Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN1CCCC1=O.Cl[C:9]1[CH:10]=[C:11]([C:16]2[CH:20]=[C:19]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)=[CH:24][CH:23]=3)[O:18][N:17]=2)[C:12]([NH2:15])=[N:13][CH:14]=1.C(O)=O.C(N(CC)C(C)C)(C)C>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>[N:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[CH2:29][O:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][C:19]2[O:18][N:17]=[C:16]([C:11]3[C:12]([NH2:15])=[N:13][CH:14]=[CH:9][CH:10]=3)[CH:20]=2)=[CH:23][CH:24]=1
Reactant: Nc1ncc(Cl)cc1-c1cc(Cc2ccc(OCc3ccccn3)cc2)on1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O=CO
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncccc1-c1cc(Cc2ccc(OCc3ccccn3)cc2)on1
Temperature: 100 °C
Reaction time: 0.58 h
Yield: 6.5 %

Procedure:
To a N-methylpyrrolidinone (4 mL) solution of 5-chloro-3-(5-(4-(pyridin-2-ylmethoxy)-benzyl)-isoxazol-3-yl)-pyridin-2-ylamine (141 mg, 0.359 mmol) described in Manufacturing Example 189-1-2 were added tetrakis(triphenylphosphine)palladium (0) (42 mg, 36 μmol), formic acid (20 μL, 0.58 mmol), and N,N-diisopropylethylamine (193 μL, 1.08 mmol), which was stirred under nitrogen atmosphere for 5 hours and 35 minutes at 100° C. Water was added to the reaction mixture at room temperature, which was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure. The residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid), and then further purified by NH silica gel column chromatography (ethyl acetate:methanol=10:1) to obtain the title compound (8.3 mg, 6.5%).
Reaction SMILES: C([O:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:6]1)(=O)C.[OH-].[K+]>C(O)C.O>[C:14]1([C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:12]=2[CH2:13][CH:5]([OH:4])[CH2:6]3)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(=O)OC1Cc2cccc(-c3ccccc3)c2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: OC1Cc2cccc(-c3ccccc3)c2C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.3 %

Procedure:
A mixture of 1.22 g (0.0048 mole) of 4-phenyl-2-indanyl acetate, prepared as described above, and 0.39 g (0.007 mole) of potassium hydroxide in 10 ml of absolute ethanol and 5 ml of water was stirred at room temperature for approximately 18 hours. The reaction mixture was concentrated, and water was added to the residue, forming a precipitate. The precipitate was collected on a filter paper and dried to give 0.79 g of (+)-4-phenyl-2-indanol, mp 87°-92° C., EE 50%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:24]3[C:19](=[CH:20][N:21]=[CH:22][CH:23]=3)[N:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:17]=2Cl)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:32][C:33]1[C:34]([CH3:41])=[C:35]([OH:40])[C:36]([CH3:39])=[CH:37][CH:38]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:24]3[C:19](=[CH:20][N:21]=[CH:22][CH:23]=3)[N:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:17]=2[O:40][C:35]2[C:36]([CH3:39])=[CH:37][CH:38]=[C:33]([F:32])[C:34]=2[CH3:41])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2c(Cl)n(-c3ccccc3)c3cnccc23)CC1
Reactant: Cc1ccc(F)c(C)c1O
Product: Cc1ccc(F)c(C)c1Oc1c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c2ccncc2n1-c1ccccc1

Procedure:
The title compound was prepared analogously as described in example 1, step 6, from the compound of example 16, step 5, (100 mg, 227 μmol) and 3-fluoro-2,6-dimethylphenol.
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]2[CH2:11][CH:10]([OH:12])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28].O>ClCCl>[C:13]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:11][CH:10]([O:12][S:27]([CH3:26])(=[O:29])=[O:28])[CH2:9]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CS(=O)(=O)Cl
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Reaction time: 0.08 h
Yield: 83.9 %

