Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=2[F:30])=[C:4]([CH:12]=[C:13]([CH2:16][NH:17][O:18][CH2:19][CH2:20][OH:21])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6].CCN(CC)CC.C1C[O:41][CH2:40][CH2:39]1>>[C:40]([N:17]([CH2:16][C:13]1[C:14]([F:15])=[C:2]([F:1])[C:3]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=2[F:30])=[C:4]([CH:12]=1)[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6])[O:18][CH2:19][CH2:20][OH:21])(=[O:41])[CH3:39]
Reactant: C1CCOC1
Reactant: O=C(NOCCO)c1cc(CNOCCO)c(F)c(F)c1Nc1ccc(I)cc1F
Solvent: CCN(CC)CC
Product: CC(=O)N(Cc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F)OCCO
Reaction time: 12 h

Procedure:
CH3CO2H (300 mg), EDC.HCl (958 mg), and HODhbt (816 mg) were mixed in CH2Cl2 (5 mL) for 2 hours to give an active ester solution. A portion of this solution (0.2 mL) was added to a solution of 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-ethoxyamino)-methyl]-benzamide (80 mg) obtained in Example 6 and NEt3 (29 μL) in THF, and the mixture was stirred for 12 hours. The reaction mixture was washed with 0.3 N aqueous HCl and aqueous NaHCO3, and subjected to silica gel chromatography (CH2Cl2/MeOH as a developing solvent) to give the title compound (12.0 mg).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[N:7]2.[O:33]1[CH2:38][CH2:37][CH:36]([C:39](Cl)=[O:40])[CH2:35][CH2:34]1>>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:14][CH2:15][N:16]([C:39]([CH:36]3[CH2:37][CH2:38][O:33][CH2:34][CH2:35]3)=[O:40])[CH2:17][CH2:18]1)=[N:7]2
Reactant: O=C(Cl)C1CCOCC1
Reactant: Cc1c(N2CCNCC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1
Product: Cc1c(N2CCN(C(=O)C3CCOCC3)CC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

Procedure:
Prepared according to Procedure R using 5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)-2-(piperazin-1-yl)quinolin-4-amine (40.0 mg, 0.09 mmol) and tetrahydro-2H-pyran-4-carbonyl chloride to give (4-(5,7-difluoro-3-methyl-4-(5-morpholinopyridin-3-ylamino)quinolin-2-yl)piperazin-1-yl)(tetrahydro-2H-pyran-4-yl)methanone. 1H NMR (DMSO-d6) δ ppm 1.55-1.67 (m, 4H), 2.10 (br s, 3H), 2.91-2.96 (m, 1H), 3.05 (t, J=4.4 Hz, 4H), 3.24 (br s, 2H), 3.33-3.43 (m, 3H), 3.64 (br s, 2H), 3.69 (t, J=4.0 Hz, 7H), 3.85-3.88 (m, 2H), 6.51 (d, J=2.0 Hz, 1H), 7.13-7.19 (m, 1H), 7.25-7.29 (m, 1H,), 7.52 (d, J=2.0 Hz, 1H), 7.78 (d, J=2.4 Hz, 1H), 8.36 (s, 1H). Mass Spectrum (ESI) m/e=553.4 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][C:5]2=[O:12].[Si:13](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1C=CN=C1>CN(C=O)C>[Si:13]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][C:5]2=[O:12])([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1CCOc2ccc(O)cc21
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](Oc1ccc2c(c1)C(=O)CCO2)(c1ccccc1)c1ccccc1
Temperature: 60 °C

Procedure:
A mixture of 6-hydroxy-2,3-dihydro-4H-chromen-4-one (1.65 g, 10.1 mmol), tert-butyldiphenylsilylchloride (6.87 g, 25.2 mmol), and imidazole (2.1 g, 30.3 mmol) in degassed DMF (30 mL) was heated at 60° C. for 18 hours. The solvent was removed in vacuo and the residue purified by silica gel chromatography, eluting with hexane—20% EtOAc, to yield the titled product.
Reaction SMILES: [CH3:1][C:2]1[C:11]([N+:12]([O-])=O)=[C:10]([NH:15][CH3:16])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:17](O)(=O)C>[Pd].C(OCC)(=O)C>[CH3:17][N:15]1[C:10]2[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([CH3:1])[C:11]=2[N:12]=[CH:16]1
Reactant: CC(=O)O
Reactant: CNc1ccc(C(=O)OC)c(C)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(ncn2C)c1C
Reaction time: 18 h
Yield: 95.5 %

