Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)#[N:2].[C:16]([O:20][C:21]([NH:23][CH2:24][CH2:25][CH2:26]Br)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:16]([O:20][C:21]([NH:23][CH2:24][CH2:25][CH2:26][N:6]1[CH2:7][CH2:8][C:3]([C:1]#[N:2])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])[CH2:4][CH2:5]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: Cc1ccccc1C1(C#N)CCNCC1
Reactant: CC(C)(C)OC(=O)NCCCBr
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1C1(C#N)CCN(CCCNC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 4-cyano-4-(o-tolyl)piperidine (5.00 g, 24.9 mmol) and 1-(tert-butoxycarbonylamino)-3-bromopropane (16, 6.55 g, 27.5 mmol) in DMF (100 mL) was treated with diisopropylethylamine (4.50 mL, 25.8 mmol) at room temperature. The resulting mixture was stirred at room temperature (3 d). The solvent was removed in vacuo and the residue dissolved in dichloromethane and sodium bicarbonate solution. The aqueous layer was extracted with two additional portions of dichloromethane and the combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. Flash chromatography on silica gel (5% methanol/dichloromethane) afforded the title compound (25).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[C:4]2[CH2:11][O:10][CH2:9][CH2:8][C:5]=2[NH:6][N:7]=1.Cl[CH2:15][C:16]([N:18]1[CH2:23][CH2:22][CH2:21][C:20]2[N:24]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[N:25]=[CH:26][C:19]1=2)=[O:17].C([O-])([O-])=O.[K+].[K+]>C1COCC1.CN(C=O)C>[F:33][C:30]1[CH:31]=[CH:32][C:27]([N:24]2[C:20]3[CH2:21][CH2:22][CH2:23][N:18]([C:16](=[O:17])[CH2:15][N:6]4[C:5]5[CH2:8][CH2:9][O:10][CH2:11][C:4]=5[C:3]([C:2]([F:12])([F:1])[F:13])=[N:7]4)[C:19]=3[CH:26]=[N:25]2)=[CH:28][CH:29]=1
Reactant: O=C(CCl)N1CCCc2c1cnn2-c1ccc(F)cc1
Reactant: FC(F)(F)c1n[nH]c2c1COCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(Cn1nc(C(F)(F)F)c2c1CCOC2)N1CCCc2c1cnn2-c1ccc(F)cc1
Temperature: 55 °C
Yield: 45.8 %

