Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:22]([C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1)#[N:23]>C1(C)C=CC=CC=1>[C:22]([C:24]1[CH:32]=[CH:31][C:27]([C:28]([O:14][CH:11]2[CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9][CH2:10]2)=[O:29])=[CH:26][CH:25]=1)#[N:23]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: OC1CCN(Cc2ccccc2)CC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: N#Cc1ccc(C(=O)OC2CCN(Cc3ccccc3)CC2)cc1
Yield: 61.4 %

Procedure:
2.0 g (0.01 mol) of 1-benzyl-4-hydroxypiperidine and 1.4 ml (0.01 mol) of triethylamine were dissolved in 100 ml of toluene and treated with 1.6 g (0.00966 mol) of 4-cyanobenzoyl chloride. The mixture was boiled at reflux for 2 hrs., the precipitate was filtered off and the filtrate was concentrated. The residue was chromatographed over silica gel with ethyl acetatelhexane (1:1). 1.9 g (61%) of 1-benzyl-piperidin-4-yl 4-cyano-benzoate were obtained as brownish crystals; m.p. 110°-111°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.[N-:11]=[N+:12]=[N-:13].[Na+]>CN(C)C=O.O>[N:11]([CH2:7][C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[N+:12]=[N-:13]
Reactant: COc1ccc(CCl)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CN=[N+]=[N-])cc1
Temperature: 23 °C
Reaction time: 15 h
Yield: 100.2 %

Procedure:
To a stirred solution of 4-methoxybenzyl chloride (25.0 g, 156 mmol) in N,N-dimethylformamide (75 mL) was added sodium azide (11.5 g, 177 mmol). The reaction mixture was stirred at 23° C. for 15 h, then diluted with water (300 mL). The mixture was extracted with diethyl ether (3×75 mL) and the combined organic layers were washed with water (2×100 mL). The organic layer was dried (MgSO4), filtered, and evaporated under reduced pressure to afford the title compound (25.5 g) as a pale yellow oil. The title compound was used directly in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[Li]CCCC.[CH3:18][C:19]1[C:20](=O)[CH:21]([CH3:26])[CH:22]([CH3:25])[C:23]=1[CH3:24].Cl.N>C1COCC1>[CH3:12][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[C:2]([C:20]3[CH:19]([CH3:18])[C:23]([CH3:24])=[C:22]([CH3:25])[C:21]=3[CH3:26])[CH:3]=[CH:4][CH:5]=2)[N:10]=1
Reactant: Cc1ccc2cccc(Br)c2n1
Reactant: CC1=C(C)C(C)C(C)C1=O
Agent: Cl
Agent: N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1=C(C)C(C)C(c2cccc3ccc(C)nc23)=C1C
Temperature: 25 °C
Yield: 60 %

Procedure:
A solution of 4.4 q of 8-bromo-2-methylquinoline (20 mmol) in 50 ml of THF was cooled to −78° C., and 8.8 ml of n-BuLi (2.5 M in hexane, 22 mmol) were added dropwise with stirring. After the mixture had been stirred for 10 minutes, 3.5 g of 2,3,4,5-tetramethylcyclopentenone (25 mmol) were added dropwise, and the solution was warmed to room temperature, refluxed for one hour and cooled. Ice and hydrochloric acid were added to about pH 1, the mixture was neutralized using ammonia solution, the phases were separated, and the aqueous phase was extracted with pentane. After the combined organic extracts had been dried, the pentane was removed under reduced pressure, and the brown oil which remained was distilled under a high vacuum (b.p.: 115° C./0.01 mbar). 1-(2-Methyl-8-quinolyl)-2,3,4,5-tetramethylcyclopentadiene was obtained as a yellow, viscous oil in a yield of 60% (3.2 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([O:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)(=[O:12])=[O:11])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([CH2:36]O)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.O>[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([CH2:36][O:1][C:2]2[CH:3]=[C:4]([O:9][S:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[CH:14]=3)(=[O:12])=[O:11])[CH:5]=[C:6]([CH3:8])[CH:7]=2)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2cccc(C(F)(F)F)c2)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(OCC2CCN(C(=O)OC(C)(C)C)CC2)cc(OS(=O)(=O)c2cccc(C(F)(F)F)c2)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 70.8 %

