Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:22]=2[NH:21][C:20]([CH3:23])=[C:19]3[S:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:27]1([S:24]([C:19]2[C:18]3[C:22](=[C:14]([N:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[CH:15]=[CH:16][CH:17]=3)[NH:21][C:20]=2[CH3:23])(=[O:25])=[O:26])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: Cc1[nH]c2c(N3CCN(C(=O)OC(C)(C)C)CC3)cccc2c1S(=O)(=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1[nH]c2c(N3CCNCC3)cccc2c1S(=O)(=O)c1ccccc1
Yield: 17.9 %

Procedure:
4-(3-Benzenesulfonyl-2-methyl-1H-indol-7-yl)-piperazine-1-carboxylic acid tert-butyl ester (0.25 g) was dissolved in 2 mL of dichloromethane and 2 mL of trifluoroacetic acid was added. After 10 min the mixture was concentrated in vacuo, taken into water, and washed with ether. The aqueous layer was basified with ammonium hydroxide, extracted with dichloromethane, and the extract was dried (sodium sulfate) and evaporated to afford the crude free base which was crystallized from dichloromethane-ether to afford 35 mg of 3-benzenesulfonyl-2-methyl-7-piperazin-1-yl-1H-indole (601), m.p. 188-190° C.
Reaction SMILES: [O:1]=[S:2]1(=[O:38])[CH2:6][CH2:5][CH:4]=[C:3]1[C:7]1[CH:37]=[CH:36][C:10]2[NH:11][C:12]([C:17]3[C:22](=[O:23])[N:21]([CH2:24][C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[N:20]4[CH:32]=[CH:33][CH:34]=[C:19]4[C:18]=3[OH:35])=[N:13][S:14](=[O:16])(=[O:15])[C:9]=2[CH:8]=1.[H][H].C(OCC)C>CN(C)C=O.[Pd]>[O:38]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]1[CH:37]=[CH:36][C:10]2[NH:11][C:12]([C:17]3[C:22](=[O:23])[N:21]([CH2:24][C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[N:20]4[CH:32]=[CH:33][CH:34]=[C:19]4[C:18]=3[OH:35])=[N:13][S:14](=[O:16])(=[O:15])[C:9]=2[CH:8]=1
Reactant: O=c1c(C2=NS(=O)(=O)c3cc(C4=CCCS4(=O)=O)ccc3N2)c(O)c2cccn2n1Cc1ccc(F)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=c1c(C2=NS(=O)(=O)c3cc(C4CCCS4(=O)=O)ccc3N2)c(O)c2cccn2n1Cc1ccc(F)cc1
Reaction time: 1 h
Yield: 27.8 %

Procedure:
3-[7-(1,1-Dioxo-4,5-dihydro-1H-1λ6-thiophen-2-yl)-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl]-1-(4-fluoro-benzyl)-4-hydroxy-pyrrolo[1,2-b]pyridazin-2-one (Example 11b, 0.100 g, 0.180 mmol) was dissolved in N,N-dimethylformamide (15 mL) at 25° C. Palladium on carbon (5%, 0.250 g) was added and the atmosphere in the reaction flask replaced with hydrogen from a balloon. After stirring for 1 h under a hydrogen balloon, the mixture was filtered through Celite. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm, 0→3% methanol in dichloromethane) to afford a yellow solid. Trituration of this material with diethyl ether afforded the desired product, 3-[7-(1,1-dioxo-tetrahydro-1λ6-thiophen-2-yl)-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl]-1-(4-fluoro-benzyl)-4-hydroxy-pyrrolo[1,2-b]pyridazin-2-one (0.028 g, 0.050 mmol, 28% yield). 1H NMR (400 MHz, DMSO-d6) δ: 2.08-2.18 (1H, m), 2.23-2.29 (1H, m), 2.32-2.43 (1H, m), 3.20-3.28 (1H, m), 3.31-3.37 (1H, m), 4.56-4.61 (1H, m), 5.65 (2H, s), 6.60 (2H, d, J=7.0 Hz), 6.59-6.61 (1H, m), 7.02-7.03 (1H, m), 7.14-7.18 (2H, m), 7.42-7.46 (1H, m), 7.67-7.75 (2H, m), 7.87 (1H, bs), 13.73 (1H, s). LC-MS (ESI) calcd for C25H21FN4O6S2 556.09, found 557.15 [M+H+].
