Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)(OC([N:7]([CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][S:29]([C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:39]([NH:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[O:40])=[CH:34][CH:33]=2)(=[O:31])=[O:30])=[CH:24][CH:23]=1)[CH2:8][C@H:9]([OH:19])[C:10]1[CH:11]=[CH:12][C:13]2[N:14](N=N[N:18]=2)[CH:15]=1)=O)C.O.O.[Sn](Cl)Cl.Cl>CO>[OH:19][C@H:9]([C:10]1[CH:15]=[N:14][C:13]([NH2:18])=[CH:12][CH:11]=1)[CH2:8][NH:7][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][S:29]([C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:39]([NH:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[O:40])=[CH:34][CH:33]=2)(=[O:31])=[O:30])=[CH:24][CH:23]=1
Reactant: CCCCCCNC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(CCN(C[C@H](O)c3ccc4nnnn4c3)C(=O)OC(C)(C)C)cc2)cc1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CO
Product: CCCCCCNC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(CCNC[C@H](O)c3ccc(N)nc3)cc2)cc1
Yield: 131.1 %

Procedure:
A mixture of 0.302 g (0.44 mmol) of the tetrazine from Example 4, 0.20 g (0.88 mol) of tin(II) chloride dihydrate and 0.3 ml of concentrated aqueous hydrochloric acid in 2 mL of methanol was heated at reflux for 5 h. The reaction mixture was concentrated and the residue purified by reverse-phase MPLC (C8, 47%methanol/53 0.1% trifluoroacetic acid buffer) to give 0.32 g (78%) of the title compound as its bistrifluoroacetate salt: 1H NMR (400 MHz, CD3OD) δ7.96 (dd, 1H, J=2.0, 9.2 Hz), 7.86 (d, 1H, J=2.0 Hz), 7.59 (d, 2H, J=8.8 Hz), 7.43 (d, 2H, J=8.8 Hz), 7.14 (d, 2H, J=8.4 Hz), 7.07 (d, 2H, J=8.4 Hz), 7.03 (d, 1H, J=9.2 Hz), 4.92 (m, 1H), 3.23 (m, 2H), 3.15 (m, 2H), 2.93 (m, 2H, 4.0 Hz), 1.49 (t, 2H, J=6.0 Hz), 1.32 (m, 8H), 0.91 (t, 3H, J=6.0 Hz); CI MS m/z 555(M+1).
Reaction SMILES: [C:1]1(=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:7][CH2:8][C:9]1[C:14]([Cl:15])=[CH:13][CH:12]=[C:11]2[N:16]([C:31]3[C:32]4[C@H:39]([CH3:40])[CH2:38][CH2:37][C:33]=4[N:34]=[CH:35][N:36]=3)[CH2:17][C:18]3([CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[C:10]=12.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C(Cl)Cl>[Cl:15][C:14]1[C:9]([CH2:8][NH:7][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:10]2[C:18]3([CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[CH2:17][N:16]([C:31]3[C:32]4[C@H:39]([CH3:40])[CH2:38][CH2:37][C:33]=4[N:34]=[CH:35][N:36]=3)[C:11]2=[CH:12][CH:13]=1
Reactant: C[C@@H]1CCc2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)CC4)c4c3ccc(Cl)c4CN)c21
Reactant: O=C1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: C[C@@H]1CCc2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)CC4)c4c3ccc(Cl)c4CNC3CCCC3)c21
Reaction time: 8 h
Yield: 57.4 %

