Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14](F)=[CH:13][CH:12]=1.[H-].[Na+].[NH:22]1[CH:26]=[CH:25][N:24]=[CH:23]1>CN(C=O)C>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14]([N:22]2[CH:26]=[CH:25][N:24]=[CH:23]2)=[CH:13][CH:12]=1
Reactant: COC(=O)c1ccccc1C(=O)c1ccc(F)cc1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1C(=O)c1ccc(-n2ccnc2)cc1
Temperature: 120 °C

Procedure:
A solution of methyl-2-(4-fluorobenzoyl)benzoate (5.31 g, 21 mmol) in 23 mL of DMF is added dropwise to a solution of NaH (0.91 g, 23 mmol) and imidazole (1.43 g, 21 mmol) in 35 mL of DMF. The resulting mixture is heated at 120° C. for 20 hours under N2. After cooling, the product is poured onto ice and extracted with CHCl3 (4×30 mL). The combined extracts are dried (Na2SO4) and evaporated to give crude product. Chromatographic purification of the crude residue on silica gel (using EtOAc as the eluent) gives pure methyl-2-[4(1H-imidazol-1-yl)benzoyl]benzoate. M.P. 134.5°-136.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]([NH:14][C@@H:15]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[N:29]=[C:30]4[C:35]([CH3:36])=[CH:34][CH:33]=[CH:32][N:31]4[CH:37]=3)=[CH:24][CH:23]=2)[CH2:16][CH2:17][C:18]([OH:20])=O)=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].C([N:40](CC)CC)C.ClC(OCC)=O>C1COCC1>[NH2:40][C:18](=[O:20])[CH2:17][CH2:16][C@@H:15]([NH:14][C:12](=[O:13])[C:4]1[CH:5]=[CH:6][C:7]([O:8][CH:9]([CH3:10])[CH3:11])=[C:2]([Cl:1])[CH:3]=1)[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[N:29]=[C:30]3[C:35]([CH3:36])=[CH:34][CH:33]=[CH:32][N:31]3[CH:37]=2)=[CH:26][CH:27]=1
Reactant: CCN(CC)CC
Reactant: Cc1cccn2cc(-c3ccc(C[C@@H](CCC(=O)O)NC(=O)c4ccc(OC(C)C)c(Cl)c4)cc3)nc12
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Product: Cc1cccn2cc(-c3ccc(C[C@@H](CCC(N)=O)NC(=O)c4ccc(OC(C)C)c(Cl)c4)cc3)nc12
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 90 %

