Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:12][C:5]2[N:6]=[C:7]([CH3:11])[CH:8]=[C:9]([NH2:10])[C:4]=2[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:31][C:32]1[CH:42]=[CH:41][C:35]([CH2:36][S:37](Cl)(=[O:39])=[O:38])=[CH:34][CH:33]=1>C1COCC1.O>[Cl:31][C:32]1[CH:33]=[CH:34][C:35]([CH2:36][S:37]([NH:10][C:9]2[CH:8]=[C:7]([CH3:11])[N:6]=[C:5]3[S:12][C:2]([CH3:1])=[C:3]([C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=4)[C:4]=23)(=[O:39])=[O:38])=[CH:41][CH:42]=1
Reactant: COc1cccc(-c2c(C)sc3nc(C)cc(N)c23)c1
Reactant: O=S(=O)(Cl)Cc1ccc(Cl)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(-c2c(C)sc3nc(C)cc(NS(=O)(=O)Cc4ccc(Cl)cc4)c23)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 13.2 %

Procedure:
To a stirred solution of 2,6-dimethyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-4-amine (100 mg, 0.352 mmol) (Description 4) in THF (2 mL) cooled in an ice bath was added LiHMDS (1M solution in THF) (0.774 mL, 0.774 mmol). The reaction mixture was stirred at RT for 45 min before the addition of 4-chlorobenzylsulfonyl chloride (198 mg, 0.879 mmol). The reaction mixture was then stirred at RT for a further 16 h and was then cooled in an ice bath before the addition of LiHMDS (1M solution in THF) (0.352 mL, 0.352 mmol). The reaction mixture was stirred at RT for 1 h before the addition of 4-chlorobenzylsulfonyl chloride (79.2 mg, 0.352 mmol). The reaction mixture was stirred at RT for a further 16 h and then diluted with water (10 mL) and the aqueous layer extracted with DCM (3×20 mL). The combined organic extracts were dried over a phase separating column and concentrated. The residue was purified by MDAP (basic conditions), to afford the title compound (22 mg). LCMS (A) m/z: 473 [M+1]+, Rt 1.42 min (basic).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])=[CH:4][N:3]=1.[O:17]1CCC[CH2:18]1.C([Li])CCC.CN(C)C=O>C(OCC)C>[Si:10]([O:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([CH2:18][OH:17])=[N:3][CH:4]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(Br)nc1
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1ccc(CO)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
To a mixture of 2-bromo-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)pyridine (11 g) and tetrahydrofuran (450 mL) was added n-butyllithium (1.6 M hexane solution, 25.3 mL) at −78° C., and the reaction mixture was stirred for 1 hr. Then, N,N-dimethylformamide (3.17 mL) was added at −78° C., and the temperature of the mixture was raised to room temperature and stirred for 16 hr. The reaction mixture was diluted with diethyl ether, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in methanol (200 mL), sodium borohydride (1.95 g) was added at 0° C., and the reaction mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure, and the obtained residue was extracted with saturated aqueous ammonium chloride solution and ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (7.53 g, 64%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[C:9]1[CH2:18][CH2:17][C:12]2([O:16][CH2:15][CH2:14][O:13]2)[CH2:11][CH2:10]1>C(O)C.[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]1[CH2:18][CH2:17][C:12]2([O:13][CH2:14][CH2:15][O:16]2)[CH2:11][CH2:10]1
Reactant: Clc1ccccc1C=C1CCC2(CC1)OCCO2
Agent: [Pd]
Solvent: CCO
Product: Clc1ccccc1CC1CCC2(CC1)OCCO2
Yield: 72.1 %

