Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][CH2:16][O:17][CH2:18][C:19]([OH:21])=O)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:22])[CH:4]=1.Cl.Cl.[N:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]2([OH:38])[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:27][CH:26]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[OH:38][C:32]1([CH2:31][C:28]2[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=2)[CH2:37][CH2:36][N:35]([C:19](=[O:21])[CH2:18][O:17][CH2:16][CH2:15][N:13]([CH3:14])[S:10]([C:6]2[C:5]([CH3:22])=[CH:4][C:3]([O:2][CH3:1])=[CH:8][C:7]=2[CH3:9])(=[O:11])=[O:12])[CH2:34][CH2:33]1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)CCOCC(=O)O)c(C)c1
Reactant: OC1(Cc2ccncc2)CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C)c(S(=O)(=O)N(C)CCOCC(=O)N2CCC(O)(Cc3ccncc3)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N,N′-Carbonyldiimidazole (77 mg, 0.475 mmol) was added to a solution of 2-(2-(4-methoxy-N,2,6-trimethylphenylsulfonamido)-ethoxy)acetic acid (acid unit S2) (150 mg, 0.453 mmol) in methylene chloride (7 ml), and the mixture was stirred for 1 h at room temperature. A solution of 4-(pyridin-4-ylmethyl)piperidin-4-ol dihydrochloride (120 mg, 0.453 mmol) dissolved in methylene chloride (3 ml) and triethylamine (0.18 ml) was then added, and the reaction mixture was stirred overnight at room temperature. Saturated sodium bicarbonate solution (10 ml) was then added to the reaction mixture, and the aqueous phase was then extracted with methylene chloride (20 ml). The combined organic phases were extracted with saturated sodium chloride solution (10 ml), dried with sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography with ethyl acetate/methanol (10:1). Yield: 130 mg (57%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])[CH2:4]1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32](O)=[O:33])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([NH:1][CH2:2][CH:3]3[CH2:8][CH2:7][CH2:6][N:5]([C:9]4[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=4)[C:12]([O:14][CH3:15])=[O:13])[CH2:4]3)=[O:33])=[CH:28][CH:27]=2)=[CH:24][CH:25]=1
Reactant: O=C(O)c1ccc(-c2ccc(Cl)cc2)cc1
Reactant: COC(=O)c1cccc(N2CCCC(CN)C2)c1
Product: COC(=O)c1cccc(N2CCCC(CNC(=O)c3ccc(-c4ccc(Cl)cc4)cc3)C2)c1
Yield: 82.3 %

Procedure:
Using methyl 3-[3-(aminomethyl)piperidin-1-yl]benzoate (76.2 mg, 0.307 mmol) and 4′-chlorobiphenyl-4-carboxylic acid (77.2 mg, 0.332 mmol), the same procedure was followed as in Step 61e of Example 61 to give 117 mg (82%) of the desired compound as a pale yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH:6]=[C:7]2[CH2:16][CH2:15][C:14]3[CH:13]=[C:12]([C:17]([O:19]CC)=[O:18])[CH:11]=[CH:10][C:9]=3[C:8]2=O)=[CH:4][CH:3]=1.[NH:25]([C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[C:33](=[O:37])[NH:32][CH2:31][CH2:30]2)[NH2:26].C(O)C.[O-]CC.[Na+]>CN(C)C=O>[F:1][C:2]1[CH:24]=[CH:23][C:5]([CH:6]2[CH:7]3[C:8]([C:9]4[CH:10]=[CH:11][C:12]([C:17]([OH:19])=[O:18])=[CH:13][C:14]=4[CH2:15][CH2:16]3)=[N:26][N:25]2[C:27]2[CH:28]=[C:29]3[C:34](=[CH:35][CH:36]=2)[C:33](=[O:37])[NH:32][CH2:31][CH2:30]3)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc2c(c1)CCC(=Cc1ccc(F)cc1)C2=O
Reactant: NNc1ccc2c(c1)CCNC2=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: O=C(O)c1ccc2c(c1)CCC1C2=NN(c2ccc3c(c2)CCNC3=O)C1c1ccc(F)cc1
Temperature: 80 °C
Yield: 63 %