Procedure:
A mixture of methyl 2-methyl-4-(methylamino)-3-nitrobenzoate (90 mg, 0.4 mmol), 10% palladium on charcoal (Degussa type, 90 mg), acetic acid (124 uL, 1.5 mmol), and ethyl acetate (20 mL) was shaken in a Parr hydrogenation apparatus at 40 psi for 18 hours. The reaction mixture was then filtered and concentrated. The residue was dissolved in formic acid was stirred at 100° C. for 1.5 hour. The reaction mixture was concentrated, quenched with ice-water (15 mL) and the pH was adjusted to basic by portion-wise sodium bicarbonate addition then extracted with ethyl acetate. The combined extract was washed with water (2×30 mL), brine (30 mL), dried over sodium sulfate, filtered and concentrated to give methyl 1,4-dimethyl-1H-benzimidazole-5-carboxylate (78 mg, 95% yield). MS (EI) for C 1H12N2O2: 205 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][CH2:12][C:11](=[O:15])[CH2:10]2)[C:5]([F:16])=[CH:4][N:3]=1.[CH3:17][Mg]Br.[NH4+].[Cl-].CCOC(C)=O>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][CH2:12][C:11]([CH3:17])([OH:15])[CH2:10]2)[C:5]([F:16])=[CH:4][N:3]=1
Reactant: O=C1CCC[C@H](Nc2nc(Cl)ncc2F)C1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(O)CCC[C@H](Nc2nc(Cl)ncc2F)C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of (3S)-3-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]cyclohexanone (1.83 g, 7.49 mmol) in THF (100 mL) was added methylmagnesium bromide (21.4 ml of 1.4M solution, 29.96 mmol) at room temperature. The reaction mixture was stirred at room temperature for 5 minutes. To the reaction mixture was added aqueous saturated NH4Cl solution and EtOAc. The organic phase was washed with brine and dried with MgSO4, filtered and concentrated in vacuo. The two spots were separated by silica gel chromatography (120g silica gel column).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]=[CH2:16])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[CH3:17].B1C2CCCC1CCC2.[OH-:27].[Na+].OO>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][OH:27])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[CH3:17]
Reactant: [OH-]
Reactant: C=Cc1ccc(Oc2ccc(Cl)c(C)c2)cc1
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(Oc2ccc(CCO)cc2)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.8 %