Procedure:
To a solution of (4R)-4-[({3-chloro-4-[(1-methylethyl)oxy]phenyl}carbonyl)amino]-5-[4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]pentanoic acid (900 mg, 1.73 mmol) in anhydrous THF (12.4 mL) at 0° C. under nitrogen was added triethylamine (242 uL, 1.73 mmol) followed by ethyl chloroformate (174 uL, 1.82 mmol). The reaction was stirred for 40 min at 0° C. and then the solids were filtered and washed with 5 mL THF. The filtrate was added to a flask containing NH4OH (5 mL) at room temperature and the reaction mixture was stirred for 1 hour. The product was extracted from the reaction mixture with EtOAc (50 mL). The aqueous layer was extracted with EtOAc (20 mL) and then acidified with 1N HCl solution (30 mL) and re-extracted with EtOAc (10 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo to give a white solid. Purification by recrystallization from hot isopropanol afforded the title compound as a white solid (90%). ESMS [M+H]+=519.4.
Reaction SMILES: [CH2:1]([N:3]([CH2:28][CH3:29])[CH2:4][CH2:5][N:6]([S:24]([CH3:27])(=[O:26])=[O:25])[C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:23])[CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:15][CH3:16])=[CH:9][CH:8]=1)[CH3:2].C(OCC)C.[C:35]1([Mg]Br)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[Cl-].[NH4+]>O>[CH2:28]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]([S:24]([CH3:27])(=[O:26])=[O:25])[C:7]1[CH:8]=[CH:9][C:10]([C:13]([OH:23])([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:15][CH3:16])=[CH:11][CH:12]=1)[CH3:29]
Reactant: CCC(C(=O)c1ccc(N(CCN(CC)CC)S(C)(=O)=O)cc1)c1ccccc1
Reactant: Br[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOCC
Product: CCC(c1ccccc1)C(O)(c1ccccc1)c1ccc(N(CCN(CC)CC)S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
N-(2-Diethylaminoethyl)-4'-(1-oxo-2-phenylbutyl)methanesulfonanilide (24.0 g., 0.0576 mole) is dissolved in 500 ml. ethyl ether and added dropwise during 1/2 hr. to a solution of phenylmagnesium bromide (0.145 mole) in 500 ml. ethyl ether. The mixture is heated at reflux for 16 hrs. After cooling to room temperature, 100 g. of ammonium chloride in 400 ml. water is added and the solution is stirred for 15 min. The ether layer is separated and the aqueous layer is extracted with ethyl ether and the combined ether solutions are washed with water followed by 1N HCl. The acidic aqueous wash is washed with ethyl ether and basified with 50% NaOH to pH 11. The product is extracted with ethyl ether and the ether solution is washed with water and dried (MgSO4). Evaporation of the ethyl ether yields 28 g. of product as an oil (100% yield).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:16][C:17]([F:20])([F:19])[F:18])[CH:10]([CH2:14][CH3:15])[C:11]([OH:13])=O)=[CH:5][C:4]=1C(F)(F)F)#[N:2].[NH3:25]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:16][C:17]([F:18])([F:19])[F:20])[CH:10]([CH2:14][CH3:15])[C:11]([NH2:25])=[O:13])=[CH:5][C:4]=1[C:17]([F:20])([F:19])[F:18])#[N:2]
Reactant: CCC(C(=O)O)N(CC(F)(F)F)c1ccc(C#N)c(C(F)(F)F)c1
Reactant: N
Product: CCC(C(N)=O)N(CC(F)(F)F)c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Synthesized as described in example 3 using 2-[[4-cyano-3-(trifluoromethyl)phenyl](2,2,2-trifluoroethyl)amino]butanoic acid and ammonia: 1H NMR (400 MHz, CDCl3) δ 7.60 (d, J=9.0 Hz, 1H), 7.17 (d, J=2.6 Hz, 1H), 7.03 (dd, J=9.0, 2.8 Hz, 1H), 6.38 (bs, 1H), 6.27 (bs, 1H), 4.25-4.04 (m, 3H), 2.15 (m, 1H), 1.91 (m, 1H), 0.99 (t, J=7.4 Hz, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].I[CH2:12][C:13]([NH2:15])=[O:14].C(=O)([O-])[O-].[K+].[K+]>>[C:13]([CH2:12][O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[O:14])[NH2:15]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: NC(=O)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Product: NC(=O)COc1ccc([N+](=O)[O-])cc1
Yield: 33.5 %

Procedure:
A mixture of 4-nitrophenol (2.8 g), iodoacetamide (3.72 g) and potassium carbonate (2.8 g) in DHF (50 ml) was reacted. The product so obtained was recrystallised from a mixture of ethyl acetate and hexane to give 4-(carbamoylmethoxy)nitrobenzene (1.32 g), m.p. 153°-156° C. The product so obtained was dissolved in ethyl acetate and hydrogenated in the presence of a 10% Pd/C catalyst. The product so obtained was recrystallised from a mixture of ethyl acetate and hexane to give 4-(carbamoylmethoxy)aniline (0.58 g), m.p. 125°-127° C.;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:22]([O-:24])=[O:23])[C:5]([OH:21])=[C:6]([CH:8](Cl)[C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([N+:16]([O-:18])=[O:17])[C:10]=2[OH:19])[CH:7]=1.[CH2:25]([OH:29])[CH:26]([CH3:28])[CH3:27].[H-].[Na+]>O>[CH2:25]([O:29][CH:8]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([N+:16]([O-:18])=[O:17])[C:10]=1[OH:19])[C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[C:4]([N+:22]([O-:24])=[O:23])[C:5]=1[OH:21])[CH:26]([CH3:28])[CH3:27]
Reactant: CC(C)CO
Reactant: O=[N+]([O-])c1cc(Cl)cc(C(Cl)c2cc(Cl)cc([N+](=O)[O-])c2O)c1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC(C)COC(c1cc(Cl)cc([N+](=O)[O-])c1O)c1cc(Cl)cc([N+](=O)[O-])c1O