Procedure:
To ethyl 6-(4-fluorobenzylidene)-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate (Preparation 16; 303 mg, 1.07 mmol) and 6-hydrazinyl-3,4-dihydroisoquinolin-1(2H)-one (240 mg, 1.3 mmol) (U.S. Pat. No. 6,432,974, Kelly et al., Aug. 13, 2002, intermediate 2) was added ethanol (8 mL) and 21% sodium ethoxide in ethanol (1.5 mL, 4 mmol) in a vial. The vial was flushed with argon and heated at 80° C. overnight with stirring. The reaction was quenched with 1M hydrogen chloride (8 mL) and diluted with water to give a precipitate. The precipitate was collected by vacuum filtration to give a yellow solid. The solid was dissolved in of dimethylformamide (3 mL) and purified by reverse phase chromatography with 45-75% acetonitrile/water to give (±)-3-(4-fluorophenyl)-2-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid as a 25/75 mixture of the cis/trans-diastereomers (290 mg, 0.68 mmol, 63% yield). ES-MS m/z 430 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[N:18]([CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[C:19]=[O:20]>>[CH:21]1([NH:18][C:19]([NH:13][CH2:12][CH:8]2[O:9][CH2:10][CH2:11][N:6]([CH2:5][C:4]3[CH:14]=[CH:15][C:16]([Cl:17])=[C:2]([Cl:1])[CH:3]=3)[CH2:7]2)=[O:20])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=C=NC1CCCCC1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Product: O=C(NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1)NC1CCCCC1

Procedure:
Example 7 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 3 (0.025 g) and isocyanatocyclohexane (17.4 μl) to give the title compound (0.0298 g). LC-MS (System A): Rt 2.26 mins, Mass Spectrum m/z 400 [MH+].
Reaction SMILES: [CH:1]1([C:4]2[CH:13]=[C:12]3[C:7]([C:8](SC)=[N:9][C:10]([C:14]([F:23])([F:22])[C:15]4[CH:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=4)=[N:11]3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.ClC1C=C(C=CC=1)C(OO)=O.[CH3:37][C:38]1[NH:42][N:41]=[C:40]([NH2:43])[CH:39]=1>C(Cl)Cl.C1COCC1>[CH:1]1([C:4]2[CH:13]=[C:12]3[C:7]([C:8]([NH:43][C:40]4[CH:39]=[C:38]([CH3:37])[NH:42][N:41]=4)=[N:9][C:10]([C:14]([F:23])([F:22])[C:15]4[CH:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=4)=[N:11]3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: CSc1nc(C(F)(F)c2ccc(F)cn2)nc2cc(C3CC3)ccc12
Reactant: Cc1cc(N)n[nH]1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1cc(Nc2nc(C(F)(F)c3ccc(F)cn3)nc3cc(C4CC4)ccc23)n[nH]1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 7.7 %