Procedure:
Cyclopentanone (17.4 mg, 0.207 mmol) was added to a solution of (R)-tert-butyl 4-(aminomethyl)-5-chloro-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (20 mg, 0.041 mmol) in DCE (2 mL). The reaction was allowed to stir at room temperature for 15 minutes, at which point Na(OAc)3BH (22 mg, 0.103 mmol) was added. The reaction was allowed to stir overnight. The reaction mixture was diluted with DCM, washed with saturated aqueous NaHCO3 solution and brine, dried with MgSO4 and concentrated. The residue was purified by column chromatography (15:1, DCM:MeOH) to give (R)-tert-butyl 5-chloro-4-((cyclopentylamino)methyl)-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (13 mg, 54%) as an oil. LCMS (APCI+) m/z 552/554 [M+H]+; Rt=4.79 min. This material was taken up into DCM (2 mL), and 2N HCl in ether was added (1 mL). The reaction was allowed to stir for 1 hour, at which point it was concentrated to give (R)—N-((5-chloro-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-4-yl)methyl)propan-2-amine trihydrochloride salt (12 mg, 52%) as a solid. 1H NMR (D2O, 400 MHz) δ 8.53 (s, 1H), 7.74 (d, J=8.8 Hz, 1H), 7.40 (d, J=8.8 Hz, 1H), 4.55-4.39 (m, 3H), 4.17-4.15 (m, 1H), 3.84-3.38 (m, 7H), 3.17-2.97 (m, 4H), 2.44-1.67 (m, 14H). LCMS (APCI+) m/z 452/454 [M+H]+; Rt=2.52 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:32]=[C:31]([O:33][CH2:34][CH3:35])[CH:30]=[CH:29][C:4]=1[C:5]([N:7]1[CH2:12][CH2:11][CH:10]([N:13]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH:16]([C:24]([O:26]CC)=O)[C:14]2=[O:15])[CH2:9][CH2:8]1)=[O:6].O.[NH2:37][NH2:38]>C(O)C>[CH3:1][O:2][C:3]1[CH:32]=[C:31]([O:33][CH2:34][CH3:35])[CH:30]=[CH:29][C:4]=1[C:5]([N:7]1[CH2:12][CH2:11][CH:10]([N:13]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH:16]([C:24]([NH:37][NH2:38])=[O:26])[C:14]2=[O:15])[CH2:9][CH2:8]1)=[O:6]
Reactant: CCOC(=O)C1Cc2ccccc2N(C2CCN(C(=O)c3ccc(OCC)cc3OC)CC2)C1=O
Reactant: NN
Solvent: CCO
Solvent: O
Product: CCOc1ccc(C(=O)N2CCC(N3C(=O)C(C(=O)NN)Cc4ccccc43)CC2)c(OC)c1
Yield: 84.3 %

Procedure:
To 1-[1-(2-methoxy-4-ethoxybenzoyl)-4-piperidinyl]-3-ethoxycarbonyl-3,4-dihydrocarbostyril (1.1 g) are added hydrazine monohydrate (1.1 g) and ethanol (15 ml) and the mixture is refluxed with heating for 7 hours. The reaction mixture is concentrated and the residue is purified by silica gel column chromatography (solvent: dichloromethane→dichloromethane:methanol=20:1) to give 1-[1-(2-methoxy-4-ethoxybenzoyl)4-piperidinyl]-3-hydrazinocarbonyl-3,4-dihydrocarbostyril (0.9 g) as white amorphous form.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][C@@H:3]([OH:5])[CH3:4].N1C=CN=C1.CN(C)C=O.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>ClCCl>[Si:17]([O:6][CH2:1][CH2:2][C@@H:3]([OH:5])[CH3:4])([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@H](O)CCO
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@H](O)CCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 0° C. solution of (S)—(+)-1,3-butanediol (2.1 g, 23.3 mmol), imidazole (1.74 g, 25.6 mmol), and N,N-dimethylformamide (1.0 mL) in dichloromethane (40 mL) was treated with tert-butyl-dimethylsilyl chloride (3.68 g, 23.3 mmol). The reaction mixture was warmed to room temperature, stirred overnight, quenched with saturated aqueous ammonium chloride and extracted with dichloromethane. The combined dichloromethane layers were dried (MgSO4), filtered and concentrated to afford of the desired product of sufficient purity for subsequent use without further purification in near quantitative yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[C:7]([CH2:10][CH2:11]I)[C:6]=2[CH:13]=1.[N:14]1([C:20]2[CH:21]=[CH:22][CH:23]=[C:24]3[C:29]=2[N:28]=[CH:27][CH:26]=[CH:25]3)[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(N(CC)C(C)C)(C)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[C:7]([CH2:10][CH2:11][N:17]3[CH2:18][CH2:19][N:14]([C:20]4[CH:21]=[CH:22][CH:23]=[C:24]5[C:29]=4[N:28]=[CH:27][CH:26]=[CH:25]5)[CH2:15][CH2:16]3)[C:6]=2[CH:13]=1
Reactant: c1cnc2c(N3CCNCC3)cccc2c1
Reactant: Clc1ccc2occ(CCI)c2c1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ccc2occ(CCN3CCN(c4cccc5cccnc45)CC3)c2c1