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)[N:3]=1.[Cl:22][C:23]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:24]=1[NH2:25].Cl.[OH-].[Na+]>O.C(O)C>[Cl:22][C:23]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:24]=1[NH:25][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)[N:3]=1
Reactant: COc1ccc(Cl)c(N)c1
Reactant: FC(F)(F)c1ccc(-c2nc(Cl)cc(C(F)(F)F)n2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(Cl)c(Nc2cc(C(F)(F)F)nc(-c3ccc(C(F)(F)F)nc3)n2)c1
Yield: 4.4 %

Procedure:
A mixture of crude 4-chloro-2-[6-(trifluoromethyl)-3-pyridinyl]-6-(trifluoromethyl)pyrimidine (50 mg, 0.152 mmol), 2-chloro-5-methoxyaniline (50 mg, 0.229 mmol) and 2N HCl (150 μl) in water:ethanol (2:1, 10 ml) was refluxed for 120 h. The mixture was cooled to room temperature and basified with aqueous 2N NaOH to pH 10-12. The mixture was extracted with ethyl acetate (75 ml), washed with water (2×20 ml), with aqueous saturated NaCl (1×20 ml) and dried over anhydrous sodium sulfate. The ethyl acetate solution was rotary evaporated to dryness and the residue was purified by preparative TLC to give a white solid (3 mg, 4%). 1H NMR (CDCl3): 9.72 (s, 1H), 8.90 (dd, J=3.0, 7.8 Hz, 1H), 7.81 (d, J=8.1 Hz, 1H), 7.75 (s, 1H), 7.40 (d, J=9.3 Hz, 1H), 7.36 (s, 1H), 6.99 (s, 1H), 6.75 (dd, J=3.0, 8.7 Hz, 1H), 3.86 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[CH:12]=[CH:11][NH:10][C:7]2=[N:8][CH:9]=1)([O-:3])=[O:2].C(N(CC)CC)C.[C:20]1([S:26](Cl)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C1C=CN=CC=1.ClCCl.CN(C)C=O>[C:20]1([S:26]([N:10]2[C:7]3=[N:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[C:6]3[CH:12]=[CH:11]2)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=[N+]([O-])c1cnc2[nH]ccc2c1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 75.1 %

Procedure:
To a mixture of 5-nitro-1H-pyrrolo[2,3-b]pyridine (2.0 g, 12.3 mmol), triethylamine (2.48 g, 24.6 mmol), 4-dimethylaminopyridine (0.15 g, 1.23 mmol) in dichloromethane/N,N-dimethylformamide (1:1, 60 mL) was added benzenesulfonyl chloride (3.25 g, 18.4 mmol) at 0° C. After stirring for 48 h at room temperature, the reaction was quenched with water (50 mL) and extracted with dichloromethane (2×120 mL). The organic layer was washed with a saturated sodium bicarbonate (2×30 mL), water (2×30 mL), brine (50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel from QingDao, 200-300 mesh, 33% dichloromethane/hexanes) to afford 1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridine (2.8 g, 76%) as a yellow solid: LC/MS m/e calcd for C13H9N3O4S [M+H]+ 304.30, observed 303.9.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[C:5](I)=[CH:4][N:3]=1.[C:14]([C:16]1[CH:17]=[N:18][N:19]([CH2:21][C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[CH:20]=1)#[CH:15].C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[Br:1][C:2]1[N:3]=[CH:4][C:5]2[CH:15]=[C:14]([C:16]3[CH:17]=[N:18][N:19]([CH2:21][C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[CH:20]=3)[N:8]([S:9]([CH3:12])(=[O:11])=[O:10])[C:6]=2[CH:7]=1
Reactant: C#Cc1cnn(CC(=O)N(C)C)c1
Reactant: CS(=O)(=O)Nc1cc(Br)ncc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)C(=O)Cn1cc(-c2cc3cnc(Br)cc3n2S(C)(=O)=O)cn1
Temperature: 60 °C
Yield: 41.4 %

Procedure:
Bis(triphenylphosphine)palladiumdichloride (69 mg, 0.099 mmol) was added to a solution of N-(2-bromo-5-iodopyridin-4-yl)methanesulfonamide (Preparation 8, 0.5 g, 1.98 mmol), 2-(4-ethynyl-1H-pyrazol-1-yl)-N,N-dimethylacetamide (Preparation 101, 0.3 g, 1.7 mmol), triethylamine (1.05 g, 1.05 mmol) and copper iodide (19.5 mg, 0.098 mmol) in DMF (5 ml). The reaction mixture was heated for 1 hour at 60° C. The reaction was cooled to room temperature and diluted with ethyl acetate. The organic solution was washed with water, brine and dried over sodium sulphate. The solvent was removed in vacuum and the crude product purified on silica gel column chromatography eluting with a gradient of 10 to 20% methanol in ethyl acetate to afford the title compound as a white powder (0.3 g, 88%). 1H-NMR (500 MHz, d6-DMSO): δ 2.86 (s, 3H), 3.04 (s, 1H), 3.42 (s, 3H), 5.2 (s, 2H), 6.96 (s, 1H), 7.76 (s, 1H), 8.05 (s, 2H), 8.72 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:8]1=[O:14])=[O:5].[CH:20](OC)(OC)OC.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C(#N)C>[Br:19][C:16]1[CH:15]=[C:3]2[C:2](=[CH:18][CH:17]=1)[N:1]=[CH:20][N:6]([CH:7]1[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:8]1=[O:14])[C:4]2=[O:5]
Reactant: Nc1ccc(Br)cc1C(=O)NC1CCC(=O)NC1=O
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: O
Product: O=C1CCC(n2cnc3ccc(Br)cc3c2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
A solution of 2-amino-N-(2,6-dioxo-piperidin-3-yl)-5-bromo-benzamide (0.51 g, 1.5 mmol) and trimethyl orthoformate (2 mL) and p-toluene sulfonic acid (150 mg) in acetonitrile (10 mL) was heated to reflux for 12 hours. To the mixture, was added water (70 mL), and stirred at room temperature for 2 hours. The suspension was filtered and washed with ethyl acetate (10 mL). The solid in NMP (3 mL) was heated at 80° C. To the solution, was added water (1.5 mL), and the mixture was allowed to cool to room temperature. The suspension was filtered and washed with NMP (1 mL) and ethyl acetate (10 mL) to give 3-(6-bromo-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as a white solid (350 mg, 68% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 30/70 CH3CN/0.1% H2PO4, 4.18 min (99.9%); mp: 312-314° C.; 1H NMR (DMSO-d6) δ 2.14-2.21 (m, 1H, CHH), 2.60-2.74 (m, 2H, 2CHH), 2.83-2.93 (m, 1H, CHH), 5.51 (brs, 1H, NCH), 7.68 (d, J=9 Hz, 1H, Ar), 8.03 (dd, J=2, 9 Hz, 1H, Ar), 8.24 (d, J=2 Hz, 1H, Ar), 8.42 (5, 1H, CH), 11.19 (s, 1H, NH); NMR (DMSO-d6) δ 22.45, 30.93, 55.49, 119.83, 122.96, 128.23, 129.65, 137.61, 146.52, 147.94, 158.66, 169.75, 172.46; LCMS: MH=336, 338; Anal Calcd for C13H10N3O1Br+0.3H2O: C, 45.72; H, 3.13; N, 12.30; Br, 23.39. Found: C, 45.46; H, 2.75; N, 12.15; Br, 22.81.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:10])[CH2:4]/[CH:5]=[CH:6]/[C:7](O)=[O:8].C(Cl)(C(Cl)=O)=O.NC1[N:26]=[CH:25][N:24]=[C:23]2C=1[N:20]([C:36]1[CH:41]=[CH:40][C:39]([O:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[CH:38][CH:37]=1)[C:21](=[O:35])[N:22]2[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([NH:33][CH3:34])[CH:28]=1.[C:49](#[N:51])[CH3:50]>CN(C=O)C.C(Cl)Cl>[NH2:51][C:49]1[N:26]=[CH:25][N:24]=[C:23]2[C:50]=1[N:20]([C:36]1[CH:41]=[CH:40][C:39]([O:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[CH:38][CH:37]=1)[C:21](=[O:35])[N:22]2[C:27]1[CH:28]=[C:29]([N:33]([CH3:34])[C:7](=[O:8])/[CH:6]=[CH:5]/[CH2:4][N:3]([CH3:10])[CH3:2])[CH:30]=[CH:31][CH:32]=1
Reactant: CN(C)C/C=C/C(=O)O
Reactant: CC#N
Reactant: CNc1cccc(-n2c(=O)n(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)c1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(C)C/C=C/C(=O)N(C)c1cccc(-n2c(=O)n(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