Procedure:
To the solution of 1-chloro-4-[(4-ethenylphenyl)oxy]-2-methylbenzene (2.46 g, 10.05 mmol) in dry THF (30 mL), was added 9-BBN (30.2 mL, 15.08 mmol) at 0° C. The mixture was stirred at room temperature overnight, and quenched with water (3 mL), followed by aq. NaOH (13.00 mL, 39.0 mmol), and 30% H2O2 (13.00 mL, 126 mmol). The reaction mixture was heated at 50° C. for 3 h. Then THF was removed under reduced pressure, and the residue was diluted with EA. The organic layer was washed with water and brine, dried over anhydrous Na2SO4 and concentrated and purified by flash chromatography to afford the title compound (1.13 g, 42.8% yield) as colorless oil. LCMS: rt=3.49 min, [M+H+]=245
Reaction SMILES: C([NH:9][C:10]([NH:12][CH:13]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[S:11])(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].C1COCC1>CO.O>[CH:13]1([NH:12][C:10]([NH2:9])=[S:11])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C(NC(=S)NC1CCCCCCC1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: NC(=S)NC1CCCCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-benzoyl-3-cyclooctylthiourea (14.3 g, 49.1 mmol) and potassium carbonate (34.6 g, 250 mmol) in methanol (200 mL), water (100 mL), and THF (100 mL) was stirred at ambient temperature overnight. The low boiling solvents were removed in vacuo, and the residue was partitioned between EtOAc and water. The organic portion was washed with brine, and concentrated in vacuo. The title compound was obtained as a white solid after flash column chromatography (0 to 100% of ethyl acetate in hexanes). MS m/z: 187.1 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[C:14]2[O:13][CH:12]([CH3:15])[C:11](=[O:16])[N:10]([CH:17]3[CH2:20][N:19]([C:21](=[O:23])[CH3:22])[CH2:18]3)[CH2:9][C:8]=2[C:7]([F:24])=[C:6]([Cl:25])[CH:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+].C(O)(=O)C>CO.C(OCC)(=O)C.O>[C:21]([N:19]1[CH2:20][CH:17]([N:10]2[CH2:9][C:8]3[C:7]([F:24])=[C:6]([Cl:25])[CH:5]=[C:4]([CH:1]([OH:3])[CH3:2])[C:14]=3[O:13][CH:12]([CH3:15])[C:11]2=[O:16])[CH2:18]1)(=[O:23])[CH3:22]
Reactant: CC(=O)c1cc(Cl)c(F)c2c1OC(C)C(=O)N(C1CN(C(C)=O)C1)C2
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: CC(=O)N1CC(N2Cc3c(F)c(Cl)cc(C(C)O)c3OC(C)C2=O)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 9-acetyl-4-(1-acetylazetidin-3-yl)-7-chloro-6-fluoro-2-methyl-4,5-dihydro-1,4-benzoxazepin-3(2H)-one (112 mg, 0.304 mmol) in methanol (5.6 mL) at −10° C. was treated with sodium tetrahydroborate (17 mg, 0.456 mmol) and stirred for 30 min at 0° C. The reaction mixture was quenched with acetic acid (86 μL, 1.52 mmol) at 0° C. and then diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated to give a crude residue. Purification via preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) gave two fractions. Each fraction contained a pair of enantiomers: peak 1 (30 mg, 27%) and peak 2 (50 mg, 44%). Peak 1: LCMS calculated for C17H21ClFN2O4 (M+H)+: m/z=371.1; found: 371.1. Peak 2: LCMS calculated for C17H21ClFN2O4 (M+H)+: m/z=371.1; found: 371.1.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:17]2[CH2:21][CH2:20][N:19]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([NH:29]C(=O)OC(C)(C)C)=[CH:25][CH:24]=3)[C:18]2=[O:37])[S:5][C:6]=1[C:7](=[O:16])[NH:8][CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][N:19]2[CH2:20][CH2:21][N:17]([C:4]3[S:5][C:6]([C:7]([NH:8][CH2:9][C:10]4[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=4)=[O:16])=[C:2]([CH3:1])[CH:3]=3)[C:18]2=[O:37])=[CH:28][CH:27]=1
Reactant: Cc1cc(N2CCN(Cc3ccc(NC(=O)OC(C)(C)C)cc3)C2=O)sc1C(=O)NCc1cccnc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(N2CCN(Cc3ccc(N)cc3)C2=O)sc1C(=O)NCc1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
A mixture of tert-butyl 4-((3-(4-methyl-5-(pyridin-3-ylmethylcarbamoyl)-thiophen-2-yl)-2-oxoimidazolidin-1-yl)methyl)phenylcarbamate (0.18 g, 0.34 mmol) and trifluoroacetic acid (2 mL) in dichloromethane (2 mL) was stirred at ambient temperature for 2 h and concentrated. The residue was taken up in saturated aqueous sodium bicarbonate solution (25 mL) and extracted with dichloromethane (2×50 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluted with 0-10% methanol in dichloromethane to afford the title compound as a cream solid in 46% yield (0.07 g): mp 118-120° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.52 (s, 1H), 8.44 (s, 1H), 8.30 (t, J=5.9 Hz, 1H), 7.70 (d, J=7.9 Hz, 1H), 7.53 (dd, J=7.9, 4.8 Hz, 1H), 6.93 (d, J=8.4 Hz, 2H), 6.52 (d, J=8.4 Hz, 2H), 6.18 (s, 1H), 5.09 (br s, 2H), 4.38 (d, J=5.9 Hz, 2H), 4.18 (s, 2H), 3.80-3.72 (m, 2H), 3.40-3.32 (m, 2H), 2.36 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 162.9, 155.3, 148.8, 148.0, 147.8, 142.7, 139.1, 135.4, 135.0, 128.9, 123.4, 123.0, 119.7, 113.8, 111.8, 46.8, 42.4, 40.9, 15.7; MS (ES+) m/z 422.2 (M+1).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20].C(O)(C)C.CCCCCC>C(O)CCC>[Cl:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH:20][C:2]1[C:3]2[CH:10]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CCOC(=O)c1cc2c(Cl)ncnc2[nH]1
Reactant: Nc1cccc(Cl)c1
Solvent: CCCCCC
Solvent: CCCCO
Solvent: CC(C)O
Product: CCOC(=O)c1cc2c(Nc3cccc(Cl)c3)ncnc2[nH]1
Temperature: 25 °C