Procedure:
A mixture of 3-(trifluoromethyl)-1,4,6,7-tetrahydropyrano[4,3-c]pyrazole (0.050 g, 0.26 mmol), 2-chloro-1-[1-(4-fluorophenyl)-6,7-dihydro-5H-pyrazolo[4,3-b]pyridine-4-yl]ethanone (0.050 g, 0.17 mmol) and K2CO3 (0.130 g, 0.94 mmol) in THF (0.8 mL) and DMF (0.4 mL) was heated at 55° C. for 1 hr. It was then cooled to rt. The mixture was partitioned between EtOAc (50 mL) and sat. NaHCO3 (30 mL). The organic layer was separated, dried over Na2SO4, concentrated in vacuo, and purified by reverse phase HPLC to afford the desired product (0.035 g, 55%). 1H NMR (400 MHz, CDCl3) δ 8.38 (s, 1H), 7.44 (dd, J=8.8, 4.6 Hz, 2H), 7.17 (dd, J=8.8, 8.0 Hz, 2H), 5.13 (s, 2H), 4.75 (s, 2H), 3.98 (t, J=5.4 Hz, 2H), 3.87 (m, 2H), 2.85 (t, J=6.2 Hz, 2H), 2.79 (t, J=5.6 Hz, 2H), 2.10 (m, 2H); MS: (ES) m/z calculated for C21H19F4N5O2 [M+H]+ 450.1, found 450.1.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([N:9]=[C:10]=[O:11])[CH3:8].[C:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=2)=[C:16]([C:27]([F:30])([F:29])[F:28])[CH:15]=1)#[N:13].Cl>C(OCC)(=O)C>[CH2:7]([NH:9][C:10]([N:23]1[C:24]([CH3:26])=[CH:25][C:21]([O:20][C:17]2[CH:18]=[CH:19][C:14]([C:12]#[N:13])=[CH:15][C:16]=2[C:27]([F:28])([F:29])[F:30])=[N:22]1)=[O:11])[CH3:8]
Reactant: Cc1cc(Oc2ccc(C#N)cc2C(F)(F)F)n[nH]1
Reactant: CCN=C=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCNC(=O)n1nc(Oc2ccc(C#N)cc2C(F)(F)F)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
Potassium carbonate (0.23 g, 1.7 mmol) and ethyl isocyanate (0.11 g, 1.5 mmol) were added to a solution of 3-(4-cyano-2-trifluoromethylphenyloxy)-5-methylpyrazole (0.40 g, 1.5 mmol) in ethyl acetate (10 ml), and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate (10 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/10), to give a yellowish solid of N-ethyl-3-(4-cyano-2-trifluoromethylphenyloxy)-5-methylpyrazole-1-carboxamide (0.35 g, yield: 69.0%). mp: 103-105° C.; 1H-NMR (CDCl3, TMS, ppm): δ 1.23 (t, J=7.3 Hz, 3H), 2.63 (d, J=0.7 Hz, 3H), 3.39 (dq, J=5.9 and 7.2 Hz, 2H), 5.85 (q, J=0.7 Hz, 1H), 6.80-7.00 (m, 1H), 7.38 (d, J=8.7 Hz, 1H), 7.81 (dd, J=1.8 and 8.7 Hz, 1H), 7.99 (d, J=1.8 Hz, 1H).
Reaction SMILES: Cl.[C:2]1([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[S:13][CH:14]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=1[CH2:32][C:33](O)=[O:34]>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:30])([F:31])[F:29])=[CH:24][C:23]=1[CH2:32][C:33]([N:18]1[CH2:19][CH2:20][CH:15]([C:12]2[S:13][CH:14]=[C:10]([CH2:9][CH2:8][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[N:11]=2)[CH2:16][CH2:17]1)=[O:34]
Reactant: O=C(O)Cc1cc(C(F)(F)F)ccc1Cl
Reactant: c1ccc(CCc2csc(C3CCNCC3)n2)cc1
Agent: Cl
Product: O=C(Cc1cc(C(F)(F)F)ccc1Cl)N1CCC(c2nc(CCc3ccccc3)cs2)CC1

