Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8](=[O:25])[NH:7][N:6]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][O:35]1.CN(C)C=O>C(OCC)(=O)C>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8](=[O:25])[N:7]([CH2:33][CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][O:35]2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1n[nH]c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: BrCC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1nn(CC2CCCCO2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 37.6 %

Procedure:
A mixture of 4′-[(3-butyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl]biphenyl-2-carbonitrile (1.13 g), potassium carbonate (0.94 g), 2-(bromomethyl)tetrahydro-2H-pyran (0.90 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.55 g, 38%).
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([CH:14]([OH:30])[C:15]3[N:19]4[N:20]=[C:21]([C:24]5[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=5)[CH:22]=[CH:23][C:18]4=[N:17][CH:16]=3)=[CH:10][N:9]2[CH:31]=1)=O.C([O-])([O-])=O.[K+].[K+].O>C1COCC1.CO>[NH2:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([CH:14]([C:15]3[N:19]4[N:20]=[C:21]([C:24]5[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=5)[CH:22]=[CH:23][C:18]4=[N:17][CH:16]=3)[OH:30])=[CH:10][N:9]2[CH:31]=1
Reactant: Cn1cc(-c2ccc3ncc(C(O)c4ccc5nc(NC(=O)C(F)(F)F)cn5c4)n3n2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cn1cc(-c2ccc3ncc(C(O)c4ccc5nc(N)cn5c4)n3n2)cn1
Temperature: 90 °C

Procedure:
(rac)-2,2,2-Trifluoro-N-(6-{hydroxy-[6-(1-methyl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-3-yl]-methyl}-imidazo[1,2-a]pyridin-2-yl)-acetamide (Example 153, 120 mg, 0.263 mmol) was dissolved in THF/MeOH 1:1 (2 mL). K2CO3 was added (363 mg, 2.63 mmol) with water (1 mL) and the RM was heated over night at 90° C. After concentration under reduced pressure, the residue was purified by flash chromatography (CombiFlash® Companion System®, with 12 g RediSep® silica gel column, DCM/MeOH=8:2->DCM/MeOH/H2O/ammonia=80:19:0.5: 0.5) to afford the title compound (MH+=361, 1H NMR in DMSO-d6: .8.5 (s, 1H); 8.4 (s, 1H); 8.1 (s, 1H); 8.0 (d, 1H); 7.6 (s, 1H); 7.5 (d, 1H), 7.1 (q, 2H), 7.0 (s, 1H); 6.2 (s, 2H); 5.0 (s, 2H); 3.9 (s, 3H)).
Reaction SMILES: Br[C:2]1[C:11]([O:12][C:13]2[C:22]3[C:17](=[CH:18][C:19]([O:25][CH3:26])=[C:20]([O:23][CH3:24])[CH:21]=3)[N:16]=[CH:15][CH:14]=2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[N:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:24][O:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][C:19]=1[O:25][CH3:26])[N:16]=[CH:15][CH:14]=[C:13]2[O:12][C:11]1[C:2]([C:30]2[CH:31]=[CH:32][N:27]=[CH:28][CH:29]=2)=[N:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: COc1cc2nccc(Oc3cc4ccccc4nc3Br)c2cc1OC
Reactant: OB(O)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3cc4ccccc4nc3-c3ccncc3)c2cc1OC
Temperature: 25 °C
Yield: 26.1 %

Procedure:
4-(2-Bromo-quinolin-3-yloxy)-6,7-dimethoxy-quinoline (compound 281) (50 mg), tetrakistriphenylphosphine palladium(0) (14 mg), and 4-pyridineboronic acid (42 mg) were suspended in a mixed solvent composed of N,N-dimethylformamide (1 ml) and a 2 N aqueous potassium carbonate solution (1 ml), and the suspension was stirred at 80° C. for 2.5 hr. The reaction solution was cooled to room temperature, the reaction solution was then filtered, and the solvent was removed from the filtrate by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-chloroform to give the title compound (13 mg, yield 26%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.ClC(Cl)(O[C:19](=[O:25])OC(Cl)(Cl)Cl)Cl.[F:27][C:28]1[CH:29]=[C:30]([C:34]2[C:42]([C:43]([NH2:45])=[O:44])=[C:37]3[CH2:38][NH:39][CH2:40][CH2:41][N:36]3[N:35]=2)[CH:31]=[CH:32][CH:33]=1>C1COCC1>[C:43]([C:42]1[C:34]([C:30]2[CH:31]=[CH:32][CH:33]=[C:28]([F:27])[CH:29]=2)=[N:35][N:36]2[CH2:41][CH2:40][N:39]([C:19]([NH:1][CH:2]3[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]3)=[O:25])[CH2:38][C:37]=12)(=[O:44])[NH2:45]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: NC(=O)c1c(-c2cccc(F)c2)nn2c1CNCC2
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)N2CCn3nc(-c4cccc(F)c4)c(C(N)=O)c3C2)CC1
Reaction time: 0.5 h
Yield: 80.3 %