To a suspension of (E)-4-(dimethylamino)but-2-enoic acid hydrochloride salt (95 mg, 0.57 mmol) in acetonitrile (5 mL) was added 1 drop of DMF before introducing (COCl)2 (0.25 mL, 2.86 mmol). Resulting mixture was stirred at room temperature for 2 hours. Concentrated and dissolved in DCM (2 mL) before introduced to the solution of 6-amino-9-(3-(methylamino)phenyl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one (32) (100 mg, 0.24 mmol) in DCM (2 mL). Resulting solution was stirred at room temperature for 2 hours before quenched the reaction with MeOH (2 mL). Solvent was removed and the residue was pre-purified by column chromatography (silica gel, 0 to 10% methanol in methylene chloride (1% Et3N)) followed by preparative HPLC (RP, C18, 10 to 95% acetonitrile in water (0.2% NH3)) to give (E)-N-(3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)phenyl)-4-(dimethylamino)-N-methylbut-2-enamide (33) (60 mg, 47%) as white solid. LC-MS (ESI): m/z (M+1) 536. 1H NMR (400 MHz, DMSO) δ 8.11 (s, 1H), 7.72-7.56 (m, 3H), 7.51-7.33 (m, 5H), 7.23-7.09 (m, 5H), 6.65 (dt, J=15.2, 6.1 Hz, 1H), 6.04 (d, J=16.6 Hz, 1H), 5.90 (br, 2H), 3.27 (s, 3H), 2.99 (s, 2H), 2.10 (s, 6H).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C1COCC1.[C:12]([C@H:15]1[CH2:19][CH2:18][CH2:17][N:16]1[C:20]1[N:28]=[C:27]2[C:23]([N:24]=[CH:25][N:26]2[CH2:29][CH3:30])=[C:22]([NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=2)[N:21]=1)(=O)[NH2:13]>O>[NH2:13][CH2:12][C@H:15]1[CH2:19][CH2:18][CH2:17][N:16]1[C:20]1[N:28]=[C:27]2[C:23]([N:24]=[CH:25][N:26]2[CH2:29][CH3:30])=[C:22]([NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=2)[N:21]=1
Reactant: CCn1cnc2c(Nc3cccc(Cl)c3)nc(N3CCC[C@@H]3C(N)=O)nc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCn1cnc2c(Nc3cccc(Cl)c3)nc(N3CCC[C@@H]3CN)nc21
Temperature: 0 °C

Procedure:
A suspension of 56 mg (1.47 mmol) of LiAlH4 in 2 ml of abs. THF is added to a suspension of 150 mg of 2-[(R)-(−)-2-carbamoyl-pyrrolidin-1-yl]-6-(3-chloro-phenyl-amino)-9-ethyl-9H-purine (cf. Example 45) in 10 ml of abs. THF and the mixture is stirred at 80° C. for 22 h. After further addition of 56 mg of LiAlH4, the mixture is allowed to react further for 18 h. 5 ml of WATER are then added dropwise, with ice/water cooling, and the reaction mixture is then poured onto 50 ml of ice/water. The mixture is extracted three times with ethyl acetate. The combined organic extracts are washed twice with water and once with saturated sodium chloride solution and dried over magnesium sulfate. After filtration, the filtrate is concentrated under reduced pressure. The resulting crude product (oil) is purified by means of column chromatography and digestion in diisopropyl ether. 2-[(R)-2-Aminomethyl-pyrrolidin-1-yl]-6-(3-chloro-phenyl-amino)-9-ethyl-9H-purine is obtained; m.p. 126–129° C.; FAB-MS: (M+H)+=372, HPLC: tret (grad20/2)=11.09 minutes.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:17]=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=3)[CH:10]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:30](Cl)(=[O:33])[CH:31]=[CH2:32]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:17]=[C:18]([NH:22][C:30](=[O:33])[CH:31]=[CH2:32])[CH:19]=[CH:20][CH:21]=3)[CH:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C=CC(=O)Cl
Reactant: Nc1cccc(Nc2cc(Nc3cccc(Br)c3)ncn2)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CC(=O)Nc1cccc(Nc2cc(Nc3cccc(Br)c3)ncn2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
