Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][CH2:5][NH:6][C:7](=[O:21])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]CCC)=[N+:2]=[N-:3].N([CH2:25][CH2:26]N)=[N+]=[N-].C(N(CC)CC)C>ClCCl>[N:1]([CH2:4][CH2:5][NH:6][C:7]([C:8]1[CH:9]=[CH:10][C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:26][CH:25]=1)=[O:21])=[N+:2]=[N-:3]
Reactant: CCCCCCCCCCCCCC(=O)NCCN=[N+]=[N-]
Reactant: [N-]=[N+]=NCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: [N-]=[N+]=NCCNC(=O)c1ccc(-c2ccccc2)cc1
Yield: 85.1 %

Procedure:
As in the synthesis of N-(2-azidoethyl)tetradecanamide, (0.283 g, 1.31 mmol) was reacted with 2-azidoethanamine (0.113 g, 1.31 mmol) and triethylamine (0.264 g, 2.61 mmol) in dichloromethane (5 mL) to give N-(2-azidoethyl)biphenyl-4-carboxamide (0.297 g, 85% yield). 1H NMR (300 MHz, CDCl3) δ 7.88 (d, 2H), δ 7.67 (m, 4H), δ 7.44 (m, 3H), δ 6.63 (s, 1H), δ 3.67 (q, J=6.0, 1.8 Hz, 2H), δ 3.58 (t, J=6.0 Hz, 2H) ppm; 13C NMR (75 MHz, CDCl3) δ 167.8, 144.8, 140.1, 132.9, 129.2, 128.3, 127.8, 127.5, 127.4, 51.2, 39.7 ppm; HRMS (ESI) calcd for C15H14N4O (M+) 266.1168. found 266.1162.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[CH:14]([C:15]2[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][N:16]=2)[CH2:13][C:12]([C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])=[N:11]1.C(N(CC)CC)C.[CH:41]1([S:44](Cl)(=[O:46])=[O:45])[CH2:43][CH2:42]1>ClCCl>[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[CH:14]([C:15]2[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][N:24]([S:44]([CH:41]4[CH2:43][CH2:42]4)(=[O:46])=[O:45])[CH2:23][CH2:22]3)[CH:18]=[CH:17][N:16]=2)[CH2:13][C:12]([C:27]([F:33])([F:32])[C:28]([F:29])([F:30])[F:31])=[N:11]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2cc(N3CCNCC3)ccn2)c(F)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(C1CC1)N1CCN(c2ccnc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.2 %

Procedure:
1-(2,4-Difluoro-phenyl)-5-[4-(piperazin-1-yl)-pyridin-2-yl]-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole hydrochloride (30.0 mg, 0.06 mmol) prepared in Example 182, triethylamine (42.0 uL, 0.30 mmol) and cyclopropanesulfonyl chloride (9.0 uL, 0.09 mmol) were added to dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 1 hour, washed with distilled water, 1N hydrochloride, a saturated solution of sodium hydrogen carbonate, and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1) to give 15.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][N:7]2[CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:2].[NH2:19][OH:20].Cl.C([O-])([O-])=O.[Na+].[Na+]>CCO>[OH:20][NH:19][C:1](=[NH:2])[C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][N:7]2[CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: NO
Reactant: CCOC(=O)CCn1ccc2c(C#N)cccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CCn1ccc2c(C(=N)NO)cccc21
Temperature: 50 °C
Reaction time: 8 h
Yield: 103.9 %