Procedure:
To a solution of 1-diphenylmethylazetidin-3-ol (see Preparation 10) (65.9 g, 275.7 mmol) in dry dichioromethane (700 ml) at 0° C. under nitrogen was added triethylamine (57 ml, 1.2 mol. equiv.). After five minutes, methanesulphonyl chloride (25.6 ml, 1.5 mol. equiv.) was added and the mixture stirred for one hour. Water (300 ml) was then added and the mixture extracted with dichloromethane (3×300 ml). The combined organic layers were dried over magnesium sulphate. The solution was then filtered and the solvent removed from the filtrate under reduced pressure. The residue was chromatographed using silica gel eluting with methanol:dichloromethane (1:49, by volume) to give the title compound (73.4 g) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2([C:13]#[N:14])[CH2:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2([CH2:13][NH2:14])[CH2:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc(C2(C#N)CCC2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(C2(CN)CCC2)n1
Temperature: 25 °C
Yield: 94.6 %

Procedure:
To a stirred solution of 1-(6-methoxypyridin-2-yl)cyclobutanecarbonitrile (1.7 g, 8.8 mmol, 1.0 equiv) in THF (20 mL) was added lithium aluminum hydride solution (1.0 M in THF, 11 mL, 11 mmol, 1.1 equiv). The mixture was refluxed for 1.5 hours and allowed to cool to room temperature. Water (0.43 mL) was added slowly followed by 0.43 mL of 3 M NaOH and then three additions of 0.43 mL of water (Fieser and Fieser workup). The resulting mixture was filtered through diatomaceous earth and rinsed with THF. The combined organics were dried over Na2SO4 and concentrated to dryness to give the desired product (1.6 g, 97%) as a viscous oil.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([O:11][CH3:12])[CH:3]=1.[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>C(O)C.C1(P([Pd-4](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)C=CC=CC=1>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=1
Reactant: COc1cc(I)cc([N+](=O)[O-])c1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc(-c2ccccc2)cc([N+](=O)[O-])c1
Yield: 80.7 %

Procedure:
1-Iodo-3-methoxy-5-nitro-benzene (279 mg, 1 mmol), phenylboronic acid (146 mg, 1.2 mmol), potassium carbonate (2M, 1.0 ml) and tetrakis(triphenylphosphino)palladium(0) are dissolved in ethanol (0.5 ml) and toluene (10 ml) and the mixture heated to 90° C. for 24 h. The volatile components are removed in vacuo and the residue codistilled twice with toluene. Flash chromatography (silica, eluent dichloromethane/cyclohexane 1:2) affords the product (185 mg, 81%) as light brown solid. MS: m/e=229 (M+).
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].CC1(C)C(C)(C)OB([C:26]2[CH:31]=[CH:30][C:29]([C@H:32]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH3:33])=[CH:28][CH:27]=2)O1>>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:8]2[NH:7][C:6](=[O:14])[C:5]3[S:15][CH:16]=[CH:17][C:4]=3[C:3]=2[C:2]=1[C:26]1[CH:27]=[CH:28][C:29]([C@H:32]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH3:33])=[CH:30][CH:31]=1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc([C@@H](C)NC(=O)OC(C)(C)C)cc1
Yield: 60.7 %

Procedure:
Following Step 1 from General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (480 mg, 1.5 mmol) was reacted with (R)-tert-butyl 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethylcarbamate (800 mg, 2.3 mmol) to afford the desired product (410 mg, 59%) as a brown solid: ESI MS m/z 451 [C25H26N2O4S+H]+.
Reaction SMILES: C([O:8][C:9](=[O:28])[C@@H:10]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)C1C=CC=CC=1>C(O)C.[C].[Pd]>[C:24]([O:23][C:21]([NH:20][C@@H:10]([CH2:11][CH2:12][CH2:13][N:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1)[C:9]([OH:28])=[O:8])=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCN1CCCCC1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H](CCCN1CCCCC1)C(=O)O
Reaction time: 1 h