A solution of 3-[6-(3-bromophenylamino)-pyrimidin-4-ylamino]phenylamine (250 mg, 0.7 mmol) and triethylamine (180 mg, 1.75 mmol) in 5 mL of THF was stirred at RT. Acryloyl chloride (80 mg, 0.9 mmol) was added into the reaction mixture and it was stirred at RT for 1 h. The solvent was removed by vacuum evaporation and the crude product was purified by flash chromatography on silica gel with EtOAc/DCM solvent system to afford 115 mg (40% yield) of the title compound as a light colored solid. MS (m/z): MH+=410, 412. 1H NMR (DMSO): 10.15 (s, 1H), 9.36 (s, 1H), 9.28 (s, 1H), 8.34 (s, 1H), 8.02 (s, 1H), 8.00 (s, 1H), 7.51-7.11 (m, 5H), 6.47 (dd, 1H, J1=10.1 Hz, J2=17.0 Hz), 6.27 (dd, 1H, J1=1.9 Hz, J2=17.0 Hz), 6.20 (s, 1H), 5.76 (dd, 1H, J1=10.1 Hz, J2=1.9 Hz) ppm.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=2)[N:5]=[C:4]([O:17][C:18]2[C:25]([CH3:26])=[CH:24][C:21]([C:22]#[N:23])=[CH:20][C:19]=2[CH3:27])[CH:3]=1.[Br:28]Br.[OH-].[Na+].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>ClCCl.O>[CH3:27][C:19]1[CH:20]=[C:21]([C:22]#[N:23])[CH:24]=[C:25]([CH3:26])[C:18]=1[O:17][C:4]1[N:5]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=2)[N:7]=[C:2]([NH2:1])[C:3]=1[Br:28]
Reactant: Cc1cc(C#N)cc(C)c1Oc1cc(N)nc(Nc2ccc(C#N)cc2)n1
Reactant: BrBr
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: Cc1cc(C#N)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc(N)c1Br
Temperature: 2.5 °C
Reaction time: 4 h

Procedure:
4-[[6-amino-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]-3,5-dimethyl-benzonitrile (10 gm) was dissolved in dichloromethane (100 ml) at 0 to 5° C. and then added bromine solution (4.7 gm in 50 ml of dichloromethane). The reaction mass was stirred for 4 hours at 0 to 5° C. and then added water (100 ml). The pH of the reaction mass was adjusted to 9 to 10 with sodium hydroxide solution (4N, 10 ml). Sodium metabisulphite solution (0.5 gm in 2 ml of water) was added to the reaction mass and pH of the reaction mass was maintained between 7.5 to 8.5 with sodium hydroxide solution (4N, 10 ml). The separated solid was filtered and dried at 50 to 55° C. to obtain crude etravirine.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH2:17]([O:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[C:27]([O:33][CH2:34][O:35][CH3:36])[CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>O1CCCC1>[CH2:17]([O:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:27]([O:33][CH2:34][O:35][CH3:36])[CH:26]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COCOc1cc(OCc2ccccc2)ccc1C=O
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C=Cc1ccc(OCc2ccccc2)cc1OCOC
Yield: 99.3 %

Procedure:
To a suspension of 55% sodium hydride dispersion in mineral oil (1.57 g, 36.0 mmol) in tetrahydrofuran (100 ml) was added ethyl diethylphosphonoacetate (7.17 g, 32.0 mmol) at 0° C. with stirring, and the resulting mixture was stirred for 30 minutes at 0° C. under a nitrogen atmosphere. Subsequently, a solution of 4-benzyloxy-2-methoxymethoxy-benzaldehyde (7.46 g, 27.4 mmol) obtained in step (b) of Example 197 in tetrahydrofuran was added at 0° C. with stirring, and the resulting mixture was stirred for 2 hours at 0° C. under a nitrogen atmosphere. After stirring, water (200 ml) was added, and the resulting mixture was extracted with ethyl acetate (200 ml×2). The organic layer was washed successively with water (100 ml×1) and saturated aqueous sodium chloride solution (100 ml×1), dried-over anhydrous sodium sulfate, filtered, and evaporated in vacuo to afford the crude product. The crude product was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (5:1-1:1) as the eluent to afford the title compound (9.32 g, yield: 99%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=2)[N:3]=1.[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>ClCCl.O1CCCC1>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH:14]3[CH2:15][CH2:16][CH2:17][CH2:18][O:13]3)[CH:8]=2)[N:3]=1