Procedure:
Ethyl 3-(4-cyano-1H-indol-1-yl)propanoate (D54) (3.44 g), NH2OH.HCl (1.97 g) and Na2CO3 (5.96 g) were dissolved in EtOH (75 ml). This mixture was heated at 50° C. overnight. A further portion of NH2OH.HCl (985 mg) was added and the mixture stirred at 70° C. overnight. The reaction mixture was then filtered and evaporated to give the title compound (4.06 g). MS (ES): C14H17N3O3 requires 275; found 276 (MH+)
Reaction SMILES: [N:1](C1C=C2C(=O)OC(=O)C2=CC=1)=[C:2]=[O:3].[CH:15]1[C:20](C(Cl)=O)=[CH:19][C:18]2[C:24]([O:26][C:27](=[O:28])[C:17]=2[CH:16]=1)=[O:25].C(O)(=O)/C=C/C=C/C.C1(=O)OC(=O)C=C1>>[N:1]([C:16]1[CH:15]=[CH:20][CH:19]=[C:18]2[C:24]([O:26][C:27](=[O:28])[C:17]=12)=[O:25])=[C:2]=[O:3]
Reactant: O=C=Nc1ccc2c(c1)C(=O)OC2=O
Reactant: O=C(Cl)c1ccc2c(c1)C(=O)OC2=O
Agent: C/C=C/C=C/C(=O)O
Agent: O=C1C=CC(=O)O1
Product: O=C=Nc1cccc2c1C(=O)OC2=O

Procedure:
4-isocyanato phthalic acid anhydride; trimellitic acid anhydride chloride; 4-chlorosulphonyl-1,8-naphthalic acid anhydride; and the Diels-Alder reaction product of sorbic acid and maleic acid anhydride.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[CH3:7][N:8]([CH3:12])[CH2:9]CO>>[C:1]([O:5][CH2:6][CH2:7][N:8]([CH3:12])[CH3:9])(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)OC
Reactant: CN(C)CCO
Product: C=CC(=O)OCCN(C)C

Procedure:
The mass of 2-dimethylaminoethyl acrylate thus obtained was 685 g, wherein 0.0128 wt % of methyl acrylate and 0.0185 wt % of 2-dimethylamino ethanol, that is 0.0313 wt % of the total, were contained, therefore, 2-dimethylaminoethyl acrylate with a small amount of raw components could be obtained.
Reaction SMILES: Cl.[CH2:2]([NH2:4])[CH3:3].C[Al](C)C.[Cl:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[N:18]=[CH:17][C:16]([CH3:20])=[C:15]2[C:21]1[CH:22]=[C:23]([CH:35]=[CH:36][CH:37]=1)[O:24][C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=1)[C:28]([O:30]C)=O.O>C1(C)C=CC=CC=1>[Cl:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[N:18]=[CH:17][C:16]([CH3:20])=[C:15]2[C:21]1[CH:22]=[C:23]([CH:35]=[CH:36][CH:37]=1)[O:24][C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=1)[C:28]([NH:4][CH2:2][CH3:3])=[O:30]
Reactant: COC(=O)c1cccc(Oc2cccc(-c3c(C)cnc4c(Cl)cccc34)c2)c1
Reactant: CCN
Agent: C[Al](C)C
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: CCNC(=O)c1cccc(Oc2cccc(-c3c(C)cnc4c(Cl)cccc34)c2)c1
Temperature: 62.5 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of ethylamine hydrochloride (41 mg, 0.50 mmol) in toluene (2 mL) at ambient temperature under nitrogen is added 2.0M trimethylaluminum in toluene (0.25 mL, 0.50 mmol). After 0.5 h, methyl 3-[3-(8-chloro-3-methylquinolin-4-yl)phenoxy]benzoate (101 mg, 0.25 mmol) is added and the reaction heated at 60-65° C. for 16 h. The cooled reaction is treated with water (2 mL), then 2M aq HCl (1 mL) and extracted with dichloromethane (2×5 mL). The combined extracts are dried (MgSO4), concentrated in vacuo, and the resulting oil is chromatographed on silica gel using 50:50, then 75:25 ethyl acetate:hexane as eluent. The title compound is isolated as a glass (Rf˜0.3 in first solvent system, 101 mg). MS (ES) m/z 417.2; HRMS: calcd for C25H21ClN2O2+H+, 417.13643; found (ESI, [M+H]+), 417.1357.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[O:13][C:14]1[CH:19]=[C:18]([C:20]([NH:22][C:23]2[CH:27]=[CH:26][N:25]([CH3:28])[N:24]=2)=[O:21])[CH:17]=[C:16]([O:29][C@@H:30]([CH3:33])[CH2:31][OH:32])[CH:15]=1)[C:5]([O:7]CC)=[O:6].O.[OH-].[Li+]>C1COCC1.O>[F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[O:13][C:14]1[CH:19]=[C:18]([C:20]([NH:22][C:23]2[CH:27]=[CH:26][N:25]([CH3:28])[N:24]=2)=[O:21])[CH:17]=[C:16]([O:29][C@@H:30]([CH3:33])[CH2:31][OH:32])[CH:15]=1)[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)c1ccc(Oc2cc(O[C@@H](C)CO)cc(C(=O)Nc3ccn(C)n3)c2)c(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](CO)Oc1cc(Oc2ccc(C(=O)O)cc2F)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 95.8 %

