Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22](O)=[O:23])=[C:15]3[N:14]=2)[CH:7]=1.[CH:27]1([NH2:30])[CH2:29][CH2:28]1>>[CH:27]1([NH:30][C:22]([C:21]2[CH:20]=[N:19][N:16]3[CH:17]=[CH:18][C:13]([N:9]4[CH2:10][CH2:11][CH2:12][C@@H:8]4[C:6]4[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=4[O:25][CH3:26])=[N:14][C:15]=23)=[O:23])[CH2:29][CH2:28]1
Reactant: COc1ccc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)O)c2n1
Reactant: NC1CC1
Product: COc1ccc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)NC3CC3)c2n1
Yield: 68 %

Procedure:
Prepared by the method described in Example 1 using (R)-5-(2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation G) and cyclopropylamine to yield the title compound as a white solid (19 mg, 68% yield). MS (apci) m/z=396.0 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH:6]=[C:7]2[C:16](=O)[C:15]3[C:10](=[CH:11][C:12]([C:18]([O:20]C)=[O:19])=[CH:13][CH:14]=3)[O:9][CH2:8]2)=[CH:4][CH:3]=1.Cl.[Cl:25][C:26]1[CH:33]=[C:32]([NH:34][NH2:35])[CH:31]=[CH:30][C:27]=1[C:28]#[N:29].O1CCCC1>>[Cl:25][C:26]1[CH:33]=[C:32]([N:34]2[CH:6]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:23][CH:22]=3)[CH:7]3[CH2:8][O:9][C:10]4[CH:11]=[C:12]([C:18]([OH:20])=[O:19])[CH:13]=[CH:14][C:15]=4[C:16]3=[N:35]2)[CH:31]=[CH:30][C:27]=1[C:28]#[N:29]
Reactant: COC(=O)c1ccc2c(c1)OCC(=Cc1ccc(F)cc1)C2=O
Reactant: N#Cc1ccc(NN)cc1Cl
Agent: Cl
Solvent: C1CCOC1
Product: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)cc4OCC3C2c2ccc(F)cc2)cc1Cl
Yield: 18 %

Procedure:
The title compound was prepared from methyl 3-(4-fluorobenzylidene)-4-oxochroman-7-carboxylate; Preparation 30 (155 mg, 0.50 mmol) and 2-chloro-4-hydrazinylbenzonitrile hydrochloride; Preparation 1 (153 mg, 0.75 mmol) according to Method B and Method C. The crude product was purified by reverse-phase HPLC (acetonitrile/water/0.05% trifluoroacetic acid) to give 2-(3-chloro-4-cyanophenyl)-3-(4-fluorophenyl)-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylic acid (41 mg, 0.09 mmol, 18% yield). The title compound was largely present as (±)-(3SR,3aSR)-2-(3-chloro-4-cyanophenyl)-3-(4-fluorophenyl)-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylic acid. ES-MS m/z 448 (M+H).
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[C:9]([C:11]([OH:13])=O)[CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[NH2:14]/[C:15](=[N:36]\O)/[C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:25][C:26]2[CH:27]=[C:28]([NH:32][C:33](=[O:35])[CH3:34])[CH:29]=[CH:30][CH:31]=2)(=[O:24])=[O:23])=[CH:18][CH:17]=1>O1CCOCC1.CN(C=O)C>[C:33]([NH:32][C:28]1[CH:27]=[C:26]([NH:25][S:22]([C:19]2[CH:18]=[CH:17][C:16]([C:15]3[N:36]=[C:11]([C:9]4[N:10]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:6]=[CH:7][CH:8]=4)[O:13][N:14]=3)=[CH:21][CH:20]=2)(=[O:24])=[O:23])[CH:31]=[CH:30][CH:29]=1)(=[O:35])[CH3:34]
Reactant: CC(=O)Nc1cccc(C(=O)O)n1
Reactant: CC(=O)Nc1cccc(NS(=O)(=O)c2ccc(/C(N)=N/O)cc2)c1
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CC(=O)Nc1cccc(NS(=O)(=O)c2ccc(-c3noc(-c4cccc(NC(C)=O)n4)n3)cc2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1,1-Carbonyldiimidazole (9.78 g) dissolved in dioxane (100 ml) is added dropwise to 6-acetylaminopyridine-2-carboxylic acid (10.86 g) in a mixture of dioxane (100 ml) and DMF (60 ml) and the mixture is stirred at room temperature for 3 h. N-{3-[({4-[(Z)-Amino(hydroxyimino)methyl]phenyl}sulfonyl)amino]phenyl}acetamide is then added as a solid and the reaction mixture is stirred at room temperature for 16 h. Subsequently, the reaction mixture is stirred at 100° C. for 4 h and then poured onto ice/water. The product is left to stand for 10 min, collected by filtration, washed with water (three times) and dried in a vacuum oven. 25.55 g (90% of theory) of product are obtained as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[N-:10]([C:13]#[N:14])[C:11]#[N:12].[Na+]>>[CH3:9][O:8][C:5]1[N:6]=[CH:7][C:2]([NH:1][C:13]([NH2:14])=[N:10][C:11]#[N:12])=[CH:3][CH:4]=1
Reactant: COc1ccc(N)cn1
Reactant: N#C[N-]C#N
Agent: [Na+]
Product: COc1ccc(NC(N)=NC#N)cn1