Procedure:
A solution of 6.9 grams (0.026 mole) of 8-(2-chlorophenylmethylene)-1,4-dioxaspiro[4.5]decane in about 50 mL of ethanol and 0.4 gram (catalyst) of 10% palladium on charcoal were placed in a hydrogenation bottle and hydrogenated using a Parr hydrogenation apparatus. Upon the theoretical uptake of hydrogen, the reaction mixture was filtered to remove the catalyst. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography using silica gel. Elution was accomplished using 33% ethyl acetate in hexane. The product-containing fractions were combined and concentrated under reduced pressure, yielding 5.0 grams of 8-(2-chlorophenylmethyl)-1,4-dioxaspiro[4.5]decane. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[C:16]([O-])(O)=O.[Na+]>CO>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:16])=[O:5]
Reactant: O=C(O)c1ccc(F)cc1F
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 97 %

Procedure:
A solution of 2,4-difluorobenzoic acid (1.5808 g, 10.00 mmol) in methanol (15 ml) was cooled to 0° C. in ice-water bath. To the mixture was added dropwise a solution of thionyl chloride (1.46 ml, 20.02 mmol) in methanol (10 ml). The mixture was gradually warmed to room temperature and stirred for 24 hours. The mixture was added to sat. NaHCO3 aqueous solution, extracted three times with ether and dried over MgSO4. The mixture was concentrated and purified by silica gel chromatography (hexane/ether=5/1) to give the title compound (1.6743 g; 97%).
Reaction SMILES: [N:1]1([C:6]2[N:7]=[C:8]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[C:9]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[N:11]([CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])[C:10]=3[N:26]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:32]>>[ClH:32].[N:1]1([C:6]2[N:7]=[C:8]([N:27]3[CH2:28][CH2:29][CH2:30][CH2:31]3)[C:9]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[N:11]([CH2:18][C:19]([OH:21])=[O:20])[C:10]=3[N:26]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)Cn1c2ccccc2c2c(N3CCCC3)nc(N3CCCC3)nc21
Agent: Cl
Product: O=C(O)Cn1c2ccccc2c2c(N3CCCC3)nc(N3CCCC3)nc21

Procedure:
A mixture of (2,4-Di-1-pyrrolidinyl-9H-pyrimido[4,5-b]indol-9-yl)acetic acid, t-butyl ester (VI, EXAMPLE 7, 2.5 g) in aqueous hydrochloric acid (1.0 M) is heated at reflux for 2 hr. The mixture is then cooled and concentrated to approximately one third of the original volume. Filtration of the resulting solid gives the title compound, mp 250-253°; NMR (CDCl3) 8.07, 7.35, 5.21, 4.10, 3.73 and 2.11 δ; IR (neat) 2925, 1736, 1627, 1608, 1568, 1445 and 1193 cm-1.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[CH2:3][N:4]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[N:5]1.[Cl:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[C:29]([Cl:31])[CH:30]=1.[F-].[Cs+]>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:1][C:2]([F:23])([F:22])[CH2:3][N:4]1[C:9](=[O:10])[C:8]([C:27]2[CH:26]=[C:25]([Cl:24])[CH:30]=[C:29]([Cl:31])[CH:28]=2)=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[N:5]1
Reactant: CS(=O)(=O)c1ccc(-c2cnn(CC(F)(F)F)c(=O)c2Cl)cc1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Agent: [Pd]
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: COCCOC
Product: CS(=O)(=O)c1ccc(-c2cnn(CC(F)(F)F)c(=O)c2-c2cc(Cl)cc(Cl)c2)cc1
Temperature: 25 °C
Yield: 58 %