Procedure:
A solution of 3-trifluoromethylbenzenesulfonic acid 3-hydroxy-5-methylphenyl ester (332 mg, 1.0 mmol), as prepared in the preceding step, N-(tert-butoxycarbonyl)-4-piperidinemethanol (215 mg, 1.0 mmol), as prepared in step f of Example 1, and triphenylphosphine (263 mg, 1.0 mmol) in tetrahydrofuran (10 mL at 0° C. was treated with diethyl azodicarboxylate (175 mg, 1.0 mmol). The reaction mixture was stirred at 0° C. for 2 h and at room temperature for 3 h. Water (50 mL) was added. The reaction mixture was extracted into ethyl acetate (3×50 mL), washed sequentially with saturated NaHCO3 (2×50 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography (1:2 ethyl acetate:hexane) to give the title compound as a colorless liquid (375 mg, 70%). 1H-NMR (300 MHz, CDCl3) δ 1.26 (m, 2H), 1.47 (s, 9H), 1.77 (m, 2H), 1.89 (m, 1H), 2.24 (s, 3H), 2.73 (t, 2H), 3.67 (d, 2H), 4.13 (m, 2H), 6.34 (d, 1H), 6.36 (s, 1H), 6.62 (s, 1H), 7.72 (t, 1H), 7.94 (d, 1H), 8.09 (d, 2H).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[NH:7][C:6]2[CH2:8][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][C:5]=2[N:4]=1.[CH3:20][Si]([N-][Si](C)(C)C)(C)C.[K+].CI>O1CCCC1>[CH3:20][N:4]1[CH:5]2[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:8][CH:6]2[N:7]=[C:3]1[C:2]([F:1])([F:18])[F:19]
Reactant: CC(C)(C)OC(=O)N1Cc2nc(C(F)(F)F)[nH]c2C1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: CN1C(C(F)(F)F)=NC2CN(C(=O)OC(C)(C)C)CC21
Temperature: 25 °C

Procedure:
To a solution of tert-butyl 2-(trifluoromethyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate (90 mg) in tetrahydrofuran (3 mL) at −20° C. was added potassium bis(trimethylsilyl)amide solution (0.714 mL 0.5M in toluene). The mixture was stirred at −20° C. for 30 min at which point methyl iodide (0.04 mL) was added and the reaction slowly was warmed to ambient temperature over 1 h. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution (5 mL). The phases were separated and the aqueous phase extracted with dichloromethane (3×10 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, evaporated in vacuo and the resulting product used without further purification. LC/MS 292.2 (M+1).
Reaction SMILES: [C:1]([NH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].CN(C)CCN(C)C.[Li]CCCC.[I:27]I>C1COCC1>[CH3:3][C:2]([CH3:5])([CH3:4])[C:1]([NH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[I:27])=[O:6]
Reactant: II
Reactant: CC(C)(C)C(=O)Nc1cccnc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1cnccc1I
Temperature: -78 °C
Reaction time: 2 h
Yield: 20.9 %

Procedure:
The 3-(Pivaloylamino)pyridine 15 (1.9 g, 11 mmol) and tetramethylethylene-diamine (4.0 mL, 26 mmol) were dissolved in dry THF (60 mL) and cooled to −78° C. While maintaining the temperature between −78° C. and −65° C., nBuLi (2.5 M solution in hexanes, 10.6 mL, 26.5 mmol) was added dropwise. The reaction was allowed to warm to −10° C. for 2 h, and then cooled back down to −78° C. Iodine (6.73 g, 26.5 mmol) dissoved in dry THF (20 mL) was added slowly. After stirring for 2 h at −78° C., the reaction was quenched with ice. Excess iodine was destroyed with addition of saturated potassium thiosulfate solution. The product was extracted with CH2Cl2, and the organic layers were washed with brine. The mixture was concentrated in vacuo to a black oil which was chromatographed (1:1 EtOAc/Hexanes; 2:1 EtOAc/Hexanes) to give 700 mg (23%) of 2,2-dimethyl-N-(4-iodo-3-pyridinyl)propanamide as a yellow solid. 1HNMR (DMSO-d6 300 MHz) δ 9.24 (s, 1H), 8.35 (s, 1H), 8.04 (d, 1H), 7.95 (d, 1H), 1.26 (s, 9H). MS (ES+)=305.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:27]=[CH:28][C:29]=1[Cl:30])[O:8][C:9]1[CH:26]=[CH:25][C:12]([CH2:13][NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[C:16]=2[CH3:24])=[CH:11][CH:10]=1)[CH:2]=[CH2:3].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:27]=[CH:28][C:29]=1[Cl:30])[O:8][C:9]1[CH:26]=[CH:25][C:12]([CH2:13][N:14]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[C:16]=2[CH3:24])=[CH:11][CH:10]=1)[CH:2]=[CH2:3]
Reactant: BrCc1ccccc1
Reactant: C=CCOc1cc(Oc2ccc(CNc3cccc([N+](=O)[O-])c3C)cc2)ccc1Cl
Product: C=CCOc1cc(Oc2ccc(CN(Cc3ccccc3)c3cccc([N+](=O)[O-])c3C)cc2)ccc1Cl