Procedure:
4-[4-(2-Phenylethyl)-1,3-thiazol-2-yl]piperidine hydrochloride (II-1, 309 mg) is reacted analogously to Example I-63 with [2-chloro-5-(trifluoromethyl)phenyl]acetic acid (262 mg). After chromatographic purification, this gives 2-[2-chloro-5-(trifluoromethyl)phenyl]-1-{4-[4-(2-phenylethyl)-1,3-thiazol-2-yl]piperidin-1-yl}ethanone (210 mg).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:10][C@H:11]2[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]2)=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[Br:1][C:2]1[C:3]([NH:10][C@H:11]2[CH2:16][CH2:15][CH2:14][N:13]([S:27]([CH3:26])(=[O:29])=[O:28])[CH2:12]2)=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1
Reactant: CSc1ncc(Br)c(N[C@H]2CCCNC2)n1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ncc(Br)c(N[C@H]2CCCN(S(C)(=O)=O)C2)n1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of (5-bromo-2-methylsulfanyl-pyrimidin-4-yl)-(S)-piperidin-3-yl-amine (2.9 g, 9.6 mmol) and diisopropylethylamine (3.7 g, 28 mmol) in dichloromethane (50 ml) was cooled to 5° C. and treated with a solution of methanesulfonyl chloride (1.21 g, 10.5 mmol) in dichloromethane (20 ml). This was stirred at room temperature for 14 hours, washed with water, dried (MgSO4) and evaporated to give (5-bromo-2-methylsulfanyl-pyrimidin-4-yl)-((S)-1-methanesulfonyl-piperidin-3-yl)-amine as a white solid. MS (ES+): 382 (2602-33).
Reaction SMILES: [C:1]([N:3]=[C:4]1[N:8]([C:9]2[C:14]3[CH:15]=[C:16]([C:19]([O:21]CC)=[O:20])[CH:17]=[CH:18][C:13]=3[O:12][C:11]([CH3:25])([CH3:24])[CH:10]=2)[CH2:7][CH2:6][S:5]1)#[N:2].[I-].[Li+]>N1C(C)=CC=CC=1C.C(OCC)(=O)C.Cl>[C:1]([N:3]=[C:4]1[N:8]([C:9]2[C:14]3[CH:15]=[C:16]([C:19]([OH:21])=[O:20])[CH:17]=[CH:18][C:13]=3[O:12][C:11]([CH3:25])([CH3:24])[CH:10]=2)[CH2:7][CH2:6][S:5]1)#[N:2]
Reactant: CCOC(=O)c1ccc2c(c1)C(N1CCSC1=NC#N)=CC(C)(C)O2
Agent: Cl
Agent: [I-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: Cc1cccc(C)n1
Product: CC1(C)C=C(N2CCSC2=NC#N)c2cc(C(=O)O)ccc2O1
Yield: 59.4 %

Procedure:
A mixture of ethyl 4-(2-cyanoiminothiazolidin-3-yl)-2,2-dimethyl-2H-1-benzopyran-6-carboxylate (1.15 g) and lithium iodide (3.44 g) in 2,6-lutidine (11.5 ml) was refluxed overnight. The resulting mixture was dissolved in a mixture of ethyl acetate and 10% hydrochloric acid, and the organic layer was separated and washed with brine. The extract was dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel (elution with 30:1 to 4:1 chloroform-methanol) followed by recrystallization from ethanol to give 4-(2-cyanoiminothiazolidin-3-yl)-2,2-dimethyl-2H-1-benzopyran-6-carboxylic acid (0.63 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9]([CH3:11])=[O:10])=[CH:4][N:3]=1.[N-:12]=[N+]=[N-].[Na+].S(=O)(=O)(O)O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9]([CH3:11])(=[NH:12])=[O:10])=[CH:4][N:3]=1
Reactant: CS(=O)Cc1ccc(Cl)nc1
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CS(=N)(=O)Cc1ccc(Cl)nc1
Temperature: 0 °C
Yield: 34 %