Procedure:
A solution of 5-amino-2-methoxypyridine and sodium dicyanamide was processed as described in Example 71A to provide the desired product.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[N:7]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].S(OC)(O[CH3:25])(=O)=O>C1(C)C=CC=CC=1>[C:1]([C:5]1[N:6]([CH3:25])[N:7]([CH2:17][CH:18]2[CH2:19][CH2:20]2)/[C:8](=[N:10]/[C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])/[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)C(F)(F)F)n(CC2CC2)n1
Reactant: COS(=O)(=O)OC
Solvent: Cc1ccccc1
Product: Cn1c(C(C)(C)C)c/c(=N\C(=O)C(F)(F)F)n1CC1CC1
Temperature: 25 °C
Yield: 71.7 %

Procedure:
A mixture of Example 9D (11.6 g, 40 mmol) and dimethyl sulfate (20.2 g, 160 mmol) in toluene (10 mL) was heated at 80° C. for 24 hours. The mixture was cooled to room temperature, and concentrated under pressure. The residue was purified by flash chromatography (silica gel, eluted with a gradient of 10-50% hexane in solvent B, solvent B: 10:1:0.5 ethyl acetate:methanol:triethylamine) to afford 8.7 g (72%) of title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.41-0.53 (m, 4H), 1.15-1.27 (m, 1H), 1.38 (s, 9H), 3.98 (s, 3H), 4.20 (d, J=7.12 Hz, 2H), 6.70 (s, 1H); MS (ESI) m/z 304 [M+H]+, 302 [M−H].
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:8]2)=[O:4].[C:30]([O:34][C:35](=[O:41])[C:36]([CH3:40])([CH3:39])[CH2:37][NH2:38])([CH3:33])([CH3:32])[CH3:31]>CCO>[C:30]([O:34][C:35](=[O:41])[C:36]([CH3:40])([CH3:39])[CH2:37][NH:38][C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[CH:8]2)=[O:4])([CH3:33])([CH3:31])[CH3:32]
Reactant: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reactant: CC(C)(C)OC(=O)C(C)(C)CN
Solvent: CCO
Product: CC(C)(C)OC(=O)C(C)(C)CNC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 140 °C
Yield: 53.5 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (30 mg, 0.078 mmol) and 3-amino-2,2-dimethyl-propionic acid tert-butyl ester (40 mg, 0.233 mmol) in EtOH (2 mL) was heated at 140° C. for 6 h in a microwave reactor. Solvent was evaporated in vacuo, and the residue was purified by silica gel chromatography (0-15% EtOAc/hexanes+2% AcOH) to give 22 mg of the title compound as a yellow oil. 1H NMR (CDCl3, 200 MHz): δ=13.2 (s, 1H), 8.35 (s, 1H), 8.28 (t, 1H, J=6.2 Hz), 8.18 (s, 1H), 7.75-7.90 (m, 2H), 7.20-7.60 (m, 8H), 5.65 (s, 2H), 3.50 (d, 2H, J=6.6 Hz), 1.47 (s, 9H), 1.21 (s, 6H).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:7]([CH3:36])=[C:8]([NH:14][C:15]([C:17]2[S:18][CH:19]=[CH:20][C:21]=2[S:22]([N:25]([C:29]2[O:33][N:32]=[C:31]([CH3:34])[C:30]=2[CH3:35])COC)(=[O:24])=[O:23])=[O:16])[C:9]([CH3:13])=[CH:10][C:11]=1[CH3:12])(=[O:3])[CH3:2]>C(O)(=O)C.O.S(=O)(=O)(O)O>[C:1]([O:4][CH2:5][C:6]1[C:7]([CH3:36])=[C:8]([NH:14][C:15]([C:17]2[S:18][CH:19]=[CH:20][C:21]=2[S:22](=[O:24])(=[O:23])[NH:25][C:29]2[O:33][N:32]=[C:31]([CH3:34])[C:30]=2[CH3:35])=[O:16])[C:9]([CH3:13])=[CH:10][C:11]=1[CH3:12])(=[O:3])[CH3:2]
Reactant: COCN(c1onc(C)c1C)S(=O)(=O)c1ccsc1C(=O)Nc1c(C)cc(C)c(COC(C)=O)c1C
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)OCc1c(C)cc(C)c(NC(=O)c2sccc2S(=O)(=O)Nc2onc(C)c2C)c1C
Temperature: 80 °C
Yield: 27.9 %

