Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:12]([C@H:13]3[CH2:17][CH2:16][CH2:15][NH:14]3)=[N:11][N:10]=[C:9]2[CH3:18])=[CH:5][CH:4]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1.C(N(CC)C(C)C)(C)C>ClCCl>[Cl:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:9]([CH3:18])=[N:10][N:11]=[C:12]2[C@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[C:29]([NH:28][C:25]2[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=2)=[O:30])=[CH:5][CH:4]=1
Reactant: Cc1nnc([C@H]2CCCN2)n1Cc1ccc(Cl)cc1
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nnc([C@H]2CCCN2C(=O)Nc2ccc(Cl)cc2)n1Cc1ccc(Cl)cc1
Yield: 87.3 %

Procedure:
(R)-4-(4-chlorobenzyl)-3-methyl-5-(pyrrolidin-2-yl)-4H-1,2,4-triazole hydrochloride (58 mg, 0.2 mmol) was dissolved in dichloromethane (2 ml). 4-chlorophenyl isocyanate (0.031 ml, 0.2 mmol) and N,N-diisopropylethylamine-(0.050 ml) were added while stirring. The reaction mixture was stirred for 12 h then evaporated to dryness. Purification by silica gel column chromatography (methanol/dichloromethane gradient, 0-15% methanol) afforded the desired product as a white amorphous solid (75.1 mg, 87%).
Reaction SMILES: [OH:1][C@H:2]([CH2:32][OH:33])[CH2:3][N:4]1[C:9](=[O:10])[C:8]2[C:11]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]#[C:26][Si](C)(C)C)=[CH:21][C:20]=3[F:31])=[C:12]([F:17])[C:13](=[O:16])[N:14]([CH3:15])[C:7]=2[N:6]=[CH:5]1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C(Cl)Cl>C1COCC1>[OH:1][C@H:2]([CH2:32][OH:33])[CH2:3][N:4]1[C:9](=[O:10])[C:8]2[C:11]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]#[CH:26])=[CH:21][C:20]=3[F:31])=[C:12]([F:17])[C:13](=[O:16])[N:14]([CH3:15])[C:7]=2[N:6]=[CH:5]1
Reactant: Cn1c(=O)c(F)c(Nc2ccc(C#C[Si](C)(C)C)cc2F)c2c(=O)n(C[C@H](O)CO)cnc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: C#Cc1ccc(Nc2c(F)c(=O)n(C)c3ncn(C[C@H](O)CO)c(=O)c23)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
To a mixture of (S)-3-(2,3-dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-((trimethylsilyl)ethynyl)phenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione 21A in THF (3 mL) was added 1M solution of TBAF (0.14 mL, 0.14 mmol, 1.75 eq). The reaction mixture was stirred at ambient temperature for 1 hour. The solvent was removed under vacuum and the residue was purified by flash chromatography with 2:8 MeOH:DCM to yield the desired product (S)-3-(2,3-dihydroxypropyl)-5-(4-ethynyl-2-fluorophenylamino)-6-fluoro-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (example 21) as an off-white solid (10 mg, 30% yield). 1H NMR (400 MHz, MeOD) δ ppm 3.54 (s, 1H) 3.60 (d, J=5.05 Hz, 2H) 3.72 (s, 3H) 3.75-3.83 (m, 1H) 3.93-4.00 (m, 1H) 4.41 (dd, J=13.52, 2.91 Hz, 1H) 7.11 (td, J=8.15, 5.68 Hz, 1H) 7.21-7.29 (m, 2H) 8.40 (s, 1H). [M+H] calc'd for C19H16F2N4O4, 403; found, 403.
Reaction SMILES: [C:1]1([C:17]([O:19][CH3:20])=[O:18])[N:2]=[CH:3][N:4]2[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][C:5]=12.C1C(=O)N([Br:28])C(=O)C1>C(#N)C.C(Cl)Cl>[Br:28][C:3]1[N:4]2[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH2:6][C:5]2=[C:1]([C:17]([O:19][CH3:20])=[O:18])[N:2]=1
Reactant: COC(=O)c1ncn2c1CN(C(=O)OC(C)(C)C)CC2
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: CC#N
Product: COC(=O)c1nc(Br)n2c1CN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.1 %

