Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][CH2:2][C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[O:4].[B-](F)(F)(F)F.CN(C(O[N:33]1[C:38](=[O:39])[CH2:37][CH2:36][C:34]1=[O:35])=[N+](C)C)C.CCN(C(C)C)C(C)C.Cl>C1COCC1>[O:35]=[C:34]1[CH2:36][CH2:37][C:38](=[O:39])[N:33]1[O:18][C:17](=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:3](=[O:4])[CH2:2][I:1]
Reactant: O=C(O)CCCCCCCCCCCNC(=O)CI
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CI)NCCCCCCCCCCCC(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 12-(2-Iodoacetylamino)dodecanoic acid (460 mg) in THF (10 ml) was added TSTU (415 mg) and DIPEA (0.315 ml). After stirring at room temperature for 2 h, the mixture was pored in to 0.5 N HCl (200 ml) and was extracted with ethyl acetate (2×200 ml). The combined organic layers was washed with 0.1 N HCl and brine, dried with magnesium sulphate and concentrated. The residue was used without further purification. Yield, 99% (575 mg). LC-MS, M/z: 481.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:8]2[NH:9][C:10]([Cl:12])=[N:11][C:7]=2[CH:6]=1)=[O:4].CCN(C(C)C)C(C)C.Cl[CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30]>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:8]2[N:9]([CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30])[C:10]([Cl:12])=[N:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: COCCOCCl
Reactant: COC(=O)c1ccc2[nH]c(Cl)nc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COCCOCn1c(Cl)nc2cc(C(=O)OC)ccc21
Reaction time: 18 h

Procedure:
To a mixture of 2-chloro-1H-benzoimidazole-5-carboxylic acid methyl ester (2.00 g, 9.50 mmol) and THF (17 mL) was added DIPEA (2.46 mL, 14.3 mmol) followed by 1-chloromethoxy-2-methoxy-ethane (1.30 mL, 11.4 mmol) at 23° C. After stirring for 18 h the reaction mixture was concentrated under reduced pressure. The residue was purified (FCC) (5-50% EtOAc/hexanes) to yield the titled compound as a mixture of regioisomers (1.71 g, 60%). MS (ESI/CI): mass calcd. for C13H15ClN2O4, 298.1; m/z found, 299.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 8.34-8.31 (m, 1H), 8.21-8.20 (m, 1H), 7.98 (dd, J=8.6, 1.6 Hz, 1H), 7.91 (dd, J=8.5, 1.6 Hz, 1H), 7.83 (dd, J=8.6, 0.5 Hz, 1H), 7.74 (dd, J=8.5, 0.5 Hz, 1H), 5.78 (s, 1H), 5.73 (s, 1H), 3.89 (d, J=6.3 Hz, 6H), 3.64-3.60 (m, 5H), 3.43-3.39 (m, 5H), 3.17 (d, J=2.6 Hz, 6H).
Reaction SMILES: Br[C:2]1[S:6][C:5](/[CH:7]=[CH:8]/[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.C1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:31][S:32][C:33]1[N:38]=[C:37]([Sn](CCCC)(CCCC)CCCC)[CH:36]=[CH:35][N:34]=1>CN1C(=O)CCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:31][S:32][C:33]1[N:38]=[C:37]([C:2]2[S:6][C:5](/[CH:7]=[CH:8]/[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=2)[CH:36]=[CH:35][N:34]=1
Reactant: CC(=O)/C=C/c1ccc(Br)s1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnc(SC)n1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc([As](c2ccccc2)c2ccccc2)cc1
Solvent: CN1CCCC1=O
Product: CSc1nccc(-c2ccc(/C=C/C(C)=O)s2)n1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
A mixture of (E)-4-(5-bromo-thiophen-2-yl)-but-3-en-2-one (1 g, 4.34 mmol), triphenylarsine (319 mg, 1.04 mmol), cuprous iodide (99 mg, 0.52 mmol) and Pd2(dba)3 (119 mg, 0.13 mmol) in 25 ml of NMP was heated to 80° C. To this hot solution 2-methylsulfanyl-4-tributylstannanyl-pyrimidine (1.8 g, 4.34 mmol) dissolved in 10 ml of NMP was added dropwise over a period of 10 minutes. Stirring was continued for 24 hours. The solvent was then removed in vacuo and the residue partitioned between water and EtOAc. The aqueous layer was separated and extracted once more with EtOAc. The combined organic extracts were washed with water and brine, dried over sodium sulfate and evaporated. The crude was purified by chromatography on silicagel (EtOAc/hexane:2/3) to give a yellow solid. Yield: 480 mg (40%).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:7](=[O:11])[N:8]([CH2:9][CH3:10])[C:4]=2[CH:3]=1.[O:20]=[S:21]1(=[O:37])[C:25]2[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:24]=2[C:23](=[O:31])[N:22]1[CH2:32][CH2:33][CH2:34][CH2:35]Br>>[O:37]=[S:21]1(=[O:20])[C:25]2[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:24]=2[C:23](=[O:31])[N:22]1[CH2:32][CH2:33][CH2:34][CH2:35][N:15]1[CH2:16][CH2:17][CH:12]([N:6]2[C:5]3[CH:18]=[CH:19][C:2]([F:1])=[CH:3][C:4]=3[N:8]([CH2:9][CH3:10])[C:7]2=[O:11])[CH2:13][CH2:14]1
Reactant: O=C1c2cc(Cl)ccc2S(=O)(=O)N1CCCCBr
Reactant: CCn1c(=O)n(C2CCNCC2)c2ccc(F)cc21
Product: CCn1c(=O)n(C2CCN(CCCCN3C(=O)c4cc(Cl)ccc4S3(=O)=O)CC2)c2ccc(F)cc21

