Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC1C=NC=CC=1.C(NC(OC1CCOC1=O)=O)(C)(C)C.[C:22]([NH:26][C:27]([O:29][CH:30]([CH2:40][CH2:41]I)[C:31]([NH:33][C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1)=[O:32])=[O:28])([CH3:25])([CH3:24])[CH3:23]>>[C:22]([NH:26][C:27]([O:29][CH:30]1[CH2:40][CH2:41][N:33]([C:34]2[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=2)[C:31]1=[O:32])=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)NC(=O)OC(CCI)C(=O)Nc1cccnc1
Agent: CC(C)(C)NC(=O)OC1CCOC1=O
Agent: Nc1cccnc1
Product: CC(C)(C)NC(=O)OC1CCN(c2cccnc2)C1=O

Procedure:
By a procedure similar to that described in Example 1, 3-aminopyridine (0.47 g), scaled to 3-t-butylcarbamoyloxytetrahydrofuran-2-one (1.0 g) etc., gave a crude product (3.1 g) containing approximately 20 mole % of 2-t-butylcarbamoyloxy-4-iodo-N(pyridin-3-yl)butanamide. The desired product was apparently unstable in the mixture and to chromatography on silica. NMR (CDCl3) for product only: δ 1.38(9H,s); 2.46(2H,m); 3.25(2H,t); 5.12(1H,bs); 5.25(1H,dd); 7.29(1H,m): 8.17(1H,dd); 8.36(1H,dd); 8.58(1H,d). Base-catalysed cyclisation of this crude material gave Compound 8 (0.18 g, m.p. 129°-131° C.) after several chromatographic separations on silica using dichloromethane-ethanol (19:1) as eluant. NMR (CDCl3): δ 1.35(9H,s); 2.12(1H,m); 2.77(1H,m); 3.86(2H,m); 4.90(1H,bs); 5.36(1H,t); 7.33(1H,dd); 8.28(1H,m); 8.44(1H,dd); 8.76(1H,d). MS: M+ 277.
Reaction SMILES: [C-:1]#[N:2].[K+].C#N.[C:6]([O:11][CH3:12])(=[O:10])[C:7]([CH3:9])=[CH2:8]>CN1CCCC1=O>[C:1]([C:7]([CH3:9])([CH3:8])[C:6]([O:11][CH3:12])=[O:10])#[N:2].[C:6]([O:11][CH3:12])(=[O:10])[C:7]([CH3:9])=[CH2:8]
Reactant: [C-]#N
Agent: C#N
Agent: C=C(C)C(=O)OC
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COC(=O)C(C)(C)C#N
Temperature: 120 °C

Procedure:
A 500 milliliter (hereinafter abbreviated to "mL") flask equipped with a stirrer, a thermometer and two dropping funnels was charged with 203 g of N-methylpyrrolidone and 1.35 g of potassium cyanide, and to the content in the flask were added dropwise 40 g of prussic acid and 163 g of methyl methacrylate over a period of 4 hours, while the content was maintained at a temperature of 120° C. After the completion of the dropwise addition, the content was maintained at 120° C. for 2 hours to complete the reaction. As a result, methyl cyanoisobutyrate was formed at a conversion of methyl methacrylate (MMA) of 88.3% and at a selectivity of 98.1% based on the reacted MMA.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]([Li])[CH2:7][CH2:8][CH3:9]>CCCCCC>[C:3]1([C:4]2([CH:5]=[O:1])[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:2]=1
Reactant: C1CCOC1
Reactant: [Li]CCCC
Solvent: CCCCCC
Product: O=CC1(c2ccccc2)CCCC1
Temperature: -78 °C