Procedure:
The Intermediate 1G (3.20 g, 11.38 mmol) was dissolved in acetonitrile and NBS (2.43 g, 13.65 mmol) was added. The reaction mixture was stirred at room temperature overnight. The mixture was concentrated and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give a yellow solid. The solid was dissolved in DCM and passed through a silica gel plug, eluting with 10% methanol in DCM to give product Intermediate 1H as a yellow solid (3.90 g, 95%).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:12]=[C:11](Cl)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:14][CH3:15])[CH:9]=2)[N:4]=1.[NH:16]1[CH:20]=[N:19][CH:18]=[N:17]1.CN(C)C=O.[OH-].[NH4+]>O>[N:16]1([C:11]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([O:14][CH3:15])[CH:9]=3)[N:4]=[C:3]([CH3:2])[CH:12]=2)[CH:20]=[N:19][CH:18]=[N:17]1
Reactant: COc1ccc2nc(C)cc(Cl)c2c1
Reactant: c1nc[nH]n1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2nc(C)cc(-n3cncn3)c2c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
A mixture of 2.44 g of 2-methyl-4-chloro-6-methoxy-quinoline-hydrochloride, 1.38 g of 1,2,4-triazole and 10 ml of dimethyl formamide is stirred at 80° C. for 3 hours whereupon the reaction mixture is poured into 100 ml of water and neutralized with 2 ml of a concentrated ammonium hydroxide solution. The precipitated product is filtered. Thus 2.09 g of the desired compound are obtained, yield 87%, mp.: 117°-118° C.
Reaction SMILES: C([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH2:13][C:14]2[N:18]([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:17]3[CH:24]=[CH:25][C:26]([C:28]([NH2:30])=[NH:29])=[CH:27][C:16]=3[N:15]=2)[C:5]1=[O:31])(C)=C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH3:22][CH:21]([CH3:23])[CH2:20][CH2:19][N:18]1[C:17]2[CH:24]=[CH:25][C:26]([C:28]([NH2:30])=[NH:29])=[CH:27][C:16]=2[N:15]=[C:14]1[CH2:13][N:6]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:4][C:5]1=[O:31]
Reactant: C=C(C)n1c(=O)n(Cc2nc3cc(C(=N)N)ccc3n2CCC(C)C)c2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CCn1c(Cn2c(=O)[nH]c3ccccc32)nc2cc(C(=N)N)ccc21
Yield: 95.6 %