Procedure:
To a solution of tert-butyl 4-aminopiperidine-1-carboxylate (308 mg, 1.537 mmol) and TEA (0.536 mL, 3.84 mmol) in THF (3 mL) was added triphosgene (228 mg, 0.768 mmol) at 0° C. and stirred for 30 min. at the same temperature. A solution of Intermediate 4J (200 mg, 0.768 mmol) in THF was added and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water and the aqueous layer was extracted with ethyl acetate (3×5 mL) The combined organic layer was washed with 10% NaHCO3 (2×5 mL), water, dried over Na2SO4, filtered and concentrated. The crude product was purified using reverse phase HPLC method to afford Intermediate 97A (300 mg, 80%) as a white solid. MS(ES): m/z=487 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 7.51-7.55 (m, 1H), 7.42-7.51 (m, 2H), 7.35 (bs, 1H), 7.22 (m, 1H), 7.15 (bs, 1H), 6.70 (d, J=7.53 Hz, 1H), 4.72 (s, 2H), 4.14 (t, J=4.8 Hz, 2H), 3.89 (m, 2H), 3.84 (t, J=4.4 Hz, 2H), 3.65 (m, 1H), 2.85-2.78 (m, 2H), 1.75 (m, 2H), 1.41 (s, 9H), 1.32 (m, 2H).
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH:10]12[CH2:15][CH:14]1[C:13](=[O:16])[O:12][C:11]2=O>>[CH2:1]([N:9]1[C:11](=[O:12])[CH:10]2[CH:14]([CH2:15]2)[C:13]1=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=C1OC(=O)C2CC12
Reactant: CCCCCCCCN
Product: CCCCCCCCN1C(=O)C2CC2C1=O
Temperature: 180 °C

Procedure:
A mixture of n-octylamine (24.2 g) and 3-oxabicyclo[3.1.0]hexane-2,4-dione (20.0 g) was heated at 180° C. for 2.5 hours and was then cooled to room temperature. The mixture was distilled in vacuo (boiling point 140-142° C. @ 0.1 mmHg) to give the title compound as a colourless oil.
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].[O:6]1[CH2:11][CH2:10][CH:9](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:8][CH2:7]1>CN(C=O)C.CCOCC>[O:6]1[CH2:11][CH2:10][CH:9]([S:3][C:1](=[O:4])[CH3:2])[CH2:8][CH2:7]1
Reactant: Cc1ccc(S(=O)(=O)OC2CCOCC2)cc1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(=O)SC1CCOCC1
Temperature: 50 °C

