Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:13]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])CCC(OC)=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[OH:32]O>C(O)(C)C>[CH2:1]([N:13]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[OH:32])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCN(CCCCCCCCCCCC)CCC(=O)OC
Reactant: OO
Solvent: CC(C)O
Product: CCCCCCCCCCCCN(O)CCCCCCCCCCCC
Yield: 43.4 %

Procedure:
Using the general procedure of Example 2, 87.6 grams (0.2 mol) of the product of Example 5 in 800 ml of isopropanol is oxidized using 9.7 ml (0.25 mol) of 70% aqueous hydrogen peroxide solution to give 32.1 grams (44% yield) of the above-named product as a white solid melting at 85°-86° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-])=O.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.[C:32]([O:35][C:36]1[CH:43]=[CH:42][C:39]([CH:40]=[CH2:41])=[CH:38][CH:37]=1)(=[O:34])[CH3:33].C(N(CC)C(C)C)(C)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH:41]=[CH:40][C:39]1[CH:42]=[CH:43][C:36]([O:35][C:32](=[O:34])[CH3:33])=[CH:37][CH:38]=1
Reactant: O=[N+]([O-])c1ccccc1Br
Reactant: C=Cc1ccc(OC(C)=O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Oc1ccc(C=Cc2ccccc2N)cc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a solution of 1-bromo-2-nitrobenzene (2.0 g), palladium(II) acetate (112 mg) and 2-(di-tert-butylphosphino)biphenyl (150 mg) in acetonitrile (20 ml) were sequentially added 4-acetoxystyrene (1.7 ml) and N,N-diisopropylethylamine (5 ml) under a nitrogen atmosphere, and the solution was stirred for 3 hours at 80° C. The solution was extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. Obtained by purifying the residue by silica gel column chromatography (hexane-ethyl acetate system), acetic acid 4-[2-(2-nitrophenyl)vinyl]phenyl ester (840 mg) was used according to an analogous synthetic method to Example 57 to provide the title compound (330 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([C:24](O)=[O:25])=[C:12]2[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[BH4-].[Na+].Cl>O1CCCC1.CN(C)C=O.COCCOC>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:22])[CH3:23])[C:13]([CH2:24][OH:25])=[C:12]2[C:27]1[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)Cn1c(C(=O)O)c(-c2ccc(F)cc2)c2cc(OCc3ccccc3)ccc2c1=O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [BH4-]
Solvent: COCCOC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)Cn1c(CO)c(-c2ccc(F)cc2)c2cc(OCc3ccccc3)ccc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
To a solution of 6-benzyloxy-4-(4-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylic acid (3.79 g, 8.5 mmol) in tetrahydrofuran (30 mL) were added oxalyl chloride (0.9 mL, 10.2 mmol) and N,N-dimethylformamide (3 drops), and the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in tetrahydrofuran (20 mL). The obtained solution was added dropwise to a suspension of sodium tetrahydroborate (1.13 g, 30 mmol) in 1,2-dimethoxyethane (30 mL) at 0° C. The obtained mixture was stirred at 0° C. for 1 h. The reaction mixture was poured into 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 6-benzyloxy-4-(4-fluorophenyl)-3-hydroxymethyl-2-isobutyl-1(2H)-isoquinolinone (3.31 g, 90.2%) as crystals.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[NH2:30][C:31]1[CH:32]=[CH:33][C:34]([F:47])=[C:35]([C@:37]2([CH3:46])[C:42]([F:44])([F:43])[CH2:41][O:40][C:39]([NH2:45])=[N:38]2)[CH:36]=1.C([O-])(O)=O.[Na+]>CO>[NH2:45][C:39]1[O:40][CH2:41][C:42]([F:43])([F:44])[C@:37]([C:35]2[CH:36]=[C:31]([NH:30][C:8]([C:5]3[CH:4]=[N:3][C:2]([Cl:1])=[CH:7][N:6]=3)=[O:10])[CH:32]=[CH:33][C:34]=2[F:47])([CH3:46])[N:38]=1
Reactant: O=C(O)c1cnc(Cl)cn1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: O
Solvent: CO
Product: C[C@]1(c2cc(NC(=O)c3cnc(Cl)cn3)ccc2F)N=C(N)OCC1(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
5-Chloropyrazine-2-carboxylic acid (367 mg, 2.31 mmol) was combined with MeOH (25 ml) to give a colorless solution. 4-(4,6-Dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (DMTMM, 705 mg, 2.55 mmol) was added at 0° C. and the solution was stirred at 0° C. for 30 min. A solution of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A 8.1, 600 mg, 2.31 mmol) in MeOH (10 ml) was added dropwise and the reaction mixture was stirred overnight at 0° C. Sat. aq. NaHCO3 was added and the product was extracted with three portions of AcOEt. The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The crude material was purified by flash chromatography (SiO2, 50 g, 50 to 100% EtOAc in heptane). White solid (540 mg, 58%). MS (ISP): m/z=400.1 [M+H]+.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].C([Li])CCC.[CH2:12]([O:15][C:16]([N:18]([CH2:26][CH:27]=[O:28])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[CH:13]=[CH2:14].[Cl-].[NH4+]>O1CCCC1.CCCCCC.C(OCC)(=O)C>[CH2:12]([O:15][C:16]([N:18]([CH2:26][CH:27]([OH:28])[C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])[CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:17])[CH:13]=[CH2:14]
Reactant: C#C[Si](C)(C)C
Reactant: C=CCOC(=O)N(CC=O)Cc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=CCOC(=O)N(Cc1ccccc1)CC(O)C#C[Si](C)(C)C
Reaction time: 1 h

