Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]3[N:18]=[N:19][NH:20][CH:21]=3)=[C:9]([OH:22])[C:8]2=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:25].C1(N2C=CC(CCCC3N=NNC=3)=C(O)C2=S)C=CC=CC=1>>[C:1]1([N:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]3[N:18]=[N:19][NH:20][CH:21]=3)=[C:9]([OH:22])[C:8]2=[S:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=c1c(O)c(CCCCc2c[nH]nn2)ccn1-c1ccccc1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: Oc1c(CCCc2c[nH]nn2)ccn(-c2ccccc2)c1=S
Product: Oc1c(CCCCc2c[nH]nn2)ccn(-c2ccccc2)c1=S
Yield: 85.2 %

Procedure:
Reaction of 159c (0.055 g, 0.18 mmol) and P4S10 (0.051 g, 0.115 mmol) under neat conditions as described for synthesis of 162b gave compound 162c (0.032 g, 55%) as a olive green solid. δ 8.50 (s, 1H), 7.81 (m, 3H), 7.36 (m, 4H), 6.94 (d, J=7.6 Hz, 1H), 6.62 (t, J=6.8 Hz, 1H), 4.54 (t, J=7.6 Hz, 2H), 4.46 (t, J=6.4 Hz, 2H), 2.03 (m, 4H). 13C NMR (100 MHz, CDCl3) δ 168.51, 155.08, 147.73, 131.02, 130.36, 128.79, 128.13, 125.58, 119.91, 113.87, 112.10, 56.96, 49.41, 27.02, 25.08. HRMS (EI) calcd for C17H18N4OS [M]+ 326.1201. found 326.1200.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH2:12]([O:14][C:15]([CH:17]1[CH2:22][CH2:21][CH:20](O)[CH2:19][CH2:18]1)=[O:16])[CH3:13].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH2:12]([O:14][C:15]([C@H:17]1[CH2:22][CH2:21][C@@H:20]([N:8]2[C:4]3[N:5]=[CH:6][N:7]=[C:2]([Cl:1])[C:3]=3[C:10]([I:11])=[CH:9]2)[CH2:19][CH2:18]1)=[O:16])[CH3:13]
Reactant: Clc1ncnc2[nH]cc(I)c12
Reactant: CCOC(=O)C1CCC(O)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)[C@H]1CC[C@@H](n2cc(I)c3c(Cl)ncnc32)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Into the THF (5 mL) solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (prepared according to: L. B. Townsend et al., J. Med. Chem. 1990, 33 (7), 1984-92) (140 mg, 0.500 mmol), 4-hydroxycyclohexanecarboxylic acid ethyl ester (104 mg, 0.600 mmol; Aldrich, cis/trans mixture), and PPh3 (263 mg, 1.00 mmol) was added DIAD (203 mg, 1.00 mmol) dropwise at 0° C. under N2 over 5 min. The reaction was then stirred at rt for 2 days. After that time, the solvent was evaporated, and the residue was purified by chromatography on silica gel, eluting with 200 mL of 5%, 10%, 20% and 30% EtOAc/hexane to obtain cis-4-(4-chloro-5-iodopyrrolo[2,3-d]pyrimidin-7-yl)-cyclohexanecarboxylic acid ethyl ester as a white solid, which was further purified by HPLC. 1H NMR (CDCl3, 400 MHz): δ=1.32 (t, 3H, J=7.2 Hz), 1.74-1.78 (m, 2H), 1.88-1.98 (m, 4H), 2.33-2.36 (m, 2H), 2.75-2.77 (m, 1H), 4.23 (q, 2H, J=7.2 Hz), 4.73-4.81 (m, 1H), 7.45 (s, 1H), 8.60 (s, 1H). MS (ES+): 433.9/435.9 [MH+]. HPLC: tR=4.0 min (polar—5 min).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH:6]=[CH:7][CH:8]=1.[Li+].[CH3:17][CH:18]([N-]C(C)C)C.C(I)C>C1COCC1>[CH2:17]([CH:10]([CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:14])([F:15])[F:1])[CH:4]=1)[C:11]([OH:13])=[O:12])[CH3:18]
Reactant: O=C(O)CCc1cccc(C(F)(F)F)c1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCI
Solvent: C1CCOC1
Product: CCC(Cc1cccc(C(F)(F)F)c1)C(=O)O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
1 eq. of 3-(3-trifluoromethylphenyl)propionic acid was converted, in THF and at -78° C., into the dianion using 2 eq. of LDA (stirring for 30 min. at -78° C., then 30 min. at RT). 2 eq. of ethyl iodide were then added at -78° C. and the mixture was subsequently stirred at RT. Acidic working-up using 2N HCl and purification by chromatography yielded 2-ethyl-3-(3-trifluoromethylphenyl)-propionic acid.
Reaction SMILES: [CH3:1][Si:2]([CH3:22])([CH3:21])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[N:18]=[C:17]([CH2:19][OH:20])[CH:16]=[CH:15][CH:14]=2)=[N:8]1.C(N(CC)C(C)C)(C)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C(Cl)(Cl)Cl>[CH3:32][S:33]([O:20][CH2:19][C:17]1[N:18]=[C:13]([NH:12][C:9]2[CH:10]=[CH:11][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:22])([CH3:21])[CH3:1])[N:8]=2)[CH:14]=[CH:15][CH:16]=1)(=[O:35])=[O:34]
Reactant: C[Si](C)(C)CCOCn1ccc(Nc2cccc(CO)n2)n1
Reactant: CS(=O)(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1ccc(Nc2cccc(COS(C)(=O)=O)n2)n1
Reaction time: 1 h