Procedure:
Starting with 4-(5-fluoro-3-ethyl-2-oxo-1-benzimidazolinyl)piperidine and 1,1-dioxido-2-(4-bromobutyl)-5-chloro-1,2-benzisothiazol-3(2H)-one and following the procedure of Example 1, the title compound was obtained as the HCl salt, melting point 266-268° C. The NMR was consistent with the structure.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[C:21]2[CH2:20][CH2:19][C@H:18]3[C@H:14]([CH2:15][C:16](=O)[N:17]3[CH2:22][CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[C:13]=2[CH:12]=[CH:11][CH:10]=1.[OH-].[Na+].[O-]S([O-])(=O)=O.[Na+].[Na+]>C1COCC1.O>[CH3:7][O:8][C:9]1[C:21]2[CH2:20][CH2:19][C@H:18]3[C@H:14]([CH2:15][CH2:16][N:17]3[CH2:22][CH2:23][CH2:24][N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: COc1cccc2c1CC[C@H]1[C@@H]2CC(=O)N1CCCN1CCOCC1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc2c1CC[C@H]1[C@@H]2CCN1CCCN1CCOCC1
Yield: 88.4 %

Procedure:
0.99 g (0.02595 mol) of lithium aluminum hydride was suspended in 50 ml of THF under argon. A solution of 4.47 g (0.01298 mol) of rac-cis-1,3,3a,4,5,9b-hexahydro-6-methoxy-3-(3-morpholin-4-yl-propyl)-2H-benzo[e]indol-2-one in 50 ml of THF was added dropwise thereto and the mixture was boiled under reflux for 2 hours. 1.0 ml of water, 1.0 ml of a 4N aqueous NaOH solution and 3.0 ml of water were cautiously added dropwise thereto in succession, whereupon the mixture was boiled at reflux until a complete white precipitate had resulted. After the addition of dry Na2SO4, filtration and concentration there was obtained an oil which was chromatographed over silica gel with ethyl acetate/methanol 1:1. There were obtained 3.79 g (88%) of oily rac-cis-2,3,3a,4,5,9b-hexahydro-6-methoxy-3-(3-morpholin-4-yl-propyl)-1H-benzo[e]indole.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:12]([C@H:15]2[C@H:20]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C@@H:19]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C@H:18]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C@@H:17]([CH2:45][O:46][CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[O:16]2)=[CH:11][C:3]=1[CH2:4][C:5]1[S:9][C:8](N)=[N:7][N:6]=1.N([O-])=O.[Na+].[ClH:58]>C(O)(=O)C.O.[Cu]>[Cl:58][C:8]1[S:9][C:5]([CH2:4][C:3]2[CH:11]=[C:12]([C@H:15]3[C@H:20]([O:21][CH2:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[C@@H:19]([O:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C@H:18]([O:37][CH2:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C@@H:17]([CH2:45][O:46][CH2:47][C:48]4[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=4)[O:16]3)[CH:13]=[CH:14][C:2]=2[Cl:1])=[N:6][N:7]=1
Reactant: Nc1nnc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)s1
Reactant: Cl
