Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:16])([CH3:15])[C:3]([NH:5][CH2:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1)=[O:4]>CO.Cl.[Pd]>[CH3:1][C:2]([CH3:16])([CH3:15])[C:3]([NH:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:11][NH2:12])=[CH:13][CH:14]=1)=[O:4]
Reactant: CC(C)(C)C(=O)NCc1ccc(C#N)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(C)(C)C(=O)NCc1ccc(CN)cc1

Procedure:
Bubble nitrogen for 15 min into a solution of 4-[(2,2-dimethyl-propionylamino)-methyl]-benzonitrile (0.4 g, 1.85 mmol) in methanol (50 mL) with concentrated HCl (8 drops). Add 10% Pd/C (Degussa type E101, 40 mg) and submit the mixture to hydrogenation at atmospheric pressure overnight. Filter the catalyst through Celite® and concentrate in vacuo to obtain the hydrochloride salt of the title compound. Add saturated aqueous NaHCO3 and extract twice with EtOAc. Dry the combined organic extracts over MgSO4, filter and concentrate in vacuo to obtain the title compound as a yellow oil (315 mg, 77%). MS (ES+) m/z: 221 (M+H)+.
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([Cl:20])=[N:9][S:10][C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH3:19])=[CH:14][CH:13]=1)(=O)=O.[F:21][C:22]1[CH:23]=[C:24]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:25]=[C:26]([F:29])[C:27]=1O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:20][C:8]1[C:7]([CH2:6][O:5][C:27]2[C:26]([F:29])=[CH:25][C:24]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:23][C:22]=2[F:21])=[C:11]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH3:19])=[CH:14][CH:13]=2)[S:10][N:9]=1
Reactant: CCOC(=O)CCc1cc(F)c(O)c(F)c1
Reactant: CCc1ccc(-c2snc(Cl)c2COS(C)(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cc(F)c(OCc2c(Cl)nsc2-c2ccc(CC)cc2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed [3-chloro-5-(4-ethylphenyl)-1,2-thiazol-4-yl]methyl methanesulfonate (20 mg, 0.05 mmol, 1.00 equiv), ethyl 3-(3,5-difluoro-4-hydroxyphenyl)propanoate (16 mg, 0.07 mmol, 1.20 equiv), potassium carbonate (25 mg, 0.18 mmol, 3.00 equiv), N,N-dimethylformamide (2 mL). The resulting solution was stirred overnight at 25° C. The reaction was then quenched by the addition of 5 mL of water. The resulting solution was extracted with 3×5 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 1×10 mL of brine. The mixture was dried over anhydrous sodium sulfate. The residue was applied onto the TLC with ethyl acetate/petroleum ether (1:15). This resulted in 20 mg (71%) of ethyl 3-(4-[[3-chloro-5-(4-ethylphenyl)-1,2-thiazol-4-yl]methoxy]-3,5-difluorophenyl)propanoate as colorless oil.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH3:20])[C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=2[CH:19]=1.[CH3:21][C:22]1[CH:23]=[C:24]([SH:29])[CH:25]=[CH:26][C:27]=1[CH3:28]>>[CH3:21][C:22]1[CH:23]=[C:24]([S:29][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[C:9]([CH3:20])[C:10]3[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=3[CH:19]=2)[CH:25]=[CH:26][C:27]=1[CH3:28]
Reactant: Cc1ccc(S)cc1C
Reactant: Cc1cc(OCCCCCl)cc2c1NC(=O)OC2(C)C
Product: Cc1ccc(SCCCCOc2cc(C)c3c(c2)C(C)(C)OC(=O)N3)cc1C

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4,4,8-trimethyl-4H-3,1-benzoxazin-2-one and 3,4-dimethyl-thiophenol.
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[C:16]([F:17])=[CH:15][N:14]=[C:13]([O:18]C)[CH:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1.[Cl-].[NH+]1C=CC=CC=1.C(OCC)(=O)C>CN(C=O)C>[CH:1]1([CH:4]([C:11]2[C:16]([F:17])=[CH:15][N:14]=[C:13]([OH:18])[CH:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1
Reactant: CCOC(=O)CC(c1cc(OC)ncc1F)C1CC1
Agent: [Cl-]
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CC(c1cc(O)ncc1F)C1CC1
Temperature: 130 °C
Reaction time: 2 h
Yield: 126.2 %