Procedure:
A mixture of potassium thioacetate (10.21 g; 87.62 mmol) and toluene-4-sulfonic acid tetrahydro-pyran-4-yl ester (11.23 g; 43.81 mmol) in DMF (100 mL) was heated at 50° C. for 12 hours, cooled to room temperature, diluted with ether, washed with water, saturated NaHCO3 and brine and dried (MgSO4). Removal of the volatiles in vacuo provided a residue which was taken forward without additional purification.
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:8]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[C@H:7]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[C@@H:6]([CH2:29][O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[O:5][CH:3]1[OH:4].C(N(C(C)C)CC)(C)C.[F:49][C:50]([F:55])([F:54])[C:51](O)=[O:52].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(OCC)(=O)C>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][O:9][C@H:8]2[C@H:7]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[C@@H:6]([CH2:29][O:30][CH2:31][C:32]3[CH:33]=[CH:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=3)[O:5][CH:3]([OH:4])[C@@H:2]2[NH:1][C:51](=[O:52])[C:50]([F:55])([F:54])[F:49])=[CH:12][CH:13]=1
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc(COC[C@H]2OC(O)[C@H](N)[C@@H](OCc3ccc(OC)cc3)[C@@H]2OCc2ccc(OC)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: COc1ccc(COC[C@H]2OC(O)[C@H](NC(=O)C(F)(F)F)[C@@H](OCc3ccc(OC)cc3)[C@@H]2OCc2ccc(OC)cc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
To a solution of the amine 64 (75.6 mmol) in dry chloroform (400 ml) at 0° C. was added diisoproplyethylamine (113.4 mmol) and trifluoroacetic acid (16.0 mL, 113.4 mmol). The resulting reaction mixture was then stirred for 30 min after which time the reaction was allowed to return to room temperature and stir for a further 1 h. At this time the reaction was cooled to 0° C. and further diisoproplyethylamine (113.4 mmol) and trifluoroacetic acid (113.4 mmol) added, the reaction was allowed to return to room temperature and stirred for 3 h. The reaction mixture was then poured into dilute sodium hydrogen carbonate and the mixture stirred for 30 min. The solid was washed with water, transferred to a flask and dried by co-evaporation with acetonitrile to give the crude product. Ethyl acetate was then added to the residue and the resulting suspension refluxed for 2 h. Petrol ether (˜300 mL) was then added to this, the mixture cooled to room temperature, and the resulting solid filtered and dried under high vacuum to give the desired product 65 as a solid (77%), δH (400 MHz; CDCl3) 3.04-3.17 (1 H, m), 3.54-3.60 (2 H, m), 3.61-3.71 (2 H, m), 3.79 (3 H, s), 3.80 (3 H, s), 3.81 (3 H, s), 4.01 [dt, J 3.0 Hz and J 10.4 Hz] and 4.16 [dt, J 3.7 Hz and J 10.1 Hz] (1 H), 4.43 (2 H, t, J 10.4 Hz), 4.50-4.60 (2 H, m), 4.66-4.78 (2 H, m), 5.23 (1 H, d, J 4.0 Hz), 6.11 (1 H, br d, J 2.9 Hz), 6.80-6.90 (6 H, m), 7.06 (2 H, d, J 11.1 Hz), 7.18 (2 H, d, J 12.6 Hz) and 7.24 (2 H, d, J 11.1 Hz); LCMS [M+Na]+=658.2.
Reaction SMILES: [CH:1]1[C:17]2[CH:16]=[C:15]3[C:7](=[C:8]4[C:13](=[N:14]3)[CH:12]=[CH:11][CH:10]=[CH:9]4)[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:18]([Br:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CCOCC>C(Cl)(Cl)Cl>[BrH:25].[CH2:18]([NH+:6]1[C:7]2[C:15]([N:14]=[C:13]3[C:8]=2[CH:9]=[CH:10][CH:11]=[CH:12]3)=[CH:16][C:17]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]1=2)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: c1ccc2[nH]c3c4ccccc4nc-3cc2c1
Reactant: BrCc1ccccc1
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: Br
Product: C1=C2N=c3ccccc3=C2[NH+](Cc2ccccc2)c2ccccc21
Temperature: 140 °C
Yield: 99.1 %

Procedure:
A suspension of quindoline (1.0 g, 4.6 mmol) from Example 2, benzyl bromide (3 mL, 8.5 mmol) and chloroform (5 mL) was heated in a bomb at 140° C. for 48 hours. After cooling, the reaction mixture was dissolved in a small amount chloroform. Ether (100 mL) was added, and the resulting precipitate was filtered and washed with ether to give 1.78 g (100%) of 5-benzylquindolinium hydrobromide as a greenish-yellow solid. A portion of the 5-benzyl quindolinium hydrobromide (0.9 g) obtained above was purified by LPLC on neutral alumina (Fisher) eluting with 1-2% MeOH in CHCl3. The product containing fractions were combined, redissolved in a small amount of chloroform, and acidified with a solution of 1.0M HCl in ether to give, after filtration and drying, 0.20 g (25%) of 5-benzylquindolinium hydrochloride as yellow crystals, mp 241°-242° C.; 1H NMR (DMSO-d6) δ 13.40 (s, 1H, NH), 9.49 (s, 1H, H11), 8.68 (d, J=8.2, 1H, H6), 8.53 (d, J=8.8, 1H, H4), 8.31 (d, J=8.4, 1H, H1), 8.12 (t, J=6.4, 1H, H3), 7.96 (t, J=7.6, 1H, H8), 7.90 (d, J=5.2, 2H, H2 and H9), 7.42-7.32 (m, 4H, H7 and arom), 7.22 (d, J=6.4, 2H), 6.84 (s, 2H, NCH2); 13C NMR (DMSO-d6) δ 146.14, 138.11, 135.21, 134.16, 133.84, 133.28, 133.00, 130.23, 129.19, 128.14, 127.21, 126.41, 126.10, 126.02, 125.24, 121.65, 117.59, 113.53, 112.86; MS (EI, m/z) 308.1 (M+ -1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:28][CH2:29][OH:30])[C:5]([C:7]1[CH:8]=[N:9][N:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][C@H:23]3[CH3:27])=[CH:14][CH:13]=2)[CH:11]=1)=[O:6].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)(Cl)Cl.O>[OH:1][CH:2]1[O:30][CH2:29][CH2:28][N:4]([C:5]([C:7]2[CH:8]=[N:9][N:10]([C:12]3[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:26][CH2:25][CH2:24][C@H:23]4[CH3:27])=[CH:16][CH:17]=3)[CH:11]=2)=[O:6])[CH2:3]1
Reactant: C[C@@H]1CCCN1CCCOc1ccc(-n2cc(C(=O)N(CCO)CCO)cn2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClC(Cl)Cl
Solvent: O
Product: C[C@@H]1CCCN1CCCOc1ccc(-n2cc(C(=O)N3CCOC(O)C3)cn2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 2.2 %