Procedure:
To a solution of N2-(3-acetoxymethyl-2,4,6-trimethylphenyl)-3-[N-(3,4-dimethylisoxazol-5-yl)-N-methoxymethylaminosulfonyl]-2-thiophenecarboxamide (0.78 g, 1.46 mmol) in acetic acid (7 mL) and water (3 mL) was added 2 N sulfuric acid (3 drops). The reaction was heated at 80° C. for 4 hours, then allowed to cool to room temperature. The mixture was poured into ice water (50 mL), extracted with ethyl acetate (3×50 mL), washed with saturated sodium chloride (50 mL), dried (MgSO4), then concentrated. The residue was purified by reverse-phase HPLC (20-80% acetonitrile in water) which gave N2-(3-acetoxymethyl-2,4,6-trimethylphenyl)-3-[(3,4-dimethyl-5-isoxazolyl)sulfamoyl]-2-thiophenecarboxamide (0.2 g, 28%) as an off-white powder, mp 75-77° C. 1H NMR (400 MHZ, DMSO-d6) δ7.85 (d, J=5.12 Hz, 1H), 7.34 (d, J=5.12 Hz, 1H), 7.00 (s, 1H), 5.12 (s, 2H), 2.30 (s, 3H), 2.20 (s, 3H), 2.17 (s, 3H), 2.07 (s, 3H), 2.02 (s, 3H), 1.65 (s, 3H) ppm. IR (KBr) 3458, 1738, 1646, 1356, 1181 cm−1. And N2-(3-hydroxymethyl-2,4,6-trimethylphenyl)-3-[(3,4-dimethyl-5-isoxazolyl)sulfamoyl]-2-thiophenecarboxamide (45 mg, 6.9%), ratio 4:1 respectively, as a white powder, mp 100-115° C. 1H NMR (400 MHZ, DMSO-d6) δ7.84 (3, J=5.12 Hz, 1H), 7.34 (d, J=5.16 Hz, 1H), 6.92 (s, 1H), 4.48 (s, 2H), 2.33 (s, 3H), 2.23 (s, 3H), 2.14 (s, 3H), 2.07 (s, 3H), 1.65 (s, 3H). IR (KBr) 3439, 1651, 1341, 1181 cm−1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH3:13])[C:9](=O)[CH2:8][CH2:7][C:6]2([CH3:16])[CH3:15].[CH3:17]C[Mg+].[Br-]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10]([C:9]([CH3:17])=[CH:8][CH2:7][C:6]2([CH3:16])[CH3:15])=[CH:11][C:12]=1[CH3:13]
Reactant: COc1cc2c(cc1C)C(=O)CCC2(C)C
Reactant: CC[Mg+]
Agent: [Br-]
Product: COc1cc2c(cc1C)C(C)=CCC2(C)C
Yield: 42.2 %