Procedure:
Under a nitrogen atmosphere, to a solution of ethyl 3-cyclopropyl-3-(5-fluoro-2-methoxypyridin-4-yl)propanoate (1.38 g) obtained in step A in DMF (2.5 mL) was added pyridinium chloride (5.97 g), and the mixture was stirred at 130° C. for 2 hr. To the reaction mixture was added ethyl acetate at 0° C., and the resulting precipitate was removed by filtration. The solvent in the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (1.65 g) as a pale-yellow oil.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:31])[CH2:9][C@H:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([Cl:17])[CH:11]=2)[C@@H:7]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[N:6]([C@@H:25]([CH2:28][CH3:29])[CH2:26]O)[C:5]1=[O:30])[CH:2]=[CH2:3].[CH2:32]([S:34]([NH2:37])(=[O:36])=[O:35])[CH3:33]>>[CH2:1]([C@@:4]1([CH3:31])[CH2:9][C@H:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([Cl:17])[CH:11]=2)[C@@H:7]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[N:6]([C@@H:25]([CH2:28][CH3:29])[CH2:26][NH:37][S:34]([CH2:32][CH3:33])(=[O:36])=[O:35])[C:5]1=[O:30])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cc(F)cc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CO)C1=O
Reactant: CCS(N)(=O)=O
Product: C=CC[C@@]1(C)C[C@H](c2cc(F)cc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CNS(=O)(=O)CC)C1=O

Procedure:
(3S,5R,6S)-3-allyl-5-(3-chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one (100 mg, 0.215 mmol; Example 393, Step B) and ethanesulfonamide (70.5 mg, 0.646 mmol) were coupled by the procedure as described in Example 202, Step C to form the title compound, isolated after silica gel chromatography (4 g column; eluent 0 to 50% EtOAC/hexanes) as an off-white solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:30]=[CH:29][C:6]([CH2:7][N:8]2[CH2:13][CH:12]3[CH:10]([CH:11]3[CH2:14][NH:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[C:18]([F:28])[CH:17]=3)[CH2:9]2)=[CH:5][CH:4]=1)[CH3:2].CCN(C(C)C)C(C)C.[S:40]1[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=2[CH:42]=[C:41]1[C:49](Cl)=[O:50].C([O-])(O)=O.[Na+]>ClCCCl>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH2:13][CH:12]3[CH:10]([CH:11]3[CH2:14][N:15]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[C:18]([F:28])[CH:17]=3)[C:49]([C:41]3[S:40][C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=4[CH:42]=3)=[O:50])[CH2:9]2)=[CH:29][CH:30]=1)[CH3:2]
Reactant: CCc1ccc(CN2CC3C(CNc4ccc(N5CCOCC5)c(F)c4)C3C2)cc1
Reactant: O=C(Cl)c1cc2ccccc2s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1ccc(CN2CC3C(C2)C3CN(C(=O)c2cc3ccccc3s2)c2ccc(N3CCOCC3)c(F)c2)cc1
Reaction time: 1 h

