmol), and DAla-Gly-OBzl .circle-solid.HCl prepared as in Example 34A (9.95 g, 36.5 mmol). The pH of the resulting solution was adjusted to ~8 (measured by spotting the reaction mixture on moistened Hydrion paper) and the reaction mixture was allowed to stir at room temperature for 12 h thereafter. The solution was concentrated in vacuo and the residue was dissolved in water (50 ml). This solution was extracted with ethyl acetate (3×100 ml). The combined ethyl acetate layers were washed with 1N sodium bisulfate (50 ml), saturated sodium bicarbonate (50 ml) and brine (50 ml). The ethyl acetate solution was dried (magnesium sulfate), filtered and allowed to sit for 12 h undisturbed. Collection of the crystals by filtration and drying at high vacuum afforded 13.4 g (70% yield) of pure product: 1H NMR (DMSO-d6) δ 1.22 (d, J=7.2 Hz, 3H), 1.23 (d, J=7.2 Hz, 3H), 1.38 (s, 9H), 3.58 (d, J=6.0 Hz, 2H), 3.73 (d, J=4.8 Hz, 2H), 3.91 (dd, J =6.0, 3.0 Hz, 2H), 4.32 (m, 2H), 5.14 (s, 2H), 6.91 (t, J=4.8 Hz, 1H), 7.38 (s, 5H), 7.97 (d, J=8.1 Hz, 1H), 8.02 (d, J=6.9 Hz, 1H), 8.19 (t, J=5.4 Hz, 1H), 8.33 (t, J=5.4 Hz, 1H).
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl[C:22]([O:24][CH2:25][CH:26]=[CH2:27])=[O:23]>>[CH2:25]([O:24][C:22]([N:20]=[C:16]([N:7]1[CH2:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH2:8]1)[O:17][CH2:18][CH3:19])=[O:23])[CH:26]=[CH2:27]
Reactant: C=CCOC(=O)Cl
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Product: C=CCOC(=O)N=C(OCC)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and allyl chloroformate, there is obtained ethyl N-allyloxycarbonyl-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate, m.p. 76°-77.5° C.;
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:20]3[CH2:23][CH2:22][CH2:21]3)[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([OH:19])[CH:11]=3)=[CH:4][C:3]=1[Cl:24].Cl[C:26]1[N:31]=[CH:30][CH:29]=[CH:28][N:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:20]3[CH2:23][CH2:22][CH2:21]3)[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][C:26]2[N:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[CH:11]=3)=[CH:4][C:3]=1[Cl:24]
Reactant: N#Cc1c(-c2ccc(N)c(Cl)c2)n(C2CCC2)c2cc(O)ccc12
Reactant: Clc1ncccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#Cc1c(-c2ccc(N)c(Cl)c2)n(C2CCC2)c2cc(Oc3ncccn3)ccc12
Reaction time: 1 h
Yield: 91.4 %

Procedure:
2-(4-Amino-3-chloro-phenyl)-1-cyclobutyl-6-hydroxy-1H-indole-3-carbonitrile (0.67 g, 2 mmol), prepared in step ZA, was dissolved in DMF (7 mL), followed by the addition of 2-chloro-pyrimidine (0.34 g, 3 mmol) and cesium carbonate (1.3 g, 4 mmol). The mixture was brought to 70° C. and stirred for 1 h. After cooling, the solid was filtered and washed with EtOAc. The filtrate was washed with water and brine, dried, concentrated and triturated with ether to provide 2-(4-amino-3-chloro-phenyl)-1-cyclobutyl-6-(pyrimidin-2-yloxy)-1H-indole-3-carbonitrile (0.76 g, 91%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N+:4]([O-:8])[CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O.[N+:14]([O-])([OH:16])=[O:15].C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:1][C:2]1[CH:3]=[N+:4]([O-:8])[CH:5]=[CH:6][C:7]=1[N+:14]([O-:16])=[O:15]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc[n+]([O-])c1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Cc1c[n+]([O-])ccc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 50 %

Procedure:
3-Methylpyridine 1-oxide (2 g, 18.3 mmol, Step a) was added slowly to the round bottom flask containing sulfuric acid (7 mL, 128 mmol). The mixture was cooled to 0° C. and nitric acid (5.7 mL, 128 mmol) was added drop wise. The resulting reaction mixture was heated at 90-100° C. for 2 hours. The reaction mixture was poured onto crushed ice and sodium carbonate was added portion wise. The aqueous phase was extracted with chloroform. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum to get 3-methyl-4-nitropyridine 1-oxide (1.4 g, 50%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([Br:8])[CH:7]=1.[Br:10]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([Br:8])[CH:7]=1)[CH2:9][Br:10]
Reactant: Cc1cc(Br)cc(Br)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: BrCc1cc(Br)cc(Br)c1
Reaction time: 8 h
Yield: 48.4 %