Procedure:
Following General Procedure F, 6-methoxy-4,4,7-trimethyl-3,4-dihydro-2H-naphthalen-1-one (compound 30, 1.0 g, 4.6 mmol) was reacted with a solution of 3 M EtMgBr (8 mL, 23.0 mmol), and the crude product was purified by flash column (hexane:ethyl acetate=96:4) to give 0.42 g (40%) of the title compound as a clear oil. PNMR (300 MHz, CDCl3) δ 1.36 (t, 3 H, J=6.0 Hz), 1.46 (s, 6 H), 2.35 (d, 2 H, J=4.5 Hz), 2.42 (s, 3 H), 2.65 (q, 2 H, J=7.5 Hz), 4.03 (s, 3 H), 5.82 (t, 1 H, J=2.5 Hz), 7.02 (s, 1 H), 7.28 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:48]=[CH:47][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16]([C:18]3[N:19](COCC[Si](C)(C)C)[C:20]([S:29]([C:32]4[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=4)(=[O:31])=[O:30])=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)[N:22]=3)=[O:17])=[CH:8]2)=[CH:4][CH:3]=1.Cl>C(O)C.Cl.CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16]([C:18]3[NH:19][C:20]([S:29]([C:32]4[CH:33]=[CH:34][C:35]([CH3:38])=[CH:36][CH:37]=4)(=[O:30])=[O:31])=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)[N:22]=3)=[O:17])=[CH:8]2)=[CH:47][CH:48]=1
Reactant: Cc1ccc(S(=O)(=O)c2c(-c3ccccn3)nc(C(=O)c3cn(Cc4ccc(Cl)cc4)c4ccccc34)n2COCC[Si](C)(C)C)cc1
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)c2[nH]c(C(=O)c3cn(Cc4ccc(Cl)cc4)c4ccccc34)nc2-c2ccccn2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 0.1 %

Procedure:
To a solution of [1-(4-chloro-benzyl)-1H-indol-3-yl]-[4-pyridin-2-yl-5-(toluene-4-sulfonyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-methanone (15 mg, 21.5 mmol) in Ethanol (1 mL) was added 5 drops of 2N HCl. The solution was stirred at room temperature for 18 hours. A solution of 1 M HCl in ether (0.5 mL) was then added and the reaction mixture was heated to 70° C. for 2 hours. The volatile components were then removed under reduced pressure. Flash silica gel chromatography (2:1 hexane/ethyl acetate to 1:1 hexane/ethyl acetate to ethyl acetate to 4:1 ethyl acetate/methanol) afforded the product [1-(4-chloro-benzyl)-1H-indol-3-yl]-[4-pyridin-2-yl-5-(toluene-4-sulfonyl)-1H-imidazol-2-yl]-methanone as a yellow powder (12 mg, 98%). 1H NMR (CDCl3) δ2.3 (s, 3H), 5.3 (s, 2H), 7.0 (d, 2H, J=7), 7.1-7.3 (m, 9H), 7.8 (t, 1H, J=7), 7.9 (d, 2H, J=7), 8.4 (d, 1H, J=7), 8.6 (s, 1H), 8.7 (d, 1H, J=7), 8.85 (s, 1H). ESMS calcd for (C31H23ClN4O3S): 566.2; found: 567.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:17])=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[N:6][CH:7]=1.[H-].[Na+].[P:20](Cl)([O:25][CH2:26][CH3:27])([O:22][CH2:23][CH3:24])=[O:21]>C1COCC1>[CH2:23]([O:22][P:20]([NH:17][C:3]1[C:2]([F:1])=[CH:7][N:6]=[C:5]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)[N:4]=1)(=[O:21])[O:25][CH2:26][CH3:27])[CH3:24]
Reactant: CCOP(=O)(Cl)OCC
Reactant: Nc1nc(OCc2ccc(F)cc2)ncc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOP(=O)(Nc1nc(OCc2ccc(F)cc2)ncc1F)OCC
Yield: 10.8 %