Procedure:
Under an argon atmosphere, 29.0 g (128 mmol) of 4-chloro-6-ethoxycarbonyl-7H-pyrrolo[2,3-d]pyrimidine and 18.0 ml (171 mmol) of 3-chloro-aniline in 430 ml of n-butanol are stirred at 100° C. for 3 hours (almost dissolved after ≈1 hour, then a thick suspension forms). The reaction mixture is cooled to ~50° C., then 400 ml of isopropanol/hexane (1:1) are added thereto. The reaction mixture is then cooled to RT and the product is filtered off and washed with isopropanol and hexane. Stirring from diethyl ether yields the title compound: 1H-NMR (DMSO-d6) 13.0 and 10.53 (2 sb, 2HN), 8.48 (s, 1H), 8.13 (m, 1H), 7.78 (dm, J=8, 1H), 7.76 (s, 1H), 7.45 (t, J=8, 1H), 7.21 (dm, J=8, 1H), 4.37 (q, J=7, 2H), 1.37 (t, J=7, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)[N:10]=[C:4]2[CH:3]=1.[I:17]N1C(=O)CCC1=O>C(#N)C>[I:17][C:8]1[N:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][C:4]2=[N:10][C:9]=1[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1
Reactant: Cc1ccn2cc(-c3ccncc3)nc2c1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: Cc1ccn2c(I)c(-c3ccncc3)nc2c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of 7-methyl-2-pyridin-4-ylimidazo[1,2-a]pyridine (6.52 g, 31.1 mmol), N-iodosuccinimide (7.0 g, 31.1 mmol) and ACN (180 ml) is stirred at RT for 17 h. The precipitate is collected, washed with ACN and dried. Yield: 4.4 g (42%). HPLC-MS: M+H=336; tR=1.55 min (*Method—3).
Reaction SMILES: [ClH:1].Cl.[CH2:3]([NH:11][CH2:12][C@H:13]([NH:15][S:16]([C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[N:24][CH:23]=[CH:22]2)(=[O:18])=[O:17])[CH3:14])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C=O.[C:31]([BH3-])#N.[Na+]>C(O)C>[ClH:1].[ClH:1].[CH3:31][N:11]([CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:12][C@H:13]([NH:15][S:16]([C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[N:24][CH:23]=[CH:22]2)(=[O:18])=[O:17])[CH3:14]
Reactant: [BH3-]C#N
Reactant: C[C@H](CNCCc1ccccc1)NS(=O)(=O)c1ccc2cnccc2c1
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: C[C@H](CN(C)CCc1ccccc1)NS(=O)(=O)c1ccc2cnccc2c1
Yield: 75.4 %

Procedure:
The compound of Example 23 (54 mg) was N-methylated by the action of paraformaldehyde (50 mg) and sodium cyanoborohydride (63 mg) in ethanol to obtain a crude product. Subsequently, 21 mg of the title compound was obtained as a gray solid (35%) with reference to the method of Step 3 of Example 1.
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=O)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1>>[CH3:19][C:20]1[CH:26]=[CH:25][C:23]([NH:24][C:13](=[O:15])[C:12]2[CH:16]=[CH:17][CH:18]=[C:10]([S:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)(=[O:8])=[O:9])[CH:11]=2)=[CH:22][CH:21]=1
Reactant: Cc1ccc(N)cc1
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCCCC2)c1
Product: Cc1ccc(NC(=O)c2cccc(S(=O)(=O)N3CCCCC3)c2)cc1

Procedure:
The entitled compound was produced according to the method of Example 73 but using 3-(piperidin-1-ylsulfonyl)benzoic acid and 4-methylaniline as the starting materials.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[C:12]([O:13][CH2:14][O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=[C:9]([O:19][CH2:20][O:21][CH3:22])[C:8]=1[O:23][CH3:24]>CCCCCCC>[CH3:18][O:17][C:11]1[CH:10]=[C:9]([O:19][CH2:20][O:21][CH3:22])[C:8]([O:23][CH3:24])=[C:7]([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH3:7])[C:12]=1[O:13][CH2:14][O:15][CH3:16]
Reactant: COCOc1cc(OC)c(OCOC)c(CCCCCBr)c1OC
Solvent: CCCCCCC
Product: CCCCC#CCCCCCc1c(OC)c(OCOC)cc(OC)c1OCOC