Procedure:
The product from Example 91D and benzyl bromide was processed as described in Example 6B to provide the title compound.
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][C:12]1[NH:13][C:14](=[O:53])[C:15]2[N:16]=[CH:17][N:18]([C:51]=2[N:52]=1)[C@@H:19]1[O:50][C@H:24]([CH2:25][O:26][C:27]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[C@@H:22]([OH:23])[C@H:20]1[OH:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.ClCC(C#N)[CH2:66][O:67][CH2:68][CH:69]([C:72]#[N:73])CCl.C(=O)(O)[O-].[Na+]>ClCCCl>[O:1]([CH2:8][C:9]([NH:11][C:12]1[NH:13][C:14](=[O:53])[C:15]2[N:16]=[CH:17][N:18]([C:51]=2[N:52]=1)[C@@H:19]1[O:50][C@H:24]([CH2:25][O:26][C:27]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[C@@H:22]([OH:23])[C@H:20]1[O:21][CH2:66][O:67][CH2:68][CH2:69][C:72]#[N:73])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(=O)[nH]c(NC(=O)COc5ccccc5)nc43)[C@H](O)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: N#CC(CCl)COCC(C#N)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(=O)[nH]c(NC(=O)COc5ccccc5)nc43)[C@H](OCOCCC#N)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reaction time: 1 h
Yield: 47.8 %

Procedure:
N2-Phenoxyacetyl-5′-O-(4,4′-dimethoxytrityl)guanosine (720 mg, 1 mmol) was dissolved in 4 mL of 1,2-dichloroethane, and 452 mg of diisopropylethylamine (3.5 mmol) was added, and 365 mg of dibutylstannyl dichloride (1.2 mmol) was added subsequently. Then, the reaction was performed at room temperature for 1 hour. Then, the reaction was performed at 80° C., and 155.4 mg of chloromethyl 2-cyanoethylether (1.3 mmol) was added dropwise, and the solution was stirred for 60 minutes. After the reaction completed, the reaction solution was mixed with an aqueous saturated sodium bicarbonate solution, and was subjected to extraction with methylene chloride. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained mixture was purified by 30 g of silica gel column chromatography to obtain N2-phenoxyacetyl-5′-O-(4,4′-dimethoxytrityl)-2′-O-(2-cyanoethoxymethyl)guanosine (384 mg; yield 48%).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:31]=[CH:30][N:29]=[C:28]([C:32]([OH:34])=O)[CH:27]=1.CCN(C(C)C)C(C)C.[CH3:44][C@@H:45]1[NH:50][CH2:49][CH2:48][N:47]([S:51]([C:54]2[CH:59]=[CH:58][C:57]([C:60]([F:63])([F:62])[F:61])=[CH:56][CH:55]=2)(=[O:53])=[O:52])[CH2:46]1>CN(C=O)C>[Cl:25][C:26]1[CH:31]=[CH:30][N:29]=[C:28]([C:32]([N:50]2[CH2:49][CH2:48][N:47]([S:51]([C:54]3[CH:55]=[CH:56][C:57]([C:60]([F:63])([F:61])[F:62])=[CH:58][CH:59]=3)(=[O:52])=[O:53])[CH2:46][C@@H:45]2[CH3:44])=[O:34])[CH:27]=1
Reactant: C[C@H]1CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCN1
Reactant: O=C(O)c1cc(Cl)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCN1C(=O)c1cc(Cl)ccn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 39.4 %