Procedure:
To a mixture of 10 mg of (6-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)amino)pyridin-2-yl)methanol, 27 μl of N,N-diisopropylethylamine and 1 ml of chloroform was added 7.3 μl of methanesulfonyl chloride at room temperature followed by stirring for 1 hour. The reaction mixture was washed with brine, and the organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was then concentrated in vacuo to give the title compound.
Reaction SMILES: [C:1]12([OH:11])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.ClC(Cl)(Cl)[C:14]([N:16]=C=O)=[O:15].CO.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[C:14](=[O:15])([O:11][C:1]12[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2)[NH2:16]
Reactant: OC12CC3CC(CC(C3)C1)C2
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: NC(=O)OC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
1-Adamantanol (1.52 g, 10.0 mmol) in dichloromethane (30 mL) was mixed with trichloroacetyl isocyanate (1.40 mL, 11.8 mmol) at 0° C., then warmed to room temperature and stirred for 2 hours. After completion of the reaction, the reaction solution was evaporated under reduced pressure, and the resulting crude reaction product was mixed with methanol (15 mL) and saturated aqueous potassium carbonate and stirred at 50° C. for 1 day. After completion of the reaction, the methanol was removed by vacuum distillation, and the residue was filtered. The resulting solid was washed with water and dried under reduced pressure to give the desired product (74% yield, 2 steps).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C:7](=[O:13])[CH2:6][CH2:5]2.Cl[CH2:15][CH:16]1[CH2:20][O:19][C:18]([CH3:22])([CH3:21])[O:17]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH3:21][C:18]1([CH3:22])[O:17][CH:16]([CH2:15][O:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][C:10]=2[O:11][CH3:12])[C:7](=[O:13])[CH2:6][CH2:5]3)[CH2:20][O:19]1
Reactant: COc1cc2c(cc1O)CCC2=O
Reactant: CC1(C)OCC(CCl)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(cc1OCC1COC(C)(C)O1)CCC2=O
Temperature: 95 °C
Reaction time: 72 h