Procedure:
To a solution of crude N-t-butoxycarbonyl-(S)-2-amino-5-(1-piperidinyl)pentanoic acid benzyl ester in ethanol (1.5 mL) was added 5% palladium-carbon (15.0 mg) and the mixture was stirred for 1 hour under hydrogen atmosphere. The insoluble materials were removed by suction filtration using selite, and the residue was washed with ethanol (10 mL). The filtrate and washings were collected and concentrated under vacuum to obtain crude N-t-butoxycarbonyl-(S)-2-amino-5-(1-piperidinyl)pentanoic acid (69.0 mg) as a colorless oily material.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[OH:15])[O:3]1.C(=O)([O-])[O-].[K+].[K+].F[C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1>CN(C=O)C>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:16])([CH3:1])[O:3][B:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)[O:5]1
Reactant: CC1(C)OB(c2ccccc2O)OC1(C)C
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)OB(c2ccccc2Oc2ccc([N+](=O)[O-])cc2)OC1(C)C
Temperature: 120 °C
Reaction time: 18 h

Procedure:
To a solution of 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (2.00 g, 9.09 mmol) in DMF was added potassium carbonate (2.51 g, 18.2 mmol) and 1-fluoro-4-nitrobenzene (0.964 ml, 9.09 mmol). The reaction mixture was flushed with nitrogen, sealed, and heated to 120° C. After 18 h, water was added and the mixture was extracted 2× with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo, and the crude was purify by silica gel chromatography, eluting with 0-15% EtOAc/hexanes to give 4,4,5,5-tetramethyl-2-(2-(4-nitrophenoxy)phenyl)-1,3,2-dioxaborolane as a white solid. MS m/z=342 [M+1]+. Calc'd for C18H20BNO5: 341.17.
Reaction SMILES: [OH-].[Li+].[Br:3][C:4]1[N:5]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]([CH:25]3[CH2:27][CH2:26]3)=[CH:17][CH:16]=2)[C:6]([S:9][CH2:10][C:11]([O:13]C)=[O:12])=[N:7][N:8]=1.C1COCC1.Cl>O.C(O)C>[Br:3][C:4]1[N:5]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]([CH:25]3[CH2:27][CH2:26]3)=[CH:17][CH:16]=2)[C:6]([S:9][CH2:10][C:11]([OH:13])=[O:12])=[N:7][N:8]=1
Reactant: COC(=O)CSc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: O=C(O)CSc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 93 %

Procedure:
A solution of lithium hydroxide (98 mg, 4.1 mmol) in water (10 mL) was added dropwise over 5 mins to a solution of methyl 2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthio)acetate (prepared as described in example I above; 1.14 g, 2.7 mmol) in ethanol (10 mL) and THF (10 mL) at 0° C. The mixture was stirred at 0° C. for a further 45 mins and then neutralized to pH 7 by the addition of 0.5N HCl solution at 0° C. The resulting mixture was concentrated in vacuo to ⅕th of its original volume, then diluted with water (−20 mL) and acidified to pH 2-3 by the addition of 0.5N HCl to produce a sticky solid. (If the product comes out as an oil during acidification, extraction with DCM is recommended.) The tan solid was collected by vacuum filtration and dried under high vacuum at 50° C. for 16 h in the presence of P2O5 to yield 2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid (1.02 g, 93%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](O)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].N1CCCCC1.[OH:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH:24]1[C:29]1[CH:36]=[CH:35][C:32](C=O)=[CH:31][CH:30]=1>C(O)C>[OH:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH:24]1[C:29]1[CH:36]=[CH:35][C:32]([CH:11]=[CH:10][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[CH:31][CH:30]=1
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Reactant: O=Cc1ccc(C2CNCCN2CCO)cc1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=[N+]([O-])c1ccc(C=Cc2ccc(C3CNCCN3CCO)cc2)cc1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A one liter three necked flask fitted with a dropping funnel, mechanical stirrer, and condenser is charged with 34.35 g of 4-nitrophenylacetic acid. Piperidine (16.2 g) is added dropwise over a period of 30 minutes. At the end of the addition period, 44.46 g of 4-[N-(2-hydroxyethyl)piperazinyl]benzaldehyde is added. The mixture is heated at 100° C. for three hours, and at 130° C. for three hours. After cooling, the resultant semi-solid mass is ground up in ethanol in a blender, then filtered, washed with water, and vacuum dried. The crude solid is recrystallized from chlorobenzene: m.p. 221°-224° C.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]=1[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]#[N:26])=[CH:19][CH:18]=1.BrB(Br)Br>>[OH:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]=1[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]#[N:26])=[CH:19][CH:18]=1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(CCC#N)cc1
Agent: BrB(Br)Br
Product: N#CCCc1ccc(-c2c(O)ccc3[nH]c(=O)c4sccc4c23)cc1
Yield: 12.4 %