Procedure:
A mixture of 2-(5-chloro-1-benzofuran-3-yl)ethyl iodide (305 mg. 1 mmol) (obtained by the above mentioned process) and 8-piperazino quinoline (213 mg, 1 mmol) was heated at 120° C. in DMSO in the presence of N,N-diisopropylethylamine (5 ml, excess) for 24 hrs. Afterwards, the reaction mixture was quenched with water and extracted with chloroform. The organic layer was washed with water and dried over anhydrous MgSO4 and concentrated to dryness. The dark colored solid was purified by silica-gel column chromatography by initially eluting it with 70% ethyl acetate:hexane and then with 5% methanol:ethyl acetate. 8-{4-[2-(5-chloro-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-quinoline was isolated as a yellow oil. Yield: 120 mg (30%); (M+H): 392; 1HNMR (400 MHz, CDCl3): δ 8.86˜8.85 (dd, J1=1.8 Hz, J2=1.8 Hz, 1H); 8.03˜8.01 (dd, J1=1.8 Hz, J2=1.8 Hz, 1H); 7.57˜7.10 (m, 8H); 3.51˜2.50 (m, 12H).
Reaction SMILES: CO[C:3](=O)[CH2:4][C:5]1[C:6]([CH3:21])=[N:7][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[C:9]=1[CH3:10].[CH2:23]([O:25][C:26](=[O:36])CCC1C(C)=NNC=1C)[CH3:24]>>[CH2:23]([O:25][C:26](=[O:36])[CH2:3][CH2:4][C:5]1[C:6]([CH3:21])=[N:7][N:8]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=2)[C:9]=1[CH3:10])[CH3:24]
Reactant: COC(=O)Cc1c(C)nn(Cc2ccc([N+](=O)[O-])cc2)c1C
Reactant: CCOC(=O)CCc1c(C)n[nH]c1C
Product: CCOC(=O)CCc1c(C)nn(Cc2ccc([N+](=O)[O-])cc2)c1C

Procedure:
Intermediate 8.1.1 can be prepared according to the method described for intermediate 1.1.2, employing in the alkylation reaction 3-(3,5-dimethyl-1H-pyrazol-4-yl)-propionic acid ethyl ester (Akos, MFCD03834497) instead of (3,5-dimethyl-1H-pyrazol-4-yl)-acetic acid methyl ester.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([NH:5][C:6]1[CH:15]=[CH:14][C:13]2[C:12]([CH3:17])([CH3:16])[CH2:11][CH2:10][C:9]([CH3:19])([CH3:18])[C:8]=2[CH:7]=1)=[O:4].[OH-].[K+].I[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>CS(C)=O.O>[F:1][C:2]([F:20])([F:21])[C:3]([N:5]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:6]1[CH:15]=[CH:14][C:13]2[C:12]([CH3:16])([CH3:17])[CH2:11][CH2:10][C:9]([CH3:19])([CH3:18])[C:8]=2[CH:7]=1)=[O:4]
Reactant: CCCCCI
Reactant: CC1(C)CCC(C)(C)c2cc(NC(=O)C(F)(F)F)ccc21
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCCCCN(C(=O)C(F)(F)F)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 0 °C
Reaction time: 24 h