Procedure:
2-(2,2,2-Trifluoroethyl)-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (150 mg, 0.409 mmol) (Example 193E) was dissolved in anhydrous DME (8 mL) and heated to reflux with 3,5-dichlorobenzeneboronic acid in presence of CsF (150 mg, 0.98 mmol) and tetrakis(triphenylphosphine)-palladium (17.38 mg, 0.015 mmol) for 6 hours. After cooling to room temperature the reaction mixture was diluted with water and extracted with ethyl acetate (100 mL). The organic layer was washed with brine, dried over MgSO4, and evaporated in vacuo. The compound was purified on a silica gel column, eluting with 30% ethyl acetate in pentanes, to provide the title compound (yield: 110 mg, 58%). 1H NMR (300 MHz, CDCl3) δ 3.08 (s, 3H), 4.88 (q, J=9 Hz, 2H), 7.06 (d, J=1.5 Hz, 9 Hz, 2H), 7.31 (t, J=1.5 Hz, 1H), 7.36 (d, J=9 Hz, 2H), 7.94 (s, 1H), 7.96 (d, J=9 Hz, 2H). MS (DCI/NH3) m/z 496 (M+NH4)+. Anal. calc. for C19H13Cl2F3N2O3S: C, 47.81; H, 2.75; N, 5.87. Found: C, 47.77; H, 2.75; N, 5.65
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3]([C:5]1[CH:17]=[C:16]([O:18]CC2C=CC=CC=2)[C:8]2[N:9]=[C:10]([CH:13]([CH3:15])[CH3:14])[N:11]([CH3:12])[C:7]=2[CH:6]=1)=[O:4].C(O)(=O)C>CO.[Pd]>[CH3:26][N:2]([CH3:1])[C:3]([C:5]1[CH:17]=[C:16]([OH:18])[C:8]2[N:9]=[C:10]([CH:13]([CH3:15])[CH3:14])[N:11]([CH3:12])[C:7]=2[CH:6]=1)=[O:4]
Reactant: CC(C)c1nc2c(OCc3ccccc3)cc(C(=O)N(C)C)cc2n1C
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)c1nc2c(O)cc(C(=O)N(C)C)cc2n1C
Yield: 118.9 %

Procedure:
A solution of 3.6 g (10.3 mmol) 7-benzyloxy-2-isopropyl-3-methyl-3H-benzimidazole-5-carboxylic acid dimethylamide and 900 μl acetic acid in 70 ml methanol was hydrogenated over 885 mg 10% Pd/C in autoclave (5 bar H2) at 50° C. for 15 h. The catalyst was filtered off and the filtrate was concentrated in vacuo to afford 3.2 g (100%) of the title compound as a grey wax.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[CH:13]=[C:12]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:22]=2[NH:21][N:20]=[C:19]3[NH2:23])[N:11]=[C:10]2[N:24]([CH3:27])[N:25]=[CH:26][C:9]=12.[CH3:28][S:29]([C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)(=[O:31])=[O:30]>CN(C=O)C>[CH3:27][N:24]1[C:10]2=[N:11][C:12]([C:14]3[CH:15]=[CH:16][CH:17]=[C:18]4[C:22]=3[NH:21][N:20]=[C:19]4[NH2:23])=[CH:13][C:8]([O:38][C:35]3[CH:34]=[CH:33][C:32]([S:29]([CH3:28])(=[O:31])=[O:30])=[CH:37][CH:36]=3)=[C:9]2[CH:26]=[N:25]1
Reactant: Cn1ncc2c(Cl)cc(-c3cccc4c(N)n[nH]c34)nc21
Reactant: CS(=O)(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1ncc2c(Oc3ccc(S(C)(=O)=O)cc3)cc(-c3cccc4c(N)n[nH]c34)nc21
Temperature: 155 °C
Yield: 44 %