Procedure:
A mixture of bis(5-chloro-2-hydroxy-3-nitrophenyl)methyl chloride (5 g) and isobutanol (50 ml) was stirred at a temperature of 0° C. and sodium hydride (1 g) was added portionwise. On completion of the addition the mixture was stirred for a further hour and poured into water. The aqueous solution was extracted into ether/petroleum ether and the solvents removed by distillation under reduced pressure. The residue was recrystallised from petroleum ether (b.p. 40°-60° C.) to give 4.3 g of bis(5-chloro-2-hydroxy-3-nitrophenyl)methyl isobutyl ether m.p. 95° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13](=[O:15])[CH3:14])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[N+:16]([C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:27]=1[NH:26][CH:25]=[C:24]2[CH:28]=O)([O-:18])=[O:17]>>[N+:16]([C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:27]=1[NH:26][CH:25]=[C:24]2/[CH:28]=[CH:14]/[C:13]([C:5]1[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:15])([O-:18])=[O:17]
Reactant: O=Cc1c[nH]c2c([N+](=O)[O-])cccc12
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Product: COc1cc(C(=O)/C=C/c2c[nH]c3c([N+](=O)[O-])cccc23)cc(OC)c1OC
Yield: 44.2 %

Procedure:
Substantially the same procedure as in Example 1 was repeated using 3',4',5'-trimethoxyacetophenone (630 mg) and 7-nitroindole-3-carboxaldehyde (552 mg) to give Compound 44 (491 mg).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)=[CH2:2].C(O)(=O)C.[C:17]1([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[C:17]1([N:23]2[CH2:28][CH2:27][N:26]([CH2:2][CH2:1][C:3]3[CH:12]=[CH:11][C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[N:4]=3)[CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C=Cc1ccc2ccccc2n1
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CC(=O)O
Solvent: CCO
Product: c1ccc(N2CCN(CCc3ccc4ccccc4n3)CC2)cc1
Temperature: 100 °C

Procedure:
To a mixture of 2-vinylquinoline (0.1 mole, 15g.) and glacial acetic acid (0.1 mole, 6 g.) in ethanol (95%, 100 ml.) N-phenylpiperazine (0.1 mole) was added and the solution was refluxed for 15 hrs. The solvent was removed and the remaining oil was heated in vacuo (1 mm. Hg) to 100°C. The oil left in the flask crystallized out on cooling and was recrystallized from ether-petroleum ether to give the titular product m.p. 79°C.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:13][CH2:14][NH:15][C:16]([C:18]1[CH:22]=[C:21]([C:23](=[O:32])[C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[F:31])[O:20][N:19]=1)=[O:17].C(=O)([O-])O.[Na+]>CO.O>[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:13][CH2:14][NH:15][C:16]([C:18]1[CH:22]=[C:21]([CH:23]([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[F:31])[OH:32])[O:20][N:19]=1)=[O:17]
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cc(C(=O)c2cc(F)ccc2F)on1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cc(C(O)c2cc(F)ccc2F)on1
Temperature: 25 °C
Reaction time: 4 h
Yield: 44.2 %

Procedure:
Sodium borohydride (0.02 g; 0.530 mmol) was added to a solution of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-(2,5-difluorobenzoyl)isoxazole-3-carboxamide (0.167 g; 0.388 mmol) in methanol (3 mL) and stirred at room temperature for 4 hours: as the reaction did not evolve anymore, some fresh sodium borohydride was added (0.02 g; 0.530 mmol) to the reaction and the resulting mixture was left stirring overnight. The mixture was diluted in a solution of sodium hydrogencarbonate saturated in water and extracted with ethyl acetate, dried and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.074 g (61%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-((2,5-difluorophenyl)(hydroxy)methyl)isoxazole-3-carboxamide as a white solid.
Reaction SMILES: [N:1]([CH:4]([C:9]1[C:14]2[N:15]3[CH2:21][CH2:20][CH2:19][N:18]([C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=4[Cl:29])[C:16]3=[N:17][C:13]=2[C:12]([Cl:30])=[CH:11][CH:10]=1)[C:5]([F:8])([F:7])[F:6])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[Cl:30][C:12]1[C:13]2[N:17]=[C:16]3[N:18]([C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=4[Cl:29])[CH2:19][CH2:20][CH2:21][N:15]3[C:14]=2[C:9]([CH:4]([NH2:1])[C:5]([F:6])([F:7])[F:8])=[CH:10][CH:11]=1
Reactant: [N-]=[N+]=NC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C(F)(F)F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C(F)(F)F
Yield: 104.5 %