Procedure:
To 7-cyclopropyl-2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-(methylthio)quinazoline from Step A (137 mg, 0.378 mmol) in DCM (5 mL) at 0° C. was added 70% meta-chloroperoxybenzoic acid (139 mg, 0.567 mmol). The mixture was stirred for at 0° C. for 20 min, then DCM (15 mL) was added and the mixture was washed with saturated aq NaHCO3 (20 mL) and saturated aq sodium thiosulfate (20 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. To the residue was added 5-methyl-1H-pyrazol-3-amine (0.107 g, 1.01 mmol) in THF (5 mL) and the mixture was stirred at room temperature for 40 min and then concentrated under reduced pressure. The residue was purified by reverse phase HPLC (Phenomenex C-18 reverse phase column, eluted with gradient of solvent B=0.05% AcOH/CH3CN and solvent A=0.05% aq AcOH) to afford 7-cyclopropyl-2-(difluoro(5-fluoropyridin-2-yl)methyl)-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine (12 mg, 8%) 1H NMR (300 MHz, DMSO-d6) δ 12.07-12.19 (m, 1H), 10.51-10.63 (m, 1H), 8.66 (s, 1H), 8.54 (d, J=8.7 Hz, 1H), 7.94-8.04 (m, 2H), 7.51 (s, 1H), 7.36 (d, J=8.7 Hz, 1H), 5.97 (s, 1H), 2.10-2.21 (m, 4H), 1.09 (dd, J=2.3, 8.1 Hz, 2H), 0.87-0.94 (m, 2H); LC-MS (ESI) m/z 411 (M+H)+
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH:13]([CH3:15])[C:12](=[O:16])[NH:11][C:10]2[CH:17]=[N:18][C:19]([Cl:21])=[N:20][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH3:23].[H-].[Na+]>CN(C)C=O>[CH2:1]([N:8]1[CH2:14][CH:13]([CH3:15])[C:12](=[O:16])[N:11]([CH3:23])[C:10]2[CH:17]=[N:18][C:19]([Cl:21])=[N:20][C:9]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: CC1CN(Cc2ccccc2)c2nc(Cl)ncc2NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1CN(Cc2ccccc2)c2nc(Cl)ncc2N(C)C1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 93.3 %

Procedure:
To an ice cooled mixture of 1.38 g (0.0046 mole) of (rac)-9-benzyl-2-chloro-7-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-42), 0.43 mL (0.0068 mole) of iodomethane and 15 mL of dimethylformamide was added 0.27 g (0.0068 mole) of a 60% oil dispersion of sodium hydride. The mixture was stirred at 0 degrees for 2 hours and then partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed successively with water and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with hexanes-ethyl acetate (100:0-60:40) to give 1.36 g of (rac)-9-benzyl-2-chloro-5,7-dimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one as white powder (VII-42).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[C:14]([CH2:15][CH3:16])=[CH:13][C:12]([CH2:17][CH3:18])=[CH:11][C:10]=2[CH2:19][CH3:20])=[C:5]([O:21][CH2:22]SC)[C:4]([CH3:25])=[N:3]1.S(Cl)([Cl:29])(=O)=O>C(Cl)(Cl)Cl>[Cl:29][CH2:22][O:21][C:5]1[C:4]([CH3:25])=[N:3][N:2]([CH3:1])[C:7](=[O:8])[C:6]=1[C:9]1[C:14]([CH2:15][CH3:16])=[CH:13][C:12]([CH2:17][CH3:18])=[CH:11][C:10]=1[CH2:19][CH3:20]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCc1cc(CC)c(-c2c(OCSC)c(C)nn(C)c2=O)c(CC)c1
Solvent: ClC(Cl)Cl
Product: CCc1cc(CC)c(-c2c(OCCl)c(C)nn(C)c2=O)c(CC)c1
Reaction time: 2.5 h

Procedure:
To a mixture of 0.31 g of 2,6-dimethyl-5-methylthiomethoxy-4-(2,4,6-triethylphenyl)-3(2H)-pyridazinone [compound (I-2-2)] and 3 mL of chloroform, 0.08 mL of sulfuryl chloride was added, followed by stirring under ice cooling for 2.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:4) to obtain 0.14 g of 5-chloromethoxy-2,6-dimethyl-4-(2,4,6-triethylphenyl)-3(2H)-pyridazinone [compound (I-5-1)]. Melting point: 103 to 104° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:6]=1.[Li]CCCC.[C:31]([C:34]1[CH:39]=[CH:38][C:37]([S:40]([N:43]([C:48]2[CH:53]=[CH:52][C:51]([CH3:54])=[CH:50][C:49]=2[CH3:55])[CH2:44][CH:45]([CH3:47])[CH3:46])(=[O:42])=[O:41])=[CH:36][CH:35]=1)(=[O:33])[CH3:32]>O1CCCC1>[CH3:55][C:49]1[CH:50]=[C:51]([CH3:54])[CH:52]=[CH:53][C:48]=1[N:43]([CH2:44][CH:45]([CH3:47])[CH3:46])[S:40]([C:37]1[CH:38]=[CH:39][C:34]([C:31]([OH:33])([CH3:32])[CH2:1][C:2]2[N:3]=[N:4][N:5]([C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:6]=2)=[CH:35][CH:36]=1)(=[O:42])=[O:41]
Reactant: CC(=O)c1ccc(S(=O)(=O)N(CC(C)C)c2ccc(C)cc2C)cc1
Reactant: Cc1nnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(C(C)(O)Cc3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c(C)c1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 15.3 %