Procedure:
HATU (411 mg, 1.08 mmol) was added to a solution of 4-chloro-2-pyridinecarboxylic acid (142 mg, 0.90 mmol) in DMF (4 ml) and the mixture was treated with DIPEA (0.394 ml, 2.25 mmol). This mixture was stirred for ca. 10 min at ambient temperature. (3S)-3-Methyl-1-{[4-(trifluoromethyl)phenyl]sulfonyl}piperazine (Description 2) (333 mg, 1.082 mmol) was then added and stirring was continued for 1.5 h. The reaction mixture was partitioned between DCM and sat aq. NaHCO3 solution (20 ml each). The layers were separated and the aqueous was washed with further DCM (2×20 ml). The combined organics were concentrated to leave a dark brown gum. Purification by silica chromatography (Biotage SP4, 25S cartridge), eluting with 12-100% ethyl acetate in isohexane, gave a pale yellow gum, shown to be impure by LCMS and NMR analysis. Further purification by MDAP gave the title compound as a colourless glass (159 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[C:15]([Cl:16])=[C:14]3[O:17][CH2:18][O:19][C:13]3=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[ClH:20].[C:21]1([CH2:27][C:28](=[NH:32])OCC)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)C>[ClH:16].[Cl:20][C:11]1[CH:12]=[C:13]2[O:19][CH2:18][O:17][C:14]2=[CH:15][C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:28](=[NH:32])[CH2:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ncccc1OCc1ccc2c(c1Cl)OCO2
Reactant: CCOC(=N)Cc1ccccc1
Agent: Cl
Solvent: CCO
Product: N=C(Cc1ccccc1)Nc1ncccc1OCc1cc2c(cc1Cl)OCO2
Yield: 10.7 %

Procedure:
2-Amino-3-(6-chloro-4,5-methylenedioxybenzyloxy)pyridine (6 g, 21.6 mmol) and ethyl phenylacetimidate hydrochloride (5.17 g, 26 mmol) in ethanol (150 ml) were heated under reflux for 3 hrs. The solvent was evaporated and the residue purified by flash chromatography (silica, 1% methanol/dichloromethane), trituration with ether and recrystallisation from ethanol to give the tire compound (1.0 g), m.p. 189° C. (softening 170° C.).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:13][C:14]1[CH:34]=[CH:33][C:17]([CH2:18][N:19]2[C:23]3=[N:24][CH:25]=[CH:26][CH:27]=[C:22]3[C:21]([CH2:28][C:29]([O:31]C)=[O:30])=[N:20]2)=[CH:16][CH:15]=1)=[O:12].O.[OH-].[Li+].Cl>O1CCCC1.O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:18][N:19]2[C:23]3=[N:24][CH:25]=[CH:26][CH:27]=[C:22]3[C:21]([CH2:28][C:29]([OH:31])=[O:30])=[N:20]2)=[CH:33][CH:34]=1)=[O:12]
Reactant: COC(=O)Cc1nn(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)c2ncccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cc1nn(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)c2ncccc12
Yield: 49.3 %

Procedure:
Methyl 2-[1-[4-(2-naphthamido)benzyl]-1H-pyrazolo[3,4-b]pyridin-3-yl]acetate (60 mg, 0.13 mmol) and lithium hydroxide monohydrate (10 mg, 0.24 mmol) were added into a mixed solution of tetrahydrofuran (5 mL) and water (20 mL), and reacted at room temperature for 2 hours. Tetrahydrofuran was rotate evaporated. The pH was adjusted to 3 with 1 mol/L hydrochloric acid. It was extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The organic phase was rotate evaporated to dryness to obtain a light brown solid 28 mg, at a yield of 49.3%.
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4].N1C=CC=CC=1.Cl.[CH2:15]([NH:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>O>[CH2:15]([NH:31][C:32]1[CH:33]=[CH:34][C:35]([C:36]([NH:1][C:2]([CH3:7])([C:3]([OH:5])=[O:4])[CH3:6])=[O:37])=[CH:39][CH:40]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)Cl)cc1
Reactant: CC(C)(N)C(=O)O
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)NC(C)(C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 5.24 g. of α-aminoisobutyric acid, 50 ml. of pyridine, and 25 ml. of H2O was stirred while 21.1 g. of 4-(hexadecylamino)benzoyl chloride hydrochloride was added. The mixture was stirred for 18 hours at ambient temperature and filtered. The filtrate was evaporated and the residual yellow glass was dissolved in 1 N NaOH solution. The solution was extracted with diethyl ether and then acidified with 6 N HCl. The precipitate was collected, dried, and recrystallized from acetone, melting point 199°-202° C.
Reaction SMILES: BrC[CH2:3][CH2:4][N:5]1[C:13]([S:14][C:15]2[C:24]([I:25])=[CH:23][C:18]3[O:19][CH2:20][CH2:21][O:22][C:17]=3[CH:16]=2)=[N:12][C:11]2[C:6]1=[N:7][CH:8]=[N:9][C:10]=2[NH2:26].[Br:27]CCCBr.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Br:27][CH2:3][CH2:4][N:5]1[C:13]([S:14][C:15]2[C:24]([I:25])=[CH:23][C:18]3[O:19][CH2:20][CH2:21][O:22][C:17]=3[CH:16]=2)=[N:12][C:11]2[C:6]1=[N:7][CH:8]=[N:9][C:10]=2[NH2:26]
Reactant: BrCCCBr
Reactant: Nc1ncnc2c1nc(Sc1cc3c(cc1I)OCCO3)n2CCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1nc(Sc1cc3c(cc1I)OCCO3)n2CCBr
Temperature: 25 °C
Reaction time: 3 h