Agent: [Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Clc1nnc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 22 %

Procedure:
To a mixture of 5-(2-chloro-5-((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-tetrahydro-2H-pyran-2-yl)benzyl)-1,3,4-thiadiazol-2-amine (4.0 mmol) from Step 1 and copper (0.04 g, 0.62 mmol) in hydrochloric acid (37%, 6 mL) and acetic acid (30 mL) at 0° C. was slowly added sodium nitrite (2.8 g, 40 mmol) while maintaining an internal reaction temperature below 10° C. After 1 h stirring at 0° C., the resulting mixture was stirred with gradual warming to ambient temperature over 2 h. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and evaporated in vacuo. Flash chromatography on a Biotage® purification apparatus (silica gel, 10 to 60% ethyl acetate in hexanes) yielded the title compound (0.66 g, 0.86 mmol, 22%) as yellow oil.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:5]=[C:6]([C:10]2[N:11]=[C:12]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[NH:13][CH:14]=2)[CH:7]=[CH:8][CH:9]=1.Cl[C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[NH:26][CH:27]=[N:28]2.C(N(CC)CC)C>CC(O)C>[F:22][C:2]([F:1])([F:21])[O:3][C:4]1[CH:5]=[C:6]([C:10]2[N:11]=[C:12]([CH:15]3[CH2:16][CH2:17][N:18]([C:24]4[N:32]=[CH:31][N:30]=[C:29]5[C:25]=4[NH:26][CH:27]=[N:28]5)[CH2:19][CH2:20]3)[NH:13][CH:14]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: Clc1ncnc2nc[nH]c12
Reactant: FC(F)(F)Oc1cccc(-c2c[nH]c(C3CCNCC3)n2)c1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: FC(F)(F)Oc1cccc(-c2c[nH]c(C3CCN(c4ncnc5nc[nH]c45)CC3)n2)c1
Temperature: 80 °C
Yield: 64.9 %

Procedure:
Add 4-(4-(3-(trifluoromethoxy)phenyl)-1H-imidazol-2-yl)piperidine (200 mg, 0.642 mmol), 6-chloropurine (105 mg, 0.679 mmol), and triethylamine (95 μL, 0.681 mmol) to 2-propanol (5 mL). Heat the mixture at 80° C. for 3 h. Cool the mixture to room temperature and concentrate in vacuo. Triturate the solid in CH2Cl2 (10 mL). Purify the remaining solid by silica gel chromatography (60 g, eluting with 40% methanol/methylene chloride, 0.500 L) to provide 6-(4-(4-(3-(trifluoromethoxy)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-7H-purine (179 mg, 65%).
Reaction SMILES: [CH:1]1([C:4]#[C:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=2[C:14](=[O:22])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C1(C)C=CC=CC=1>[CH:1]1([C:4]2[C:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[C:14]([OH:22])[C:7]3[C:6]([CH:5]=2)=[CH:11][C:10]([O:12][CH3:13])=[CH:9][CH:8]=3)[CH2:2][CH2:3]1
Reactant: COc1ccc(C(=O)Cc2ccccc2)c(C#CC2CC2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1ccc2c(O)c(-c3ccccc3)c(C3CC3)cc2c1
Yield: 38.3 %