Procedure:
To a solution of (trimethylsilyl)acetylene (23.75 ml) in tetrahydrofuran (250 ml) was added a 1.6M solution of butyllithium in hexane (105 ml) below -60° C. After stirring for one hour, a solution of 2-(N-allyloxycarbonyl-N-benzylamino)acetaldehyde (32.86 g) in tetrahydrofuran (30 ml) was added to the mixture below -60° C. The solution was stirred at the same condition for one hour and an aqueous saturated ammonium chloride (100 ml) was added to the reaction mixture below -60° C. After stirring at the ambient temperature for one hour, ethyl acetate (300 ml) was poured into the mixture. The solution was washed with brine (150 ml×2), dried over magnesium sulfate, and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (300 g) and eluted with a mixture of hexane and ethyl acetate (9:1, V/V) to give 1-(N-allyloxycarbonyl-N-benzylamino)-4-trimethylsilyl-3-butyn-2-ol (19.77 g) as a syrup.
Reaction SMILES: [Br:1][C:2]1[C:10]([N+:11]([O-])=O)=[CH:9][C:8]2[C:4](=[C:5]([C:21]#[N:22])[N:6]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[N:7]=2)[CH:3]=1.C1COCC1.O.[Cl-].[NH4+]>CO.[Fe]>[NH2:11][C:10]1[C:2]([Br:1])=[CH:3][C:4]2[C:8]([CH:9]=1)=[N:7][N:6]([C:14]1[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=1)[C:5]=2[C:21]#[N:22]
Reactant: N#Cc1c2cc(Br)c([N+](=O)[O-])cc2nn1-c1ccc(F)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1c2cc(Br)c(N)cc2nn1-c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 0.7 %

Procedure:
To a suspension of 5-bromo-2-(4-fluorophenyl)-6-nitro-2H-indazole-3-carbonitrile (500 mg, 139 mmol) in a mixture of methanol (50 mL), THF (5 mL) and water (2.5 mL) was added ammonium chloride (370 mg, 6.91 mmol) followed by iron powder (386 mg, 6.91 mmol). The mixture was heated to 80° C. and stirred vigorously for 90 min. The resulting suspension was filtered through celite and washed with EtOAc. The filtrate was concentrated, and the residue was suspended in water and extracted with EtOAc. The organic layer was contracted to give 6-amino-5-bromo-2-(4-fluorophenyl)-2H-indazole-3-carbonitrile (310 mg, 68%) as a yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 7.99 (s, 1H), 7.80˜7.82 (m, 2H), 7.23˜7.57 (m, 2H), 7.03 (s, 1H), 4.40 (s, 2H). MS (M+H)+: 331/333.
Reaction SMILES: CS(C)=O.Cl[C:6]1[N:7]([CH2:29][CH:30]2[CH2:32][CH2:31]2)[C:8]2[C:13]([N:14]=1)=[C:12]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[N:11]=[C:10]([C:21]1[CH:22]=[N:23][C:24]([NH:27][CH3:28])=[N:25][CH:26]=1)[N:9]=2.[CH3:33][C@H:34]1[CH2:39][NH:38][CH2:37][C@@H:36]([CH3:40])[NH:35]1>ClCCl.CO>[CH:30]1([CH2:29][N:7]2[C:6]([N:38]3[CH2:37][C@H:36]([CH3:40])[NH:35][C@H:34]([CH3:33])[CH2:39]3)=[N:14][C:13]3[C:8]2=[N:9][C:10]([C:21]2[CH:22]=[N:23][C:24]([NH:27][CH3:28])=[N:25][CH:26]=2)=[N:11][C:12]=3[N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH2:32][CH2:31]1
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: CNc1ncc(-c2nc(N3CCOCC3)c3nc(Cl)n(CC4CC4)c3n2)cn1
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CO
Product: CNc1ncc(-c2nc(N3CCOCC3)c3nc(N4C[C@@H](C)N[C@@H](C)C4)n(CC4CC4)c3n2)cn1
Reaction time: 5 h
Yield: 89.2 %