Procedure:
Following General Procedure F, 3-[4-(8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl]propanenitrile (45 mg, 0.13 mmol) was reacted with tribromoborane (3 mL) to afford the desired product (5.6 mg, 13%) as a white solid: 1H NMR (500 MHz, CD3OD) δ 7.53 (d, J=5.4 Hz, 1H), 7.48 (d, J=7.9 Hz, 2H), 7.39 (d, J=8.9 Hz, 1H), 7.28 (d, J=7.9 Hz, 2H), 7.16 (d, J=8.9 Hz, 1H), 5.96 (d, J=5.4 Hz, 1H), 3.10 (t, J=3.8 Hz, 2H), 2.89 (t, J=7.1 Hz, 2H); ESI MS m/z 347 [C20H14N2O2S+H]+; HPLC >99% (AUC), tR=10.99 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:25][CH3:26])=[C:17]([O:20][CH2:21][CH2:22][CH2:23]Cl)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].C([O-])([O-])=O.[K+].[K+].[CH3:33][N:34]1[CH2:39][CH2:38][CH2:37][CH:36]2[CH2:40][NH:41][CH2:42][CH:35]12>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:25][CH3:26])=[C:17]([O:20][CH2:21][CH2:22][CH2:23][N:41]4[CH2:40][CH:36]5[CH:35]([N:34]([CH3:33])[CH2:39][CH2:38][CH2:37]5)[CH2:42]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCCl
Reactant: CN1CCCC2CNCC21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CC2CCCN(C)C2C1
Temperature: 80 °C
Reaction time: 7 h
Yield: 31.7 %

Procedure:
A mixture of N-(3-chloro-4-fluorophenyl)-6-(3-chloropropoxy)-7-methoxyquinazolin-4-amine (1.50 g), K2CO3 (5.00 g) and 1-methyloctahydro-1H-pyrrolo[3,4-b]pyridine (0.90 g) in 25 mL of DMF was stirred at 80° C. for 7 h, poured into 50 mL of ice-water and extracted with CH2Cl2 (50 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and chromatographed with a silica gel column (eluting agent: 20:1 (v/v) DCM/MeOH) to give the title compound as a pale yellow solid (0.60 g, 35.00%), HPLC: 95.00%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 501.1 (M+1); 1H NMR (400 MHz, d6-DMSO) δ: 1.52-1.62 (m, 4H), 1.97-2.00 (m, 3H), 2.07-2.09 (m, 2H), 2.08-2.11 (m, 4H), 2.51-2.56 (m, 1H), 2.57-2.61 (m, 2H), 2.88-2.92 (m, 2H), 3.94 (s, 3H), 4.18 (t, J=8.6 Hz, 2H), 7.19 (s, 1H), 7.44 (t, J=10.4 Hz, 1H), 7.82 (s, 2H), 8.13 (t, J=6.8 Hz, 1H), 8.50 (s, 1H) ppm.
Reaction SMILES: C([O:8]C1C=CC(C(=O)C)=CC=1CO)C1C=CC=CC=1.[CH2:20]([O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[CH:30][C:29]=1[NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)C.O>[CH2:20]([O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([CH:35]=[O:8])=[O:36])=[CH:30][C:29]=1[NH:37][S:38]([CH3:41])(=[O:39])=[O:40])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(=O)c1ccc(OCc2ccccc2)c(CO)c1
Reactant: CC(=O)c1ccc(OCc2ccccc2)c(NS(C)(=O)=O)c1
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)Nc1cc(C(=O)C=O)ccc1OCc1ccccc1