Procedure:
A solution of ethyl 3-fluoro-4-(3-[(1S)-2-hydroxy-1-methylethoxy]-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenoxy)benzoate (1.8 g, 3.94 mmol) in THF (60 mL) was added to a solution of lithium hydroxide monohydrate (0.83 g, 19.7 mmol) in water (30 mL). The mixture was stirred at RT for 72 hours and the THF removed in vacuo. The aqueous layer was extracted into ethyl acetate (100 mL) to remove any impurities, then acidified with 1M hydrochloric acid and extracted into ethyl acetate (2×100 mL). The combined extracts were dried (MgSO4) and the solvent removed in vacuo to give the desired compound (1.62 g).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>Cl>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:16]=[CH:15][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:29])([F:28])[F:30])=[CH:23][CH:22]=1)(=[O:20])=[O:19]
Reactant: COC(=O)c1ccc(-c2nc(CS(=O)(=O)c3ccc(C(F)(F)F)cc3)c(C)o2)cc1
Agent: Cl
Product: Cc1oc(-c2ccc(C(=O)O)cc2)nc1CS(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 88.7 %

Procedure:
A solution of methyl 4-(5-methyl-4-((4-(trifluoromethyl)phenylsulfonyl)methyl)oxazol-2-yl)benzoate (700 mg, 1.59 mmol, 1.00 equiv) in 6N hydrochloric acid (30 mL) was refluxed for 8 h. The reaction mixture was cooled to room temperature and diluted with 100 g of water/ice. The solid was collected by filtration, washed with 2×20 mL of water and dried in a vacuum oven to afford 0.6 g (89%) of 4-(5-methyl-4-((4-(trifluoromethyl)phenylsulfonyl)methyl)oxazol-2-yl)benzoic acid as a white solid.
Reaction SMILES: [SH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[H-].[Na+].Br[CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>CN(C=O)C>[CH:14]1([S:1][C:2]2[N:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=C(O)c1cccnc1S
Reactant: BrC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)c1cccnc1SC1CCCCC1
Reaction time: 0.5 h

Procedure:
2-Mercapto-nicotinic acid (0.5 g, 3.22 mmol) was dissolved in DMF (5 mL), and the solution was cooled to 0˜5° C. NaH (0.64 g, 16.11 mmol) was added slowly thereto, and the mixture was stirred at 0˜5° C. for 30 minutes. Bromo-cyclohexane (1.19 mL, 9.66 mmol) was added thereto, and the mixture was stirred at room temperature for 12 hours. After the termination of the reaction, the reactant was concentrated under reduced pressure, and the residue was diluted with water. 3N HCl was used to adjust the pH of the solution to 2˜3, and the solution was extracted with EtOAc. The organic layer was dried with MgSO4 and concentrated under reduced pressure to obtain the title compound, which was used in the next step without a separate purification process.
Reaction SMILES: Cl[C:2]1[C:10]2[C:5](=[N:6][C:7]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[N:8][CH:9]=2)[N:4]([CH3:21])[N:3]=1.CC1(C)C(C)(C)OB([C:30]2[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=2)O1>>[NH2:34][C:33]1[CH:35]=[CH:36][C:30]([C:2]2[C:10]3[C:5](=[N:6][C:7]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[N:8][CH:9]=3)[N:4]([CH3:21])[N:3]=2)=[CH:31][CH:32]=1
Reactant: CCN(CC)CCCCNc1ncc2c(Cl)nn(C)c2n1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Product: CCN(CC)CCCCNc1ncc2c(-c3ccc(N)cc3)nn(C)c2n1