Procedure:
A dimethyl sulfoxide solution (1.0 ml) of 5-[8-chloro-9-(cyclopropylmethyl)-6-morpholin-4-yl-9H-purin-2-yl]-N-methylpyrimidin-2-amine (112.3 mg, 0.23 mmol) and cis-2,6-dimethylpiperazine (105.7 mg, 0.93 mmol) was heated at 140° C., stirred for 5 hours, and left standing to cool followed by the addition of dichloromethane-methanol (10:1) and the resulting mixture was washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous sodium sulfate, the mixture was filtrated, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative thin layer silica gel chromatography (dichloromethane:methanol=10:1) to give the title compound (98.2 mg, 89%) as a light brown solid.
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9]([N:11]2[CH2:17][CH2:16][CH2:15][CH2:14]C[C:12]2=[O:18])=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C1(=O)NCCCC1>>[N+:1]([C:4]1[O:8][C:7]([C:9]([N:11]2[CH2:17][CH2:16][CH2:15][CH2:14][C:12]2=[O:18])=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C1CCCCCN1C(=O)c1ccc([N+](=O)[O-])o1
Agent: O=C1CCCCN1
Product: O=C1CCCCN1C(=O)c1ccc([N+](=O)[O-])o1

Procedure:
Synthesized as for N-(5-nitro-2-furoyl)caprolactam (Example XIII) using valerolactam (Aldrich) in place of caprolactam.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([N:12]2[C:17]3=[N:18][C:19]([NH:22][CH3:23])=[N:20][CH:21]=[C:16]3[CH2:15][N:14]([C:24]3[C:29]([F:30])=[C:28]([O:31][CH3:32])[CH:27]=[C:26]([O:33][CH3:34])[C:25]=3[F:35])[C:13]2=[O:36])[CH2:8][CH2:7]1)=[O:5])C.CO.[OH-].[Na+]>O>[F:35][C:25]1[C:26]([O:33][CH3:34])=[CH:27][C:28]([O:31][CH3:32])=[C:29]([F:30])[C:24]=1[N:14]1[CH2:15][C:16]2[C:17](=[N:18][C:19]([NH:22][CH3:23])=[N:20][CH:21]=2)[N:12]([CH:9]2[CH2:10][CH2:11][CH:6]([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]2)[C:13]1=[O:36]
Reactant: CCOC(=O)C1CCC(N2C(=O)N(c3c(F)c(OC)cc(OC)c3F)Cc3cnc(NC)nc32)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CNc1ncc2c(n1)N(C1CCC(C(=O)O)CC1)C(=O)N(c1c(F)c(OC)cc(OC)c1F)C2
Temperature: 50 °C
Yield: 63 %

Procedure:
To a 250-mL round-bottomed flask was added Ethyl-4-[3-(2,6-difluoro-3,5-dimethoxy-phenyl)-7-methylamino-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-1-yl]-cyclohexanecarboxylate (crude 1.5 mmol), methanol (70 mL), water (20 mL), and sodium hydroxide (600 mg, 15 mmol), and the mixture was heated to 50° C. for 3 days. The crude reaction solution was then concentrated to less than 10 mL in vacuo, and then the volume was increased to 50 mL with water. The pH was then adjusted to 4 with 6 M hydrochloric acid, and the resulting white precipitate was collected by filtration and dried in vacuo overnight to deliver the title compound (460 mg, 63% yield for 2 steps) as a white solid: mp 148° C., LRMS: 478.2 (M+H).
Reaction SMILES: [H-].[Na+].[NH2:3][C@@H:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C@H:7]([OH:14])[CH2:6][CH2:5]1.F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([C:25]3([N:30]([CH3:32])[CH3:31])[CH2:29][CH2:28][CH2:27][CH2:26]3)=[N:23][N:24]=2)[CH:21]=1>CN(C=O)C>[CH3:31][N:30]([CH3:32])[C:25]1([C:22]2[N:20]3[CH:21]=[C:16]([O:14][C@H:7]4[C:8]5[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=5)[C@@H:4]([NH2:3])[CH2:5][CH2:6]4)[CH:17]=[CH:18][C:19]3=[N:24][N:23]=2)[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Reactant: CN(C)C1(c2nnc3ccc(F)cn23)CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)C1(c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)CCCC1
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 64.9 %