Procedure:
9-(3-Bromopropyl)-8-(7-iodo-2,3-dihydrobenzo[b][1,4]dioxin-6-ylthio)-9H-purin-6-amine (S9-5). A mixture of S9-3 (0.213 g, 0.5 mmol), 1,3-dibromopropane (0.512 g, 2.5 mmol) and Cs2CO3 (0.184 g, 0.75 mmol) in anhydrous DMF (6 mL) was stirred at room temperature for 3 h. Solids were filtered and the filtrate was condensed under reduced pressure to give a residue that was purified by preparative thin layer chromatography (CHCl3:MeOH—NH3 (7N), 20:1) to give S9-5 (0.104 g, 38%). 1H NMR (CDCl3, 500 MHz) δ 8.26 (s, 1H), 7.32 (s, 1H), 6.94 (s, 1H), 5.6 (br s, 2H), 4.27 (t, J=7.0 Hz, 2H), 4.10-4.17 (m, 4H), 3.32 (t, J=7.0 Hz, 2H), 2.26 (m, 2H); MS (ESI) m/z 547.9/549.8 [M+H]+.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[N:19]=2)[CH:7]=1)=[O:5].[CH2:26]([O:28][C:29]1[CH:34]=[CH:33][C:32](I)=[CH:31][C:30]=1[CH3:36])[CH3:27].C([Mg]Cl)(C)C>C1COCC1>[Br:24][C:20]1[N:19]=[C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15](=[O:16])[C:6]([C:4](=[O:5])[C:32]3[CH:33]=[CH:34][C:29]([O:28][CH2:26][CH3:27])=[C:30]([CH3:36])[CH:31]=3)=[CH:7]2)[CH:23]=[CH:22][CH:21]=1
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Reactant: CCOc1ccc(I)cc1C
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCOc1ccc(C(=O)c2cn(Cc3cccc(Br)n3)c3ccccc3c2=O)cc1C

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60 from 120 mg (0.30 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 1 mL THF and 172 mg (0.66 mmol) of 1-ethoxy-4-iodo-2-methyl-benzene in 1 mL THF with 0.34 mL 2M isopropylmagnesium chloride. Yield: 53 mg of a white powder. LC-MSD, m/z for C25H21BrN2O3 [M+H]+=477.0, 479.0; HPLC retention time: 2.6 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[S:17][C:16]([NH:18][C:19](=[O:21])[CH3:20])=[N:15][C:14]=2[CH3:22])[CH:5]=[C:6]([Cl:12])[C:7]=1[S:8](=[O:11])(=[O:10])N.[CH3:23][NH:24][CH3:25]>>[Cl:12][C:6]1[CH:5]=[C:4]([C:13]2[S:17][C:16]([NH:18][C:19](=[O:21])[CH3:20])=[N:15][C:14]=2[CH3:22])[CH:3]=[C:2]([Cl:1])[C:7]=1[S:8](=[O:10])(=[O:11])[N:24]([CH3:25])[CH3:23]
Reactant: CC(=O)Nc1nc(C)c(-c2cc(Cl)c(S(N)(=O)=O)c(Cl)c2)s1
Reactant: CNC
Product: CC(=O)Nc1nc(C)c(-c2cc(Cl)c(S(=O)(=O)N(C)C)c(Cl)c2)s1