Procedure:
To a stirred mixture of 2-chloro-5-[(methylsulfinyl)methyl]pyridine (B) (7.34 g, 39 mmol) and sodium azide (4.04 g, 62 mmol) in chloroform (80 mL) cooled to 0° C. was slowly added sulfuric acid at a rate such that the temperature did not rise above 8° C. After the addition was over, the ice-water bath was removed and the mixture was heated at 55° C. for 2.5 h. The solvent was decanted into a separation funnel and the residue was stirred and dissolved in water. After a few minutes, the aqueous mixture was made basic to pH 8 by slowly adding solid Na2CO3 and then saturated with solid NaCl. The extra salt was removed by filtration (a portion of the filtrate was sucked into trap and was not recovered) and the filtrate was extracted with CH2Cl2 three times. The combined organic layer was dried over Na2SO4, filtered, concentrated and the residue was triturated in CH2Cl2-ether (1:10, v/v) solvent. The white solid was filtered, washed with CH2Cl2-ether (1:10, v/v) and dried to give 2.70 g of -chloro-5-[(methylsulfon-imidoyl)methyl]pyridine (C) in 34% yield as a white solid (m.p. 134.5-136° C.). LC-MS (ELSD): mass calcd for C7H9ClN2OS [M+H]+ 203.67. Found: 203.22.
Reaction SMILES: B.[OH:2][C:3]1[CH:11]=[C:10]([I:12])[CH:9]=[CH:8][C:4]=1[C:5](O)=[O:6].O>C1COCC1>[OH:2][C:3]1[CH:11]=[C:10]([I:12])[CH:9]=[CH:8][C:4]=1[CH2:5][OH:6]
Reactant: O=C(O)c1ccc(I)cc1O
Agent: B
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccc(I)cc1O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A 1M solution of borane in THF was added dropwise at 0° C. to a solution of 2-hydroxy-4-iodobenzoic acid (13.2 g, 0.05 mol) in THF (100 ml). The mixture was stirred for 6 hours at room temperature and 20 ml of a solution of THF and water (1:1) were then added. After concentration on a rotary evaporator under vacuum at 40° C. The residue was extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous magnesium sulfate and concentrated on a rotary evaporator under vacuum at 40° C. The product was purified by flash chromatography on a column of silica (60% EtOAc, 40% heptane). Its properties were as follows:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][C:8]2[O:9][C:10]3[C:17](=[O:18])[C:16]([S:19][CH2:20][CH3:21])=[C:15]([CH2:22][CH2:23][CH3:24])[C:14](=[O:25])[C:11]=3[C:12]=2[CH3:13])=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:36])C=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:8]2[O:9][C:10]3[C:17](=[O:18])[C:16]([S:19]([CH2:20][CH3:21])=[O:36])=[C:15]([CH2:22][CH2:23][CH3:24])[C:14](=[O:25])[C:11]=3[C:12]=2[CH3:13])=[CH:26][CH:27]=1
Reactant: CCCC1=C(SCC)C(=O)c2oc(Cc3ccc(OC)cc3)c(C)c2C1=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCCC1=C(S(=O)CC)C(=O)c2oc(Cc3ccc(OC)cc3)c(C)c2C1=O

Procedure:
To a solution of the product of Example 11 (247 mg, 0.66 mmol) in CH2Cl2 (30 mL) was added m-chloroperbenzoic acid (140 mg). The reaction was complete in a few minutes, and was quenched with 10% NaCO3. The organic layer was separated, dried (Na2SO4) and the crude product was chromatographed on silica gel (30% EtOAc/hexane) to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([OH:9])[CH:3]=1.[F:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14](O)=O>>[Br:1][C:2]1[CH:8]=[CH:7][C:5]2[N:6]=[C:14]([C:13]3[CH:17]=[CH:18][CH:19]=[C:11]([F:10])[CH:12]=3)[O:9][C:4]=2[CH:3]=1
Reactant: Nc1ccc(Br)cc1O
Reactant: O=C(O)c1cccc(F)c1
Product: Fc1cccc(-c2nc3ccc(Br)cc3o2)c1

Procedure:
Preparation is carried out analogously to 4.1.a from 4-bromo-2-hydroxy-aniline and 3-fluorobenzoic acid.
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[CH:6][N:5]=[C:4]([NH2:9])[CH:3]=1.[CH3:10][N:11]1C(=O)CCC1>[C-]#N.[Zn+2].[C-]#N>[NH2:9][C:4]1[CH:3]=[C:2]([Cl:1])[C:7]([C:10]#[N:11])=[CH:6][N:5]=1
Reactant: Nc1cc(Cl)c(I)cn1
Reactant: CN1CCCC1=O
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1cnc(N)cc1Cl
Temperature: 135 °C