Procedure:
By using procedures similar to those described in the above-mentioned Example 30 (2), except that 1-bromo-5-[2,5-dimethoxy-3,6-bis(methoxymethoxy)phenyl]pentane was used in place of 1-bromo-7-[2,5-dimethoxy-3,6-bis methoxymethoxy)phenyl]heptane, there was obtained 1,4-dimethoxy-2,5-bis(methoxymethoxy)-3-(6-undecynyl)benzene. Colorless oily substance.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl.[NH2:17][OH:18].C(=O)([O-])O.[Na+]>CO>[F:1][C:2]1[CH:7]=[C:6]([C:8]([NH:17][OH:18])=[NH:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: N#Cc1ccc(-c2ccccc2)c(F)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: N=C(NO)c1ccc(-c2ccccc2)c(F)c1
Temperature: 25 °C

Procedure:
A solution of 2-fluorobiphenyl-4-carbonitrile (1.97 g, 0.01 mol), hydroxylamine hydrochloride (2.09 g, 0.03 mol) and sodium hydrogen carbonate (4.2 g, 0.05 mol) in methanol (50 mL) is heated to reflux for 7 hrs. The reaction mixture is then cooled to room temperature and filtered. The solid is washed with methanol (20 mL). The combined methanol solution is concentrated to dryness to get 2-fluoro-N-hydroxybiphenyl-4-carboxamidine which is used as such for the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][C:15]2[C:18]([F:23])=[CH:19][CH:20]=[C:21](O)[C:14]=2[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH2:54]([O:56][C:57](=[O:76])[CH2:58][C:59]1[CH:64]=[CH:63][C:62]([O:65][CH3:66])=[C:61](B2OC(C)(C)C(C)(C)O2)[CH:60]=1)[CH3:55].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl.C1(C)C=CC=CC=1.CCO.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>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][C:14]2[C:21]([C:61]3[CH:60]=[C:59]([CH2:58][C:57]([O:56][CH2:54][CH3:55])=[O:76])[CH:64]=[CH:63][C:62]=3[O:65][CH3:66])=[CH:20][CH:19]=[C:18]([F:23])[C:15]=2[CH2:16][CH2:17]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)N1CCc2c(O)ccc(F)c2CC1
Reactant: CCOC(=O)Cc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(F)c3c2CCN(C(=O)OCc2ccccc2)CC3)c1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To an ice-cooled suspension of 6-fluoro-9-hydroxy-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylic acid benzyl ester (170 mg, 0.54 mmol, 1.00 eq) in DCM (10 mL), NEt3 (0.23 mL, 1.62 mmol, 3.00 eq) and trifluoromethanesulfonic anhydride (0.14 mL, 0.81 mmol, 1.50 eq.) were added in sequence. The reaction mixture was stirred at 0° C. for 30 min and further at r.t. for 45 min. The mixture was diluted with DCM (20 mL) and washed with sat. aq. NaHCO3 soln. (2×10 mL). The org. layer was dried over MgSO4 and concentrated in vacuo. To a mixture under N2 of the resulting triflate, [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester (173 mg, 0.54 mmol, 1.00 eq.), and sodium carbonate (229 mg, 2.16 mmol, 4.00 eq.) in toluene/EtOH/water 20:4:1 (10 mL), tetrakis(triphenylphosphine) palladium (0) (31 mg, 0.03 mmol, 0.05 eq.) was added. The mixture was stirred at 100° C. for 17 hours. The mixture was allowed to cool to r.t. and concentrated in vacuo. The residue was taken up in DMF, filtered, and purified by prep. HPLC (column Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give the title compound as a brown oil.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]2[O:7][C:8]3[C:13]([C:14](=[O:16])[CH:15]=2)=[C:12]([O:17][CH3:18])[C:11]([O:19][CH3:20])=[C:10]([O:21][CH3:22])[CH:9]=3)=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:31][S:32](Cl)(=[O:34])=[O:33].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:31][S:32]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]2[O:7][C:8]3[C:13]([C:14](=[O:16])[CH:15]=2)=[C:12]([O:17][CH3:18])[C:11]([O:19][CH3:20])=[C:10]([O:21][CH3:22])[CH:9]=3)=[CH:23][CH:24]=1)(=[O:34])=[O:33]
Reactant: COc1cc2oc(-c3ccc(N)cc3)cc(=O)c2c(OC)c1OC