Procedure:
To a magnetically stirred solution of 5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-ylamine (0.10 g, 0.42 mmol) in dry THF (5 mL) under a nitrogen atmosphere was added NaH (0.017 g of a 60 wt. % suspension, 0.42 mmol) and the mixture was stirred until bubbling ceased. Diethyl chlorophosphate (0.073 g, 0.42 mmol) was added dropwise, and the mixture was stirred at ambient temperature for 1 h. The reaction mixture was evaporated to dryness and the residue dissolved in EtOAc and washed with saturated aqueous NH4Cl solution. The organic layer was separated, dried over Na2SO4, filtered, and evaporated. The crude material was purified on silica (acetone/CH2Cl2 gradient) to give 0.017 g (11%) of [5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-yl]phosphoramidic acid diethyl ester as a white solid: mp 109-111° C.; 1H NMR (300 MHz, CDCl3) δ 8.10 (t, J=1.8 Hz, 1H), 7.43 (m, 2H), 7.03 (t, J=8.5 Hz, 2H), 6.18 (br s, 1H), 5.35 (s, 2H), 4.25 (m, 4H), 1.38 (t, J=7.1 Hz, 6H); HPLC-MS (ESI) m/z 374 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6][CH2:5]1.[Cl:17][C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[C:22](Cl)[C:21]([CH3:28])=[C:20]([CH3:29])[N:19]=1.C(N(CC)CC)C>CN(C)C=O>[CH2:10]([N:7]1[CH2:6][CH2:5][CH:4]([CH2:3][CH2:2][NH:1][C:22]2[C:21]([CH3:28])=[C:20]([CH3:29])[N:19]=[C:18]([Cl:17])[C:23]=2[N+:24]([O-:26])=[O:25])[CH2:9][CH2:8]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: NCCC1CCN(Cc2ccccc2)CC1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)c1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(Cl)c([N+](=O)[O-])c(NCCC2CCN(Cc3ccccc3)CC2)c1C
Temperature: 25 °C
Reaction time: 20 h
Yield: 60.4 %

Procedure:
A solution of 4-(2-aminoethyl)-1-benzylpiperidine (9.88 g, 45.2 mmol) in N,N-dimethylformamide was added dropwise to a solution of 2,4-dichloro-5,6-dimethyl-3-nitropyridine (10.00 g, 45.2 mmol) and triethylamine (12.6 mL, 90.5 mmol) in N,N-dimethylformamide (320 mL). The reaction mixture was allowed to stir at ambient temperature for about 20 hours and then it was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The layers were separated and the aqueous layer was extracted with ethyl acetate. The organics were combined, washed with brine, dried over sodium sulfate and then concentrated under reduced pressure to provide an orange oil. The oil was purified by flash chromatography (400 mL silica gel eluting initially with 10% ethyl acetate in hexane, then with 15% ethyl acetate in hexane and finally with 40% ethyl acetate in hexane) to provide 11.00 g of N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-chloro-5,6-dimethyl-3-nitropyridin-4-amine.
Reaction SMILES: [CH3:1][O:2][C@@H:3]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:4]([OH:6])=[O:5].Br[CH2:15][C:16]#[N:17].C(N(CC)CC)C>C(#N)C>[CH3:1][O:2][C@@H:3]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:4]([O:6][CH2:15][C:16]#[N:17])=[O:5]
Reactant: CO[C@@H](Cc1ccccc1)C(=O)O
Reactant: N#CCBr
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CO[C@@H](Cc1ccccc1)C(=O)OCC#N
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 71.2 %

Procedure:
(S)-2-Methoxy-3-phenylpropanoic acid (Compounds 7a, 0.50 g, 2.50 mmol) and 2-bromoacetonitrile (1.20 g, 10.00 mmol) were dissolved in acetonitrile (60 ml). Then triethylamine (0.50 g, 4.99 mmol) was added dropwise under ice-cooling. After stirring at room temperature for 40 minutes, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate=20:1) to afford the title compound (0.39 g, 65%).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH:15]1([C:18]2[C:19]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])=[CH:20][C:21]3[O:25][C:24]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)=[C:23]([C:33]([NH:35][CH3:36])=[O:34])[C:22]=3[CH:37]=2)[CH2:17][CH2:16]1.C([O-])([O-])=O.[K+].[K+]>CN(C)P(N(C)C)(N(C)C)=O.CCOC(C)=O>[CH:15]1([C:18]2[C:19]([N:38]([C:2]3[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=3)[C:7]([O:9][CH3:10])=[O:8])[S:39]([CH3:42])(=[O:41])=[O:40])=[CH:20][C:21]3[O:25][C:24]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)=[C:23]([C:33](=[O:34])[NH:35][CH3:36])[C:22]=3[CH:37]=2)[CH2:17][CH2:16]1
Reactant: COC(=O)c1cc(F)ccc1[N+](=O)[O-]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(NS(C)(=O)=O)c(C3CC3)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOC(C)=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc([N+](=O)[O-])c(C(=O)OC)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 60 °C
Reaction time: 72 h
Yield: 55.4 %