Procedure:
The compound was sbtained as an ethanol hemiacetal, mp 125°-128° (ethanol-water) by the process of Description 54 replacing 1-(4-benzyloxy-3-hydroxymethylphenyl)ethanone by 1-(4-benzyloxy-3-methanesulphonamidophenyl)ethanone. (CDCl3) 8.75 (3H, t, J=6 Hz), 7.05 (3H, s), 5.90-6.40 (2H, m), 4.90 (1H, b), 4.80 (2H, s), 4.46 (1H, s), 2.90 (1H, d, J=8 Hz), 2.60 (5H, s), 2.20 (1H, s), 2.09 (1H, dd, J=8 Hz, 2 Hz), 1.80 (1H, d, J=2 Hz).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8](Cl)=[O:9])[C:4](=[O:11])[O:3]1.[F:13][C:14]1[CH:23]=[CH:22][C:17]([CH2:18][NH:19][O:20][CH3:21])=[CH:16][C:15]=1[CH3:24]>>[CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8]([N:19]([CH2:18][C:17]2[CH:22]=[CH:23][C:14]([F:13])=[C:15]([CH3:24])[CH:16]=2)[O:20][CH3:21])=[O:9])[C:4](=[O:11])[O:3]1
Reactant: CONCc1ccc(F)c(C)c1
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Product: CON(Cc1ccc(F)c(C)c1)C(=O)C=C1OC(C)(C)OC1=O
Yield: 95 %

Procedure:
Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with N-(4-fluoro-3-methyl-benzyl)-O-methyl-hydroxylamine as described in the preparation of compound 1-C gave the title amide as white crystals (95% yield): mp 107-108° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.75 (6H, s, CH3), 2.26 (3H, broad s, CH3), 3.69 (3H, s, OCH3), 4.75 (2H, s, NCH2), 6.39 (1H, s, CH), 6.95 (1H, m, aromatic), 7.13-7.19 (2H, m, aromatics). Anal. calcd for C16H18FNO5: C, 59.43; H, 5.61; N, 4.33. Found: C, 59.24; H, 5.47; N 4.29.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].Cl.Cl.[CH:27]1([N:30]([CH3:37])[C@H:31]2[CH2:36][CH2:35][CH2:34][NH:33][CH2:32]2)[CH2:29][CH2:28]1>>[CH:27]1([N:30]([CH3:37])[C@H:31]2[CH2:36][CH2:35][CH2:34][N:33]([C:19]([C:18]3[CH:22]=[CH:23][C:15]([N:12]4[C:13]([OH:14])=[C:9]([C:6]5[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=5[CH3:24])[CH:10]=[N:11]4)=[N:16][CH:17]=3)=[O:21])[CH2:32]2)[CH2:29][CH2:28]1
Reactant: CN(C1CC1)[C@H]1CCCNC1
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Agent: Cl
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)N3CCC[C@H](N(C)C4CC4)C3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (S)—N-cyclopropyl-N-methylpiperidin-3-amine dihydrochloride. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.68-1.16 (m, 4 H) 1.49-1.68 (m, 1 H) 1.71-2.00 (m, 2 H) 2.17-2.30 (m, 1 H) 2.43 (s, 3 H) 2.91 (d, J=12.38 Hz, 4 H) 3.18 (br. s., 1 H) 3.56 (br. s., 2 H) 3.91-4.58 (m, 1 H) 4.79 (br. s., 1 H) 7.67 (d, J=7.83 Hz, 1 H) 7.71-7.86 (m, 2 H) 8.00-8.28 (m, 2 H) 8.57 (s, 2 H) 9.53 (br. s., 1 H); ESI-MS m/z [M+H]+ 457.3.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[NH:14][C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=2[N:11]=1.[OH-].[Na+].[CH3:21]OS(OC)(=O)=O>CN(C)C=O>[CH3:21][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[NH:11][C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1
Reactant: COS(=O)(=O)OC
Reactant: c1ccc2[nH]c(-c3nc4ccccc4[nH]3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cn1c(-c2nc3ccccc3[nH]2)nc2ccccc21
Reaction time: 24 h
Yield: 39.3 %