Procedure:
To a stirring solution of [3-(4-Ethyl-benzyl)-3-aza-bicyclo[3.1.0]hex-6-ylmethyl]-(3-fluoro-4-morpholin-4-yl-phenyl)-amine prepared above (50 mg, 0.12 mmol) in 2 mL of DCE at room temperature was added DIEA (0.03 mL, 0.18 mmol) and 2-benzthiophenecarbonylchloride (0.02 mL, 0.18 mmol). After 1 hour, saturated NaHCO3 was added, and the mixture was extracted with CH2Cl2. The combined extracts were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The resulting crude material was taken up in 50% EtOAc/hexanes and the white solids were filtered off. The remaining filtrate was concentrated under reduce pressure to yield 58 mg of the desired product. 400 MHz 1H NMR (CDCl3) δ 7.60-7.68 (m, 2H), 7.24-7.31 (m, 2H),7.08-7.18 (m, 5H), 6.99-7.02 (m, 2H), 6.86-6.91 (m, 1H), 3.82-3.88 (m, 4H), 3.68 (d, J=7.47 Hz, 2H), 3.50 (brs, 2H), 3.10-3.12 (m, 4H), 2.88 (brd, J=7.47 Hz, 2H), 2.49 (q, 2H), 2.28, (brs, 2H), 1.49 (brs, 1H), 1.22-1.24 (m, 2H), 1.19 (t, 3H); MS (M+1) 570.2.
Reaction SMILES: [N:1]#[C:2]Br.[Cl:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH2:11])[C:6]=1[NH2:12]>C(#N)C.O>[Cl:4][C:5]1[C:6]2[N:12]=[C:2]([NH2:1])[NH:11][C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: Nc1cccc(Cl)c1N
Reactant: N#CBr
Solvent: O
Solvent: CC#N
Product: Nc1nc2c(Cl)cccc2[nH]1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Cyanogen bromide was added to a solution of 3-chlorobenzene-1,2-diamine (0.81 g, 0.570 mmol) in acetonitrile (10 mL) and water (2 ml) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 14 hours. The reaction was quenched with saturated aqueous sodium hydrogen carbonate (50 ml) and shaken. The resulting solid was filtered off, was washed with water and dried at reduced pressure to 0.49 g of 4-chloro-1H-benzo[d]imidazol-2-amine (yield, 49%). MS (EI): 168 (MH+).
Reaction SMILES: [CH:1]1([C:5]2[C:13]([C:14]3[NH:18][CH:17]=[N:16][N:15]=3)=[CH:12][C:8]([C:9]([OH:11])=O)=[C:7]([CH3:19])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.Cl.[F:21][C:22]1([C:28]2[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=2)[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CCN(C(C)C)C(C)C>C(OCC)(=O)C.CN(C=O)C>[CH:1]1([C:5]2[C:13]([C:14]3[NH:18][CH:17]=[N:16][N:15]=3)=[CH:12][C:8]([C:9]([N:25]3[CH2:26][CH2:27][C:22]([C:28]4[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=4)([F:21])[CH2:23][CH2:24]3)=[O:11])=[C:7]([CH3:19])[CH:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: N#Cc1ccc(C2(F)CCNCC2)cc1
Reactant: Cc1cc(C2CCC2)c(-c2nnc[nH]2)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1cc(C2CCC2)c(-c2nnc[nH]2)cc1C(=O)N1CCC(F)(c2ccc(C#N)cc2)CC1
Reaction time: 4 h
Yield: 56.4 %

Procedure:
To a 4-mL vial was added 4-cyclobutyl-2-methyl-5-(4H-1,2,4-triazol-3-yl)benzoic acid (compound 202.3, 31 mg, 0.12 mmol, 1.0 equiv), 4-(4-fluoropiperidin-4-yl)benzonitrile (compound 11.2, 31 mg, 0.13 mmol, 1.1 equiv), 1-hydroxybenzotriazole hydrate (20 wt % water) (25 mg, 0.15 mmol, 1.25 equiv), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (25 mg, 0.13 mmol, 1.1 equiv), DMF (0.6 mL) and DIEA (83 μL, 0.48 mmol, 4 equiv). The mixture was stiffed at room temperature for 4 hours then diluted with ethyl acetate (10 mL) and washed with 1 M NaH2PO4 (5 mL). The aqueous was back extracted with ethyl acetate (3 mL) and the combined organics was washed with brine (5 mL), saturated NaHCO3 (5 mL) and brine (5 mL). The organics were dried (Na2SO4), filtered and removed in vacuo. The crude residue was purified by preparative TLC (DCM/8% MeOH) to obtain the title compound as a white solid (30 mg, 56%). m/z (ES+) 444 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].C(N(CC)CC)C.[Cl:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1>C(Cl)Cl>[Cl:21][C:22]1[CH:28]=[CH:27][C:25]([NH:26][C:7](=[O:8])[C:6]2[CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[N+:11]([O-:13])=[O:12])=[CH:24][CH:23]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=C(Cl)c1cc(Cl)ccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(Cl)cc1)c1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 96.4 %