Procedure:
(Tsuruoka, A., et. al. ibid) Zinc cyanide (0.254 g, 2.17 mmol) and tetrakistriphenylphosphine palladium (0) (0.460 g, 0.394 mmol) were added to a solution of compound ii (1.00 g, 3.94 mmol) in NMP (10 mL). The reaction mixture was heated under N2(g) to 135° C. for 2 h, cooled to room temperature and partitioned between EtOAc (30 mL) and aqueous ammonia solution (0.35%, 50 mL). The organic fraction was separated, washed successively with water (2×100 mL) and brine (30 mL), dried (MgSO4) and reduced in vacuo onto SiO2. Column chromatography (SiO2), eluting with 2:1 Petrol-EtOAc to 1:1 Petrol-EtOAc, afforded compound iii. (0.360 g, 2.35 mmol, 60%) as an off-white solid.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[C:11]([CH:13]([CH3:15])[CH3:14])[CH:10]=[C:9]([CH:16]([CH3:18])[CH3:17])[C:8]=1[O:19][CH2:20][CH2:21][CH3:22].[B:23](OC(C)C)([O:28]C(C)C)[O:24]C(C)C.Cl>C1COCC1>[CH2:20]([O:19][C:8]1[C:9]([CH:16]([CH3:18])[CH3:17])=[CH:10][C:11]([CH:13]([CH3:15])[CH3:14])=[CH:12][C:7]=1[B:23]([OH:28])[OH:24])[CH2:21][CH3:22]
Reactant: CCCOc1c(Br)cc(C(C)C)cc1C(C)C
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCOc1c(B(O)O)cc(C(C)C)cc1C(C)C
Temperature: -78 °C
Reaction time: 2 h
Yield: 23.2 %

Procedure:
To a solution of n-BuLi (1.6 M in hexane, 40 mL, 64.2 mmol) in THF (150 mL) at −78° C. was added 1-bromo-3,5-diisopropyl-2-propoxy-benzene (Intermediate 3,16.0 g, 53.5 mmol) in THF (50 mL and 10 mL rinse) slowly. Thereafter 0.5 h triisopropyl borate (24.7 mL, 107 mmol) in THF (40 mL) was added slowly and the reaction was stirred at −78° C. for 1 h and at room temperature for 2 h. The reaction was then treated with 3M HCl (200 mL) at room temperature for 1.5 h, and extracted with EtOAc (×2). The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude product was washed with hexane to give 3.28 g of the title compound as a white solid. The hexane solution was filtered through a pad of SiO2 to give additional 11.0 g of the title compound as a yellow slurry containing minor impurities. This crude material was used in the next step without flirter purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CO[CH:26]1[CH2:30][CH2:29][CH:28](OC)O1.C(O)(=O)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([N:23]3[CH:26]=[CH:30][CH:29]=[CH:28]3)=[CH:21][CH:22]=2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)NCCCCOc2ccc(N)cc2)cc1
Reactant: COC1CCC(OC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)NCCCCOc2ccc(-n3cccc3)cc2)cc1
Temperature: -10 °C

Procedure:
A mixture of 3.2 g of 4-methyl-N-[4-(4-aminophenyl-oxy)butyl]benzenesulfonamide (Example 36), 1.5 g of 2,5-dimethoxytetrahydrofuran, and 50 ml of acetic acid is stirred and heated on the steam bath for 16 hours. The reaction mixture is taken to dryness in vacuo. The residue is shaken with 150 ml of dichloromethane and 150 ml of saturated sodium bicarbonate solution. The dichloromethane layer is separated, dried over Na2SO4, and diluted with 100 ml of hexane. The solution is concentrated until turbid, then cooled at -10° C. The precipitate that forms is collected, washed with hexane, and air dried; m.p. 124°-126° C.; yield, 0.2 g.
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[CH2:13]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: Oc1cccc2[nH]ccc12
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: c1ccc(COc2cccc3[nH]ccc23)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85 %