Procedure:
To a solution of 5-methyl-2-trityl-2H-tetrazole (68.5 mg, 0.21 mmol) in tetrahydrofuran (THF) (1 mL) stirred under nitrogen at −70° C., was added a solution of n-BuLi (1.6 M in hexanes, 0.144 mL, 0.231 mmol) and tetrahydrofuran (THF) (1 mL) dropwise over 1 minute. The reaction mixture was stirred at −78° C. for 45 minutes, then 4-acetyl-N-(2,4-dimethylphenyl)-N-isobutylbenzenesulfonamide (106 mg, 0.294 mmol) in tetrahydrofuran (THF) (1 mL) was added dropwise at −78° C. over 1 minute. The reaction mixture was stirred at −78° C. for 1 hour, then allowed to warm to room temperature. The reaction was carefully quenched using a few drops of water under nitrogen. Ethyl acetate (3 mL) and water (2 mL) were then added and the reaction stirred vigorously for 5 minutes. The organic phase was separated using a hydrophilic frit and concentrated in vacuo to give a residue. LCMS analysis showed incomplete reaction, so the above reaction procedure repeated using fresh n-butyl lithium solution and reintroducing the crude residue instead of new starting material, this resulted in improved conversion. The residue was then purified by flash silica (Si) chromatography (using a 0-25% ethyl acetate-cyclohexane gradient) to give the required product (22 mg) as a colourless gum. LCMS (M+1) 686, RT 1.57 mins.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=2)[C@H:10]([NH2:21])[CH2:9][C@@H:8]1[CH2:22][CH3:23])=[O:6])([CH3:3])[CH3:2].[F:24][C:25]([F:39])([F:38])[C:26]1[CH:27]=[C:28]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH:29]=O>>[CH:1]([O:4][C:5]([N:7]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([F:18])([F:19])[F:20])=[CH:14][CH:15]=2)[C@H:10]([NH:21][CH2:29][C:28]2[CH:31]=[C:32]([C:34]([F:36])([F:37])[F:35])[CH:33]=[C:26]([C:25]([F:24])([F:38])[F:39])[CH:27]=2)[CH2:9][C@@H:8]1[CH2:22][CH3:23])=[O:6])([CH3:3])[CH3:2]
Reactant: CC[C@H]1C[C@@H](N)c2cc(C(F)(F)F)ccc2N1C(=O)OC(C)C
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: CC[C@H]1C[C@@H](NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2cc(C(F)(F)F)ccc2N1C(=O)OC(C)C