Procedure:
To a solution of 1-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-1H-pyrazole-4-carboxylic acid bis-(2-hydroxyethyl)-amide obtained in Example 20 (1.0 g) in chloroform (8 mL), Dess-Martin reagent (1.1 g) was added and stirred at room temperature for 16 hours. The reaction mixture was diluted with water and extracted with chloroform. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting solvent: chloroform:methanol=4:1) and further purified by preparative TLC (1 mm thickness, developing solvent: chloroform:methanol=9:1) to give the titled compound (0.022 g) as a colorless amorphous substance.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][CH2:10][CH2:11][OH:12].[OH-].[K+].C(O)C.[C:18](=S)=[S:19]>O>[SH:19][C:18]1[N:8]([CH2:9][CH2:10][CH2:11][OH:12])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: Nc1ccccc1NCCCO
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: OCCCn1c(S)nc2ccccc21
Reaction time: 6 h

Procedure:
To a stirred mixture of 93 parts of 3-(2-aminophenyl)amino-1-propanol, 45.5 parts of potassium hydroxide and 600 parts of an ethanol solution 85% in water are added dropwise 60.8 parts of carbon disulfide. Upon completion, stirring is continued for 6 hours at reflux temperature. The reaction mixture is evaporated and the residue is taken up in 1500 parts of water. The whole is filtered over hyflo and the filtrate is acidified with acetic acid. The oily product solidifies on scratching. It is filtered off, washed with water and dried, yielding 2-mercapto-1H-benzimidazole-1-propanol; mp. 110° C.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.CCCCCC.[CH:17]1([CH:22]([CH3:28])[CH2:23][CH2:24][CH2:25][C:26]#N)[CH2:21][CH2:20][CH2:19][CH2:18]1.[OH:29]S(O)(=O)=O>CC(OC)(C)C.CO>[CH:17]1([CH:22]([CH3:28])[CH2:23][CH2:24][CH2:25][CH:26]=[O:29])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CC(CCCC#N)C1CCCC1
Reactant: O=S(=O)(O)O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: COC(C)(C)C
Solvent: CCCCCC
Solvent: CO
Product: CC(CCCC=O)C1CCCC1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 51.5 %

Procedure:
Diisobutylaluminum hydride (60 ml of 1.0 M solution in hexane) was added at −65° C. to a hexane (50 ml) solution of 5-cyclopentylhexanenitrile (5.0 g; 30 mmol; from example 11). After stirring at −70° C. for 0.5 hour, and at room temperature for 3 hours, methanol (1.8 ml) was added, and the stirring continued for 20 minutes. 10% H2SO4 (48 ml) was added, and the reaction mixture was diluted with MTBE (150 ml). The organic layer was separated, washed with saturated sodium bicarbonate solution (300 ml) and brine (3×300 ml), dried (MgSO4), concentrated in vacuo, and bulb-to-bulb distilled (100° C./0.2 torr) to give 2.6 g (51.5% yield) of 5-cyclopentylhexanal.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][N:3]=1.[H-].[Na+].Cl[CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.CO.C(Cl)Cl>CN(C)C=O>[N:16]1([CH2:15][CH2:14][NH:1][C:2]2[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[O:4][N:3]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: ClCCN1CCOCC1
Reactant: Nc1noc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CO
Product: c1ccc2c(NCCN3CCOCC3)noc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.7 %