Procedure:
To a solution of 5-chloro-2-nitrobenzoyl chloride (23 g, 100 mmol) in methylene chloride (200 mL) at 0° C. was added triethylamine (16 mL, 115 mmol), followed by 4-chloroaniline (14 g, 110 mmol). The mixture was stirred for 20 minutes at 0° C., then warmed to ambient temperature. After 5 hours, the mixture was concentrated of all volatiles in vacuo. The residual solid was dissolved in ethyl acetate (400 mL) and washed with water (200 mL), 1M hydrochloric acid (2×200 mL), 1M sodium bicarbonate (200 mL) and brine (200 mL) and dried over MgSO4. Concentration and drying in vacuo afforded 30 g (93% yield) of N-(4-chlorophenyl)-5-chloro-2-nitrobenzamide; NMR (CDCl3) 8.1 (d, 1), 7.7 (br, 1), 7.6 (m, 2), 7.5 (d, 2), 7.3 (d, 2) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][S:10][C:3]=12.[Li]CCCC.CCOCC.Br[C:22]1[CH:27]=[CH:26][C:25]([CH:28]2[O:33][CH2:32][CH2:31][CH2:30][O:29]2)=[CH:24][N:23]=1>C1COCC1.[Cl-].[Zn+2].[Cl-].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:29]1[CH2:30][CH2:31][CH2:32][O:33][CH:28]1[C:25]1[CH:26]=[CH:27][C:22]([C:9]2[S:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH:8]=2)=[N:23][CH:24]=1
Reactant: Brc1ccc(C2OCCCO2)cn1
Reactant: Clc1ccnc2ccsc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: Clc1ccnc2cc(-c3ccc(C4OCCCO4)cn3)sc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.1 %

Procedure:
To a solution of chlorothienopyridine 6 (22.93 g, 135 mmol) in THF (325 mL) at −5° C./−10° C. in a 1 L round-bottom flask was added n-BuLi (2.5 M in hexanes, 54.1 mL, 135 mmol) over 20 min. After 30 min, a solution of zinc chloride in ether (1M, 135 mL, 135 mmol) was added at −5° C./−10° C. over 20 min and the reaction mixture was allowed to warm-up to r.t. After 1 h, the bromide 28 (27.5 g, 113 mmol) and Pd(PPh3)4 (1.953 g, 1.169 mmol) in THF (48.8 mL) were added and the mixture was heated to reflux for 2 h, cooled down to r.t. and concentrated. The residue was diluted with DCM (1000 mL)/H2O (800 mL)/NH4OH (200 mL), stirred at r.t. for 1 h and the phases were separated. The aqueous phase was extracted with DCM (2×100 mL), the organic phase and the extracts were combined, dried over anhydrous Na2SO4, filtered and concentrated. The residue was triturated with MTBE (100 mL) and collected by filtration (washed with MTBE, 2×20 mL) to give 29 (23.73 g, 71.3 mmol, 63.3% yield) as a beige solid. MS (m/z): 333.1 (M+1)
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]3[O:17][CH2:16][CH2:15][C:13]3=2)[CH:8]=[CH:7]1.[OH-].[Na+].O.CN(C)[C:23](=[O:25])[CH3:24]>>[C:23]([C:8]1[C:9]2[C:14](=[C:13]3[CH2:15][CH2:16][O:17][C:12]3=[CH:11][CH:10]=2)[NH:6][CH:7]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)N(C)C
Reactant: c1cc2ccc3c(c2[nH]1)CCO3
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(=O)c1c[nH]c2c3c(ccc12)OCC3
Temperature: 25 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
To stirred N,N-dimethylacetamide (2.1 mL) under Ar at 0° C. was added phosphorous oxychloride (1.0 mL, 10.7 mmol) dropwise over 10 min. The resultant pale yellow mixture was allowed to warm to ambient temperature, then a solution of 7,8-dihydrofuro[2,3-g]indole (800 mg, 5.0 mmol) in N,N-dimethylacetamide (1.5 mL) was added over 3 min and the mixture was stirred for 2 h. The resultant suspension was heated at 65° C. for 30 min, then cooled in an ice-water bath. Ice (10 g) was added portionwise to the stirred mixture followed by the cautious addition of 20% aqueous sodium hydroxide (10 mL), then water (15 mL). The resultant mixture was heated to reflux for 10 min then cooled to room temperature and diluted with ice-water (50 mL). The suspension was filtered-off and dried to give the crude product (870 mg, 86%) as a beige solid. Recrystallisation from hot ether (10 mL) afforded the product (746 mg, 74%) as a cream-coloured solid: m.p. 233-234.5° C.; NMR (400 MHz, DMSO-d6) δH 2.41 (3H, s), 3.32 (1H, 2H, t, J 8.5 Hz), 4.58 (2H, t, J 8.5 Hz), 6.69 (1H, d, J 8.5 Hz), 7.91 (1H, d, J 8.5 Hz), 8.18 (1H, d, J 3.0 Hz) and 11.76 (1H, br s).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([O:16][CH2:17][CH:18]=[CH2:19])=[O:15])=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=O.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:30][C:31]1[N:36]=[C:35]([CH3:37])[CH:34]=[CH:33][N:32]=1>C1COCC1>[Cl:30][C:31]1[N:36]=[C:35]([CH2:37][C:5]([C:4]2[C:3]([O:2][CH3:1])=[C:12]([NH:13][C:14](=[O:15])[O:16][CH2:17][CH:18]=[CH2:19])[CH:11]=[CH:10][CH:9]=2)=[O:7])[CH:34]=[CH:33][N:32]=1
Reactant: C=CCOC(=O)Nc1cccc(C(=O)OC)c1OC
Reactant: Cc1ccnc(Cl)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCOC(=O)Nc1cccc(C(=O)Cc2ccnc(Cl)n2)c1OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 65.5 %