Procedure:
A solution of 2,2,2-trifluoro-N-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-acetamide (29) (15.05 g, 40.7 mmole) in 105 mL dimethylsulfoxide (DMSO) was treated with potassium hydroxide (3.38 g) and then cooled to 0° C. Iodopentane (7.9 mL) in 15 mL DMSO was added dropwise to the reaction mixture and the temperature was allowed to rise to 23° C. The reaction mixture was stirred at room temperature for 24 hours, diluted with 200 mL of water and extracted with two 200 mL portions of ether. The combined organic extracts were washed with four 200 mL portions of cold water, dried over MgSO4, filtered and concentrated in vacuo to give a brown oil. The product was purified by flash chromatography (SiO2, 1:15 ethyl acetate/hexanes) to afford 14.36 g of 2,2,2-trifluoro-N-pentyl-N-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-acetamide (31) as a pale yellow oil.
Reaction SMILES: [NH2:1][C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[ClH:16].[CH2:17](O)[CH3:18]>>[ClH:16].[CH2:17]([O:14][C:13](=[O:15])[C@H:2]([CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)[NH2:1])[CH3:18]
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: CCO
Agent: Cl
Product: CCOC(=O)[C@@H](N)Cc1c[nH]c2ccccc12

Procedure:
A mixture of L-tryptophan (14.3 g, 0.07 mol) in 200 ml of ethanol containing ~7 g of anhydrous HCl was refluxed for 5 hours. The mixture was cooled and the solid which separated was recrystallized from ethanol/ether. Yield 17.4 g (92.5%), m.p. 226°-228° C. The product has the formula: ##STR1505## The product may also be named ethyl L-2-amino-3-indolepropionate.
Reaction SMILES: C([O:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[C:8]([CH:15]=[CH2:16])[CH:9]=[CH:10][CH:11]=2)[N:6]=1)(=O)C.O>CO>[OH:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[C:8]([CH:15]=[CH2:16])[CH:9]=[CH:10][CH:11]=2)[N:6]=1
Reactant: C=Cc1cccc2ccc(OC(C)=O)nc12
Solvent: CO
Solvent: O
Product: C=Cc1cccc2ccc(O)nc12
Temperature: 55 °C
Yield: 100.4 %

Procedure:
18.6 g (87.3 mmol) of 2-acetoxy-8-vinylquinoline, 290 ml of water and 290 ml of methanol are placed in a 1 l round-bottomed flask. The reaction mixture is heated at 55° C. for 2 h and then the methanol is evaporated under vacuum. Extraction is carried out with ethyl acetate (2×200 ml). The organic phases are combined, dried over magnesium sulfate, filtered and concentrated under vacuum to provide 15.0 g of 2-hydroxy-8-vinylquinoline in the form of a yellow solid; M.p.=96° C. (Quantitative yield)
Reaction SMILES: [C:1]([OH:11])(=[O:10])[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].Br[CH:13]([CH3:17])[C:14](Br)=[O:15]>>[CH3:17][CH:13]1[C:14](=[O:15])[O:3][CH:2]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1](=[O:11])[O:10]1
Reactant: CC(Br)C(=O)Br
Reactant: O=C(O)C(O)c1ccccc1
Product: CC1OC(=O)C(c2ccccc2)OC1=O
Yield: 33 %

Procedure:
3-methyl-6-phenyl-2,5-dioxane-1,4-dione (9) was synthesized by using mandelic acid and 2-bromopropionyl bromide. Recrystallization from toluene gave white crystals. Mp 153-156° C. Yield: 33%. 1H NMR (CDCl3) δ7.43 (m, 5H), 5.92 (s, 1H) 5.17 (q, 1H), 1.63 (d, 3H). 13C NMR (CDCl3 δ166.90, 165.55, 131.24, 129.95, 128.92, 127.44, 77.74, 72.77, 16.42 MS (m/q) 207.4 (M+1).
Reaction SMILES: N1C=CC=CC=1.Cl[C:8]([O:10][CH2:11][Cl:12])=[O:9].[CH2:13]([OH:19])[CH2:14][O:15][CH2:16][CH2:17][OH:18]>ClCCl>[Cl:12][CH2:11][O:10][C:8]([O:19][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][C:8]([O:10][CH2:11][Cl:12])=[O:9])=[O:9]
Reactant: O=C(Cl)OCCl
Reactant: OCCOCCO
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(OCCl)OCCOCCOC(=O)OCCl
Reaction time: 0.17 h
Yield: 86.6 %