Procedure:
To a solution of 3-amino-1,2-benzisoxazole (3.5 g) in N,N-dimethylformamide (DMF) (100 ml) was added sodium hydride (0.8 g) under nitrogen. The reaction was stirred one hour at ambient temperature. A solution of 4-(2-chloroethyl)morpholine (4.0 g) in DMF (50 ml) was added followed by heating to 120° C. for one hour. TLC (5% MeOH/DCM) analysis revealed the absence of starting material. The reaction was quenched with water and extracted with EtOAc. The organic layer was washed with water, dried (MgSO4), and concentrated in vacuo. Flash column chromatography (silica gel) eluting with 1.5-2.5% MeOH/DCM afforded the product (2.5 g), m.p. 79°-80° C.
Reaction SMILES: C1[CH:5]2[CH:6]3[CH:10]=[CH:9][CH:8]([CH:4]2C=C1)[CH2:7]3.C1CC=CC=1.[C:16]([O:20][C:21](=[O:24])C=C)([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([C:6]12[CH2:7][CH:8]([CH2:4][CH2:5]1)[CH:9]=[CH:10]2)=[O:24])([CH3:19])([CH3:18])[CH3:17]
Reactant: C1=CC2C3C=CC(C3)C2C1
Reactant: C=CC(=O)OC(C)(C)C
Agent: C1=CCC=C1
Product: CC(C)(C)OC(=O)C12C=CC(CC1)C2
Temperature: 180 °C
Yield: 100.7 %

Procedure:
200 grams of dicyclopentadiene was put into a 500-ml flask equipped with a distillatory, and then was heated for reflux at 180° C. Then, about 100 grams of cyclopentadiene cracked at about 40° C. was dropped into 200 grams of t-butylacrylate with being cooled with ice bath. The resultant solution was stirred over a night. The resultant mixture was distilled under reduced pressure (66°-67° C./1 mmHg). As a result, there was obtained 296 grams of norbornenecarboxylic acid t-butylester. The yield was 98%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH3:9])[CH:5]=[N:6][CH:7]=1.[CH2:11]([S:13]([NH2:16])(=[O:15])=[O:14])[CH3:12].[CH3:17][Mg]Br>C1(C)C=CC=CC=1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:16][S:13]([CH2:11][CH3:12])(=[O:15])=[O:14])([CH3:9])[CH3:17])[CH:5]=[N:6][CH:7]=1
Reactant: CC(=O)c1cncc(Br)c1
Reactant: C[Mg]Br
Reactant: CCS(N)(=O)=O
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: Cc1ccccc1
Product: CCS(=O)(=O)NC(C)(C)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.4 %

Procedure:
A mixture of 1-(5-bromo-pyridin-3-yl)-ethanone (200 mg, 1.000 mmol), ethanesulfonamide (136 mg, 1.250 mmol) and titanium(IV) isopropoxide (586 μL, 2.0 mmol) in toluene (20 mL) was heated to reflux for 8 h. After concentration, the residue was dissolved in THF (5 mL). A solution of methylmagnesium bromide (1000 μl, 3.00 mmol) was added dropwise at −50° C. The resulting mixture was slowly warmed up to room temperature over a course of 2 h. The mixture was stirred at this temperature overnight and quenched with NH4Cl solution. After filtration, wash with CH2Cl2 and concentration, the residue was purified by flash column (Ethyl acetate/heptane, v/v, 10% to 50%) and yielded a yellow oil (35 mg). ESI-MS m/z: 309.1 [M+1]+, Retention time=1.22 min. 1H NMR (400 MHz, CDCl3): δ 1.43 (t, J=7.4 Hz, 3H), 1.84 (s, 6H), 2.98 (q, J=7.4 Hz, 2H), 5.07 (brs, 1H), 8.04 (s, 1H), 8.66 (s, 1H), 8.77 (s, 1H).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([NH:12][C:13](=[O:16])[CH2:14]Br)[CH:3]=1.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[OH-].[K+]>CN(C=O)C>[F:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([NH:12][C:13](=[O:16])[CH2:14][NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=C(CBr)Nc1cc(F)c(F)cc1C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=C(CNc1ccccc1)Nc1cc(F)c(F)cc1C(=O)O
Temperature: 0 °C
Yield: 99.2 %