Procedure:
In starting the procedure, to a 250 ml (3-necked, round bottom) flask equipped with a nitrogen inlet tube, a rubber septum and a magnetic stirrer is added 100 ml tetrahydrofuran solution of 5.64 g (0.04 mole) of 2, benzyl-4,4,6-tetramethyl- 4,5-dihydro-1,3-oxazine. The mixture is cooled to -78° C and 0.044 mole of normal butyllithium disssolved in hexane is slowly added.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[CH:10][C:5]2=[C:4]([C:11]2([OH:17])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:3]=1.[Cl:18][C:19]1[CH:20]=[C:21]2[CH2:32][C@@H:31]([CH2:33][C:34](O)=[O:35])[C:30](=[O:37])[N:29]([CH2:38][C:39]([CH3:42])([CH3:41])[CH3:40])[CH2:28][C:22]2=[C:23]2[C:27]=1[NH:26][CH:25]=[CH:24]2.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:18][C:19]1[CH:20]=[C:21]2[CH2:32][C@@H:31]([CH2:33][C:34]([N:14]3[CH2:13][CH2:12][C:11]([C:4]4[CH:3]=[C:2]([Cl:1])[N:7]=[C:6]5[NH:8][CH:9]=[CH:10][C:5]=45)([OH:17])[CH2:16][CH2:15]3)=[O:35])[C:30](=[O:37])[N:29]([CH2:38][C:39]([CH3:42])([CH3:41])[CH3:40])[CH2:28][C:22]2=[C:23]2[C:27]=1[NH:26][CH:25]=[CH:24]2
Reactant: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ccc23)C[C@@H](CC(=O)O)C1=O
Reactant: OC1(c2cc(Cl)nc3[nH]ccc23)CCNCC1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ccc23)C[C@@H](CC(=O)N2CCC(O)(c3cc(Cl)nc4[nH]ccc34)CC2)C1=O
Temperature: 25 °C
Yield: 76.5 %

Procedure:
To 4-(6-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-ol (69 mg, 0.304 mmol) in DMF (2 mL) was added (S)-2-(7-chloro-2-neopentyl-3-oxo-1,2,3,4,5,8-hexahydroazepino[3,4-e]indol-4-yl)acetic acid (100 mg, 0.276 mmol), EDC (58.3 mg, 0.304 mmol), HOBT (41.0 mg, 0.304 mmol), at rt, followed by diisopropylethylamine (0.192 ml, 1.10 mmol). The mixture was stirred at rt over night, partial of the solvent was removed under N2, the residue was purified on reverse phase PrepHPLC to afford the expected product, (S)-7-chloro-4-(2-(4-(6-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-hydroxypiperidin-1-yl)-2-oxoethyl)-2-neopentyl-1,2,4,5-tetrahydroazepino[3,4-e]indol-3(8H)-one (126 mg, 57%) as a tan solid. 1H-NMR (400 MHz, MeOD) δ ppm 0.78-0.84 (m, 11H) 1.73 (s, 1H) 1.76-1.83 (m, 1H) 2.25-2.36 (m, 2H) 2.66-2.76 (m, 1H) 3.03 (d, J=13.35 Hz, 1H) 3.09-3.20 (m, 4H) 3.62-3.73 (m, 2H) 4.08 (d, J=12.84 Hz, 2H) 4.51 (d, J=10.83 Hz, 1H) 4.65 (d, J=17.12 Hz, 1H) 5.51 (d, J=17.12 Hz, 1H) 6.99 (d, J=3.53 Hz, 1H) 7.20-7.24 (m, 2H) 7.26-7.29 (m, 2H) 8.24 (s, 1H); Mass spec. 596.47 (MH+) calc. for C31H35Cl2N5O3 595.21.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[C:17]3[C:12]([CH2:13][CH2:14][N:15](C(OC(C)(C)C)=O)[CH2:16]3)=[CH:11][CH:10]=2)[C:5]([F:26])=[CH:4][N:3]=1>FC(F)(F)C(O)=O.ClCCl>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[C:17]3[C:12]([CH2:13][CH2:14][NH:15][CH2:16]3)=[CH:11][CH:10]=2)[C:5]([F:26])=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Nc3nc(Cl)ncc3F)cc2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1cnc(Cl)nc1Nc1ccc2c(c1)CNCC2