Procedure:
Prepared as described above in Example 15 starting from N′-(3-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-N,N-diethyl-butane-1,4-diamine and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline to give the title compound N-[3-(4-amino-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-N′,N′-diethyl-butane-1,4-diamine; 1H-NMR (MeOH): δ 1.33 (m, 6H), 1.86 (m, 4H), 3.28 (m, 4H), 3.82 (m, 2H), 3.69 (m, 2H), 3.98 (s, 3H), 7.44 (d, 2H, J=8.4 Hz), 8.07 (d, 2H, J=8.4 Hz), 9.23 (s, 1H); LC/MS (m/e)=368.2 (MH+), Rt=1.20 min.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[NH2:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([OH:17])=[O:16]>O>[CH:1]([NH:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([OH:17])=[O:16])=[O:3]
Reactant: Nc1cccc(C(=O)O)c1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: O=CO
Product: O=CNc1cccc(C(=O)O)c1
Temperature: 25 °C

Procedure:
Acetic anhydride (76 ml) was added to 98% formic acid (130 ml) and the mixture stirred at r.t. 30 min, then 3-aminobenzoic acid (15 g, 109.5 mmol) added. The mixture was stirred at r.t. for 1 h, then water (1.3 L) added and stirring continued overnight. The resultant white precipitate was collected, washed with water and dried in vacuo over P2O5 (15.4 g, 85%).
Reaction SMILES: [Br:1][C:2]1[S:12][C:5]2[CH2:6][N:7]([CH3:11])[CH2:8][CH:9]([OH:10])[C:4]=2[CH:3]=1.[Cl:13][C:14]1[CH:15]=[C:16](F)[CH:17]=[CH:18][C:19]=1[Cl:20]>>[ClH:13].[Br:1][C:2]1[S:12][C:5]2[CH2:6][N:7]([CH3:11])[CH2:8][CH:9]([O:10][C:17]3[CH:16]=[CH:15][C:14]([Cl:13])=[C:19]([Cl:20])[CH:18]=3)[C:4]=2[CH:3]=1
Reactant: CN1Cc2sc(Br)cc2C(O)C1
Reactant: Fc1ccc(Cl)c(Cl)c1
Product: CN1Cc2sc(Br)cc2C(Oc2ccc(Cl)c(Cl)c2)C1
Product: Cl

Procedure:
The same method as in Example 3 was conducted using 2-bromo-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 12) instead of 6-methyl-4,5,6,7-tetrahydrofuro[2,3-c]pyridin-4-ol (Reference Example 1) and was conducted using 3,4-dichloro-1-fluorobenzene instead of 1,3-difluorobenzene to give the objective compound.
Reaction SMILES: [OH-].[Na+].[CH2:3]([C:10]1[C:18]2[C:13](=[CH:14][C:15]([OH:23])=[C:16]([C:19]([O:21]C)=[O:20])[CH:17]=2)[NH:12][N:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl>CO.O>[CH2:3]([C:10]1[C:18]2[C:13](=[CH:14][C:15]([OH:23])=[C:16]([C:19]([OH:21])=[O:20])[CH:17]=2)[NH:12][N:11]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1cc2c(Cc3ccccc3)n[nH]c2cc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc2c(Cc3ccccc3)n[nH]c2cc1O
Reaction time: 3 h