Procedure:
3,5-Dibromotoluene (27.0 g; 108.0 mmol), N-bromosuccinimide (19.2 g; 108.0 mmol), and benzoyl peroxide (0.32 g) were added to benzene (200 ml), and the mixture was refluxed for 2.5 hours. The mixture was brought to room temperature, and the solvent was evaporated under reduced pressure. The residue was taken up in n-hexane (200 ml), and the mixture was left to stand overnight at room temperature. Crystals that precipitated were filtered off, and the filtrate was concentrated under reduced pressure, to thereby yield 17.2 g of the target compound (yield: 48.3%).
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[N:12][N:13]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[N:14]=2)[CH:5]=1.O.[OH-].[Li+]>O1CCCC1>[CH3:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][N:13]2[N:12]=[N:11][C:10]([C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:24])=[O:2])=[N:14]2)=[CH:21][CH:20]=1
Reactant: COC(=O)c1cccc(-c2nnn(Cc3ccc(OC)cc3)n2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(Cn2nnc(-c3cccc(C(=O)O)c3)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.7 %

Procedure:
The ester prepared in Step (b) (10.4 g, 0.032 mol) was suspended in aqueous tetrahydrofuran (20 mL, 1:1) followed by the addition of lithium hydroxide monohydrate (4 g, 0.096 mol) in one portion. Dissolution occurred after stirring at room temperature for 30 minute. The solution was stirred for an additional 16 hours. The THF was concentrated in vacuo and the aqueous solution was acidified to pH=1 using concentrated HCl. The resulting precipitate was collected by filtration and recrystallized from hexane/ethyl acetate to give the title compound (10 g, 100%) as a white solid. 1H NMR (DMSO-d6) δ 8.6 (s, 1H), 8.3 (d, 1H), 8.1 (d, 1H), 7.7 (t, 1H), 7.4 (d, 2H), 6.9 (d, 2H), 6.9 (s, 2H), 3.7 (s, 3H) ppm.
Reaction SMILES: [Na].N.[OH:3][C:4]1[C:9]([CH3:10])=[CH:8][C:7]([CH:11]([CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])O)=[CH:6][C:5]=1[CH3:18]>C(O)C.C(OCC)C>[CH3:18][C:5]1[CH:6]=[C:7]([CH2:11][CH2:13][Si:14]([CH3:15])([CH3:17])[CH3:16])[CH:8]=[C:9]([CH3:10])[C:4]=1[OH:3]
Reactant: Cc1cc(C(O)C[Si](C)(C)C)cc(C)c1O
Agent: N
Agent: [Na]
Solvent: CCOCC
Solvent: CCO
Product: Cc1cc(CC[Si](C)(C)C)cc(C)c1O

Procedure:
Mix sodium metal (520 mg, 22.6 mmol) and liquid ammonia (13 mL). To this solution add, by dropwise addition, a solution of 4-hydroxy-3,5-dimethyl-α-[(trimethylsilyl)-methyl]benzenemethanol (2.22 g, 10 mmol) in ethyl alcohol (0.5 g) and ethyl ether (5 ml). After the blue color disappears, cautiously add water (13 mL), extract with ethyl ether, dry (MgSO4), and evaporate the solvent. Purify the residue by silica gel chromatography to yield the title compound.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([CH:15]([CH3:24])[CH:16](O)[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.Cl>N1C=CC=CC=1>[C:1]([C:9]1[CH:10]=[C:11]([C:15]([CH3:24])=[CH:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(O)C(C)c1cccc(C(=O)c2ccccc2)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)CC=C(C)c1cccc(C(=O)c2ccccc2)c1
Temperature: 0 °C
Yield: 91.3 %