Procedure:
A solution of 2-chloro-5-fluoro-N4-[2-(t-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-4-pyrimidineamine in 40% trifluoroacetic acid/dichloromethane was stirred at rt for 30 min. Removal of the solvent left an oily residue which was suspended in water, made basic with NaHCO3, and extracted with ethyl acetate. Purification by column chromatography over silica gel provided 2-chloro-5-fluoro-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl)-4-pyrimidineamine. 1H NMR (CDCl3): δ 8.04 (d, 1H, J=3.0 Hz), 7.37 (dd, 1H, J=2.4 and 8.4 Hz), 7.27 (d, 1H, J=1.5 Hz), 7.11 (d, 1H, J=8.4 Hz), 6.92 (s, 1H), 4.04 (s, 2H), 3.15 (t, 2H, J=6.0 Hz), 2.79 (t, 2H, J=6.0 Hz); 19F NMR (282 MHz, CDCl3): −44648; LCMS: purity: 97%; MS (m/e): 279(MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:16]3[CH:15]=[C:14]([C:17]([O:19]C)=[O:18])[NH:13][C:12]=3[CH2:11][CH2:10]2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.O.[OH-].[Li+].C1COCC1>CO>[CH3:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:16]3[CH:15]=[C:14]([C:17]([OH:19])=[O:18])[NH:13][C:12]=3[CH2:11][CH2:10]2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: COC(=O)c1cc2c([nH]1)CCC2c1cc(C)cc(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1cc(C)cc(C2CCc3[nH]c(C(=O)O)cc32)c1

Procedure:
The title compound was synthesized from methyl 4-(3,5-dimethylphenyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (150 mg, 0.45 mmol) and lithium hydroxide monohydrate (108 mg, 4.5 mmol), according to General Procedure 7. A 1:1 mixture of THF and methanol (10 mL) was used. The resulting product was purified by chromatography over silica gel (gradient 0 to 100% EtOAc in heptane over 20 min) to give the title compound. 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.16-2.22 (m, 1H), 2.24 (s, 6H), 2.66-2.92 (m, 3H), 4.08 (t, J=7.35 Hz, 1H), 6.51 (s, 1H), 6.78 (s, 2H), 6.80 (s, 1H). LCMS m/e 256 (M+H) and 95% pure by HPLC.
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH3:18])[CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][C:11]([O:14]C)=[C:12]([F:13])[C:7]=2[N:6]([CH3:16])[C:5]1=[O:17].CC(C)=O.C(=O)=O.B(Br)(Br)Br>ClCCl>[CH3:1][C:2]([CH3:19])([CH3:18])[CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][C:11]([OH:14])=[C:12]([F:13])[C:7]=2[N:6]([CH3:16])[C:5]1=[O:17]
Reactant: COc1ccc2c(c1F)n(C)c(=O)n2CC(C)(C)C
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: CC(C)=O
Solvent: ClCCl
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc(O)c(F)c21
Reaction time: 15 h