Procedure:
To a solution of methyl 2-(methyloxy)-3-{[(2-propen-1-yloxy)carbonyl]amino}benzoate (123 g, 464 mmol), in dry THF (800 mL) at −10° C., LiHMDS (1M in THF, 1440 mmol, 1440 mL) was added dropwise and the solution was allowed to stir for 1 h at 0° C. A solution of 2-chloro-4-methylpyrimidine (72 g, 560 mmol) in THF (150 mL) was then added dropwise to the solution of ester and base at 0° C. over 20 min. The solution was allowed to stir 1 h at rt. TLC showed the reaction was complete. The reaction was quenched by addition of the saturated aqueous NH4Cl (800 mL) at 0° C. The reaction mixture was extracted with EtOAc (1 L×3). The combined organic layers were washed with water and brine successively, dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by flash column on silica gel, eluting with DCM. This solution was evaporated to obtain a solid. The orange solid was triturated with a small amount of EtOAc and filtered, rinsing with diethyl ether to give the title compound of Step E (109.9 g, 67.8% yield). 1H NMR (400 MHz, CDCl3) δ ppm 13.64-13.68 (br, 1H), 8.38 (d, J=5.3 Hz, 1H), 8.15-8.21 (m, 1H), 7.31-7.39 (m, 2H), 7.15-7.18 (m, 1H), 6.87 (d, J=5.3 Hz, 1H), 6.19 (s, 1H), 5.92-6.15 (m, 1H), 5.23-5.40 (m, 2H), 4.66-4.70 (m, 2H), 3.76 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.C1C=C(Cl)C=C(C(OO)=[O:17])C=1>ClCCl.[OH-].[Na+]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N+:3]=1[O-:17]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(Br)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1ccc(Br)[n+]([O-])c1
Temperature: 30 °C
Reaction time: 8 h

Procedure:
Into a round-bottom flask, was placed a solution of 2-bromo-5-methylpyridine (10.0 g, 58.1 mmol, 1.00 equiv) in dichloromethane (250 mL). mCPBA (15.0 g, 86.9 mmol, 1.50 equiv) was added in several batches at room temperature. The resulting solution was stirred overnight at 30° C., then diluted with 50 mL of 2N sodium hydroxide (aq.). The pH value of the solution was adjusted to 10 with 2N sodium hydroxide (aq.). The aqueous phase was extracted with 3×100 mL of dichloromethane and the combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to yield 11.0 g (91%) of 2-bromo-5-methylpyridin-1-ium-1-olate as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[C:6]=2Cl.[C-:19]#[N:20].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[C:6]=2[C:19]#[N:20]
Reactant: Fc1ccc(-n2nc3cc(Br)ccc3c2Cl)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1c2ccc(Br)cc2nn1-c1ccc(F)cc1
Temperature: 130 °C
Yield: 54.1 %

Procedure:
To a stirred solution of compound (xiii) (4.49 g, 12.86 mmol) in DMF (50 mL) was added sodium cyanide (1.34 g, 27.73 mmol) at RT and the reaction mixture was then heated at 130° C. for 2 h. The reaction mixture was then diluted with saturated FeCl3 solution and extracted with EtOAc (3×75 mL). The combined organic layers were washed with water, dried (Na2SO4) and concentrated to give the crude product which was purified by column chromatography on 100-200 mesh silica gel eluting with EtOAc/hexane (2-4%) to give 6-bromo-2-(4-fluorophenyl)-2H-indazole-3-carbonitrile (xiv) (2.2 g, 50%) as white solid. ESI-MS m/z calculated for [M+H]+: 317.99; found: 317.90.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[C:25]([C:28](O)=[O:29])[NH:26][CH:27]=2)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[C:25]([C:28]([NH:15][C:12]3[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:14][CH:13]=3)=[O:29])[NH:26][CH:27]=2)=[CH:19][CH:18]=1
Reactant: Nc1ccc(OCCN2CCCC2)cc1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c[nH]1
Product: O=C(Nc1ccc(OCCN2CCCC2)cc1)c1cc(-c2ccc(Cl)cc2)c[nH]1
Yield: 56.2 %