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 133 mg, 3.34 mmol) in DMF (5 mL) was added Intermediate A (136 mg, 0.83 mmol) and the reaction mixture was stirred for 20 min. A solution of Intermediate 99c (207 mg, 0.83 mmol) in DMF (3 mL) was added and the reaction mixture was heated at 60° C. for 90 min. After cooling, the reaction mixture was quenched by careful addition of MeOH and then loaded onto an SCX cartridge. The cartridge was washed with MeOH and the product eluted with 2M NH3 in MeOH. The product containing fractions were concentrated in vacuo and the resultant residue was purified by FCC on silica, using a gradient of 0-10% (2M NH3 in MeOH) in DCM, to give the title compound (211 mg, 65%). LCMS (Method 4): Rt 1.49 min, m/z 392 [MH+].
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[N:9][C:8]2[N:4]([N:5]=[C:6]3[CH2:14][N:13]([C:15]([C:17]4[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=4[O:24][CH:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)=[O:16])[CH2:12][C:7]3=2)[C:3]=1[CH3:31].[O:32]1[CH2:35][C:34](=O)[CH2:33]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[Cl:1][C:2]1[C:10]([CH3:11])=[N:9][C:8]2[N:4]([N:5]=[C:6]3[CH2:14][N:13]([C:15]([C:17]4[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=4[O:24][CH:25]4[CH2:30][CH2:29][N:28]([CH:34]5[CH2:35][O:32][CH2:33]5)[CH2:27][CH2:26]4)=[O:16])[CH2:12][C:7]3=2)[C:3]=1[CH3:31]
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccc(F)cc1OC1CCNCC1)C3
Reactant: O=C1COC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccc(F)cc1OC1CCN(C2COC2)CC1)C3
Yield: 68.8 %

Procedure:
A mixture of Example 64 (110 mg; 0.25 mmol; 1 eq.), 3-oxetanone (22 μL; 0.37 mmol; 1.5 eq.) and sodium triacetoxyborohydride (53 mg; 0.25 mmol; 1 eq.) in DCE (6 mL) was stirred at 50° C. for 16 hours. The reaction mixture was diluted with DCM, washed with sat. aq. NaHCO3, dried over sodium sulfate and concentrated in vacuo. Crystallization from EA afforded the title compound (86 mg, 69%) as an off-white solid. 1H NMR (CDCl3) δ 7.34 (td, J=8.1, 6.6 Hz, 1H), 6.80-6.63 (m, 2H), 5.07-4.92 (m, 2H), 4.66 (br s, 2H), 4.61-4.47 (m, 4H), 4.47-4.33 (m, 1H), 3.43-3.28 (m, 1H), 2.92 (s, 1.8H), 2.86 (s, 1.2H), 2.70 (s, 1.2H), 2.63 (s, 1.8H), 2.44-2.28 (m, 2H), 2.23-2.10 (m, 2H), 2.03-1.90 (m, 2H), 1.90-1.73 (m, 2H). HPLC (max plot) 97.1%, Rt 2.90 min. UPLC/MS: (MS+) 500.5 ([M+H]+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:8][C:9]1[CH:10]=[C:11](O)[CH:12]=[CH:13][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>>[Br:8][C:9]1[CH:14]=[C:13]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: Oc1cccc(Br)c1
Reactant: Brc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Product: Brc1cccc(-c2ccccn2)c1
Temperature: 200 °C
Reaction time: 3 h
Yield: 78.4 %