Procedure:
Potassium hydroxide (0.42 g) was added to 4-hydroxyindole (1.00 g) in DMF (25 ml), and the solution was stirred at room temperature for 15 minutes. Benzyl bromide (1.00 ml) was added to the solution, and the solution was stirred at room temperature for 1.5 hours. Since the reaction was not completed, benzyl bromide (0.20 ml) was further added and the solution was stirred for 5 hours. After removing the solvent under reduced pressure, water (50 ml) was added to the residue and the resultant was extracted with ether (3×50 ml). The organic layers were washed with saturated brine, and dried over sodium sulfate. After removing solids by filtration, the solvent was removed under reduced pressure and the obtained crude product was purified by silica gel column chromatography to obtain the desired product (1.43 g, yield: 85%).
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([NH:11][C:12]1[CH:13]=[C:14]([C:18]2[CH2:19][CH2:20][N:21]([CH2:24][CH2:25][CH2:26][NH:27]C(=O)OC(C)(C)C)[CH2:22][CH:23]=2)[CH:15]=[CH:16][CH:17]=1)(=[O:10])[CH3:9].C([O-])(O)=O.[Na+]>ClCCl>[NH2:27][CH2:26][CH2:25][CH2:24][N:21]1[CH2:20][CH:19]=[C:18]([C:14]2[CH:13]=[C:12]([NH:11][C:8](=[O:10])[CH3:9])[CH:17]=[CH:16][CH:15]=2)[CH2:23][CH2:22]1
Reactant: CC(=O)Nc1cccc(C2=CCN(CCCNC(=O)OC(C)(C)C)CC2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1cccc(C2=CCN(CCCN)CC2)c1
Temperature: 25 °C

Procedure:
A 1:1 solution of TFA:CH2Cl2 (5 mL) was added to tert-butyl N-(3-{4-[3-(acetylamino)phenyl]-1,2,3,6-tetrahydro-1-pyridinyl}propyl)carbamate in dichloromethane (5 mL). The resulting solution was stirred at room temperature for 1–3 days, saturated NaHCO3 was added until pH>6, the organic layer was separated, and dried in vacuo, giving the desired product (45 mg): 1H NMR (CDCl3) δ 7.68 (br, 1H), 7.35 (dm, 1H, J=7.8 Hz), 7.25 (apparent t, 1H, J=7.8 Hz), 7.15 (dm, 1H, J=7.8 Hz), 6.12 (m, 1H), 3.22 (m, 2H), 3.03 (t, 2H, J=7.3 Hz), 2.78 (t, 2H, J=5.5 Hz), 2.70–2.50 (m, 4H), 2.10 (s, 3H), 1.87 (p, 2H, J=7.3 Hz).
Reaction SMILES: [CH:1]([S:4](Cl)(=[O:6])=[O:5])([CH3:3])[CH3:2].[NH2:8][CH2:9][C:10]1[N:18]=[C:17]2[C:13]([N:14]=[CH:15][N:16]2[C@H:19]2[C@H:23]([OH:24])[C@H:22]([OH:25])[C@@H:21]([CH2:26][O:27][CH3:28])[O:20]2)=[C:12]([NH:29][CH2:30][CH:31]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:11]=1>N1C(C)=CC=CC=1C>[OH:24][C@@H:23]1[C@H:22]([OH:25])[C@@H:21]([CH2:26][O:27][CH3:28])[O:20][C@H:19]1[N:16]1[CH:15]=[N:14][C:13]2[C:17]1=[N:18][C:10]([CH2:9][NH:8][S:4]([CH:1]([CH3:3])[CH3:2])(=[O:6])=[O:5])=[N:11][C:12]=2[NH:29][CH2:30][CH:31]([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@H](O)[C@@H]1O
Reactant: CC(C)S(=O)(=O)Cl
Solvent: Cc1cccc(C)n1
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNS(=O)(=O)C(C)C)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 24.7 %