Procedure:
A solution of 1-(2,2-dimethylpropyl)-4-fluoro-5-methoxy-3-methyl-1,3-dihydro-2H-benzimidazol-2-one (7-5, 193 mg, 0.73 mmol) in anhydrous Dichloromethane (10 ml) was cooled to −78 deg C. (Acetone/dry ice) and treated with Boron tribromide (1M in DCM, 1.45 ml, 1.45 mmol, 2 eq). The resulting mixture was allowed to slowly wann to 23 deg C. over 15 h. The reaction was only ˜75% complete by LC/MS, so it was treated with more BBr3 (360 ml, 0.36 mmol, 0.5 eq). The reaction was stirred at 23 deg C. for 1 h, then was carefully quenched by pouring directly into a solution of saturated aqueous NaHCO3 cooled to 0 deg C. The aqueous mixture was extracted with Methylene Chloride (2×200 ml), and the combined organic layers were dried over Na2SO4 and concentrated, thereby providing the title compound, 1-(2,2-dimethylpropyl)-4-fluoro-5-hydroxy-3-methyl-1,3-dihydro-2H-benzimidazol-2-one (7-6), as a green-tan solid. 1H NMR (500 MHz, CDCl3) δ 6.65-6.73 (m, 2H), 3.61 (m, 5H), 1.02 (s, 9H). LRMS m/z: Calc'd for C13H17FN2O2 (M+H) 253.3, found 253.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:29][CH2:30][N:31]3[C@H:36]4[CH2:37][CH2:38][C@@H:32]3[CH2:33][CH:34]([N:39]3[C:43]5[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=5[N:41]=[C:40]3[CH3:48])[CH2:35]4)[CH2:13][CH2:12][N:11]([C:14]([C@@H:16]([NH:21]C(=O)OC(C)(C)C)[C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Cl>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:29][CH2:30][N:31]3[C@H:36]4[CH2:37][CH2:38][C@@H:32]3[CH2:33][CH:34]([N:39]3[C:43]5[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=5[N:41]=[C:40]3[CH3:48])[CH2:35]4)[CH2:13][CH2:12][N:11]([C:14](=[O:15])[C@@H:16]([NH2:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCN(C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)CC1
Agent: Cl
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCN(C(=O)[C@@H](N)C(C)(C)C)CC1
Yield: 99 %

Procedure:
2,2-dichloro-N-{(1S)-1-[(4-(3-fluorophenyl-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]-2,2-dimethylpropyl}acetamide was obtained from treating 1,1-dimethylethyl {(1S)-1-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]-2,2-dimethylpropyl}carbamate, example 915, (0.591 g, 0.90 mmol) with HCl as outlined in the procedure for Example 890 to form (2S)-1-(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)-3,3-dimethyl-1-oxo-2-butanamine (0.500 g, 99%). 2S)-1-(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)-3,3-dimethyl-1-oxo-2-butanamine (0.050 g, 0.09 mmol), Dichloro-acetyl chloride (0.013 g, 0.09 mmol) and DIEA (0.034 g, 0.534 mmol) were reacted following the procedure outlined in Example 890 to give the title compound, 2,2-dichloro-N-{(1S)-1-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl) carbonyl]-2,2-dimethylpropyl}acetamide (0.036 g, 60%) as an oil. ES-LCMS m/z 670 (M+1).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:12]1[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=1)[N:6]2[CH3:11].[N:18]1([C:24]2[CH:25]=[C:26]([CH:37]=[CH:38][CH:39]=2)[O:27][CH2:28][C:29]([N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[O:30])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C(N(CC)CC)C>C(O)(C)C>[CH3:11][N:6]1[C:5]([C:12]2[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=2)=[N:4][C:3]2[C:7]1=[N:8][CH:9]=[N:10][C:2]=2[N:21]1[CH2:22][CH2:23][N:18]([C:24]2[CH:39]=[CH:38][CH:37]=[C:26]([O:27][CH2:28][C:29](=[O:30])[N:31]3[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]3)[CH:25]=2)[CH2:19][CH2:20]1
Reactant: O=C(COc1cccc(N2CCNCC2)c1)N1CCCCC1
Reactant: Cn1cc(-c2nc3c(Cl)ncnc3n2C)cn1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: Cn1cc(-c2nc3c(N4CCN(c5cccc(OCC(=O)N6CCCCC6)c5)CC4)ncnc3n2C)cn1
Temperature: 25 °C
Yield: 9.9 %