Procedure:
The title compound is prepared by an analagous procedure to N-[5-(3,5-dichloro-4-sulfamoyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 6) by replacing ammonia with dimethylamine.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[CH2:8]([O:15][CH2:16][CH:17]([NH:35][OH:36])[CH2:18][S:19]([N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[C:32]([Cl:34])[N:31]=[CH:30][N:29]=2)[CH2:24][CH2:23]1)(=[O:21])=[O:20])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O1CCCC1.C(O)=O>[CH2:8]([O:15][CH2:16][CH:17]([N:35]([OH:36])[CH:1]=[O:3])[CH2:18][S:19]([N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[C:32]([Cl:34])[N:31]=[CH:30][N:29]=2)[CH2:24][CH2:23]1)(=[O:21])=[O:20])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=S(=O)(CC(COCc1ccccc1)NO)N1CCN(c2cc(Cl)ncn2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Solvent: C1CCOC1
Product: O=CN(O)C(COCc1ccccc1)CS(=O)(=O)N1CCN(c2cc(Cl)ncn2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Acetic anhydride (31.5 ml) was added directly to formic acid (126 ml). The solution was stirred at room temperature for 30 minutes. A solution of 1-{[3-benzyloxy-2-(hydroxyamino)propyl]sulphonyl}-4-(6-chloropyrimidin-4-yl)piperazine (29.5 g) in tetrahydrofuran (150 ml) and formic acid (25 ml), was added in portions to the above solution at 25° C. over 25 minutes. The solution was stirred at room temperature for 1 hour. The solution was evaporated (water-bath temperature 30° C.) and the residual gum was dissolved in ethyl acetate (500 ml). This solution was treated with saturated aqueous sodium hydrogen carbonate solution (2×250 ml) and the mixture (pH8) was stirred at room temperature for 16 hours. The ethyl acetate layer was separated, washed with saturated brine (100 ml), dried (Na2SO4), and evaporated to dryness. The residual foam was dissolved in methanol (70 ml) and the solution was stirred for 16 hours. The solution was evaporated to dryness (water-bath temperature 30° C.) The residual foam was stirred in ethanol (250 ml), solid separated and the mixture was stirred for 18 hours. The solid was collected by filtration, slurry washed with diethyl ether (100 ml), and dried to give N-[2-(benyloxy)-1-({[4(6-chloropyrimidin-4-yl)piperazino]sulphonyl}methyl)ethyl]-N-hydroxyformamide (25.5 g). mp 118-120° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([CH2:10][C:11]([O:13]CC)=[O:12])=[C:8]([S:16][CH2:17][C:18]([O:20]CC)=[O:19])[CH:7]=[CH:6][CH:5]=1)[CH3:2].[OH-].[K+]>C(O)C.O>[CH2:1]([O:3][C:4]1[C:9]([CH2:10][C:11]([OH:13])=[O:12])=[C:8]([S:16][CH2:17][C:18]([OH:20])=[O:19])[CH:7]=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOC(=O)CSc1cccc(OCC)c1CC(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOc1cccc(SCC(=O)O)c1CC(=O)O

Procedure:
To a solution of ethyl 6-ethoxy-2-(ethoxycarbonyl-methylthio)-phenylacetate (17.8 g) in ethanol (112 mL) is added a solution of potassium hydroxide (85%, 7.21 g) in water (28 mL). The solution is refluxed for 2 hours, is concentrated in vacuo to remove the ethanol, and is diluted with water (200 mL). Hydrochloric acid (12 N, 10.0 mL) is added. The product which originally precipitates as an oil slowly crystallizes. After crystallization is complete the solid is filtered off, air-dried for 2 hours and then dried in vacuo at 50° to obtain 6-ethoxy-2-(carboxymethylthio)phenylacetic acid, m.p. 147°-150°.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[CH3:12])#[N:2].[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][N:20]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[NH:24][CH2:23][CH2:22][CH2:21]2)[CH:14]=1>>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([N:24]2[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[N:20]([CH2:19][C:15]3[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=3)[CH2:21][CH2:22][CH2:23]2)=[O:9])=[CH:5][C:4]=1[CH3:12])#[N:2]
Reactant: Cc1cc(C(=O)O)ccc1C#N
Reactant: c1cncc(CN2CCCNc3ccccc32)c1
Product: Cc1cc(C(=O)N2CCCN(Cc3cccnc3)c3ccccc32)ccc1C#N

Procedure:
The carboxylic acid from Example C (0.31 g, 1.93 mmol) was reacted with 1-(3-pyridyl)methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine from Example 16A (0.39 g, 1.61 mmol) according to the procedure in Example 1A. The product was purified by flash chromatography on silica (eluant EtOAc); yield 0.28 g (45%).