Procedure:
Isopropylsulphonyl chloride (120 mg, 0.84 mmol) was added to a stirred solution of (2R,3R,4S,5R)-2-{2-(aminomethyl)-6-[(2,2-diphenylethyl)amino}-9H-purin-9-yl}-5-(methoxymethyl)tetrahydro-3,4-furandiol (408 mg, 0.8 mmol) (example 1) in 2,6-lutidine (10 ml). The mixture was stirred at room temperature for 24 hr followed by stirring at 50° C. for a further 5 days. A second portion of isopropylsulphonyl chloride (120 mg, 0.84 mmol) and lutidine (4 ml) were added and the reaction stirred at 50° C. for 24 hr. A third portion of isopropylsulphonyl chloride (120 mg, 0.84 mmol) was added and heating at 50° C. continued for a further 24 hr. At the end of this period the solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and aqueous ammonia. The organic phase was separated and the solvent removed under reduced pressure to give a residue which was purified by column chromatography on silica gel eluting with a solvent system of dichloromethane:methanol:ammonia (98:2:0.1) increasing to dichloromethane:methanol:ammonia (96:4:0.2). This gave the title compound (118 mg) as an oil. MS: 597 (MH+).
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:13])[C:4](=[O:12])[C@H:5]([CH2:7][S:8]([CH3:11])(=[O:10])=[O:9])[NH2:6].C(N(CC)CC)C.S=[C:22]1[CH2:26][S:25][C:24](=[O:27])[NH:23]1>C(O)C>[CH3:2][N:3]([CH3:13])[C:4](=[O:12])[C@H:5]([CH2:7][S:8]([CH3:11])(=[O:9])=[O:10])[NH:6][C:22]1[CH2:26][S:25][C:24](=[O:27])[N:23]=1
Reactant: CN(C)C(=O)[C@@H](N)CS(C)(=O)=O
Reactant: O=C1NC(=S)CS1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN(C)C(=O)[C@H](CS(C)(=O)=O)NC1=NC(=O)SC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.8 %

Procedure:
To a solution of N,N-dimethyl-3-(methylsulfonyl)-L-alaninamide hydrochloride (923 mg) and triethylamine (1.07 mL) in ethanol (10 mL) was added 4-thioxothiazolidin-2-one (533 mg) at room temperature. The reaction mixture was stirred at room temperature overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate) to give the title compound (150 mg).
Reaction SMILES: Cl.[C:2]([N:6]1[CH:14]=[C:13]2[C:8]([C:9](=[O:20])[NH:10][C:11]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:12]2)=[N:7]1)([CH3:5])([CH3:4])[CH3:3].[Cl:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][C:26]([C:32](O)=[O:33])=[CH:27][CH:28]=2)[N:23]=1>>[C:2]([N:6]1[CH:14]=[C:13]2[C:8]([C:9](=[O:20])[NH:10][C:11]3([CH2:19][CH2:18][N:17]([C:32]([C:26]4[CH:25]=[C:24]5[C:29]([CH:30]=[CH:31][C:22]([Cl:21])=[N:23]5)=[CH:28][CH:27]=4)=[O:33])[CH2:16][CH2:15]3)[CH2:12]2)=[N:7]1)([CH3:5])([CH3:3])[CH3:4]
Reactant: O=C(O)c1ccc2ccc(Cl)nc2c1
Reactant: CC(C)(C)n1cc2c(n1)C(=O)NC1(CCNCC1)C2
Agent: Cl
Product: CC(C)(C)n1cc2c(n1)C(=O)NC1(CCN(C(=O)c3ccc4ccc(Cl)nc4c3)CC1)C2

Procedure:
The title compound was prepared by a method analogous to that described for Example 3 using 2′-tert-butyl-4′,6′-dihydrospiro[piperidine-4,5′-pyrazolo[3,4-c]pyridin]-7′(2′H)-one hydrochloride salt (Intermediate 4) and 2-chloroquinoline-7-carboxylic acid (Intermediate 44). +ESI (M+H) 452.3; 1H NMR (400 MHz, CDCl3, δ): 8.12 (d, J=8.2 Hz, 1H), 7.98 (br. s., 1H), 7.88 (dd, J=8.4 Hz, 1H), 7.61 (dd, J=8.4, 1.6 Hz, 1H), 7.44 (d, J=8.6 Hz, 1H), 7.39 (s, 1H), 5.91 (br. s., 1H), 4.06-4.22 (m, 1H), 3.38-3.64 (m, 3H), 2.85 (br. s., 2H), 1.67-1.97 (m, 4H), 1.61 (s, 9H).