Procedure:
treating said cis-4-amino-2-ethyl-6-trifluoromethyl-3,4,-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester first with 3,5-bis-trifluoromethyl-benzaldehyde under acidic conditions followed by a reducing agent to form cis-4-(3,5-bis-trifluoromethyl-benzylamino)-2-ethyl-6-trifluoromethyl-3,4,-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester;
Reaction SMILES: [N:1]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[C:26](=[O:27])[CH:25]=[CH:24][CH:23]=[N:22]4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4][C@@H:3]2[CH2:6][NH:7][CH2:8][C@H:2]12.[C:28]1(=O)[CH2:31][CH2:30][CH2:29]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH:28]1([N:7]2[CH2:6][C@@H:3]3[C@@H:2]([N:1]([C:9]4[CH:14]=[CH:13][C:12]([C:15]5[CH:20]=[CH:19][C:18]([N:21]6[C:26](=[O:27])[CH:25]=[CH:24][CH:23]=[N:22]6)=[CH:17][CH:16]=5)=[CH:11][CH:10]=4)[CH2:5][CH2:4]3)[CH2:8]2)[CH2:31][CH2:30][CH2:29]1
Reactant: O=c1cccnn1-c1ccc(-c2ccc(N3CC[C@@H]4CNC[C@@H]43)cc2)cc1
Reactant: O=C1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: O=c1cccnn1-c1ccc(-c2ccc(N3CC[C@@H]4CN(C5CCC5)C[C@@H]43)cc2)cc1

Procedure:
The product from Example 85B (0.033 g, 0.092 mmol), cyclobutanone (8.00 μL, 0.101 mmol), and sodium triacetoxyborohydride (0.025 g, 0.0.120 mmol) were processed as described in Example 85C to provide the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.91 (d, J=1.7 Hz, 1H), 7.63 (s, 4H), 7.50 (d, J=8.5 Hz, 2H), 7.23 (d, J=3.7 Hz, 1H), 7.07 (d, J=8.8 Hz, 1H), 6.65 (d, J=8.5 Hz, 2H), 4.13-4.24 (m, 1H), 3.52 (q, 1H), 3.32 (q, J=7.3 Hz, 1H), 2.74-3.04 (m, 3H), 2.63 (t, 1H), 2.46 (dd, J=9.3, 2.2 Hz, 1H), 2.35 (dd, J=8.8, 4.4 Hz, 1H), 2.06-2.23 (m, 1H), 1.82-2.05 (m, 4H), 1.60-1.80 (m, 3H). MS (ESI+) m/z 413 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:12](=[O:14])(=[O:13])[CH2:11][CH2:10][C:9]([C:15]([O:17]C)=[O:16])=[CH:8][C:7]=2[CH:19]=1.Br>C(O)(=O)C>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[S:12](=[O:14])(=[O:13])[CH2:11][CH2:10][C:9]([C:15]([OH:17])=[O:16])=[CH:8][C:7]=2[CH:19]=1
Reactant: COC(=O)C1=Cc2cc(OC)ccc2S(=O)(=O)CC1
Agent: Br
Solvent: CC(=O)O
Product: O=C(O)C1=Cc2cc(O)ccc2S(=O)(=O)CC1
Yield: 82.9 %

Procedure:
A mixture of methyl 7-methoxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (300 mg), 48% hydrobromic acid (3 ml) and acetic acid (3 ml) was heated at reflux for 4 hours. After concentration under reduced pressure, 48% hydrobromic acid (3 ml) and acetic acid (3 ml) were further added to the reaction mixture, which was heated at reflux for 8 hours. After concentration under reduced pressure, the precipitated crystals were collected by filtration. The crystals were washed with diisopropyl ether to obtain 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (224 mg) as light yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[N:9]=2)[S:4][C:3]=1[C:16]([OH:18])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[NH2:53][C:54]1[CH:55]=[C:56]([NH:61][C:62](=[O:74])[C:63]2[CH:68]=[CH:67][CH:66]=[C:65]([C:69]([C:72]#[N:73])([CH3:71])[CH3:70])[CH:64]=2)[CH:57]=[CH:58][C:59]=1[CH3:60]>CN(C=O)C>[NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[N:9]=2)[S:4][C:3]=1[C:16]([NH:53][C:54]1[CH:55]=[C:56]([NH:61][C:62](=[O:74])[C:63]2[CH:68]=[CH:67][CH:66]=[C:65]([C:69]([C:72]#[N:73])([CH3:70])[CH3:71])[CH:64]=2)[CH:57]=[CH:58][C:59]=1[CH3:60])=[O:18]
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1N
Reactant: Nc1c(C(=O)O)sc2ncc(-c3ccco3)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1NC(=O)c1sc2ncc(-c3ccco3)nc2c1N
Temperature: 80 °C
Reaction time: 8 h
Yield: 34.6 %