Procedure:
2-(3-Isopropenyl-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-1-(3-methyl-butyl)-1H-benzoimidazole-5-carboxamidine (20 mg, 0.05 mmol) was dissolved in 30% TFA/CH2Cl2 and stirred at reflux for 1 h. The solvent was removed and the residues triturated with ether to give 18 mg (99%) of 1-(3-methyl-butyl)-2-(2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-1H-benzoimidazole-5-carboxamidine as a white solid as the TFA salt.
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10]Cl)=[CH:6][CH:5]=1>CC#N>[CH3:1][NH:2][CH2:10][C:7]1[CH:8]=[N:9][C:4]([CH3:3])=[CH:5][CH:6]=1
Reactant: Cc1ccc(CCl)cn1
Reactant: CN
Solvent: CC#N
Product: CNCc1ccc(C)nc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 16.6 g of 40% aqueous MeNH2 solution and 52 ml of CH3CN was cooled with ice and 6.08 g (0.043 mole in terms of pure product) of crude (6-methyl-3-pyridyl)-methyl chloride was added dropwise with constant stirring. After completion of dropwise addition, the mixture was stirred at room temperature for 1.5 hours, at the end of which time the solvent was distilled off. The solid residue was extracted with CH2Cl2 and the CH2Cl2 layer was dried over MgSO4. The CH2Cl2 was distilled off and the residue was diluted with 70 ml of Et2O and filtered to remove the insoluble matter. Finally the filtrate was concentrated to recover 4.60 g of the title compound as a crude oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:6]([Cl:13])[C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].Br[C:24]([C:26]([F:29])([F:28])[F:27])=[CH2:25].C([O-])([O-])=O.[K+].[K+]>C1COCC1.O.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>[Cl:13][C:6]1[CH:5]=[C:4]([C:24]([C:26]([F:29])([F:28])[F:27])=[CH2:25])[CH:3]=[C:2]([Cl:1])[C:7]=1[O:8][C:9]([F:10])([F:11])[F:12]
Reactant: CC1(C)OB(c2cc(Cl)c(OC(F)(F)F)c(Cl)c2)OC1(C)C
Reactant: C=C(Br)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=C(c1cc(Cl)c(OC(F)(F)F)c(Cl)c1)C(F)(F)F
Temperature: 80 °C
Yield: 71.4 %

Procedure:
A mixture of 2-(3,5-dichloro-4-(trifluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.2 g, 3.36 mmol), 2-bromo-3,3,3-trifluoroprop-1-ene (647 mg, 3.70 mmol), K2CO3 (927 mg, 6.72 mmol) and Pd(PPh3)2Cl2 (47.2 mg, 0.067 mmol) in THF (10 mL) and H2O (6 mL) was heated at 80° C. in a sealed tube for 4 h. The mixture was cooled to rt and partitioned between EA (50 mL) and H2O (50 mL). The aqueous layer was extracted with EA (50 mL) and the combined organic layers were dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by column chromatography on silica gel to give the crude desired product (780 mg; 72% yield) as colorless oil.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[OH:11])[CH:2]=C.[O:12]=[O+][O-].[BH4-].[Na+].Cl>CO>[OH:11][C:5]1[CH:6]=[CH:7][C:8]([CH3:10])=[CH:9][C:4]=1[CH2:1][CH2:2][OH:12]
Reactant: O=[O+][O-]
Reactant: C=CCc1cc(C)ccc1O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(O)c(CCO)c1
Temperature: 25 °C
Yield: 96 %

Procedure:
A solution of 8.34 g (0.05 mol) of 2-allyl-4-methylphenol in 420 ml of CH3OH containing a few crystals of Sudan III indicator was cooled to -78° C. Ozone was passed through this solution until a color change of the Sudan III indicator showed that the ozonization reaction was complete. Solid sodium borohydride (6.4 g) was added in small portions to the cold solution. When this addition was complete, the solution was allowed to warm to room temperature overnight. The solution was made acid by the addition of 6N HCl, and then was concentrated to dryness in vacuo. The residue was dissolved in ethyl acetate and was washed with water, saturated NaHCO3 solution and brine. The solution was dried, filtered, and evaporated to give 7.3 g (96%) of 2-(2-hydroxy-5-methylphenyl)ethanol.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([OH:9])[CH2:2]2.[C:10]1([N:16]=[C:17]=[S:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(OCC)(=O)C.CCOCC>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:17](=[S:18])[NH:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:2]2
Reactant: OC1CN2CCC1CC2
Reactant: S=C=Nc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: S=C(Nc1ccccc1)OC1CN2CCC1CC2
Yield: 29 %