Procedure:
A stirred solution of 6-chloro-9-methyl-8-(1-methyl-1H-pyrazol-4-yl)-9H-purine (30 mg, 0.12 mmol), 2-(3-(piperazin-1-yl)phenoxy)-1-(piperidin-1-yl)ethanone (45.5 mg, 0.15 mmol), and triethylamine (84.0 uL, 0.60 mmol) in isopropyl alcohol (2.0 mL) were heated to 80° C. for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The product was purified by preparatory HPLC (reverse-phase, acetonitrile/water with 0.1% formic acid) to give 6.1 mg (10% yield) of the title compound. 1H NMR (400 MHz, DMSO-d6): δ 8.44 (s, 1H), 8.27-8.25 (m, 1H), 8.05 (s, 1H), 7.12 (t, 1H), 6.62 (dd, 1H), 6.55 (t, 1H), 6.39-6.35 (m, 1H), 4.73 (s, 2H), 3.96 (s, 3H), 3.85 (s, 3H), 3.46-3.37 (m, 4H), 3.30-3.24 (m, 6H), 3.17 (d, 2H), 1.63-1.48 (m, 4H), 1.43 (s, 2H). MS (EI) for C27H33N9O2: 516.7 (MH+).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][C:14]([CH2:20][OH:21])([CH2:18][CH3:19])[CH2:13]1.O1C2C=CC=CC=2OC[CH:23]1CN1CCCC(COC)(C)C1>>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][C:14]([CH2:18][CH3:19])([CH2:20][O:21][CH3:23])[CH2:13]1
Reactant: CCC1(CO)CCCN(CC2COc3ccccc3O2)C1
Reactant: COCC1(C)CCCN(CC2COc3ccccc3O2)C1
Product: CCC1(COC)CCCN(CC2COc3ccccc3O2)C1

Procedure:
Prepared from [1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-ethylpiperidin-3-yl]methanol according to the procedure described for 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methoxymethyl-3-methylpiperidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=O)=[O:10])=[CH:5][CH:4]=1.[C:21]([CH2:23][C:24]([NH2:26])=[S:25])#[N:22].C(Cl)(Cl)Cl>N1CCCCC1.O>[OH:10][C:9]1([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[NH:26][C:24](=[S:25])[C:23]([C:21]#[N:22])=[C:11]1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1
Reactant: N#CCC(N)=S
Reactant: COc1ccc(C(=O)C(=O)c2ccc(OC)cc2)cc1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: C1CCNCC1
Product: COc1ccc(C2=C(C#N)C(=S)NC2(O)c2ccc(OC)cc2)cc1
Reaction time: 12 h

Procedure:
16.5 g. 4,4'-Dimethoxybenzil, 6.0 g. cyanothioacetamide and 15 drops of piperidine were boiled for 2 hours in 200 ml. chloroform on a water separator. The yellow precipitate obtained was filtered off with suction, washed with some chloroform and dried at 80° C. and 0.1 mm.Hg for 12 hours. The desired product is obtained in a yield of 17.6 g. in the form of yellow crystals; m.p. 193° C. (decomp.).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[CH:11][C:10]=1[N+:19]([O-:21])=[O:20].[CH2:22](N)[C:23]#[CH:24]>O1CCCC1>[Cl:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([CH2:24][C:23]#[CH:22])[CH2:11][C:10]=1[N+:19]([O-:21])=[O:20]
Reactant: C#CCN
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C#CCN1CC([N+](=O)[O-])=C(Cl)c2ccccc21
Reaction time: 1.5 h

Procedure:
Triethylamine (8.0 mL, 1.2 eq.) was added to a mixture of 4-chloro-3-nitroquinoline (10.0 g, 47.9 mmol, 1.0 eq.) in tetrahydrofuran (THF, 200 mL). Propargylamine (3.4 mL, 1.1 eq.) was added and the reaction mixture was stirred vigorously for 1.5 hours. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between chloroform (700 mL) and water (200 mL). The organic layer was washed with water (1×200 mL). The combined aqueous layers were back extracted with chloroform (2×150 mL). The combined organics were dried over magnesium sulfate and concentrated under reduced pressure to provide 10.59 g of 4-chloro-3-nitro-N-(2-propynyl)quinoline as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12](=[S:14])[NH2:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:16][C:17](=O)[CH2:18][CH3:19]>C(O)(C)(C)C>[CH2:18]([C:17]1[N:13]=[C:12]([CH2:11][CH2:10][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[S:14][CH:16]=1)[CH3:19]
Reactant: NC(=S)CCc1ccc([N+](=O)[O-])cc1
Reactant: CCC(=O)CBr
Solvent: CC(C)(C)O
Product: CCc1csc(CCc2ccc([N+](=O)[O-])cc2)n1
Yield: 94.9 %