Procedure:
1.4 595 μl of 2 N NaOH are added to a suspension of 112 mg of “A1” in 1.5 ml of methanol, and the mixture is stirred at 60° for 3 hours. The mixture is cooled, 0.7 ml of 2 N HCl is added, the mixture is diluted with water, the precipitate is removed, and the mixture is subjected to conventional work-up, giving 75 mg of 3-benzyl-6-hydroxy-1H-indazole-5-carboxylic acid (“A2”).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([O:10][C:11]3[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:13][CH:12]=3)=[C:8]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH:32]([CH3:34])[CH3:33])[S:7][C:6]=2[CH:35]=1.Cl[CH2:37][N:38]1[C:42](=[O:43])[C:41]2[CH:44]=[CH:45][CH:46]=[CH:47][C:40]=2[S:39]1(=[O:49])=[O:48].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[O:48]=[S:39]1(=[O:49])[C:40]2[CH:47]=[CH:46][CH:45]=[CH:44][C:41]=2[C:42](=[O:43])[N:38]1[CH2:37][O:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([O:10][C:11]3[CH:12]=[CH:13][C:14](/[CH:17]=[CH:18]/[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:15][CH:16]=3)=[C:8]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH:32]([CH3:33])[CH3:34])[S:7][C:6]=2[CH:35]=1
Reactant: CC(C)c1ccccc1-c1sc2cc(O)ccc2c1Oc1ccc(/C=C/C(=O)OC(C)(C)C)cc1
Reactant: O=C1c2ccccc2S(=O)(=O)N1CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)c1ccccc1-c1sc2cc(OCN3C(=O)c4ccccc4S3(=O)=O)ccc2c1Oc1ccc(/C=C/C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 70.7 %

Procedure:
To a solution of (E)-tert-butyl 3-(4-((6-hydroxy-2-(2-isopropylphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate (68 mg, 0.140 mmol) in acetone (2 mL) was added 2-(chloromethyl)benzo[d]isothiazol-3(2H)-one 1,1-dioxide (32.4 mg, 0.140 mmol), potassium carbonate (19.31 mg, 0.140 mmol) and potassium iodide (23.2 mg, 0.140 mmol). The resulting mixture was stirred at room temperature for 48 hours. The solvent was removed in vacuo. The resulting solid was retaken in ethyl acetate. The organic layer was washed with aqueous saturated ammonium chloride solution followed by brine. The organic layer was dried over anhydrous MgSO4 filtered and concentrated in vacuo to give the crude product, which was purified by flash chromatography (SiO2, 0-30% EtOAc/Heptane) to afford (E)-tert-butyl 3-(4-((6-((1,1-dioxido-3-oxobenzo[d]isothiazol-2(3H)-yl)methoxy)-2-(2-isopropylphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate (67.4 mg, 0.099 mmol, 71% yield). 1H NMR (400 MHz, (CD3)2SO) δ 8.37 (d, J=7.4 Hz, 1H), 8.18 (dd, J=7.4, 1.3 Hz, 1H), 8.11 (td, J=7.7, 1.3 Hz, 1H), 8.04 (t, J=7.6 Hz, 1H), 7.88 (d, J=2.2 Hz, 1H), 7.61-7.54 (m, 2H), 7.48-7.34 (m, 3H), 7.34-7.30 (m, 2H), 7.23-7.15 (m, 2H), 6.89-6.81 (m, 2H), 6.33 (d, J=16.0 Hz, 1H), 5.90 (s, 2H), 3.13 (q, J=6.9 Hz, 1H), 1.45 (s, 9H), 1.13 (d, J=6.8 Hz, 6H).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][CH2:10][CH2:11][CH2:12][N:13]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[C:22]([O-:24])=O)[CH:15]=[CH:14]1)[CH2:2]2.[Li+].C(N(CC)C(C)C)(C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>CN(C=O)C>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([N:9]1[CH2:10][CH2:11][CH2:12][N:13]3[C:21]4[C:16]([CH:15]=[CH:14]3)=[CH:17][CH:18]=[CH:19][C:20]=4[C:22]1=[O:24])[CH2:2]2
Reactant: O=C([O-])c1cccc2ccn(CCCN[C@H]3CN4CCC3CC4)c12
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1c2cccc3ccn(c23)CCCN1[C@H]1CN2CCC1CC2
Temperature: 25 °C
Reaction time: 5 h
Yield: 24.1 %