Procedure:
Potassium carbonate (0.14 g, 1.04 mmol) was added to a solution of 7-(4-chloro-1-methyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-1H-indazol-3-amine 16 (0.30 g, 0.1046 mmol) and 4-methylsulfonyl phenol 8a (0.036 g, 0.2 mmol) in 2 mL DMF. Nitrogen was bubbled through the solution. The reaction mixture was heated in a microwave at 155° C. for 40 minutes. The crude compound was purified by mass directed purification to obtain 20 mg, 40% of 105 as a yellow solid. 1H NMR (400 MHz, DMSO) δ 11.53 (s, 1H), 8.21-7.64 (m, 6H), 7.64-7.40 (m, 3H), 7.40-6.91 (m, 1H), 5.51 (s, 2H), 4.12 (m, 3H), 3.21 (m, 3H). MS (ESI) m/z 435.1 (M+1)+
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][C:30]=1[O:31][CH:32]([CH3:34])[CH3:33])[CH2:6][O:7][C:8]1[CH:16]=[CH:15][C:14]2[N:13]3[CH2:17][CH2:18][CH:19]([CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:12]3=[CH:11][C:10]=2[CH:9]=1)#[N:2].C1C(=O)N([I:42])C(=O)C1>C(Cl)Cl.CC(OC)(C)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][C:30]=1[O:31][CH:32]([CH3:34])[CH3:33])[CH2:6][O:7][C:8]1[CH:16]=[CH:15][C:14]2[N:13]3[CH2:17][CH2:18][CH:19]([CH2:20][C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[C:12]3=[C:11]([I:42])[C:10]=2[CH:9]=1)#[N:2]
Reactant: O=C1CCC(=O)N1I
Reactant: CC(C)Oc1ccc(COc2ccc3c(c2)cc2n3CCC2CC(=O)OC(C)(C)C)cc1C#N
Solvent: COC(C)(C)C
Solvent: ClCCl
Product: CC(C)Oc1ccc(COc2ccc3c(c2)c(I)c2n3CCC2CC(=O)OC(C)(C)C)cc1C#N
Temperature: 0 °C
Yield: 98.5 %

Procedure:
tert-Butyl 2-(7-(3-cyano-4-isopropoxybenzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (0.576 g, 1.251 mmol) was dissolved in DCM (12.51 mL). The reaction mixture was cooled to 0° C., and NIS (0.295 g, 1.313 mmol) was added while stirring. After stirring at 0° C. for 50 min, the reaction mixture was diluted with MTBE (60 mL), washed with water (2×20 mL), 2 M sodium thiosulfate (2×12.5 mL), brine (10 mL), and dried over MgSO4. The solvent was evaporated in vacuo to give the title compound as a light-yellow solid (0.723 g) without further purification. LCMS m/z=587.4 [M+H]+; 1H NMR (400 MHz, CD3CN) δ ppm 1.36 (d, J=6.06 Hz, 6H), 1.40 (s, 9H), 2.34-2.45 (m, 1H), 2.52 (dd, J=15.92, 9.85 Hz, 1H), 2.87 (dt, J=18.60, 8.45 Hz, 1H), 2.99 (dd, J=15.92, 3.54 Hz, 1H), 3.57-3.65 (m, 1H), 4.05 (m, 1H), 4.17 (m, 1H), 4.75 (dt, J=12.13, 6.06 Hz, 1H), 5.06 (s, 2H), 6.83-6.85 (m, 1H), 6.85-6.89 (m, 1H), 7.14 (d, J=8.72 Hz, 1H), 7.19 (d, J=8.72 Hz, 1H), 7.67 (dd, J=8.72, 2.15 Hz, 1H), 7.70 (d, J=2.15 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([CH2:7][NH:8]C=O)=[CH:5][C:4]=1[C:13]([F:16])([F:15])[F:14].[ClH:17].C(OCC)C>C(O)C>[ClH:17].[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([CH2:7][NH2:8])=[CH:5][C:4]=1[C:13]([F:14])([F:15])[F:16]
Reactant: COc1ccc(CNC=O)cc1C(F)(F)F
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: COc1ccc(CN)cc1C(F)(F)F