Procedure:
A solution of 1-[2-(Cyclopropylethynyl)-4-(methyloxy)phenyl]-2-phenylethanone (151) (0.47 g, 1.62 mmol) in toluene was treated with a KHMDS solution in toluene to give 0.18 g (38%) of the title compound (152) as a light yellow viscous oil. 1H NMR (400 MHz, CDCl3): δ 0.70-0.80 (m, 4H), 1.55-1.65 (m, 1H), 3.91 (s, 3H), 5.22 (s, 1H), 6.92 (s, 1H), 7.00-7.10 (m, 2H), 7.40-7.48 (m, 3H), 7.50-7.57 (m, 2H), 8.07 (d, J=8.9 Hz, 1H). LCMS (APCI): m/z 291 (M+H)+, m/z 289 (M−H)+.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([O:14][C:15]([NH:17][C@@H:18]([CH2:22][CH:23]=[CH2:24])[C:19]([OH:21])=O)=[O:16])([CH3:13])([CH3:12])[CH3:11].Cl.[CH:26]([C@H:28]1[CH2:33][CH2:32][CH2:31][CH2:30][NH:29]1)=[CH2:27].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[O:21]=[C:19]([N:29]1[CH2:30][CH2:31][CH2:32][CH2:33][C@@H:28]1[CH:26]=[CH2:27])[C@@H:18]([NH:17][C:15](=[O:16])[O:14][C:10]([CH3:11])([CH3:12])[CH3:13])[CH2:22][CH:23]=[CH2:24]
Reactant: C=C[C@H]1CCCCN1
Reactant: C=CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCCC[C@@H]1C=C
Temperature: 25 °C
Reaction time: 72 h
Yield: 69.7 %

Procedure:
DIPEA (1.801 gm, 13.94 mmol) was slowly added to a 0° C. mixture of (S)-2-(tert-butoxycarbonylamino)pent-4-enoic acid (1.00 gm, 4.65 mmol), (R)-2-vinylpiperidine hydrochloride (0.720 gm, 4.88 mol), EDC (1.02 gm, 5.34 mmol) and HOBt (0.818 gm, 5.34 mmol) in DCM (19 mL). The yellow reaction mixture was then stirred at rt for 3 days. The reaction mixture was concentrated to remove the DCM and the residue was partitioned between EtOAc and 0.5 N aqueous HCl. The organic phase was isolated, washed with saturated aqueous NaHCO3 and saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. The crude product was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-100% EtOAc/Hex to give tert-butyl (S)-1-oxo-1-((R)-2-vinylpiperidin-1-yl)pent-4-en-2-ylcarbamate (1.00 gm, 3.24 mmol, 69.8% yield) as a colorless oil. Anal. Calcd. for C17H28N2O3 m/z 308.3. found: 309.0 (M+H)+.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].[CH2:16]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCO>[CH2:24]([N:23]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:3][CH:2]([OH:1])[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: O=C1c2ccccc2C(=O)N1CC1CO1
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1CC(O)CN(Cc1ccccc1)Cc1ccccc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 56.2 %

Procedure:
A mixture of 2-(oxiran-2-ylmethyl)isoindoline-1,3-dione (4.06 g, 20.0 mmol) and dibenzylamine (5.0 g, 25.4 mmol) was stirred at 80° C. overnight. EtOH (50 mL) was added, and stirred at room temperature. The mixture was filtered to give white solid (4.5 g).
Reaction SMILES: [CH2:1]([C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C(OP([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])(OCC)=O)C.[H-].[Na+]>C1COCC1>[CH2:1]([C:6]1[CH:13]=[CH:12][C:9](/[CH:10]=[CH:22]/[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CCCCCc1ccc(C=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCc1ccc(/C=C/C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 100 %