Procedure:
A solution of 7-amino-2-(furan-2-yl)thieno[2,3-b]pyrazine-6-carboxylic acid 59 (66 mg, 0.253 mmol), HATU (106 mg, 0.278 mmol) and DIPEA (0.104 mL, 0.632 mmol) in DMF (2 mL) was stirred at rt for 30 min. N-(3-amino-4-methylphenyl)-3-(2-cyanopropan-2-yl)benzamide hydrochloride 6 (83 mg, 0.253 mmol) was added and stirred overnight at 80° C. Quenched in 2N HCl solution, the resulting precipitate was collected and dried. Purification by HPLC gave the title compound 7-amino-N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)-2-(furan-2-yl)thieno[2,3-b]pyrazine-6-carboxamide 60 (47 mg, 34%). NMR (400 MHz, DMSO-d6) 1.76 (s, 6H), 2.23 (s, 3H), 6.79 (dd, J=1.6 and 3.5 Hz, 1H), 7.01 (s, 2H), 7.27 (d, J=8.2 Hz, 1H), 7.46 (d, J=3.5 Hz, 1H), 7.60 (t, J=7.8 Hz, 2H), 7.75 (m, 1H), 7.82 (d, J=1.9 Hz, 1H), 7.95 (m, 1H), 8.01 (m, 1H), 8.05 (m, 1H), 9.16 (s, 1H), 9.48 (s, 1H), 10.33 (s, 1H). (m/z)=537 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]=4[O:26][C@@H:27]([CH3:32])[C:28](OC)=[O:29])[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[NH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]=4[O:26][C@@H:27]([CH3:32])[C:28](=[O:29])[N:36]4[CH2:40][CH2:39][CH2:38][CH2:37]4)[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: COC(=O)[C@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c12
Reactant: C1CCNC1
Product: C[C@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c12)C(=O)N1CCCC1
Yield: 63 %

Procedure:
Using the same procedure as in Example 26, methyl (2S)-2-[(4-{[1-(3-fluorobenzyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoate (200 mg, 0.42 mmol) was reacted with pyrrolidine (0.35 ml, 4.2 mmol) to give the title compound as a solid (135 mg, 62%), except that the mixture was heated at 55° C. for 20 hours and purified by chromatography on silica gel (eluant: 3% methanol in DCM); NMR Spectrum 1.60 (d, 3H), 1.82 (m, 2H), 1.94 (m, 2H), 3.5-3.3 (m, 3H), 3.76 (m, 1H), 5.62 (q, 1H), 5.70 (s, 2H), 7.07 (m, 3H), 7.27 (d, 1H), 7.36 (m, 2H), 7.74 (m, 2H), 7.85 (m, 1H), 8.16 (s, 1H), 8.51 (s, 1H), 8.56 (s, 1H), 11.07 (br s, 1H); Mass spectrum 511.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][CH:7]2[N:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:4]([CH2:5][CH2:6]2)[CH2:3]1.C([N-]C(C)C)(C)C.[Li+].C([C:27]([O:29][CH3:30])=[O:28])#N>O1CCCC1>[O:1]=[C:2]1[CH2:3][CH:4]2[N:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:7]([CH2:6][CH2:5]2)[CH:8]1[C:27]([O:29][CH3:30])=[O:28]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(=O)C2
Reactant: COC(=O)C#N
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1C(=O)CC2CCC1N2C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 88 %