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc2oc(-c3ccc(NS(C)(=O)=O)cc3)cc(=O)c2c(OC)c1OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
The aminoflavone 10a (0.13 g, 0.40 mmol) was dissolved in 5 mL of dry methylene chloride, then 2 mL of freshly distilled pyridine was added. The solution was cooled to 0° C. then was dropwise added freshly distilled methanesulfonyl chloride (0.6 mmol). The reaction mixture was stirred at 0° C. for 1 h and at room temperature for an additional hour, then poured into 30 mL saturated NaHCO3. The resulting mixture was extracted with methylene chloride. The combined organic layers were washed with 5% HCl to remove pyridine, dried over Na2SO4 and concentrated. The residue was purified by column chromatography on silica gel (acetone:toluene=1:5) to give 10e (0.12 g, 74%). 1H NMR (400 MHz, Acetone) δ 3.11 (s, 3H), 3.81 (s, 3H), 3.87 (s, 3H), 4.00 (s, 3H), 6.60 (s, 1H), 7.11 (s, 1H), 7.50 (d, J=8.8 Hz, 2H), 8.02 (d, J=8.8 Hz, 2H).
Reaction SMILES: NN.[CH:3]1([NH:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]2[C:25]3[C:24]([CH3:26])=[C:23]([CH3:27])[N:22]4[N:28]=[N:29][N:30]=[C:21]4[C:20]=3[N:19]=[C:18]2[CH2:31][O:32][N:33]2C(=O)C3[C:35](=CC=CC=3)[C:34]2=O)=[O:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Cl[CH2:45]Cl>C(O)C>[CH:3]1([NH:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]2[C:25]3[C:24]([CH3:26])=[C:23]([CH3:27])[N:22]4[N:28]=[N:29][N:30]=[C:21]4[C:20]=3[N:19]=[C:18]2[CH2:31][O:32][N:33]=[C:34]([CH3:45])[CH3:35])=[O:11])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: Cc1c(C)n2nnnc2c2nc(CON3C(=O)c4ccccc4C3=O)n(CCCCNC(=O)NC3CCCCC3)c12
Reactant: ClCCl
Agent: NN
Solvent: CCO
Product: CC(C)=NOCc1nc2c(c(C)c(C)n3nnnc23)n1CCCCNC(=O)NC1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Anhydrous hydrazine (0.50 mL, 16.1 mmol) was added to a stirred suspension of N-cyclohexyl-N′-[4-(8-{[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]methyl}-5,6-dimethyl-7H-imidazo[4,5-c]tetraazolo[1,5-a]pyridin-7-yl)butyl]urea (3.00 g, 5.36 mmol) in ethanol (36 mL). Over the next hour, dichloromethane (40 mL) and ethanol (20 mL) were added to prevent the reaction from solidifying. After one more hour, the solvent was removed under reduced pressure, then acetone (27 mL) and methanol (27 mL) were added. The mixture was stirred at room temperature for 2 hours, then a solid was isolated by filtration and washed with methanol. To the solid was added 1 M aqueous sodium hydroxide and the mixture was sonicated for 1 minute. The solid was isolated by filtration, washed with water, and dried under vacuum at 70° C. to provide 2.36 g of N-cyclohexyl-N′-{4-[5,6-dimethyl-8-({[(1-methylethylidene)amino]oxy}methyl)-7H-imidazo[4,5-c]tetraazolo[1,5-a]pyridin-7-yl]butyl}urea.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:11][CH2:12][CH:13]=[CH2:14])[CH2:9][OH:10])=[CH:4][CH:3]=1.[C:15]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:18])C=C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:9][OH:10])[CH2:11][CH2:12][CH:13]=[CH:14][C:15]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])=[CH:6][CH:7]=1
Reactant: C=CC(=O)OCc1ccccc1
Reactant: C=CCCC(CO)c1ccc(Br)cc1
Solvent: ClCCl
Product: O=C(C=CCCC(CO)c1ccc(Br)cc1)OCc1ccccc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 78.9 %

Procedure:
To a degassed solution of 2-(4-bromophenyl)hex-5-en-1-ol (108 mg, 0.423 mmol) in DCM (5 ml) at room temperature was added benzyl acrylate (0.191 ml, 1.270 mmol) and Grubbsll (35.9 mg, 0.042 mmol) and the mixture was stirred at 40° C. for 30 min. The mixture was concentrated and the residue was purified by flash chromatography (5 to 40% Acetone/Heptane) to give the title compound 130 mg (yield 79%). MS (ESI) m/z 490.4 (M+1). Retention time 1.49 min (condition A).