Procedure:
To a solution of 4-pentylbenzaldehyde (25 g, 142 mmol) and ethyl diethylphosphonoacetate (30 ml, 150 mmol) in THF was added sodium hydride (60%, 6 g, 150 mmol), and the mixture was stirred at room temperature for 12 hours and poured into ice water. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate anhydride, and the solvent was removed under reduced pressure to give the object compound as an oily substance. 39.6 g, (yield 100%)
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:25]=[C:24]2[C:14]([C:15]([OH:32])=[C:16]([C:27](OCC)=[O:28])[C:17](=[O:26])[C:18]32[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:13][CH:12]=1.Cl.[C:34]([O:38][C:39](=[O:42])[CH2:40][NH2:41])([CH3:37])([CH3:36])[CH3:35]>O1CCOCC1.CCOCC>[F:10][C:11]1[CH:25]=[C:24]2[C:14]([C:15]([OH:32])=[C:16]([C:27]([NH:41][CH2:40][C:39]([O:38][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:42])=[O:28])[C:17](=[O:26])[C:18]32[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:13][CH:12]=1
Reactant: CCOC(=O)C1=C(O)c2ccc(F)cc2C2(CCOCC2)C1=O
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2ccc(F)cc2C2(CCOCC2)C1=O
Temperature: 75 °C
Reaction time: 17 h
Yield: 65.4 %

Procedure:
DIPEA (0.693 mL, 3.98 mmol, 1.5 eq) was added to a mixture of ethyl 7-fluoro-4-hydroxy-2-oxo-2′,3′,5′,6′-tetrahydro-spiro[naphthalene-1,4′-pyran]-3-carboxylate (850 mg, 2.65 mmol, 1.0 eq) and glycine tert-butyl ester hydrochloride (0.534 g, 3.18 mmol, 1.2 eq) in dioxane (20 mL). The reaction mixture was stirred at 75° C. for 17 hours. The reaction mixture was then cooled to room temperature and concentrated in vacuo to give a yellow solid. The crude solid was suspended in ether and filtered to give the title compound as an off-white solid (703 mg). MS (m/e)=406.2 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:9]2[C:10]([CH3:33])([CH3:32])[CH2:11][C:12]3[CH:13]=[N:14][C:15]([NH:18][C:19]4[CH:24]=[CH:23][C:22]([N:25]5[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]5)=[CH:21][CH:20]=4)=[N:16][C:17]=3[C:8]=2[N:7]([CH3:34])[N:6]=1)=[O:4].CO.[Cl:37]CCl>O1CCOCC1>[ClH:37].[ClH:37].[ClH:37].[CH3:1][NH:2][C:3]([C:5]1[C:9]2[C:10]([CH3:32])([CH3:33])[CH2:11][C:12]3[CH:13]=[N:14][C:15]([NH:18][C:19]4[CH:20]=[CH:21][C:22]([N:25]5[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]5)=[CH:23][CH:24]=4)=[N:16][C:17]=3[C:8]=2[N:7]([CH3:34])[N:6]=1)=[O:4]
Reactant: ClCCl
Agent: CNC(=O)c1nn(C)c2c1C(C)(C)Cc1cnc(Nc3ccc(N4CCN(C)CC4)cc3)nc1-2
Solvent: CO
Solvent: C1COCCO1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 8-[4-(4-methyl-piperazin-1-yl)-phenylamino]-1,4,4-trimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylic acid methylamide (7.00 g, 15.192 mmol) dissolved into a 1:1 mixture of methanol/dichloromethane (149 mL) 4M hydrochloric acid in dioxane (12.12 mL, 48.48 mL) was added and the solution stirred at room temperature for 2 hours. After removing the solvent under reduced pressure, the reddish solid was dried at 43° C. under vacuum for 10 hours. There were obtained 8.11 g of the title compound as a red solid.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH2:12]([C:16]1[C:17]2[CH2:18][CH2:19][CH2:20][CH2:21][C:22]=2[N:23]=[C:24]2[C:29]=1[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:13][CH2:14][CH3:15]>C(Cl)Cl>[CH2:12]([C:16]1[C:17]2[CH2:18][CH2:19][CH2:20][CH2:21][C:22]=2[N+:23]([O-:6])=[C:24]2[C:29]=1[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCc1c2c(nc3c1CCCC3)CCCC2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCCCc1c2c([n+]([O-])c3c1CCCC3)CCCC2
Temperature: 25 °C
Yield: 96.4 %