Procedure:
Tetrahydrofuran (55.5 mL) was added to a flask containing tert-butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (10 g, 0.0444 mol). At −78° C., lithium diisopropylamide (24.4 mL, 0.0488 mol) was added dropwise to the reaction. The reaction was allowed to stir for 1 hr, then methyl cyanoformate (4.226 mL, 0.05326 mol) was added dropwise at −78° C. The reaction was let to stir for 5 hrs at room temperature. The reaction was quenched using saturated ammonium chloride solution. Some of the tetrahydrofuran was removed in vacuo. The remaining THF and ammonium chloride mixture was extracted using ethyl acetate three times. The combined ethyl acetate layers were washed with water and dried over sodium sulfate. The solution was filtered, was concentrated, and was purified using flash chromatography (0-100% ethyl acetate in hexane). A yellow oil was recovered (88% yield).
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][O-:16])[N:10]=[CH:9]2)C=CC=CC=1.[Na+].C1(C)C=CC=CC=1.C1OCCOCCOCCOCCOC1.Cl[CH2:53][CH2:54][CH2:55][CH:56]1[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]1>C(OCC)C>[NH:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][O:16][CH2:53][CH2:54][CH2:55][CH:56]2[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]2)[N:10]=[CH:9]1
Reactant: ClCCCC1CCCCC1
Reactant: [O-]CCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: C1COCCOCCOCCOCCO1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: c1nc(CCCOCCCC2CCCCC2)c[nH]1
Temperature: 75 °C
Reaction time: 24 h

Procedure:
5 mmol of sodium 3-[1-(triphenylmethyl)imidazol-4-yl]propoxide in 10 ml of toluene containing 0.5 mmol of 15-Crown-5 and 5 mmol of (3-chloropropyl)cyclohexane are mixed and the mixture is stirred for 24 h at 75° C. The suspension is concentrated under vacuum, the product obtained is dissolved in diethyl ether, the solution is filtered and the residue washed with petroleum ether (40°-60° C.). The filtrate obtained is concentrated and maintained for 1 h at the boiling point in a 2N aqueous/alcohol (ethanol/water) hydrochloric acid solution. The ethanol is removed under a low vacuum and the precipitate is filtered under vacuum. The solution is basified, extracted with dichloromethane and the organic phase is concentrated. The title compound obtained is recrystallized in the hydrogenmaleate form from ethanol/ diethyl ether.
Reaction SMILES: Br[C:2]1[N:6]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:3]=1[CH:26]([CH3:28])[CH3:27].[C:29]1(B(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>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>[CH:26]([C:3]1[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[CH:5][N:6]([S:7]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)(=[O:8])=[O:9])[C:2]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([CH3:27])[CH3:28]
Reactant: OB(O)c1ccccc1
Reactant: CC(C)c1c(CN(C)C(=O)OC(C)(C)C)cn(S(=O)(=O)c2ccccc2)c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC(C)c1c(CN(C)C(=O)OC(C)(C)C)cn(S(=O)(=O)c2ccccc2)c1-c1ccccc1
Yield: 36.8 %

Procedure:
Using tert-butyl {[5-bromo-4-isopropyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (596 mg), phenylboronic acid (307 mg), tetrakis(triphenylphosphine)palladium (218 mg) and sodium carbonate (401 mg), a procedure as in Reference Example 56 was performed to give the title compound as a pale-red oil (yield 218 mg, 37%).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH2:6][CH2:5]2.[NH2:13][NH2:14]>O1CCOCC1>[NH:13]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH2:6][CH2:5]2)[NH2:14]
Reactant: O=C1NCCc2cc(F)ccc21
Reactant: NN
Solvent: C1COCCO1
Product: NNc1ccc2c(c1)CCNC2=O

Procedure:
A solution of 6-fluoro-3,4-dihydro-2H-isoquinolin-1-one (3.6 g, 0.022 mole) and hydrazine (17.3 mL, 0.55 mole) was stirred at reflux in dioxane (150 mL) under nitrogen for 48 hours. The reaction mixture was concentrated under vacuo, water added (150 mL), and the product isolated by filtration. The product was thoroughly washed with diethyl ether to give the titled compound quantitatively as a white solid.