Procedure:
A mixture of 3-(4-nitrophenyl)propanethioamide (1.25 g), 1-bromo-2-butanone (0.98 g) and tert-butanol (30 mL) was heated under reflux for 30 min. The reaction mixture was concentrated, and saturated aqueous sodium hydrogen carbonate was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 4-ethyl-2-[2-(4-nitrophenyl)ethyl]-1,3-thiazole as a yellow oil (1.48 g, yield 95%) from a fraction eluted with hexane-ethyl acetate (4:1-2:1, v/v).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[C:9]([C:15]2[N:19]([CH:20]([CH3:22])[CH3:21])[N:18]=[N:17][N:16]=2)[C:10]([O:12]CC)=[O:11])=[CH:4][CH:3]=1.O1CCCC1.CO.[Li+].[OH-]>OS(O)(=O)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[C:9]([C:15]2[N:19]([CH:20]([CH3:22])[CH3:21])[N:18]=[N:17][N:16]=2)[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=C(c1ccc(F)cc1)c1ccc(F)cc1)c1nnnn1C(C)C
Agent: O=S(=O)(O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)n1nnnc1C(C(=O)O)=C(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a chilled (0° C.) solution of ethyl 3,3-bis(4-fluorophenyl)-2-[1-(1-methylethyl)-1H-tetrazol-5-yl]-2-propenoate (0.95 g, 2.39 mmoles) in 20 mL of 1:1 (v/v) mixture of tetrahydrofuran and methanol was added an aqueous solution of LiOH (4.0 mL, 3 Molar) in one single portion. The reaction mixture was stirred at 0° C. for 15 minutes followed by warming up to ambient temperature. Saponification was allowed to proceed at room temperature for four hours forming a very pale clear solution. The crude reaction mixture was diluted with 12 mL of 2M H2SO4 and the product was extracted into diethyl ether (40 mL×2). The organic layers were combined, dried over MgSO4, concentrated under reduced pressure and then vigorously dried under high vacuum (0.01 mmHg) at room temperature for 24 hours to yield the title compound. The propenoic acid was then utilized in the next step without further purification.
Reaction SMILES: Cl.Cl.Cl.N[C@H](C)CNC1SC2C=CC=CC=2N=1.C(O[C@@H]1[C@H](OC(=O)C)[C@@H](COC(=O)C)O[C@H]1N1C=NC2C1=NC(Cl)=NC=2Cl)(=O)C.C([O:50][C@@H:51]1[C@H:55]([O:56]C(=O)C)[C@@H:54]([CH2:60][O:61]C(=O)C)[O:53][C@H:52]1[N:65]1[C:87]2[N:86]=[C:85]([Cl:88])[N:84]=[C:69]([NH:70][C@H:71]([CH3:83])[CH2:72][NH:73][C:74]3[S:75][C:76]4[CH:82]=[CH:81][CH:80]=[CH:79][C:77]=4[N:78]=3)[C:68]=2[N:67]=[CH:66]1)(=O)C.C[O-].[Na+]>CO>[S:75]1[C:76]2[CH:82]=[CH:81][CH:80]=[CH:79][C:77]=2[N:78]=[C:74]1[NH:73][CH2:72][C@H:71]([NH:70][C:69]1[C:68]2[N:67]=[CH:66][N:65]([C:87]=2[N:86]=[C:85]([Cl:88])[N:84]=1)[C@@H:52]1[O:53][C@H:54]([CH2:60][OH:61])[C@@H:55]([OH:56])[C@H:51]1[OH:50])[CH3:83]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(N[C@H](C)CNc4nc5ccccc5s4)nc(Cl)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[C@@H](N)CNc1nc2ccccc2s1
Agent: C[O-]
Solvent: CO
Product: C[C@H](CNc1nc2ccccc2s1)Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 29 %