Procedure:
A solution of 6-(1-Azido-2,2,2-trifluoroethyl)-9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole (68.2 mg, 0.143 mmol) and triphenylphosphine (56.3 mg, 0.215 mmol) in tetrahydrofuran (5.0 mL) and water (0.10 mL) was stirred at 60° C. for 20 hr. The reaction mixture was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel eluting with a 30-100% ethyl acetate/n-hexane gradient mixture to give 1-[9-Chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]-2,2,2-trifluoroethanamine as a white solid (67.2 mg). To a solution of 1-[9-Chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]-2,2,2-trifluoroethanamine (67.9 mg) and pyridine (0.12 mL, 1.48 mmol) in tetrahydrofuran (5.0 mL) was added acetyl chloride (0.051 mL, 0.717 mmol) at 0° C. The mixture was stirred at 0° C. for 1 hr. Aqueous sodium hydrogen carbonate was added to the reaction mixture at room temperature and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 25-80% ethyl acetate/n-hexane gradient mixture to give the title compound (33.1 mg, 0.067 mmol, 47%) as white crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[CH2:21]([N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC1(C)OB(c2cnn(Cc3ccccc3)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.25 g 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was dissolved in 5 mL of DMF and 0.63 g cesium carbonate was added. To this suspension was added 0.17 mL of benzyl bromide and the reaction was stirred overnight at room temperature. The reaction was allowed to settle and the DMF was decanted into a flask. The remaining residue was washed and decanted twice with ethyl acetate and these washes were added to the flask with the DMF. Water was added to the ethyl acetate and DMF and the organic layer removed. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over MgSO4 and concentrated to give 0.28 g of 1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole which was used without further purification.
Reaction SMILES: [N:1]([CH2:4][C:5]([NH:7][CH:8]([CH2:13][S:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22]C2CCCCO2)[CH:17]=1)[C:9]([O:11][CH3:12])=[O:10])=[O:6])=[N+:2]=[N-:3]>Cl.CO>[N:1]([CH2:4][C:5]([NH:7][CH:8]([CH2:13][S:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=1)[C:9]([O:11][CH3:12])=[O:10])=[O:6])=[N+:2]=[N-:3]
Reactant: COC(=O)C(CSCc1cccc(OC2CCCCO2)c1)NC(=O)CN=[N+]=[N-]
Agent: Cl
Solvent: CO
Product: COC(=O)C(CSCc1cccc(O)c1)NC(=O)CN=[N+]=[N-]
Reaction time: 0.5 h
Yield: 100.7 %

Procedure:
Few drops of cone. HCl (5 drops) were added to the 44 (0.25 g) in methanol and stirred for 30 min until no starting material was seen by LCMS. After evaporation of methanol, brine was added to the reaction mixture and extracted with ethyl acetate, dried over MgSO4, concentrated and chromatographed (Hexanes/EtOAc) then 5% methanol/methylene chloride) to obtain the 0.2 g of 45 as colorless oil in quantitative yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9](O)([CH3:12])([CH3:11])[CH3:10].S(=O)(=O)(O)O>C(Cl)Cl>[C:9]([C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[OH:8])([CH3:12])([CH3:11])[CH3:10]
Reactant: Oc1ccc(F)cc1
Reactant: CC(C)(C)O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CC(C)(C)c1cc(F)ccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.2 %

Procedure:
4-Fluorophenol (5 g, 45 mmol) and tert-butanol (5.9 mL, 63 mmol) were dissolved in CH2Cl2 (80 mL) and treated with concentrated sulfuric acid (98%, 3 mL). The mixture was stirred at room temperature overnight. The organic layer was washed with water, neutralized with NaHCO3, dried over MgSO4 and concentrated. The residue was purified by column chromatography (5-15% EtOAc-Hexane) to give 2-tert-butyl-4-fluorophenol (3.12 g, 42%). 1H NMR (400 MHz, DMSO-d6) δ 9.32 (s, 1H), 6.89 (dd, J=11.1, 3.1 Hz, 1H), 6.84-6.79 (m, 1H), 6.74 (dd, J=8.7, 5.3 Hz, 1H), 1.33 (s, 9H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].[NH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>C1COCC1>[N:20]1([CH2:19][CH2:18][NH:17][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: NCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccccc1NCCN1CCOCC1
Temperature: 25 °C
Reaction time: 25 h
Yield: 96.3 %