Procedure:
4-(2-(Pyrrolidin-1-yl)ethoxy)benzenamine (35 mg) from step A was converted to the title compound (26 mg) by acylation with 4-(4-chlorophenyl)-1H-pyrrole-2-carboxylic acid (25 mg) following the procedure described in step C of Example 1. Step C. MS (ESI) 410 (M+H)+.
Reaction SMILES: [C:1]([C:5]12[CH2:12][CH2:11][C:8]([C:13]([O:15]C)=[O:14])([CH2:9][CH2:10]1)[CH2:7][CH2:6]2)([O:3]C)=[O:2].O.[OH-].[Li+]>O1CCCC1.C(O)(C)C.O>[C:13]([C:8]12[CH2:11][CH2:12][C:5]([C:1]([OH:3])=[O:2])([CH2:10][CH2:9]1)[CH2:6][CH2:7]2)([OH:15])=[O:14]
Reactant: COC(=O)C12CCC(C(=O)OC)(CC1)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C12CCC(C(=O)O)(CC1)CC2
Yield: 98 %

Procedure:
A stirred solution of 1,4-dicarbomethoxybicyclo[2.2.2]octane (31.7 g, 0.14 mole) in tetrahydrofuran (200 mL) and isopropanol (70 mL) was treated with a solution of lithium hydroxide hydrate (17.7 g, 0.42 mole) in water (200 mL), and the mixture was heated to 6°-70° C. for 2.5 h with stirring. The organic solvents were removed in vacuo, and the alkaline aqueous solution was filtered, then the filtrate was cooled on an ice bath and acidified with concentrated hydrochloric acid (40 mL). The solid was filtered, rinsed with cold water, and partially air dried overnight, then further dried under vacuum, triturated from acetonitrile, and redried in vacuo to afford 27.19 g (98%) of subject material as a white solid. No MS could be obtained. 1H NMR (d6-DMSO) δ 12.09 (br s, 2H), 1.66 (s, 12H).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:7])=[C:4]([Cl:17])[CH:3]=1.Cl.Cl[C:20]1[C:29]2[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=2)[N:23]=[CH:22][N:21]=1>>[ClH:17].[Cl:17][C:4]1[CH:3]=[C:2]([CH:16]=[CH:15][C:5]=1[C:6](=[O:7])[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[NH:1][C:20]1[C:29]2[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=2)[N:23]=[CH:22][N:21]=1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: Nc1ccc(C(=O)Nc2ccccc2)c(Cl)c1
Agent: Cl
Product: COc1cc2ncnc(Nc3ccc(C(=O)Nc4ccccc4)c(Cl)c3)c2cc1OC
Yield: 71 %

Procedure:
Using an analogous procedure to that described in Example 1, 4-amino-2-chlorobenzanilide was reacted with 4-chloro-6,7-dimethoxyquinazoline hydrochloride to give 4-[3-chloro-4-(N-phenylcarbamoyl)anilino]-6,7-dimethoxyquinazoline hydrochloride salt in 71% yield, m.p. >260° C.;
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:8][O:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:25](Br)([CH3:27])[CH3:26].O>CN(C)C=O>[CH:25]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:8][O:9]2)=[CH:4][CH:3]=1)([CH3:27])[CH3:26]
Reactant: CC(C)Br
Reactant: O=c1c(-c2ccccc2)coc2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1ccc2c(=O)c(-c3ccccc3)coc2c1

Procedure:
12 g of 7-hydroxy-isoflavone are boiled for 2 hours under a reflux condenser with 10 g of potassium carbonate and 9 g of isopropyl bromide in 40 ml of dimethyl formamide. On pouring the reaction mixture into water, the separated product is recrystallized from acetone, yielding 7-isopropoxy-isoflavone. In a similar way all the other isoflavone derivatives described in Example 7 can be prepared.