Procedure:
3-Quinuclidinol and phenyl isothiocyanate were used. The reaction solution was heated at reflux under nitrogen for 6 days. The reaction solution was chromatographed using silica gel and elution with 10% methanol in methylene chloride followed by a solution of methylene chloride/methanol/ammonium hydroxide (9:1:0.1) to afford a white foam. This foam was dissolved in ethyl acetate/ether (1:9, 10 mL/g of foam), and the resulting cloudy solution was filtered through diatomaceous earth. The resultant filtrate was evaporated under reduced pressure, and the residual foam was crystallized from ethyl acetate/hexanes (1:3) to afford the title compound (29%) as a white solid: mp 132.0-133.0° C.; FAB LRMS m /z (relative intensity, %) 263 (MH+, 14), 110 (100).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:14]3[CH:15]=[N:16][CH:17]=[C:18]([F:19])[C:13]=3[N:12]([C:20]([CH3:31])([CH3:30])[CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[F:32][C:33]([F:44])([F:43])[C:34]1[CH:35]=[N:36][N:37]([CH2:39][C:40](O)=[O:41])[CH:38]=1.CCN(C(C)C)C(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C1COCC1>[C:26]([Si:23]([CH3:24])([CH3:25])[O:22][CH2:21][C:20]([N:12]1[C:13]2[C:18]([F:19])=[CH:17][N:16]=[CH:15][C:14]=2[C:10]([C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:40](=[O:41])[CH2:39][N:37]3[CH:38]=[C:34]([C:33]([F:43])([F:32])[F:44])[CH:35]=[N:36]3)[CH:7]=[N:6][CH:5]=2)=[O:9])=[CH:11]1)([CH3:31])[CH3:30])([CH3:29])([CH3:28])[CH3:27]
Reactant: O=C(O)Cn1cc(C(F)(F)F)cn1
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(N)c2)c2cncc(F)c21
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(NC(=O)Cn3cc(C(F)(F)F)cn3)c2)c2cncc(F)c21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (5-amino-pyridin-3-yl)-{1-[2-(tert-butyl-dimethyl-silanyloxy)-1,1-dimethyl-ethyl]-7-fluoro-1H-pyrrolo[3,2-c]pyridin-3-yl}-methanone (Preparation 29, 35 mg, 79.1 μmol), (4-trifluoromethyl-pyrazol-1-yl)-acetic acid (20.7 mg, 106.9 μmol) and DIPEA (48 μL, 276.8 μmol) in THF (3 mL), T3P (166 μL, 276.8 μmol) was added and the mixture stirred at 25° C. for 18 hours. The reaction was evaporated under reduced pressure, the residue partitioned between water and ethyl acetate, the organic extracts washed with saturated sodium bicarbonate solution, dried over sodium sulphate, evaporated in vacuo and triturated with pentane-ether to afford the title compound as an off white solid (71%, 35 mg).
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Cl:11])[C:5]=1[O:12][C:13]1[N:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[N:14]=1.O.Cl>C(O)(=O)C>[Cl:11][C:6]1[C:5]([O:12][C:13]2[N:14]=[C:15]([O:21][CH3:22])[CH:16]=[C:17]([O:19][CH3:20])[N:18]=2)=[C:4]([CH:9]=[C:8]([Cl:10])[CH:7]=1)[CH:3]=[O:2]
Reactant: COc1cc(OC)nc(Oc2c(Cl)cc(Cl)cc2C(OC)OC)n1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(OC)nc(Oc2c(Cl)cc(Cl)cc2C=O)n1

Procedure:
3,5-Dichloro-2-(4,6-dimethoxypyrimidin-2-yl)oxy benzaldehyde dimethylacetal (2.1 g) was dissolved in acetic acid (50 ml), and then water (10 ml) and 35% hydrochloric acid (1 ml) were added thereto. The mixture was reacted at room temperature for 6 hours. The reaction mixture was poured into water, and extracted with toluene. The extract was washed with a 2% sodium hydroxide aqueous solution, and further washed 3 times with water. The toluene phase was dried, and concentrated under reduced pressure. The crystal thus obtained was recrystallized from a mixture of carbontetrachloride and hexane to obtain the above identified compound as a white crystal (1.0 g). (Melting point: 132°-133° C.)
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH:9]=[N:10][N:11]3[CH:16]([CH2:23][CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:17](N(OC)C)=[O:18])(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH:30]([Mg]Br)=[CH2:31].Cl>O1CCCC1>[CH:1]1([S:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH:9]=[N:10][N:11]3[CH:16]([CH2:23][CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:17](=[O:18])[CH:30]=[CH2:31])(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: C=C[Mg]Br
Reactant: CON(C)C(=O)C(CC1CCOCC1)n1ncc2c(S(=O)(=O)C3CC3)cccc21
Agent: Cl
Solvent: C1CCOC1
Product: C=CC(=O)C(CC1CCOCC1)n1ncc2c(S(=O)(=O)C3CC3)cccc21
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 84 %