Reactant: Oc1ccc2nc(Cl)ccc2c1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Clc1ccc2cc(OC3CCCCO3)ccc2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Chloroquinolin-6-ol (36 g, 0.20 mol) was dissolved in dichloromethane (500 ml) and tetrahydrofuran (500 ml). 3,4-dihydro-2H-pyran (74 ml, 0.81 mol) and p-toluenesulfonic acid (0.49 g, 0.005 mol) were added to the mixture in ice cooling water bath, followed by stirring at room temperature overnight. A 10% sodium hydroxide aqueous solution was added to the reaction mixture, followed by extraction with dichloromethane. The result was dried over potassium carbonate and subjected to filtration, and then the filtrate was concentrated under reduced pressure. The crude crystal thus obtained was recrystallized from ethanol to afford the title compound as a colorless granular compound (47 g, yield 89%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[Cl:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)=[CH:20][CH:19]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Product: O=c1[nH]c2nccc(Nc3ccc(Cl)cc3)c2c2ccccc12
Yield: 98.3 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 188 using Compound 83 (100 mg, 0.43 mmol) and 4-chloroaniline (83 mg, 0.65 mmol) to provide 192 (136 mg, 97% yield) as a white solid. LC-MS (M+H=322, obsd.=322).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH3:20])[C:5]2[NH:6][C:7](=[O:19])[C:8]3[CH:18]=[CH:17][CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.[NH:21]1[CH2:25][CH2:24][CH2:23][C@@H:22]1[CH2:26][OH:27]>>[CH2:13]([N:10]1[C:9]2[N:15]=[CH:16][CH:17]=[CH:18][C:8]=2[C:7](=[O:19])[NH:6][C:5]2[C:4]([CH3:20])=[CH:3][C:2]([N:21]3[CH2:25][CH2:24][CH2:23][C@@H:22]3[CH2:26][OH:27])=[N:12][C:11]1=2)[CH3:14]
Reactant: OC[C@H]1CCCN1
Reactant: CCN1c2ncccc2C(=O)Nc2c(C)cc(Cl)nc21
Product: CCN1c2ncccc2C(=O)Nc2c(C)cc(N3CCC[C@@H]3CO)nc21

Procedure:
The title compound, m.p. 239°-242° C., was synthesized from 2-chloro-5,11-dihydro-11-ethyl-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one and (R)-(-)-2-pyrrolidinemethanol using procedures analogous to those described above, except that the mixture was heated in a pressure bottle at 160°-170° C. for 2 hrs, and the product was crystallized from chloroform/hexane.
Reaction SMILES: [CH3:1][N:2]1[C@@H:12]2[CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[C:16]4[O:21][C@H:6]5[C:7]([CH:9]=[CH:10][C@:11]2([OH:22])[C@:5]5([C:15]=34)[CH2:4][CH2:3]1)=[O:8].C(N(CC)CC)C.[CH:30]1(C=O)[CH2:32][CH2:31]1.C(O)=O>C(#N)C>[CH2:30]1[CH:32]([CH2:1][N:2]2[C@@H:12]3[CH2:13][C:14]4[CH:19]=[CH:18][C:17]([OH:20])=[C:16]5[O:21][CH:6]6[C:7]([CH2:9][CH2:10][C@:11]3([OH:22])[C@:5]6([C:15]=45)[CH2:4][CH2:3]2)=[O:8])[CH2:31]1
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)C=C[C@@]3(O)[C@H]1C5
Reactant: O=CC1CC1
Solvent: O=CO
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CC2)C1O5
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 95.4 %

Procedure:
Into a round bottom flask was charged noroxymorphone (2.00 g, 0.007 moles), triethylamine (3.52 g, 0.035 mole, 4.85 mL), acetonitrile (15 mL), and cyclopropanecarboxaldehyde (0.98 g, 0.014 mole, 0.92 mL). The mixture was stirred for about 5 minutes at room temperature then >96% formic acid (4.0 g, 0.87 mole, 3.28 mL) was added dropwise. After stirring the mixture for 15 minutes at room temperature, dichloro(p-cymene)Ru(II) dimer (10 mg, 0.000014 moles) was added. The mixture was then stirred at room temperature for about 24 hours. HPLC indicated the reaction was complete. The reaction mixture was evaporated to a thick oil, and distilled water (5.0 mL) was added. The pH was adjusted to 9.4 using 29% NH3/H2O where a precipitate formed. The mixture was stirred overnight at room temperature. The precipitate was filtered, washed with distilled water (10 mL), and dried at 90° C. for about 24 hours. The dried precipitate yielded naltrexone base (2.28 g, 95% yield).