Procedure:
To a mixture of 1-fluoro-2-nitrobenzene (6 g, 43.0 mmol) and potassium carbonate (12 g, 86 mmol) in THF (80 mL) was added 4-(2-aminoethyl)morpholine (6.8 mL, 52.0 mmol) at 0° C. The mixture was stirred for 25 h at rt. Then the mixture was filtered through a pad of Celite and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (2/1) to afford 10.4 g (97%) of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12](/[CH:16]=[CH:17]/[C:18]#[N:19])=[CH:11][C:10]=2[CH3:20])[CH:5]=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.N>C(O)(C)C>[CH3:20][C:10]1[CH:11]=[C:12](/[CH:16]=[CH:17]/[C:18]#[N:19])[CH:13]=[C:14]([CH3:15])[C:9]=1[NH:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([C:26]#[N:27])=[CH:28][CH:29]=2)[N:7]=1
Reactant: Cc1cc(/C=C/C#N)cc(C)c1Nc1ccnc(Cl)n1
Reactant: N#Cc1ccc(N)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N
Solvent: CC(C)O
Product: Cc1cc(/C=C/C#N)cc(C)c1Nc1ccnc(Nc2ccc(C#N)cc2)n1
Temperature: 82.5 °C
Reaction time: 4 h
Yield: 77.7 %

Procedure:
To a mixture of (E)-3-(4-(2-chloropyrimidin-4-ylamino)-3,5-dimethylphenyl)acrylonitrile (40 gm), 4-aminobenzonitrile (17 gm), isopropanol (400 ml) and p-toluenesulfonic acid (20 ml) were added at room temperature. The reaction mixture was then heated to 80 to 85° C. and stirred for 4 hours. The reaction mass was then cooled to 0° C. and pH was adjusted to 10 to 11 with aqueous ammonia solution. The separated solid was filtered and then dried to provide 40 gm of rilpivirine.
Reaction SMILES: [CH3:1][N:2]1[C:6](B(O)O)=[CH:5][CH:4]=[N:3]1.Br[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[CH3:1][N:2]1[C:6]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=2)=[CH:5][CH:4]=[N:3]1
Reactant: FC(F)(F)c1ccc(Br)nc1
Reactant: Cn1nccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cn1nccc1-c1ccc(C(F)(F)F)cn1
Temperature: 25 °C

Procedure:
(1-Methyl-1H-pyrazol-5-yl)boronic acid (C1) (1.00 g, 7.94 mmol), 2-bromo-5-(trifluoromethyl)pyridine (1.79 g, 7.92 mmol), dichlorobis(triphenylphosphine)palladium(II) (279 mg, 0.397 mmol), and sodium carbonate (3.37 g, 31.8 mmol) were combined in 1,2-dimethoxyethane (30 mL) and water (3 mL), and the reaction mixture was heated at reflux for 18 hours. After the reaction had cooled to room temperature, it was concentrated in vacuo, diluted with additional water, and extracted with ethyl acetate (2×300 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification via silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane) provided the product. Yield: 630 mg, 2.77 mmol, 35%. 1H NMR (400 MHz, CD3OD) δ 3.95 (s, 3H), 6.60 (d, J=2.2 Hz, 1H), 7.58 (d, J=2.0 Hz, 1H), 7.94 (br d, J=8.2 Hz, 1H), 8.19-8.23 (m, 1H), 8.89 (br d, J=2 Hz, 1H).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:23][C:24]3[C:29]([CH3:30])=[CH:28][C:27]([OH:31])=[CH:26][C:25]=3[CH3:32])[C:20](O)=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:33]([O:35][CH:36]([O:51][CH2:52][CH3:53])[C@@H:37]([NH:39][CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[C:45]2[C:50]=1[N:49]=[CH:48][CH:47]=[CH:46]2)[CH3:38])[CH3:34].[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>ClCCl.C(OCC)(=O)C>[CH2:33]([O:35][CH:36]([O:51][CH2:52][CH3:53])[C@@H:37]([N:39]([CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[C:45]2[C:50]=1[N:49]=[CH:48][CH:47]=[CH:46]2)[C:20](=[O:21])[C@@H:19]([NH:18][C:16](=[O:17])[O:15][CH2:14][CH:12]1[C:13]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:23][C:24]1[C:29]([CH3:30])=[CH:28][C:27]([OH:31])=[CH:26][C:25]=1[CH3:32])[CH3:38])[CH3:34]
Reactant: Cc1cc(O)cc(C)c1C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: CCOC(OCC)[C@H](C)NCc1cccc2cccnc12
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@H](Cc1c(C)cc(O)cc1C)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 55.2 %