Procedure:
To a solution of 2-[4-(cyclopropylsulfonyl)-1H-indazol-1-yl]-N-methoxy-N-methyl-3-(tetrahydro-2H-pyran-4-yl)propanamide (2.30 g) in tetrahydrofuran (20 ml) was slowly added vinylmagnesium bromide (1.0M tetrahydrofuran solution: 16.4 mL) at 0° C., and the mixture was stirred at 0° C. for 20 min. The reaction mixture was poured into an ice-cooled 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to give the title compound (1.80 g, yield 84%) as a colorless oil from the fraction eluted with ethyl acetate-hexane (3:1, volume ratio). MS: 389 (MH+).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2=[CH:17][C:18]([Cl:21])=[C:19]([Cl:20])[C:12]3=[C:13]2[N:8]([CH:9]([CH3:23])[CH2:10][C:11]3=[O:22])[CH:7]=1)=[O:5])C>Cl.C(O)(=O)C>[Cl:20][C:19]1[C:12]2=[C:13]3[N:8]([CH:9]([CH3:23])[CH2:10][C:11]2=[O:22])[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[C:15](=[O:16])[C:14]3=[CH:17][C:18]=1[Cl:21]
Reactant: CCOC(=O)c1cn2c3c(c(Cl)c(Cl)cc3c1=O)C(=O)CC2C
Agent: Cl
Solvent: CC(=O)O
Product: CC1CC(=O)c2c(Cl)c(Cl)cc3c(=O)c(C(=O)O)cn1c23
Temperature: 25 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
7.08 g (0.02 mole) of 8,9-dichloro-5-methyl-6,7-dihydro-1,7-dioxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid ethyl ester was suspended in a mixture of 14 ml of concentrated hydrochloric acid and 56 ml of acetic acid, and this suspension was stirred at 110°-120° C. for 3 hours to hydrolyze the starting material. The resulting reaction solution was allowed to cool to room temperature. The precipitate which separated out was collected by filtration and washed with water to obtain 5.61 g (86.0% yield) of 8,9-dichloro-5-methyl-6,7-dihydro-1,7-dioxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid in the form of pale-yellow crystals.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([Br:15])[C:7]=2[C:8]=1[NH2:9])(=[O:3])[CH3:2].[F-].[Cs+].[CH3:18]I.O>C1COCC1>[C:1]([C:4]1[O:5][C:6]2[CH:13]=[CH:12][C:11]([O:14][CH3:18])=[C:10]([Br:15])[C:7]=2[C:8]=1[NH2:9])(=[O:3])[CH3:2]
Reactant: CI
Reactant: CC(=O)c1oc2ccc(O)c(Br)c2c1N
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2oc(C(C)=O)c(N)c2c1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.2 %

Procedure:
To a mixture of 12F (5.6 g, 0.020 mol) and CsF (9.5 g, 0.0625 mol) in THF (20 mL) was added MeI (2.9 g) dropwise at room temperature. The reaction mixture was stirred at room temperature for 1 hour, then added dropwise into water. The solids were precipitated out dissolved in ethyl acetate and purified by column chromatography on silica gel to give 12G (2.4 g, 40.7% yield).
Reaction SMILES: [CH2:1]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=[CH2:9].Br[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1>>[N+:23]([C:20]1[CH:21]=[CH:22][C:17]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:18][CH:19]=1)([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Reactant: C=CCCCCCCCc1ccccc1
Product: O=[N+]([O-])c1ccc(CCCCCCCCCc2ccccc2)cc1
Yield: 53.9 %