Procedure:
A solution of 4,5-difluoro-2-((bromoacetyl)amino)benzoic acid (31.0 g 105.4 mmol) and aniline (24 mL, 24.5 g, 263.4 mmol) in anhydrous DMF (100 mL) was heated to 95°-100° C. overnight with stirring under N2. The solution was cooled, poured into 500 mL of ice-water, and then a solution of 5% KOH was added until the pH of the solution was 10. The solution was extracted with 3×150 mL of CH2Cl2, and then the aqueous layer was separated and acidified to pH=3 using 2N HCl. The yellow precipitate which formed was filtered, washed with water, and then dried in a vacuum desiccator to yield 32.01 g (99%) of the title compound as a light-yellow solid, mp 124°-126° C.: 1H NMR (DMSO-d6) δ12.10 (s, 1H), 8.75 (dd, J=14.0, J=7.6, 1H), 7.86 (dd, J=11.6, J=1.2, 1H), 7.09 (t, J=7.2, 2H), 6.63-6.40 (m, 4H), 3.85 (s, 2H); 13C NMR (DMSO-d6) δ171.40, 167.44, 152.18 (dd, J=249, J=12.7), 148.02, 144.02 (dd, J=242, J=12.6), 138.18 (dd, J=10.6, J=2.1), 129.01, 119.66 (d, J=19), 117.22, 113.10, 112.48, 108.21 (d, J=23), 48.82; MS (El, m/z) 306 (M+).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([CH3:20])=[C:18]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][C:23]=3[F:30])[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[C:31]1([SH:37])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CCOCC>[CH:1]([O:4][C:5]([N:7]1[CH2:8][CH2:9][CH:10]([O:13][C:14]2[C:19]([CH3:20])=[C:18]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([S:37][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[NH:29])=[CH:24][C:23]=3[F:30])[N:17]=[CH:16][N:15]=2)[CH2:11][CH2:12]1)=[O:6])([CH3:3])[CH3:2]
Reactant: Cc1c(Oc2ccc(C#N)cc2F)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Reactant: Sc1ccccc1
Solvent: CCOCC
Product: Cc1c(Oc2ccc(C(=N)Sc3ccccc3)cc2F)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Reaction time: 0.5 h

Procedure:
A mixture of 4-[6-(4-cyano-2-fluoro-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester (TFA salt, 109 mg, 0.21 mmol) and thiophenol (27 μl, 0.21 mmol) in Et2O (1 mL) was stirred in an ice-bath under HBr atmosphere for 30 min. The crude compound was used for the next step without further purification. Exact mass calculated for C27H29FN4O4S 524.19, found 525.3 (MH+).
Reaction SMILES: [CH3:1]I.[CH2:3]1[O:22][C:6]2([C:11]3[CH:12]=[CH:13][C:14]4[C:19]([C:10]=3[S:9](=[O:21])(=[O:20])[NH:8][CH2:7]2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[O:5][CH2:4]1.[OH-].[Na+].O>C(O)(C)C>[CH2:3]1[O:22][C:6]2([C:11]3[CH:12]=[CH:13][C:14]4[C:19]([C:10]=3[S:9](=[O:21])(=[O:20])[N:8]([CH3:1])[CH2:7]2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[O:5][CH2:4]1
Reactant: O=S1(=O)NCC2(OCCO2)c2ccc3ccccc3c21
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CN1CC2(OCCO2)c2ccc3ccccc3c2S1(=O)=O
Reaction time: 8 h
Yield: 95 %

Procedure:
14.2 gm (0.1 mol) of methyl iodide were added dropwise, while stirring, to a solution of 11.6 gm (0.04 mol) of 2H-naphtho[2,1-e]-1,2-thiazine-4(3H)-one-1,1-dioxide-ethylene ketal in a mixture of 150 ml of isopropanol, 44 ml of 1 N sodium hydroxide and 36 ml of water. The resulting mixture was allowed to stand overnight, and the crystals which separated out were suction-filtered off washed with a mixture of isopropanol an ater (ratio by volume 2:1) and dried in vacuo, yielding 11.6 gm (95% of theory) of 2-methyl-2H-naphtho [2,1-e]-1,2-thiazine-4(3H)-one-1,1-dioxide-ethylene ketal, m.p. 169°-171° C.