Procedure:
A solution of lithium (R)-1-(3-(quinuclidin-3-ylamino)propyl)-1H-indole-7-carboxylate (574 mg, 1.7 mmol) from Step D above in DMF (8 mL) was cooled in an ice bath while N,N-diisopropylethylamine (1.3 g, 10.3 mmol) was added, followed by 1-propanephosphonic acid cyclic anhydride (T3P) (3.3 g, 10.3 mmol). The reaction mixture was stirred at room temperature for 5 h. The reaction was quenched with water and the aqueous phase was extracted with methylene chloride (3×) and the combined extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, 80:18:2 methylene chloride/methanol/concentrated ammonium hydroxide) to give (R)-2-(quinuclidin-3-yl)-2,3,4,5-tetrahydro-1H-[1,5]diazocino[3,2,1-hi]indol-1-one (127 mg, 24%) as an off-white solid: 1H NMR (300 MHz, CD3OD) δ 7.67 (d, J=6.6 Hz, 1H), 7.33 (d, J=7.5 Hz, 1H), 7.20 (d, J=3.3 Hz, 1H), 7.11 (t, J=7.8 Hz, 1H), 6.50 (d, J=3.0 Hz, 1H), 4.40-4.20 (m, 2H), 3.80-3.45 (m, 3H), 3.25-2.80 (m, 5H), 2.30-1.50 (m, 6H), 1.40-1.20 (m, 2H); MS (ESI+) m/z 310 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]([NH:22][C:23]([C:25]1[C:26]([OH:36])=[N:27][C:28]([N:31]2[CH:35]=[CH:34][CH:33]=[N:32]2)=[N:29][CH:30]=1)=[O:24])[C:10]1[CH:15]=[CH:14][C:13]([P:16]([CH3:21])(=[O:20])[O:17]CC)=[CH:12][CH:11]=1.[OH-].[Na+]>O1CCOCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]([NH:22][C:23]([C:25]1[C:26]([OH:36])=[N:27][C:28]([N:31]2[CH:35]=[CH:34][CH:33]=[N:32]2)=[N:29][CH:30]=1)=[O:24])[C:10]1[CH:15]=[CH:14][C:13]([P:16]([CH3:21])(=[O:17])[OH:20])=[CH:12][CH:11]=1
Reactant: CCOP(C)(=O)c1ccc([C@H](NC(=O)c2cnc(-n3cccn3)nc2O)c2ccc(F)cc2F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CP(=O)(O)c1ccc([C@H](NC(=O)c2cnc(-n3cccn3)nc2O)c2ccc(F)cc2F)cc1
Temperature: 80 °C

Procedure:
Ethyl 4-((S)-(2,4-difluorophenyl)(4-hydroxy-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxamido)methyl)phenyl(methyl)phosphinate, 21-e, (400 mg, 0.78 mmol) was dissolved in 2 ml of dioxane and treated with 0.2 ml of 5N NaOH. The mixture was heated at 80° C. for 30 min. Then the mixture was concentrated under vacuum. The residue was diluted with water and washed with ethyl acetate. The aqueous layer was acidified with AcOH and evaporated to dryness. The residue was used for prep-HPLC to afford the product, 21-1, (250 mg, 66%). 1H NMR (300 MHz, CD3OD): δ 8.67 (s, 1H), 8.58 (s, 1H), 7.92 (s, 1H), 7.81 (m, 2H), 7.48 (m, 3H), 7.01 (m, 2H), 6.66 (s, 1H), 6.60 (s, 1H), 1.67 (d, 3H). (M−H)−=484.0.
Reaction SMILES: [CH:1]1[N:6]=[C:5](Cl)[C:4]2[N:8]=[CH:9][N:10]([C@@H:11]3[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]3[OH:19])[C:3]=2[N:2]=1.[NH2:20][C@H:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22]1.C(N(CC)CC)C>C(O)C>[C@H:21]1([NH:20][C:5]2[C:4]3[N:8]=[CH:9][N:10]([C:3]=3[N:2]=[CH:1][N:6]=2)[C@@H:11]2[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]2[OH:19])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22]1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Reactant: N[C@@H]1CCc2ccccc21
Solvent: CCO
Solvent: CCN(CC)CC
Product: OC[C@H]1O[C@@H](n2cnc3c(N[C@@H]4CCc5ccccc54)ncnc32)[C@H](O)[C@@H]1O
Reaction time: 20 h
Yield: 59.7 %