Procedure:
General procedure M was used to convert 5.08 mmol of 15 and 5.59 mmol of 1-bromo-4-nitrobenzene to 2.74 mmol (54%) of the title compound.
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH2:11])[CH2:4]2.[Cl:12][C:13]1[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21](O)=[O:22])=[CH:15][CH:14]=1>>[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH:11][C:21](=[O:22])/[CH:20]=[CH:19]/[C:16]1[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=1)[CH2:4]2
Reactant: O=C(O)/C=C/c1ccc(Cl)cc1
Reactant: N[C@H]1CN2CCC1CC2
Agent: Cl
Product: O=C(/C=C/c1ccc(Cl)cc1)N[C@H]1CN2CCC1CC2

Procedure:
Prepared as a free base by a method analogous to that described in Example 1 from (R)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride and E-3-(4-chlorophenyl)propenoic acid; the compound was purified by chromatography on silica gel using ammoniated methanol/chloroform mixtures as the eluent; MS (ES+) 291, 293 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:28])[NH:20][C:21]([CH3:27])=[CH:22][C:23]=2[CH2:24][CH2:25][CH3:26])=[O:15])[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:13][CH2:12]3)[C:9]=2[CH:10]=1.[CH3:29][N:30]([CH3:47])[CH2:31][C:32]1[CH:37]=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][CH:33]=1>>[CH:11]1([N:8]2[C:9]3[CH:10]=[C:2]([C:35]4[CH:36]=[CH:37][C:32]([CH2:31][N:30]([CH3:47])[CH3:29])=[CH:33][CH:34]=4)[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]4[C:19](=[O:28])[NH:20][C:21]([CH3:27])=[CH:22][C:23]=4[CH2:24][CH2:25][CH3:26])=[O:15])[C:5]=3[CH:6]=[N:7]2)[CH2:13][CH2:12]1
Reactant: CN(C)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Br)cc2c1cnn2C1CC1
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(-c2ccc(CN(C)C)cc2)cc2c1cnn2C1CC1

Procedure:
The title compound was prepared in the same manner as described for example 67 from 6-bromo-1-cyclopropyl-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]-1H-indazole-4-carboxamide (0.075 g, 0.169 mmol) and N,N-dimethyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanamine (0.060 g, 0.203 mmol). The title compound was collected as a white solid (59 mg, 69%); 1H NMR (400 MHz, DMSO-d6) δ ppm 0.88 (t, J=7.33 Hz, 3H), 1.12-1.21 (m, 4H), 1.45-1.58 (m, 2H), 2.13 (s, 3H), 2.18 (s, 6H), 3.45 (s, 2H), 3.88 (quin, J=5.37 Hz, 1H), 4.41 (d, J=5.05 Hz, 2H), 5.91 (s, 1H), 7.43 (m, J=8.34 Hz, 2H), 7.80 (m, J=8.08 Hz, 2H), 7.89 (d, J=1.26 Hz, 1H), 8.04 (s, 1H), 8.32 (s, 1H), 8.68 (t, J=4.93 Hz, 1H), 11.54 (s, 1H); LC-MS (ES) m/z=498.4 [M+H].
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:6]([CH3:25])([C:17]([NH:19][C:20]1[S:21][CH:22]=[CH:23][N:24]=1)=[O:18])[CH2:5]2.[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH3:25][C:6]1([C:17]([NH:19][C:20]2[S:21][CH:22]=[CH:23][N:24]=2)=[O:18])[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([O:1][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:3]=2)[CH:7]1[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: OB(O)c1ccccc1
Reactant: CC1(C(=O)Nc2nccs2)Cc2cc(O)ccc2C1c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C(=O)Nc2nccs2)Cc2cc(Oc3ccccc3)ccc2C1c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of Example 36 (11.3 mg, 0.032 mmol), Cu(OAc)2 (8.9 mg, 1.5 eq), phenylboronic acid (11.3 mg, 2.9 mmol), triethylamine (22.6 μL, 5 eq) and powdered 4 Å molecular sieve (33.7 mg) in CH2Cl2 (2.5 mL) was stirred at room temperature for 16 h while open to the atmosphere. After filtration to remove the molecular sieve, the filtrate was concentrated and purified by reverse-phase HPLC (80-100% solvent B gradient) to give Example 155. (4.9 mg, 36%). MS Found: (M+H)+=427.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].Br[CH:17]1[CH2:21][CH2:20][O:19][CH2:18]1>C(#N)C>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH:17]1[CH2:21][CH2:20][O:19][CH2:18]1
Reactant: Oc1ccc(F)cc1Br
Reactant: BrC1CCOC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Fc1ccc(OC2CCOC2)c(Br)c1
Temperature: 85 °C
Yield: 143.7 %