Procedure:
A mixture of methyl 5-fluoro-2-nitrobenzoate (2.138 g, 10.73 mmol), 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (4.0 g, 9.94 mmol) and K2CO3 (4.12 g, 29.8 mmol) in hexamethylphosphoramide (25 mL) in a seal tube was stirred at 60° C. for 3 days. Cooled down to room temperature, the mixture was diluted with EtOAc and then filtered through a pad of Celite. The filtrate was washed with water and brine and dried over Na2SO4. Concentrated under reduced pressure, the residue was purified by flashing chromatography on silica gel eluted with 0-50% EtOAc in hexane to give the product (3.2 g, 55%) as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.00 (d, J=9.17 Hz, 1H) 7.89 (dd, J=8.78, 5.27 Hz, 2H) 7.55 (d, J=9.37 Hz, 2H) 7.50 (dd, J=9.07, 2.63 Hz, 1H) 7.44 (d, J=2.73 Hz, 1H) 7.23 (t, J=8.68 Hz, 2H) 5.81 (d, J=4.49 Hz, 1H) 3.91 (s, 3H) 3.35 (s, 3H) 3.02 (d, J=4.88 Hz, 3H) 1.86-1.96 (m, 1H) 0.97-1.05 (m, 1H) 0.89 (br. s., 2H) 0.59 (br. s., 1H). LCMS (m/z, ES+)=582 (M+H+).
Reaction SMILES: [C:1]([C@@H:3]([NH:12][C@H:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14])[C:4]1([C:7](OCC)=[O:8])[CH2:6][CH2:5]1)#[N:2].N.[H][H]>[Ni]>[C:15]1([C@@H:13]([NH:12][C@H:3]2[C:4]3([CH2:6][CH2:5]3)[C:7](=[O:8])[NH:2][CH2:1]2)[CH3:14])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: [H][H]
Reactant: CCOC(=O)C1([C@@H](C#N)N[C@@H](C)c2ccccc2)CC1
Agent: [Ni]
Agent: N
Product: C[C@H](N[C@@H]1CNC(=O)C12CC2)c1ccccc1
Temperature: 180 °C
Yield: 73.4 %

Procedure:
An autoclave was charged with 1.0 g of 1-[(S)-1-cyano-[(S)-1-phenylethylamino]methyl]-1-ethoxycarbonylcyclopropane, 1.7 ml of Raney nickel and 17 ml of ammonia-saturated ethanol, and the contents were stirred at room temperature for 1.5 hours in an atmosphere of hydrogen under a pressure of 35 kg/cm2. After completion of the reaction, the catalyst was removed by filtration and the resulting filtrate was concentrated under a reduced pressure. The resulting residue was dissolved in 20 ml of ethanol, put into an autoclave and heated at 180° C. for 8.5 hours. After completion of the reaction, the solvent was evaporated under a reduced pressure, and the resulting residue was mixed with isopropanol and stirred to obtain 621 mg (74%) of the title compound in the form of slightly yellow crystals. The thus obtained compound was recrystallized from ethanol and isopropanol, and used as a sample for analyses.
Reaction SMILES: [O:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=O)[CH2:2]1.[CH3:11][O:12][C:13](=[O:34])[CH:14]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:11][O:12][C:13](=[O:34])[CH2:14][C:3]1[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=2[O:1][CH:2]=1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1COc2ccccc21
Solvent: Cc1ccccc1
Product: COC(=O)Cc1coc2ccccc12
Reaction time: 5 h