Procedure:
For 20 hours, 1.83 g 6-chloropurine riboside, 0.95 g (R)(-)-1-aminoindane and 0.862 g triethylamine are refluxed in 50 ml absolute ethanol under nitrogen atmosphere. The solvent is evaporated to dryness and residue is treated with 50 ml cold water. The solid material is filtered, dissolved in excess ethanol, and volatiles are evaporated under reduced pressure to remove water. Residue upon treatment with ethanol affords solid material. It is filtered and dried. One more crop of the same material is obtained from the mother liquor yielding 1.46 g (60% of theory) of N(6) [1-(R)-indanyl]adenosine having a melting point of 185°-187° C.
Reaction SMILES: [N+:1]1([O-])[CH:6]=[CH:5][CH:4]=[C:3]2[CH:7]=[CH:8][C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11](=[O:12])[C:2]=12.S(Cl)(C1C=CC(C)=CC=1)(=O)=[O:19].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.O>[O:12]=[C:11]1[C:2]2[NH:1][C:6](=[O:19])[CH:5]=[CH:4][C:3]=2[CH:7]=[CH:8][C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]1=2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=c1c2ccccc2ccc2ccc[n+]([O-])c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=c1ccc2ccc3ccccc3c(=O)c2[nH]1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
To a solution of 0.75 gram (0.0034 mole) of the N-oxide thus obtained and 0.77 gram (0.0043 mole) of tosyl chloride in 37.5 milliliters of chloroform was added a solution of 0.58 gram (0.0042.mole) of potassium carbonate in 5.8 milliliters of water and the resulting mixture was stirred vigorously at room temperature for about 60 hours. At the end of this time the reaction mixture was washed with 10 percent aqueous sodium hydroxide whereupon a solid precipitated in the chloroform phase. The solid was recovered by filtration and recrystallized from isopropyl alcohol/methanol to obtain purified 1-oxo-benzo[5,6]cyclohepta[1,2-b]pyrid-2(1H)one product, m.p. 195°-196° C. The elemental analyses were as follows:
Reaction SMILES: CC(CC(C)C)=O.[CH3:8][C:9]([NH2:17])([CH3:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C.[Br:25][CH:26]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:27](Br)=[O:28]>O>[CH3:8][C:9]([NH:17][C:27](=[O:28])[CH:26]([C:30]([CH3:33])([CH3:32])[CH3:31])[Br:25])([CH3:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(N)c1ccccc1
Reactant: CC(C)(C)C(Br)C(=O)Br
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(=O)CC(C)C
Product: CC(C)(NC(=O)C(Br)C(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.8 %

Procedure:
Into a 500 ml four-necked flask, there were charged methylisobutylketone (150 ml), α,α-dimethylbenzylamine (33.8 g) and triethylamine (27.8 g), and α-bromo-tert-butylacetylbromide (64.5 g) was dropwise added thereto while stirring at room temperature. Stirring was continued for 3 hours. After completion of the reaction, water (200 ml) was added thereto and the reaction mixture was gradually heated to remove methylisobutylketone, followed by cooling at room temperature. The precipitated crystals were filtered, washed with water, dried and recrystallized from ethanol to give N-(α,α-dimethylbenzyl)-α-bromo-tert-butylacetamide (61.5 g).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]([O:13][CH3:14])=[CH:8][C:3]=1[C:4](OC)=[O:5].[CH:15]([NH2:17])=O>>[CH3:14][O:13][C:9]1[CH:8]=[C:3]2[C:2](=[CH:11][C:10]=1[CH3:12])[NH:1][CH:15]=[N:17][C:4]2=[O:5]
Reactant: NC=O
Reactant: COC(=O)c1cc(OC)c(C)cc1N
Product: COc1cc2c(=O)nc[nH]c2cc1C
Temperature: 140 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
Methyl 2-amino-5-methoxy-4-methylbenzoate (510 mg) was suspended in formamide (5 ml), and the suspension was stirred at 140° C. overnight. The precipitated crystal was washed with ether to give 6-methoxy-7-methyl-1H-quinazolin-4-one (275 mg, yield 55%).