Procedure:
To a solution of 2-bromo-4-fluorophenol (500 mg, 2.62 mmol) in acetonitrile (5 ml) was added potassium carbonate (1090 mg, 7.85 mmol) followed by 3-bromotetrahydrofuran (1000 mg, 6.62 mmol) and the resulting solution was heated to 85° C. in a Reacti-vial™ for 72 hours. The reaction mixture was cooled then the solvents removed in vacuo. tert-Butyl-dimethyl ether (20 ml) and sodium hydroxide (10% aqueous solution) (10 ml) were added and the layers were separated. The organic layer was washed with further sodium hydroxide (10% aqueous solution) (10 ml) then saturated brine solution (10 ml). The organic layer was then dried over anhydrous MgSO4 (s), filtered and evaporated in vacuo to afford crude title compound as a yellow oil (983 mg, >100%). Material was taken on without further purification.
Reaction SMILES: CO[C:3]([C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:24]=[CH:23][C:14]3[N:15]([CH3:22])[C:16](=[O:21])[C:17]([F:20])([F:19])[O:18][C:13]=3[CH:12]=2)[CH2:6]1)=[O:4].[NH3:25]>CO>[F:20][C:17]1([F:19])[C:16](=[O:21])[N:15]([CH3:22])[C:14]2[CH:23]=[CH:24][C:11]([N:7]3[CH2:6][C@H:5]([C:3]([NH2:25])=[O:4])[O:9][C:8]3=[O:10])=[CH:12][C:13]=2[O:18]1
Reactant: COC(=O)[C@H]1CN(c2ccc3c(c2)OC(F)(F)C(=O)N3C)C(=O)O1
Reactant: N
Solvent: CO
Product: CN1C(=O)C(F)(F)Oc2cc(N3C[C@H](C(N)=O)OC3=O)ccc21
Reaction time: 16 h
Yield: 44 %

Procedure:
To a stirred solution of (5R)-3-(2,2-difluoro-4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)-2-oxo-5-oxazolidinecarboxylic acid methyl ester (Step 3, 50 mg, 0.14 mmol) in MeOH (1 mL) is added 2M NH3 in MeOH (2 mL, 4 mmol). The resulting mixture is stirred for 16 h at which time the reaction is concentrated under reduced pressure and purified by silica gel chromatography (EtOAc) to give the title compound as a light yellow solid (21 mg, 44%), 1H NMR (300 MHz, DMSO) δ 7.86 (br s, 1H), 7.61 (d, 2H), 7.52-7.41 (m, 2H), 5.02 (dd, 1H), 4.28 (t, 1H), 4.02 (dd, 1H), 3.42 (s, 3H); MS for C13H11F2N3O5 m/z 328.5 (M+H)+.