Procedure:
A mixture of 2-bromopyridine (2.5 g, 15.8 mmol), 3-bromophenol (5.5 g, 31.6 mmol) and potassium carbonate (2.2 g, 15.8 mmol) was stirred at 200° C. for 3 hours. After the reaction mixture was allowed to cool, to which was then added an aqueous 1 mol/L sodium hydroxide solution, the mixture was extracted with dichloromethane, the solvent was distilled off, and the residue was purified by silica gel column chromatography and recrystallization, thereby obtaining 2.9 g of desired compound as white crystal.
Reaction SMILES: Cl.[F:2][C:3]([F:29])([F:28])[C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Br[CH2:31][C:32]#[N:33]>>[F:29][C:3]([F:2])([F:28])[C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:23]=1)[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][N:12]([CH2:31][C:32]#[N:33])[CH2:11][C@H:10]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: N#CCBr
Reactant: FC(F)(F)c1cc(CO[C@H]2CCNC[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Agent: Cl
Product: N#CCN1CC[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](c2ccccc2)C1
Yield: 86.2 %

Procedure:
The compound (0.15 g) obtained in Example 1 and bromoacetonitrile (0.082 g) were reacted and treated in the same manner as in the method described in Example 7 to obtain the title compound as colorless oil (0.13 g, 86%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][C:14]=1[N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][C:14]=1[N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1ccc(N2CCCCC2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)c1ccc(N2CCCCC2)c(N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
Ethyl 3-nitro-4-piperidin-1-ylbenzoate (2.83 g, 10.2 mmol) prepared in the Step 3-1-1 was dissolved in methanol (50 ml), and palladium 5% on carbon (500 mg) was added to the solution. The mixture was stirred under a hydrogen flow at a room temperature overnight. The mixture was filtered, and the filtrate was concentrated to give the title compound (2.23 g, 90%) as a blackish-red solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[NH:12][CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])=[C:4]([C:18]2[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH:19]=2)[CH:3]=1.C([Mg]Cl)(C)C.[Li]C(C)(C)C.CCCCC.[C:41]([O:45][CH2:46][CH3:47])(=[O:44])[CH:42]=[O:43].C1(C)C=CC=CC=1>C1COCC1>[CH2:46]([O:45][C:41](=[O:44])[CH:42]([C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[NH:15][C:14]([C:16]#[N:17])=[CH:13][N:12]=2)=[O:10])=[C:4]([C:18]2[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH:19]=2)[CH:3]=1)[OH:43])[CH3:47]
Reactant: CC1(C)CC=C(c2cc(Br)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Reactant: CCOC(=O)C=O
Agent: CC(C)[Mg]Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCCCC
Product: CCOC(=O)C(O)c1ccc(NC(=O)c2ncc(C#N)[nH]2)c(C2=CCC(C)(C)CC2)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 50 %

Procedure:
To a suspension of 4-cyano-1H-imidazole-2-carboxylic acid [4-bromo-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amide (71 mg, 0.18 mmol) (as prepared in Example 14, step (c)) in 3 mL THF at −40° C. was added a 2M solution of isopropylmagnesium chloride (i-PrMgCl) in THF (0.23 mL, 0.46 mmol) and the solution was then warmed to 0° C. and stirred for 10 min. The solution was then cooled to −78° C. and a 1.7 M solution of t-BuLi in pentane (0.28 mL, 0.48 mmol) was added dropwise and then a 40% solution of ethyl glyoxalate in toluene (0.23 mL, 0.90 mmol) was added immediately thereafter. After 5 min at −78° C. the reaction was quenched with satd NH4Cl (10 mL) and extracted with EtOAc (3×10 mL) and dried over Na2SO4 and concentrated in vacuo. The title compound was purified by flash chromatography (silica gel) eluting with 50-100% EtOAc/hexanes to give 37 mg (50%) of the title compound as a white solid. Mass spectrum (ESI, m/z): Calcd. for C23H26N4O2, 423.2 (M+H). found 423.1.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][N:20]2[C:29](=[O:30])[C:28]3[CH:31]=[CH:32][CH:33]=[C:26]4[C:27]=3[C:22](=[CH:23][CH:24]=[CH:25]4)[C:21]2=[O:34])[CH2:14][CH2:13]1.Cl.N1C=CC=CC=1>N1C=CC=CC=1>[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH:12]1[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][N:20]2[C:29](=[O:30])[C:28]3[CH:31]=[CH:32][CH:33]=[C:26]4[C:27]=3[C:22](=[CH:23][CH:24]=[CH:25]4)[C:21]2=[O:34])[CH2:16][CH2:17]1
Reactant: COc1ccc2[nH]cc(C3CCN(CCN4C(=O)c5cccc6cccc(c56)C4=O)CC3)c2c1
Agent: Cl
Solvent: c1ccncc1
Product: O=C1c2cccc3cccc(c23)C(=O)N1CCN1CCC(c2c[nH]c3ccc(O)cc23)CC1
Reaction time: 3 h