Procedure:
A mixture of 5-Hydroxy-6-indan-1-one, Intermediate H, (0.50 g, 0.0028 mol), 4-chloromethyl-2,2-dimethyl-1,3-dioxolane (0.766 mL, 0.0056 mol), potassium carbonate (1.54 g, 0.011 mol) and DMF (20.0 mL) was stirred at 95° C. for 3 days. Water (150.0 mL) was added and the mixture was extracted with ethyl acetate (2×150 mL). The organic layer was washed with sat. NaHCO3, brine and dried over Na2SO4. The solvent was then removed in vacuo to yield 5-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-6-methoxy-indan-1-one (Intermediate I) as light brown solid. MS m/z 293 (M+H)+.
Reaction SMILES: N1CCCCC1.[N+:7]([C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1)([O-:9])=[O:8].[C:18]([O:24][CH2:25][CH3:26])(=[O:23])[CH2:19][C:20]([CH3:22])=[O:21]>C(OCC)C>[N+:7]([C:10]1[CH:17]=[CH:16][C:13](/[CH:14]=[C:19](/[C:20](=[O:21])[CH3:22])\[C:18]([O:24][CH2:25][CH3:26])=[O:23])=[CH:12][CH:11]=1)([O-:9])=[O:8]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)CC(C)=O
Solvent: CCOCC
Solvent: C1CCNCC1
Product: CCOC(=O)/C(=C\c1ccc([N+](=O)[O-])cc1)C(C)=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Piperidine (0.5ml) was added to a solution of paranitrobenzaldehyde (7.5g, 0.05 moles) and ethyl acetoacetate (6.5g, 0.05 moles) and stirred at room temperature for 48 hrs. Ethyl ether (50ml) was added and stirring continued for 7 days. After removal of the ethyl ether by rotary evaporator the titled products were separated and purified by silica gel chromatography. The structure assignments were supported by NMR, infrared and uv spectra and elemental analysis (263.2).
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[C:34]1([CH2:40][C:41](Cl)=[O:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CC#N>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:41](=[O:42])[CH2:40][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C(Cc1ccccc1)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.33 h
Yield: 54.7 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.65 g, 4.26 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.60 g, 1.85 mmol) in CH3CN (50 mL). After stirring for 20 min, phenylacetyl chloride (0.35 g, 2.22 mmol) was added. The mixture was stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (70 mL). The CH2Cl2 solution was washed with 1N HCl (30 mL), H2O (30 mL), brine (30 mL) and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by chromatography (SiO2, CH2Cl2: EtOAc 6:4) to give N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}-2-phenylacetamide (0.41 g, 55%) as a white solid: mp 128-130° C.; 1H NMR (DMSO-d6) δ 11.14 (s, 1H), 8.67 (t, J=5.5 Hz, 1H), 7.80-7.61 (m, 3H), 7.29 (s, 5H), 5.19-5.12 (dd, J=5.1 and 12.4 Hz, 1H), 4.71 (d, J=5.5 Hz, 2H), 3.53 (s, 2H), 2.96-2.83 (m, 1H), 2.63-2.50 (m, 2H), 2.08-2.03 (m, 1H); 13HNMR (DMSO-d6) δ 172.77, 170.65, 169.82, 167.45, 166.93, 139.19, 136.15, 134.68, 133.18, 131.53, 129.05, 128.25, 127.13, 126.43, 121.90, 48.85, 42.24, 37.85, 30.93, 21.98; Anal. Calcd. For C22H19N3O5: C, 65.18; H, 4.72; N, 10.36. Found: C, 65.16; H, 4.75; N, 10.11.
Reaction SMILES: [C:1]([N:4]1[C:13]2[CH:8]([CH2:9][CH2:10][CH2:11][CH:12]=2)[CH2:7][C:6](=[O:14])[N:5]1[C:15](=[O:17])[CH3:16])(=[O:3])[CH3:2].C(Cl)(=O)C.[CH3:22][O:23][CH:24](OC)OC>CN(C)C=O>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[CH:22][O:23][CH3:24])[C:6](=[O:14])[N:5]1[C:15](=[O:17])[CH3:16])(=[O:3])[CH3:2]
Reactant: CC(=O)N1C(=O)CC2CCCC=C2N1C(C)=O
Reactant: COC(OC)OC
Solvent: CN(C)C=O
Solvent: CC(=O)Cl
Product: COC=C1C(=O)N(C(C)=O)N(C(C)=O)c2ccccc21
Temperature: 130 °C
Yield: 43.8 %