Procedure:
To a flask were added 1.2 g 1H,1′H-2,2′-bibenzimidazole, 0.45 g sodium hydroxide, 100 ml N,N-dimethylformamide and 1.4 g dimethylsulfate. The mixture was heated to 45 C under nitrogen for 16 hours and another 0.45 g sodium hydroxide and 2.8 g dimethylsulfate were added and the mixture was stirred at 45 C for 24 hours. Another 4.2 g of dimethylsulfate were added and the mixture was stirred at 45 C for 24 hours, then cooled to 22 C and quenched with 350 ml water. The off-white solid was filtered and washed with water. After dissolving the product in 125 ml hot ethanol, 44 ml water were added and the solution was cooled to 5 C, filtered, washed with 50% ethanol and dried leaving 0.5 g white solid.
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]([CH3:34])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:18]=[C:17]3[O:19][C:20]4[C:25]([CH:26]([C:27]5([C:30]([O:32]C)=[O:31])[CH2:29][CH2:28]5)[C:16]3=[CH:15][CH:14]=2)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:9][CH:8]=1)=[O:6].Cl.C(OCC)(=O)C>CO>[CH3:3][N:4]([CH3:34])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:18]=[C:17]3[O:19][C:20]4[C:25]([CH:26]([C:27]5([C:30]([OH:32])=[O:31])[CH2:29][CH2:28]5)[C:16]3=[CH:15][CH:14]=2)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:9][CH:8]=1)=[O:6]
Reactant: COC(=O)C1(C2c3ccccc3Oc3nc(-c4ccc(C(=O)N(C)C)cc4)ccc32)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CN(C)C(=O)c1ccc(-c2ccc3c(n2)Oc2ccccc2C3C2(C(=O)O)CC2)cc1
Temperature: 60 °C

Procedure:
A 1 N aqueous solution of NaOH (0.5 mL, 0.500 mmol) was added to a solution of the product from Step 4 (11 mg, 0.026 mmol) in MeOH (1 mL) at room temperature. The mixture was heated to 60° C. for 3 h, cooled to room temperature and adjusted pH2-3 with 1 N aqueous HCl. Following addition of ethyl acetate (60 mL), the mixture was washed with brine (10 mL), dried (MgSO4) and concentrated to give 1-(2-(4-(dimethylcarbamoyl)phenyl)-5H-chromeno[2,3-b]pyridin-5-yl)cyclopropanecarboxylic acid as crude material (11 mg), which was taken to the next step directly. MS (ES+) m/z: 415 (M+H).
Reaction SMILES: C1C(=O)N(I)C(=O)C1.[OH:9][CH:10]([CH2:22][NH:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=[C:26]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:25]=1)[CH2:11][NH:12][C:13](=O)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:13]([NH:12][CH2:11][CH:10]([OH:9])[CH2:22][NH:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=[C:26]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:25]=1)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cc1ccccc1)NCC(O)CNc1cc(-c2ccccc2)nc2ccccc12
Agent: O=C1CCC(=O)N1I
Product: OC(CNCCc1ccccc1)CNc1cc(-c2ccccc2)nc2ccccc12

Procedure:
The title compound, NIS: m/e=398 (M+H+), was prepared from (RS)-N-[2-hydroxy-3-(2-phenyl-quinolin-4-ylamino)-propyl]-2-phenyl-acetamide.