Procedure:
3.8 g of N-[4-methoxy-3-(trifluoromethyl)benzyl]formamide was dissolved in 20 ml ethanol, 2 ml conc. hydrochloric acid was added thereto, and the mixture was heated under reflux for 3 hr. After cooling, diethyl ether was added thereto, and the resulting crystals were collected by filtration to give 2.5 g of 4-methoxy-3-(trifluoromethyl)benzylamine hydrochloride.
Reaction SMILES: [CH3:1][N:2]([S:28]([C:31]1[S:32][CH:33]=[CH:34][CH:35]=1)(=[O:30])=[O:29])[C:3]1[CH:4]=[C:5]([O:23][C:24]([F:27])([F:26])[F:25])[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([O:20]CC)=[O:19])[CH2:15][N:16]=1)=[CH:8]2.[OH-].[Na+].O1CCCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C>[CH3:1][N:2]([S:28]([C:31]1[S:32][CH:33]=[CH:34][CH:35]=1)(=[O:30])=[O:29])[C:3]1[CH:4]=[C:5]([O:23][C:24]([F:25])([F:27])[F:26])[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([OH:20])=[O:19])[CH2:15][N:16]=1)=[CH:8]2
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(OC(F)(F)F)cc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)S1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CN(c1cc(OC(F)(F)F)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 15 h
Yield: 94.9 %

Procedure:
A mixture of ethyl {2-[7-[methyl(2-thienylsulfonyl)amino]-5-(trifluoromethoxy)-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetate (300 mg), 1N aqueous sodium hydroxide solution (5 mL), tetrahydrofuran (5 mL) and ethanol (5 mL) was stirred at room temperature for 15 hr. The reaction mixture was acidified with aqueous citric acid solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was crystallized from ethyl acetate-hexane to give the title compound (270 mg, yield 93%) as pale-yellow crystals. The crystals were purified by preparative HPLC, and recrystallized from ethyl acetate-hexane to give pale-yellow prism crystals. melting point 225-227° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:4]([OH:26])[CH:5]=[C:6]([C:8]2[C:17]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:16]=3[C:15]([Br:25])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:7]=1.[C:35](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:35][O:26][C:4]1[CH:5]=[C:6]([C:8]2[C:17]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:16]=3[C:15]([Br:25])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:7]=[C:2]([Br:1])[C:3]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Oc1cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc(Br)c1OCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc(Br)c1OCc1ccccc1
Yield: 100.4 %