Procedure:
To a solution of 1,2-diacetyltetrahydrocinnolin-3-one (0.34 g, 1.5 mmol) in N,N-dimethylformamide (3.6 mL) is added acetyl chloride (5 mL) and trimethylorthoformate (0.64 mL, 6.0 mmol). The mixture is heated at reflux in a 130° C. oil bath for 12 hours under a nitrogen atmosphere and then is allowed to cool to room temperature. The reaction mixture is purified in three batches via semi-preparative HPLC (Prodigy ODS3 column, 5% MeCN/95% water/0.01% trifluoroacetic acid to 100% acetonitrile over 1 hour at 10 mL/min) to give 1,2-diacetyl-4-methoxymethylene-1,4-dihydro-2H-cinnolin-3-one (0.18 g).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=3)=[C:17]([Cl:29])[CH:16]=2)[NH:7][N:6]=1.[NH:30]1[CH2:34][CH2:33][CH2:32][C@@H:31]1[CH2:35][OH:36]>>[Cl:29][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][N:30]4[CH2:34][CH2:33][CH2:32][C@@H:31]4[CH2:35][OH:36])[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][C:22]1[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=1
Reactant: OC[C@H]1CCCN1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCCl)c34)cc2Cl)cn1
Product: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCN5CCC[C@@H]5CO)c34)cc2Cl)cn1
Yield: 45 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-{3-chloro-4-[(6-methylpyridin-3-yl)oxy]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine (prepared as described in Example 16) and (R)-2-pyrrolidinemethanol to give the title compound in 45% yield; NMR Spectrum: 1.50-1.81 (m, 4H), 2.33 (dd, 1H), 2.45 (s, 3H), 2.58 (m, 1H), 2.74-2.79 (m, 1H), 3.11-3.19 (m, 1H), 3.24-3.32 (m, 3H), 4.44 (t, 2H), 7.20 (d, 1H), 7.27 (br s, 2H), 7.73 (d, 1H), 8.14 (s, 1H), 8.21 (s, 1H), 8.36 (s, 1H), 8.62 (br s, 1H); Mass Spectrum: 496 (MH+).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:31]([O:33]C(C)(C)C)=[O:32])[CH2:10][C@H:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][F:29])=[CH:22][N+:21]=1[O-:30])[C:12]([O:14]C(C)(C)C)=[O:13])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:29][CH2:28][CH2:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][C@H:11]([C:12]([OH:14])=[O:13])[CH2:10][C@@H:9]([C:31]([OH:33])=[O:32])[NH2:8])=[N+:21]([O-:30])[CH:22]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1ccc(OCCF)c[n+]1[O-])C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](C[C@H](Cc1ccc(OCCF)c[n+]1[O-])C(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
To a solution of 170 mg of di-tert-butyl (4R)—N-(tert-butoxycarbonyl)-4-{[5-(2-fluoroethoxy)-1-oxidopyridin-2-yl]methyl}-L-glutamate (0.32 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (124 μL, 5 eq) and the mixture was stirred for 2 h at room temperature. LC/MS revealed substantial quantities of starting material were present; hence an additional 5 eq of trifluoroacetic acid were added and stirring at room temperature was continued overnight. Repeated LC/MS still showed incomplete removal of the protecting groups. The mixture was evaporated, re-dissolved in trifluoroacetic acid and dichloromethane (2 mL each) and stirred at room temperature for another 2 h, whereupon the reaction was complete. The mixture was evaporated and the residue was purified by preparative HPLC (Method E), followed by lyophilisation to give 95 mg of the target compound as light brown lyophilisate in approx. 90% purity (84% purity adjusted yield).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=[O:18])=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:22]I>CN(C)P(N(C)C)(N(C)C)=O>[CH:1]1([CH2:7][CH2:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([O:19][CH3:22])=[O:18])=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CI
Reactant: O=C(O)Cc1ccc(NCCC2CCCCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)Cc1ccc(NCCC2CCCCC2)cc1
Reaction time: 1 h

Procedure:
A solution of 20.7 g. of 4-(2-cyclohexylethylamino)phenylacetic acid in 25 ml. of hexamethylphosphoramide is added to a stirred mixture of 0.800 g. of sodium hydride (57% in mineral oil) and 25 ml. of hexamethylphosphoramide. The solution which forms after one hour is treated with 11.0 g. of methyl iodide and is then stirred at 25° C. for 18 hours. Dilution with water followed by filtration affords a white solid which is crystallized from ethanol to yield methyl 4-(2-cyclohexylethylamino)phenylacetate.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7](N2CCOCC2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1NC2N(CC3C=CC=CC=3[Cl:48])N=NC=2C(=O)N=1)(C)(C)C.C(N(CC)C1C=CC=CC=1)C.O=P(Cl)(Cl)Cl>>[C:1]([C:5]1[N:6]=[C:7]([Cl:48])[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc(=O)c2nnn(Cc3ccccc3Cl)c2[nH]1
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)c1ccccc1
Product: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
5-tert-Butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine A mixture of 5-tert-butyl-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(4H)-one (12.3 mg, 38.7 μmol) and N,N-diethylaniline (12.3 μL, 77.4 μmol) in POCl3 (250 μL, 2.73 mmol) was refluxed for 3 h under N2 atmosphere. The reaction mixture was concentrated in vacuo, diluted with EtOAc, washed with cold H2O and brine, dried over Na2SO4 and concentrated in vacuo to afford crude 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine. The residue was used for the next reaction without further purification.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:5](=[O:14])[CH2:6][CH2:7][CH2:8][C:9]=2[C:10]=1[C:11]([OH:13])=O.[NH2:15][CH2:16][CH:17]([OH:25])[CH2:18][N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[OH:25][CH:17]([CH2:18][N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[CH2:16][NH:15][C:11]([C:10]1[C:9]2[CH2:8][CH2:7][CH2:6][C:5](=[O:14])[C:4]=2[NH:3][C:2]=1[CH3:1])=[O:13]
Reactant: NCC(O)CN1CCCCC1
Reactant: Cc1[nH]c2c(c1C(=O)O)CCCC2=O
Product: Cc1[nH]c2c(c1C(=O)NCC(O)CN1CCCCC1)CCCC2=O
Yield: 78 %