Procedure:
2-[(R)-(2-Amino-1-propyl)amino]benzothiazole trihydrochloride (0.065 g, 70%), m.p. 226-226° C., was subsequently obtained by hydrolysis in a mixture of 6N hydrochloric acid and ethyl acetate (2 ml), the procedure described in Example 1. This 2-[(R)-(2-amino-1-propyl)amino]benzothiazole trihydrochloride (0.06 g, 0. 19 mmol) was reacted with 9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-2,6-di-chloro-9H-purine (0.127 g, 1.2 mmol), followed by deacylation of the purified 2',3',5'-tri-O-acetyl-N-[(R)-1-(2-benzothiazolyl)amino-2-propyl]-2-chloroadenosine using sodium methoxide in methanol (to remove the 2' and 3'-acetyl groups) followed by ethylamine in ethanol, which provided the title N-[(R)-1-(2-benzothiazolyl)amino-2-propyl]-2-chloroadenosine (0.027 g, 29%) as a foam (following column chromatography), 1H NMR (DMSO-d6) δ 1.25 (3H, d, --CHCH3), 3.52-3.70 (4H, m, H-5'a , H-5'b and --CH2 --), 3.94 (1H, q, H-4'), 4.12 (1H, q, H-3'), 4.52 (1H, q, H-2'), 4.53 -4.62 (1H, m, --CHCH3), 5.07 (1H, t, 5'-OH), 5.22, 5.48 (2H, 2d, 2'- and 3'-OH), 5.84 (1H, d, H-1'), 7.01, 7.22 (2H, 2t, Ar-H), 7.43, 7.66 (2H, 2d, Ar-H), 8.14 (1H, t, N--H), 8.41 (1H, s, H-8), 8.44 (1H, d, N--H). HPLC retention time 10.7 min [gradient elution, 20-80% acetonitrile/water (containing 0. 1% TFA)].
Reaction SMILES: Cl.[NH2:2][CH:3]([CH3:18])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]([O:15]CC)=[O:14])=[CH:7][CH:6]=1.[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([O:29][CH3:30])=[C:24]([CH:28]=1)[C:25](Cl)=[O:26]>>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([O:29][CH3:30])=[C:24]([CH:28]=1)[C:25]([NH:2][CH:3]([CH3:18])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:9][CH:10]=1)=[O:26]
Reactant: CCOC(=O)CCc1ccc(CC(C)N)cc1
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Agent: Cl
Product: COc1ccc(Cl)cc1C(=O)NC(C)Cc1ccc(CCC(=O)O)cc1

Procedure:
By the reaction of ethyl β-[4-(2-aminopropyl)-phenyl]-propionate hydrochloride (m.p. 115°-117° C.) with 5-chloro-2-methoxybenzoyl chloride, there is obtained β-{4-[2-(5-chloro-2-methoxybenzamido)-propyl]-phenyl}-propionic acid; m.p. 125°-126° C., after recrystallization from isopropanol/water.
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH2:19][C:20](F)(F)F)[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.BrC1C=C[C:30]2[C:31]3[N:32]=C(C(N)=O)SC=3CCO[C:29]=2[CH:28]=1.N1C=CC=CC=1CNN>>[Br:1][C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH2:19][C:20]5[CH:28]=[CH:29][CH:30]=[CH:31][N:32]=5)[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1
Reactant: FC(F)(F)Cn1ncnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: NC(=O)c1nc2c(s1)CCOc1cc(Br)ccc1-2
Agent: NNCc1ccccn1
Product: Brc1ccc2c(c1)OCCc1sc(-c3ncnn3Cc3ccccn3)nc1-2

Procedure:
Following the procedure for 8-Bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene, 8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid amide 25 was reacted with Pyridin-2-ylmethyl-hydrazine to give 8-Bromo-2-(2-pyridin-2-ylmethyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene. MS(ESI+) 440.0/442.0.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:20][S:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1>>[CH3:20][S:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)=[CH:24][CH:23]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: CSc1ccc(C=O)cc1
Product: CSc1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-methylsulfanylbenzaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(4-methylsulfanylphenyl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.