Procedure:
To a solution of (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-hydroxy-2,6-dimethylphenyl)propanoic acid (907 mg, 2.1 mmol) and (S)-1,1-diethoxy-N-(quinolin-8-ylmethyl)propan-2-amine (Compound IX-7)(577 mg, 2.0 mmol) in dichloromethane (10 ml) was added 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (660 mg, 2.1 mmol) and the mixture was stirred at room temperature for 5 hr. The reaction mixture was diluted with ethyl acetate (50 ml) and washed with saturated sodium bicarbonate (50 ml), water (50 ml) and brine (50 ml). The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate=1:1) to obtain the title compound (775 mg, 55%).
Reaction SMILES: Cl[C:2]1[C:11]2[CH:10]=[C:9]3[N:12]=[CH:13][N:14]=[C:8]3[CH2:7][C:6]=2[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[Br:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21].Cl.N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(OCCO)C>[Br:17][C:18]1[CH:19]=[C:20]([NH:21][C:2]2[C:11]3[CH:10]=[C:9]4[N:12]=[CH:13][N:14]=[C:8]4[CH2:7][C:6]=3[N:5]=[CH:4][C:3]=2[C:15]#[N:16])[CH:22]=[CH:23][CH:24]=1
Reactant: N#Cc1cnc2c(c1Cl)C=C1N=CN=C1C2
Reactant: Nc1cccc(Br)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOCCO
Product: N#Cc1cnc2c(c1Nc1cccc(Br)c1)C=C1N=CN=C1C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.1 %

Procedure:
A mixture of 0.2 g (0.87 mmol) of 8-chloroimidazo[4,5-g]quinoline-7-carbonitrile, 0.12 mL (1.1 mmol) of 3-bromoaniline, and 0.1 g (0.87 mmol) of pyridine hydrochloride in 5.0 mL of 2-ethoxyethanol is heated at reflux temperature for 45 minutes, then cooled to room temperature. The product mixture is poured into a saturated solution of sodium bicarbonate and stirred for 0.5 hour. The solid is collected by filtration, washed with water and dried. The solid is purified by silica gel chromatography, utilizing a gradient of methylene chloride/methanol(98:2 to 93:7) to yield 0.20 g of 8-(3-bromo-phenylamino)imidazo[4,5-g]quinoline-7-carbonitrile as pink solid, mp 286-288° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[N:6][C:7]=1Cl.C(O)CCC.C(N(CC)CC)C.[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[NH2:1][C:2]1[C:7]([NH:29][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:6][CH:5]=[N:4][C:3]=1[Cl:9]
Reactant: Nc1c(Cl)ncnc1Cl
Reactant: NCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: Nc1c(Cl)ncnc1NCc1ccccc1
Temperature: 100 °C
Yield: 96.1 %

Procedure:
To a solution of 5-amino-4,6-dichloropyrimidine (8.4 g, 0.051 mol) in 1-butanol (50.0 mL, 0.547 mol) was added triethylamine (12 mL, 0.084 mol) and benzylamine (17 mL, 0.15 mol), and the mixture was heated at 100° C. for 3 hours. The reaction was cooled at 0 C, filtered and washed with ethanol. The residue was dissolved in CH2Cl2 and washed with saturated aqueous NaHCO3, and concentrated. The residue was triturated in diethyl ether to obtain 11.5 g (96%) of a light brown solid.