Procedure:
Similar procedure as Example 13, 2-methyl-7-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (S4) 0.2 g (1.0 mmol) and 1-amino-3-(piperidin-1-yl)propan-2-ol 0.34 g (2.1 mmol) was reacted to give 0.26 g (78%) of the titled compound as a white solid.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=O)[CH2:2]2.S([CH2:20][N+:21]#[C-])(C1C=CC(C)=CC=1)(=O)=O.C(O)C.CC(C)([O-])C.[K+]>C(COC)OC>[C:20]([CH:3]1[CH:4]2[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]2)[CH2:2]1)#[N:21]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=C1CN2CCC1CC2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Solvent: COCCOC
Product: N#CC1CN2CCC1CC2
Temperature: 4 °C
Reaction time: 0.5 h
Yield: 73.4 %

Procedure:
A mixture of 3-quinuclidinone (12.5 g; 0.10 moles), tosylmethyl isocyanide (25.4 g; 0.13 moles) and dry ethanol (10 ml; 0.17 moles) in dry dimethoxyethane (350 ml) was cooled in ice and treated portionwise with potassium t-butoxide (28.0 g; 0.25 moles) while maintaining the temperature between 5° C. and 10° C. After addition was complete the ice bath was removed and stirring was continued for a further 30 min. The reaction was then heated at 4° C. for 2.5 h. After cooling, the precipitate was filtered off and the filtrate concentrated in vacuo. Purification on neutral alumina (Brockmann grade 1) using 2% methanol in ethyl acetate as eluant afforded the title compound as a syrup (10.0 g: 74%) which crystallised on cooling.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:23]=[CH:22][C:13]([CH2:14][CH:15]3[S:19][C:18](=[O:20])[NH:17][C:16]3=[O:21])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.CN(C=O)C.Br[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>O>[O:20]=[C:18]1[N:17]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:16](=[O:21])[CH:15]([CH2:14][C:13]2[CH:12]=[CH:11][C:10]([N:7]3[CH2:8][CH2:9][C:4](=[O:3])[CH2:5][CH2:6]3)=[CH:23][CH:22]=2)[S:19]1
Reactant: CCOC(=O)CBr
Reactant: O=C1CCN(c2ccc(CC3SC(=O)NC3=O)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CN1C(=O)SC(Cc2ccc(N3CCC(=O)CC3)cc2)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.8 %

Procedure:
Sodium hydride (60% in mineral oil, 66 mg, 1.65 mmol) was added into a mixture of 5-[4-(4-oxo-1-piperidineyl)benzyl]-1,3-thiazolidine-2,4-dione (500 mg, 1.65 mmol) (which was obtained in Example 38) and DMF. The mixture was stirred for one hour at room temperature, and then ethyl bromoacetate (0.27 mL, 2.47 mmol) was added. The new mixture was stirred for 30 minutes, poured into water, and extracted with ethyl acetate. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography (hexanes/ethyl acetate 2/1) gave a viscous oil (295 mg, 46% yield); 1H NMR (300 MHz, DMSO-d6) δ 1.20 (t, J=7.16 Hz, 3H), 2.40 (m, 4H), 2.95-3.00 (m, 1H), 3.4 (m, 1H), 3.60 (m, 2H), 4.10 (q, J=7.16 Hz, 2H), 4.30 (s, 2H), 6.97 (m, 2H), 7.16 (m, 2H); MS (ES) m/z: 391 (MH+);
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].Br[C:19]1[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][N:20]=1>CS(C)=O.O>[Br:25][C:22]1[CH:23]=[CH:24][C:19]([O:15][CH2:14][CH:11]2[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]2)=[N:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: Brc1ccc(Br)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(Br)cn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.8 %