Procedure:
Into a 1 L round-bottomed flask equipped with a magnetic stirrer, a reflux condenser and a 250 ml addition funnel are placed 56.3 g (0.26 mol) of m-chloroperoxybenzoic acid (Note 12) and 350 mL of methylene chloride. The resulting suspension is stirred as a solution of 38.0 g (0.16 mol) of 9-n-butyl-1,2,3,4,5,6,7,8-octahydroacridine in 120 mL of methylene chloride is added rapidly. When the reaction mixture ceases to boil gently from the heat of reaction, the reaction flask is warmed to extend the reflux period to a total of 2.5 hrs. (Note 10). The reaction mixture is cooled to room temperature, extracted with 0.5M aqueous sodium hydroxide (4×450 mL), dried using anhydrous sodium sulfate and concentrated under reduced pressure using a rotary evaporator. Residual solvent is removed at 0.1 mm, yielding 40 g (99%) of 9-n-butyl-1,2,3,4,5,6,7,8-octahydroacridine-N-oxide as a yellow crystalline solid, mp 96°-100° C.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:40]1[CH:45]=[CH:44][N:43]=[CH:42][N:41]=1)[S:7]([C:10]1[C:37]([F:38])=[CH:36][C:13]([O:14][C@H:15]2[CH2:20][CH2:19][CH2:18][CH2:17][C@@H:16]2[C:21]2[C:22]([NH:32][C:33](=[O:35])[CH3:34])=[N:23][N:24](C3CCCCO3)[CH:25]=2)=[C:12]([CH3:39])[CH:11]=1)(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O.ClCCl>CO>[F:38][C:37]1[C:10]([S:7](=[O:9])(=[O:8])[NH:6][C:40]2[CH:45]=[CH:44][N:43]=[CH:42][N:41]=2)=[CH:11][C:12]([CH3:39])=[C:13]([CH:36]=1)[O:14][C@H:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C@@H:16]1[C:21]1[C:22]([NH:32][C:33](=[O:35])[CH3:34])=[N:23][NH:24][CH:25]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(C)c(O[C@H]3CCCC[C@@H]3c3cn(C4CCCCO4)nc3NC(C)=O)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)Nc1n[nH]cc1[C@H]1CCCC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1C
Yield: 62.7 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 22c by using the N-{4-[(1R*,2S*)-2-{4-[(2,4-dimethoxybenzyl)(pyrimidin-4-yl)sulfamoyl]-5-fluoro-2-methylphenoxy}cyclohexyl]-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl}acetamide (78 mg, 0.108 mmol) prepared in Example 96b, triethylsilane (0.10 mL), trifluoroacetic acid (0.50 mL), dichloromethane (2.0 mL) and methanol (1.0 mL), to yield the title compound (33.1 mg, 63%) as a colorless solid.
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[CH:5][C:4](=[O:7])[N:3]1[CH:8]([CH3:12])[C:9]([OH:11])=O.S(Cl)(Cl)=O.[Cl:17][C:18]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:19]=1[NH2:20].C(N(CC)CC)C>C1(C)C=CC=CC=1.C(Cl)Cl>[O:7]=[C:4]1[CH:5]=[CH:6][C:2](=[O:1])[N:3]1[CH:8]([CH3:12])[C:9]([NH:20][C:19]1[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=1[Cl:17])=[O:11]
Reactant: Nc1ccc(Cl)cc1Cl
Reactant: CC(C(=O)O)N1C(=O)C=CC1=O
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C(=O)Nc1ccc(Cl)cc1Cl)N1C(=O)C=CC1=O
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 34.9 %