Procedure:
A mixture of 1.6 g of 2-[2-(4-(5-methoxy-3-indolyl)piperidino)ethyl]-2,3-dihydro-1H-benz[de]isoquinoline-1,3-dione [which can be prepared according to Example 1], 1.8 g of pyridine hydrochloride and 50 ml of pyridine is boiled for 3 hours. The mixture is cooled, evaporated, worked up in the customary manner and gives 2-[2-(4-(5-hydroxy-3-indolyl)piperidino)ethyl]-2,3-dihydro-1H-benz[de]isoquinoline-1,3-dione.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11](OS(C(F)(F)F)(=O)=O)=[CH:12][CH:13]=2)[CH:8]=[C:7]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)[N:6]=1)([CH3:3])[CH3:2].[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[CH:12][CH:13]=2)[CH:8]=[C:7]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)[N:6]=1)([CH3:3])[CH3:2]
Reactant: C1CCNC1
Reactant: Cc1cc(Nc2cc3cc(OS(=O)(=O)C(F)(F)F)ccc3c(OC(C)C)n2)n[nH]1
Product: Cc1cc(Nc2cc3cc(N4CCCC4)ccc3c(OC(C)C)n2)n[nH]1

Procedure:
Similar procedure as described in the example 363 was used, starting from Trifluoro-methanesulfonic acid 1-isopropoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-6-yl ester and Pyrrolidine to give 5 mg of (1-Isopropoxy-6-pyrrolidin-1-yl-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine as a yellow solid. LC-MS m/e 352 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][N:19]=2)[C:13]([O:15]C)=[O:14])[CH:6]=[CH:7][C:8]=1[OH:9])#[N:2].[CH:20]1([CH2:24]Br)[CH2:23][CH2:22][CH2:21]1>>[C:1]([C:3]1[CH:4]=[C:5]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][N:19]=2)[C:13]([OH:15])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH2:24][CH:20]1[CH2:23][CH2:22][CH2:21]1)#[N:2]
Reactant: COC(=O)c1ccnc(-c2ccc(O)c(C#N)c2)c1
Reactant: BrCC1CCC1
Product: N#Cc1cc(-c2cc(C(=O)O)ccn2)ccc1OCC1CCC1

Procedure:
Using methyl 2-(3-cyano-4-hydroxyphenyl)isonicotinate and cyclobutylmethyl bromide, 2-[3-cyano-4-(cyclobutylmethoxy)phenyl]isonicotinic acid was obtained according to the method of Example 2. Then, 150 mg of the compound was suspended in 5 ml of methanol, and 32 mg of sodium methoxide was added to the suspension at 0° C., followed by stirring for 3 hours with gradual elevation of the temperature to room temperature. The reaction solution was concentrated under reduced pressure to obtain 115 mg of sodium 2-[3-cyano-4-(cyclobutylmethoxy)phenyl]isonicotinate.
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][CH2:7][NH:8]C(=O)C)(=[O:4])=[O:3].[ClH:12]>O>[ClH:12].[CH3:1][S:2]([NH:5][CH2:6][CH2:7][NH2:8])(=[O:4])=[O:3]
Reactant: CC(=O)NCCNS(C)(=O)=O
Agent: Cl
Solvent: O
Product: CS(=O)(=O)NCCN

Procedure:
N-[2-(Methylsulphonamido)ethyl]acetamide (14.5 g, 88.3 mmol) and concentrated hydrochloric acid (100 ml) were dissolved in water (100 ml) and heated to reflux for a total of 3 hours. After cooling, the water was removed in vacuo, and the residue was left for several days at room temperature until crystallisation was underway. Trituration with a mixture of ethanol and ether gave the title compound as a white solid which was dried in vacuo at 60° C. (7.5 g, 42.9 mmol, 49%); δH [2H6]DMSO 8.22 (2H, br s), 7.42 (1H, t), 3.23 (2H, q), 2.87 (3H, s), 2.85-2.95 (2H, m).