Procedure:
lodomethane (0.086 mL, 1.38 mmol) was added dropwise to a room temperature, stirred light suspension of a mixture [3-bromo-5-(6-bromo-benzo [b]naphtho[2,3-d]thiophen-11-yl)-2-benzyloxy-phenol (87% pure, contaminated with 2-bromo-4-(6-bromo-benzo[b]naphtho[2,3-d]thiophen-11-yl)-6-benzyloxy-phenol (13%), 0.271 g, 0.46 mmol), potassium carbonate (0.191 g, 1.38 mmol) in DMF (2 mL) over a period of twenty minutes. After the mixture was stirred at ambient temperature for 3 h., the reaction mixture was quenched with aqueous hydrochloride to pH 1 and further diluted with water (40 mL) and aqueous mixture was extracted with methylene chloride (80 mL). The organic extract was washed with water, dried with brine and anhydrous MgSO4, and concentrated to provide a mixture (279 mg, 100%) of 11-(3-methoxy-4-benzyloxy-5-bromo-phenyl)-6-bromo-benzo [b]naphtho [2,3-d ]thiophene (87%) and 11-(4-methoxy-3-benzyloxy-5-bromo-phenyl)-6-bromo-benzo [b]naphtho[2,3-d]thiophene(13%). This mixture was used for next reaction without separation. A solution of a this mixture (279 mg, 0.49 mmol) and 10% palladium on carbon (28 mg) in ethyl acetate: ethanol (1.5:10, 15 mL) was hydrogenated in a Parr vessel at 51 psi at ambient temperature for 6 h. The reaction mixture was filtered through a bed of Solka Floc and washed with hot ethyl acetate: ethanol (1.5:10). Silica gel (5 mL) was added to the filtrate. Solvent was removed and the adsorbate was flash chromatographed (eluents:petroleum ether:methylene chloride 6:4 to petroleum ether:ethyl acetate 7:3) to provide a white solid (145 mg) that contained about 73% 2-bromo-4-(benzo[b]naphtho[2,3-d]thiophen-11-yl)-6-methoxy-phenol and 27% of the title compound. The bromine was re-introduced to the 6 position of the majority (73%) of the crude according to the procedures outlined by methods in Examples 34 (acetylation of the phenol), Example 37 (bromination in the 6 position) and Example 41 (saponification of the acetyl moiety) to provide the title compound as a white solid: mp 216-218° C.; NMR (CDCl3); δ8.36 (d, J=8 Hz, 1 H), 7.83 (d, J=8 Hz, 1 H), 7.68-7.64 (m, 2 H), 7.50-7.43 (m, 2 H), 7.21 (d, J=2 Hz, 1 H), 7.18 (d, J=8 Hz, 1H), 6.93 (d, J=8 Hz, 1 H), 6.87 (d, J=8 Hz, 1H), 6.20 (s, 1 H), 3.86 (s, 3 H); MS (+FAB): [M+], 2 bromine isotope pattern; 512.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2=[C:15]([Cl:18])[CH:16]=[CH:17][N:11]2[N:10]=[C:9]1[CH:19]=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:21]([Mg]Br)=[CH2:22]>C1COCC1>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2=[C:15]([Cl:18])[CH:16]=[CH:17][N:11]2[N:10]=[C:9]1[CH:19]([OH:20])[CH:21]=[CH2:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1nn2ccc(Cl)c2c(=O)n1Cc1ccccc1
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: C=CC(O)c1nn2ccc(Cl)c2c(=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 3-benzyl-5-chloro-4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazine-2-carbaldehyde (Example 22 E, 287 mg, 1 mmol) in THF (4 mL) at −50° C. was added a vinylmagnesium bromide solution (1.5 mL of 1 M solution) under Ar. The mixture was stirred for 2 h, slowly warmed to rt over 2 h and stirred at rt for 30 min. The reaction mixture was quenched by the addition of 0.2 mL of HOAc followed by water (15 mL) and EtOAc (40 mL). The organic layer was dried over MgSO4 and concentrated in vacuo to obtain the crude title compound as a brown solid (315 mg, 100%) which was used in the next step without any further purification: 1H NMR (CDCl3) δ 7.10–7.50 (m, 6H), 6.47 (s, 1H), 6.01 (m, 1H), 5.05–5.25 (m, 4H), 5.05 (s, 1H); 13C NMR (CDCl3): δ 153.9, 149.8, 135.9, 135.4, 128.8, 127.7, 126.3, 119.8, 118.5, 113.6, 111.6, 70.4, 44.1.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@H:11]1[CH2:15][N:14](C(OC(C)(C)C)=O)[C@H:13]([C:23]([OH:25])=O)[CH2:12]1.[ClH:26].[C:27]([C@@H:29]1[CH2:33][CH2:32][CH2:31][NH:30]1)#[N:28]>CN(C=O)C>[ClH:26].[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@H:11]1[CH2:15][NH:14][C@H:13]([C:23]([N:30]2[CH2:31][CH2:32][CH2:33][C@H:29]2[C:27]#[N:28])=[O:25])[CH2:12]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](Nc2nc3ccccc3o2)C[C@H]1C(=O)O
Reactant: N#C[C@@H]1CCCN1
Agent: Cl
Solvent: CN(C)C=O
Product: N#C[C@@H]1CCCN1C(=O)[C@@H]1C[C@@H](Nc2nc3ccccc3o2)CN1