Procedure:
A suspension of DL-2,5-dioxo-α-methyl-3-pyrroline-1-acetic acid (1.5 g, 0.0086 mol) in toluene is treated with thionyl chloride (1.28 mL, 0.0176 mol), warmed to 50° C., stirred for 2 1/2 hours, cooled and concentrated in vacuo to yield a yellow oil. The oil is dissolved in methylene chloride and added to a solution of 2,4-dichloroaniline (1.54 g, 0.0086 mol) and triethylamine (1.32 mL, 0.0094 mol) in methylene chloride under nitrogen at 0° C. The reaction mixture is stirred for 1 hour at room temperature and concentrated in vacuo to give a residue. The residue is flash chromatographed using hexane/ethyl acetate (80/20) as eluent on silica gel to give the title compound as a pale yellow solid (0.94 g, 35%, mp 131° C.), identified by 1HNMR, CIMS and IR analysis.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)=[CH:3][CH:2]=1.[CH2:17]([C:19]1[NH:23][C:22]([CH:24]=O)=[C:21]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])[CH:20]=1)[CH3:18]>>[CH2:17]([C:19]1[NH:23][C:22]([CH:24]=[C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[CH:15][C:7]=3[C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[NH:11][C:10]2=[O:16])=[C:21]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])[CH:20]=1)[CH3:18]
Reactant: CCc1cc(CCC(=O)O)c(C=O)[nH]1
Reactant: O=C1Cc2c(cccc2-c2ccncc2)N1
Product: CCc1cc(CCC(=O)O)c(C=C2C(=O)Nc3cccc(-c4ccncc4)c32)[nH]1

Procedure:
4-Pyridin-4-yl-1,3-dihydroindol-2-one was condensed with 3-(5-ethyl-2-formyl-1H-pyrrol-3-yl)-propionic acid to give the title compound.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[C:18]([OH:20])=[O:19])[CH:11]=[CH:10][CH:9]=1.C(O)(=O)C.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CO>[N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[C:18]([O:20][CH3:1])=[O:19])[CH:11]=[CH:10][CH:9]=1
Reactant: O=C(O)c1cccc2cccnc12
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1cccc2cccnc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
A solution of (trimethylsilyl)diazomethane (8.0 mL of a 2.0 M solution in hexanes, 16.0 mmol) was added slowly to a suspension of quinoline-8-carboxylic acid (2.0 g, 11.5 mmol) in toluene (80 mL) and MeOH (12 mL) at 0° C. After 30 min at 0° C., the reaction mixture was warmed to room temperature and stirred for 64 h. Aqueous acetic acid was added and then enough saturated aqueous Na2CO3 was added to bring the pH to 7.5. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic phase was dried (MgSO4SO4), filtered and concentrated in vacuo. The resulting brown oil was purified on 40 g silica gel (2:1 CH2Cl2/EtOAc) to afford 1.72 g (80%) of methyl quinoline-8-carboxylate.
Reaction SMILES: [NH2:1][C:2]([C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[NH:11][C:12](=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:3].CC[O-].[Na+].Cl>C(O)C>[F:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[C:2](=[O:3])[NH:1][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:11]2
Reactant: CCOC(=O)C(=O)Nc1cccc(F)c1C(N)=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1nc2cccc(F)c2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.7 %

Procedure:
To a suspension of ethyl ((2-(aminocarbonyl)-3-fluorophenyl)amino)(oxo)acetate (2.45 g, 9.64 mmol) in ethanol (50 mL) was added dropwise sodium ethylate (20% ethanol solution, 3.61 g, 10.6 mmol) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. 1N Hydrochloric acid (20 mL) was added to the reaction mixture, and the insoluble material was collected by filtration. The solid was washed with water and diethyl ether to give the title compound as a pale-yellow powder (1.29 g, 57%).