Procedure:
A solution of 3-coumaranone (5.0 g, 37 mmol) and methyl(triphenylphosphoranylideneacetate) (13.5 g, 40 mmol) in toluene (70 mL) was heated to reflux for 25 hours. More toluene was added (50 mL), and after a further 5 hours, more methyl(triphenylphosphoranylideneacetate) (0.5 g, 1.5 mmol). After another 19 hours, a further 1.0 g (3.0 mmol) was added, and after a further 21 hours, the solvent was removed in vacuo. Column chromatography (heptane:ethyl acetate 4:1) gave the product as a brown oil, 33 mmol, 89%.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([CH3:5])=[O:4].Br[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1.[Mg].[Cl-].[NH4+]>CCOCC>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([C:3]([C:2]([F:7])([F:6])[F:1])([OH:4])[CH3:5])=[CH:10][CH:11]=1
Reactant: COc1ccc(Br)cc1
Reactant: CC(=O)C(F)(F)F
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: COc1ccc(C(C)(O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 94.2 %

Procedure:
1,1,1-Trifluoroacetone (60.4 ml; 675 mmol) dissolved in absolute ether (80 ml) was added, dropwise, at 5° to 10° C. to an ethereal Grignard solution (prepared from p-bromoanisole (84.17 g; 450 mmol) and magnesium (10.9 g; 450 mmol) in ether (600 ml)) and the mixture stirred at room temperature for 20 hours. It was then added to saturated ammonium chloride solution, extracted with ether and the extract washed with water, dried over sodium sulphate and concentrated. The precipitate was filtered off washed with hexane and the filtrate concentrated. 1-(4-methoxyphenyl)-1-trifluoromethylethanol (93.35 g=94.2% of theory) was obtained as a brown oil that was used without further purification. (The alcohol can also be coverted direct to the nitrile in a one-pot reaction.
Reaction SMILES: [O:1]1[CH:6]2[CH2:7][NH:8][CH2:9][CH:5]2[O:4][CH2:3][CH2:2]1.[Cl:10][C:11]1[CH:12]=[C:13]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:34][CH3:35])=[C:26]([O:29][CH2:30][CH2:31][CH2:32]Cl)[CH:27]=3)[N:22]=[CH:21][N:20]=2)[CH:14]=[CH:15][C:16]=1[F:17].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:10][C:11]1[CH:12]=[C:13]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:34][CH3:35])=[C:26]([O:29][CH2:30][CH2:31][CH2:32][N:8]4[CH2:7][CH:6]5[O:1][CH2:2][CH2:3][O:4][CH:5]5[CH2:9]4)[CH:27]=3)[N:22]=[CH:21][N:20]=2)[CH:14]=[CH:15][C:16]=1[F:17]
Reactant: C1COC2CNCC2O1
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CC2OCCOC2C1
Temperature: 60 °C
Yield: 25 %

Procedure:
A mixture of hexahydro-2H-[1,4]dioxino[2,3-c]pyrrole (1.0 eq), N-(3-chloro-4-fluorophenyl)-6-(3-chloropropoxy)-7-methoxyquinazolin-4-amine (710 mg, 1.8 mmol, 0.95 eq), K2CO3 (524 mg, 3.8 mmol, 2.0 eq) and KI (16 mg, 0.095 mmol, 0.05 eq) in DMF (12 mL) was heated at 60° C. for 3 h and cooled to room temperature. The reaction mixture was quenched with water (10 mL) and diluted with EtOAc (20 mL). The organic phase was separated from the mixture, and the water phase was extracted with EtOAc (20 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (20:1 (v/v) CH2Cl2/CH3OH) to give the crude product, which was recrystallized from CH2Cl2/PE to afford the title compound as a grayish-white solid (230 mg, 25.00%), HPLC: 99.11%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 489.9 (M+1); 1H NMR (400 MHz, CDCl3) δ: 2.09 (2H, m), 2.74 (4H, m), 2.99 (2H, dd, J=3.3, 10.4 Hz), 3.56 (2H, m), 3.80 (2H, m), 3.99 (3H, s), 4.12 (2H, t, J=3.5 Hz), 4.22 (2H, t, J=6.8 Hz), 7.14 (1H, t, J=8.8 Hz), 7.23 (1H, s), 7.29 (1H, d, J=15.8 Hz), 7.60 (1H, m), 7.89 (1H, dd, J=2.5, 6.5 Hz), 8.63 (1H, s) ppm.