Procedure:
(2S,4R)-4-(2-Benzoxazolyl)amino-1-tert-butoxycarbonylpyrrolidine-2-carboxylic acid (title compound of Reference Example 6, 1.0 g) and (S)-2-cyanopyrrolidine hydrochloride (0.38 g) were dissolved in DMF (10 mL), and triethylamine (0.81 mL), HOBT (0.49 g) and EDC hydrochloride (0.61 g) were successively added thereto. The mixture was stirred at room temperature for 15 hr. Water was added to the reaction mixture, and mixture was extracted with ethyl acetate. The extract was dried and the residue was evaporated under reduced pressure. The residue was purified by silica gel chromatography to give (S)-1-[(2S,4R)-4-(2-benzoxazolyl)amino-1-tert-butoxycarbonyl-2-pyrrolidinylcarbonyl]-2-cyanopyrrolidine (0.91 g) as amorphous.
Reaction SMILES: [NH:1]([C:8]1[N:12]=[C:11]([SH:13])[NH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C>[NH:1]([C:8]1[N:12]=[C:11]([S:13][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[NH:10][N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCc1ccccc1
Reactant: Sc1nc(Nc2ccccc2)n[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(CSc2nc(Nc3ccccc3)n[nH]2)cc1
Reaction time: 8 h
Yield: 88.5 %

Procedure:
To a stirring solution of the compound of Example 1 (c) (23 mg, 0.12 mmol) in 1.2 mL of DMF was added K2CO3 (17 mg, 0.12 mmol), followed by benzyl bromide (20 mg, 0.12 mmol). The mixture was stirred overnight, filtered, and purified by preparative HPLC to afford the title compound as a white solid (30 mg, 70%). 1H-NMR (400 MHz, d6-DMSO) δ9.30 (broad singlet, 1H), 7.47 (d, 2H, J=8.1 Hz), 7.39 (d, 2H, J=7.3 Hz), 7.31 (t, 2H, J=7.3 Hz), 7.23 (quartet, 3H, J=7.3 Hz), 6.82 (t, 1H, J=7.3 Hz), and 4.3 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([Cl:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].C(O[CH:18](N(C)C)[N:19]([CH3:21])[CH3:20])(C)(C)C>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([CH:8]=[CH:18][N:19]([CH3:21])[CH3:20])[C:5]([Cl:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: Cc1cc(Cl)c([N+](=O)[O-])cc1Cl
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Solvent: C1CCOC1
Product: CN(C)C=Cc1cc(Cl)c([N+](=O)[O-])cc1Cl
Temperature: 25 °C
Yield: 58 %

Procedure:
2,5-Dichloro-4-methyl-nitrobenzene (50 g, 0.24 mol) was heated at reflux, in tetrahydrofuran (200 ml), with t-butoxy-bis(dimethylamino)methane (63.3 g, 0.364 mol) for 8 hours. The reaction mixture was cooled to room temperature and slowly poured into hexanes (3L) with stirring. The desired product was collected by filtration as a dark red solid, 36.9 g, 58% yield. mp 173°-5° C. NMR (CDCl3) δ 8.01 (s, 1), 7.32 (s, 1), 7.08 (d, 1), 5.27 (d, 1), 3.00 (s, 6). Analysis Calculated for C10H10N2O2Cl2 : C, 45.99; H, 3.86; N, 10.73, Found: C, 45.91; H, 3.72; N, 10.61.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1Br)=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:20]C1C=C(B(O)O)C=CC=1>>[Cl:19][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[N:10]=[CH:9][C:8]([CH3:17])=[C:1]2[C:2]1[CH:3]=[C:4]([OH:20])[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccc2c(Br)c(Cc3ccccc3)cnc12
Reactant: OB(O)c1cccc(O)c1
Product: Cc1cnc2c(Cl)cccc2c1-c1cccc(O)c1

Procedure:
The title compound was prepared from 3-benzyl-4-bromo-8-chloro-quinoline and 3-hydroxyphenyl boronic acid according to the procedure of Example 1. MS (ES) m/z 267.9.