Procedure:
A solution of N-Boc-4-piperidinemethanol (1.0 g, 4.50 mmol) in DMSO (2 mL) was added dropwise to a suspension of NaH (60% dispersion in mineral oil, 0.27 g, 6.76 mmol) in DMSO (4 mL). The mixture was stirred at ambient temperature for 1 h, then 30 minutes at 50° C. The mixture was allowed to cool to ambient temperature, and a solution of 2,5-dibromopyridine (1.12 g, 4.73 mmol) in DMSO (4 mL) was added dropwise, and the reaction mixture was stirred at ambient temperature overnight, poured in water, then extracted with EtOAc. The organic extract was washed with water and brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as an amber oil. The crude product was purified by chromatography on a silica gel column eluted with 1:8 EtOAc/hexane to give 1.40 g (84%) of 1,1-dimethylethyl 4-{[(5-bromo-2-pyridinyl)oxy]methyl}-1-piperidinecarboxylate as a white solid after standing. 1H NMR (400 MHz, CDCl3): δ 8.16 (d, 1H, J=2.2 Hz), 7.64 (dd, 1H, Ja=8.7 Hz, Jb=2.3 Hz), 6.64 (d, 1H, J=8.8 Hz), 7.04 (d, 2H, J=8.8 Hz), 4.20-4.10 (m, 4H), 2.80-2.65 (m, 2H), 2.00-1.85 (m, 1H), 1.85-1.70 (m, 2H), 1.45 (s, 9H), 1.30-1.20 (m, 2H); LRMS (ESI), m/z 371/373 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C@H:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Br[CH2:22][C:23]1[C:24]([C:28]#[N:29])=[CH:25][S:26][CH:27]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[N:9]2[CH2:22][C:23]2[C:24]([C:28]#[N:29])=[CH:25][S:26][CH:27]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnc1[C@@H]1CCC[C@H](c2ncccc2C)N1
Reactant: N#Cc1cscc1CBr
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccnc1C1CCCC(c2ncccc2C)N1Cc1cscc1C#N
Yield: 82.1 %

Procedure:
Using General Procedure A: A solution of 3,3″-dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-cis-[2,2′;6′,2″]terpyridine (0.097 g, 0.37 mmol), 4-Bromomethyl-thiophene-3-carbonitrile (0.168 g, 0.83 mmol) (Terpstra, J. W., et al., J. Org. Chem. (1986) 51:230-238), KI (21 mg, 0.13 mmol), and DIPEA (0.15 mL, 0.86 mmol) in DMF (3 mL) was heated at 60° C. for 21 hours. Purification of the crude material by column chromatography on silica gel (20:1:1 CH2Cl2—CH3OH—NH4OH) provided 118 mg (84%) of 4-(3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-thiophene-3-carbonitrile as a tan solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH2:4][C:5](=O)[CH2:6][CH3:7].[CH3:10][NH2:11]>>[CH3:1][O:2][C:3](=[O:9])[CH:4]=[C:5]([NH:11][CH3:10])[CH2:6][CH3:7]
Reactant: CN
Reactant: CCC(=O)CC(=O)OC
Product: CCC(=CC(=O)OC)NC

Procedure:
Prepared according to the procedure described in Example 1, Step 1, using 3-oxo-pentanoic acid methyl ester and methylamine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:17](=[O:19])[CH2:16][N:15](C(OC=C)=O)[CH2:14][C:13]=3[NH:12][C:11]3[CH2:25][N:26](C(OC=C)=O)[CH2:27][C:28](=[O:29])[C:10]2=3)[CH:5]=[CH:6][C:7]=1[F:8].[ClH:35].CCOCC>C(O)C>[ClH:35].[ClH:35].[Br:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:17](=[O:19])[CH2:16][NH:15][CH2:14][C:13]=3[NH:12][C:11]3[CH2:25][NH:26][CH2:27][C:28](=[O:29])[C:10]2=3)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: C=COC(=O)N1CC(=O)C2=C(C1)NC1=C(C(=O)CN(C(=O)OC=C)C1)C2c1ccc(F)c(Br)c1
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: O=C1CNCC2=C1C(c1ccc(F)c(Br)c1)C1=C(CNCC1=O)N2
Temperature: 25 °C

Procedure:
A solution of the product from Example 4B (0.22 g, 0.41 mmol) in ethyl alcohol (5 mL) was treated with concentrated hydrochloric acid (0.10 mL) refluxed for 3 hours, allowed to cool to ambient temperature and treated with ether. The resulting solid precipitate was collected and dried to provide the title compound (0.12 g).