Procedure:
A solution of 6.2 g of ethyl 4-(m-benzoyl-phenyl)-4-methyl-3-hydroxy-butyrate (by process of Step E of Example XIX) in 60 ml of pyridine was heated at 100°C for 3 hours in the presence of 5 ml of phosphorus oxychloride and was then poured into a mixture of 200 g of ice and 65 ml of concentrated hydrochloric acid. The mixture was extracted with ether and the ether phase was washed with water, then with an aqueous saturated sodium bicarbonate solution and then water until the wash water was neutral. The solution was dried over sodium sulfate, treated with activated carbon, filtered and evaporated to dryness under reduced pressure to obtain 5.35 g of ethyl 4-(m-benzoyl-phenyl)-4-methyl-3-butenoate.
Reaction SMILES: Br[C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([C:15]([OH:18])([CH3:17])[CH3:16])=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:19]([NH2:21])=[O:20])=[CH:4][C:3]=1[Cl:22].[F:23][C:24]1[CH:25]=[C:26]2[C:31](=[C:32]([F:34])[CH:33]=1)[NH:30][C:29](=[O:35])[N:28]([C:36]1[CH:41]=[CH:40][CH:39]=[C:38](B3OC(C)(C)C(C)(C)O3)[C:37]=1[CH3:51])[C:27]2=[O:52].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2].BrC1C2C3C(=CC(C(O)(C)C)=CC=3)NC=2C(C(N)=O)=CC=1Cl.C1COCC1>[Cl:22][C:3]1[CH:4]=[C:5]([C:19]([NH2:21])=[O:20])[C:6]2[NH:7][C:8]3[C:13]([C:14]=2[C:2]=1[C:38]1[CH:39]=[CH:40][CH:41]=[C:36]([N:28]2[C:27](=[O:52])[C:26]4[C:31](=[C:32]([F:34])[CH:33]=[C:24]([F:23])[CH:25]=4)[NH:30][C:29]2=[O:35])[C:37]=1[CH3:51])=[CH:12][CH:11]=[C:10]([C:15]([OH:18])([CH3:17])[CH3:16])[CH:9]=3
Reactant: CC(C)(O)c1ccc2c(c1)[nH]c1c(C(N)=O)cc(Cl)c(Br)c12
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1c(=O)[nH]c2c(F)cc(F)cc2c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: C1CCOC1
Product: Cc1c(-c2c(Cl)cc(C(N)=O)c3[nH]c4cc(C(C)(C)O)ccc4c23)cccc1-n1c(=O)[nH]c2c(F)cc(F)cc2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
A mixture of 4-bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide [Intermediate 3] (10 mg, 0.026 mmol), 6,8-difluoro-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione [Intermediate 16] (14.1 mg, 0.034 mmol), 1,1′-bis(di-tert-butylphosphino)ferrocene palladium(II) chloride (12.8 mg, 0.020 mmol) and THF (2 mL) in a reaction vial was treated with 2 M aqueous K3PO4 (0.039 mL, 0.079 mmol). The vial was sealed and subjected to three evacuate-fill cycles with nitrogen. The mixture was stirred at room temperature overnight. The phases of the mixture were separated, the aqueous phase was extracted twice with EtOAc, and the combined organic phases were dried and concentrated. The residue was purified by column chromatography on silica gel (40 g), eluting with EtOAc -hexanes (gradient from 80-100%). The isolated material was triturated with MeOH to give a solid after filtration. The filtrate was concentrated and subjected to column chromatography on silica (40 g), eluting with DCM-MeOH—NH4OH (gradient from 90:9:1-97:2.7:0.3) to give additional solid. The two solids were combined to provide 3-chloro-4-(3-(6,8-difluoro-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide (mixture of four atropisomers) as a pale yellow solid (164 mg, 71% yield). Mass spectrum m/z 571 (M+H—H2O)+. 1H NMR (500 MHz, MeOH-d4) δ 8.04 (d, J=2.0 Hz, 1H), 7.70-7.68 (m, 1H), 7.65 (dd, J=7.2, 3.2 Hz, 1H), 7.57-7.52 (m, 1H), 7.43-7.34 (m, 3H), 7.18-7.07 (m, 1H), 6.90 (dd, J=8.4, 3.0 Hz, 1H), 1.84 (s, 3H), 1.62-1.56 (m, 6H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1([C:10](F)(F)F)[O:7][CH:6]([CH2:8][OH:9])[CH2:5][O:4]1.C1OC1C.[OH-].[K+].C1OC1>>[CH3:10][C:3]1([C:2]([F:15])([F:1])[F:14])[O:7][CH:6]([CH2:8][OH:9])[CH2:5][O:4]1
Reactant: OCC1COC(C(F)(F)F)(C(F)(F)F)O1
Agent: CC1CO1
Agent: [K+]
Agent: [OH-]
Solvent: C1CO1
Product: CC1(C(F)(F)F)OCC(CO)O1
Temperature: 125 °C
Reaction time: 3 h

Procedure:
A 2 L stirrer-equipped autoclave was charged with 2,2-bis(trifluoromethyl)-4-hydroxymethyl-1,3-dioxolane (96.1 g; 0.4 moles), propylene oxide (23.3 g; 0.4 moles), and potassium hydroxide (0.6 g). The autoclave was purged of oxygen using argon gas and then sealed. While stirring the mixture, the temperature of the autoclave was raised to 125° C. and then kept at that temperature for 3 hours. After cooling the mixture to room temperature, the autoclave was vented. Next, ethylene oxide (52.9 g; 1.2 moles) was condensed at 0° C. into the mixture with stirring. While continuing to cool the combined mixture, the autoclave was again purged of oxygen using argon gas and then sealed. While stirring the mixture, the temperature of the autoclave was raised to 130° C. and then kept at that temperature for 3 hours. After cooling the mixture to room temperature, the autoclave was vented and the crude product was transferred to a 300 mL round bottom flask. Pure product was isolated by vacuum distillation at 186° C. and 0.3 mm of Hg. The yield of product was 143 g which is 83% of the theoretical value. In the examples and test evaluations described below, this compound is abbreviated (F3)(F3)-ipg-(PO)(EO)3.