Procedure:
Pyridine (0.89 ml, 11.00 mmol) is added dropwise to a solution of chloromethyl chloroformate (1.32 ml, 14.83 mmol) and diethylene glycol (0.47 ml, 5.00 mmol) in dichloromethane (10 ml) at 7° C. with good stirring under a dry N2 atmosphere. After 10 min. at 7° C. and 6 hours at 20° C. the reaction mixture is transferred to a separating funnel with the aid of dichloromethane (10 ml). The reaction mixture is washed with hydrochloric acid (1.00 M, 10 ml), saturated aqueous sodium hydrogen carbonate (10 ml) and water (10 ml). The organic phase is dried (MgSO4) and the solvent evaporated under reduced pressure (10 mm Hg) to give 1.26 g (86%) title product. 1H NMR (300 MHz, CDCl3): δ 3.72 (m, 2×CH2 --O), 4.34 (m, 2×CH2 --O--C=O), 5.71 (s, 2×Cl--CH2 --O). 13C NMR (75 MHz, CDCl3): δ 67.6 (2×CH2 --O), 68.5 (2×CH2 --O--C=O), 72.1 (2×Cl--CH2 --O), 153.2 (2×C=O).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:13])[C:5](=[CH:10][C:11]=1[Cl:12])[C:6]([O:8][CH3:9])=[O:7].[CH2:14](Br)[CH:15]=[CH2:16].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:16]([O:13][C:4]1[CH:3]=[C:2]([NH2:1])[C:11]([Cl:12])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])[CH:15]=[CH2:14]
Reactant: C=CCBr
Reactant: COC(=O)c1cc(Cl)c(N)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cc(N)c(Cl)cc1C(=O)OC
Temperature: 25 °C

Procedure:
A mixture of methyl 4-amino-5-chlorosalicylate (5 g), allyl bromide (12.6 g), ground K2CO3 (30 g) and acetone (120 ml) is stirred at reflux for 5 hours and cooled to 25° C. The mixture is partitioned between methylene chloride and H2O, the organic layer is separated, dried (MgSO4), filtered and evaporated. The residue is recrystallized from hexanechloroform affording the desired product as a crystalline solid (M.P. 107°-109° C.).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].[CH:17]1[CH:22]=[CH:21][C:20]([CH2:23]Br)=[CH:19][CH:18]=1>CC#N>[CH2:23]([N:1]([C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([O:10][CH2:8][C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=2)=[O:9])[CH2:4][CH2:3]1)[CH2:23][C:20]1[CH:21]=[CH:22][CH:17]=[CH:18][CH:19]=1)[C:20]1[CH:21]=[CH:22][CH:17]=[CH:18][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: N[C@H]1CC[C@H](C(=O)O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(OCc1ccccc1)[C@H]1CC[C@H](N(Cc2ccccc2)Cc2ccccc2)CC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To an 80° C. heated mixture of trans-4-Aminocyclohexanecarboxylic acid (8 g, 55.97 mmol) and K2CO3 (23.4 g) in 112 mL of CH3CN, was added dropwise a solution of BnBr (23.3 mL, 195.5 mmol) in 70 mL of CH3CN by addition funnel. Reaction stirred overnight at 80° C. The reaction was cooled to room temperature and filtered. Precipitate did not form in filtrate like it did with the cis-somer so the filtrate was concentrated to an oil and carried on to next step (23.01 g, 99% yield).
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Br:15][C:16]1[C:17]([OH:41])=[C:18]([C:23]([N:26]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:24][CH:25]=1)[C:19]([O:21][CH3:22])=[O:20].O[CH2:43][C@H:44]1[CH2:48][CH2:47][CH2:46][N:45]1[C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Br:15][C:16]1[C:17]([O:41][CH2:43][C@H:44]2[CH2:48][CH2:47][CH2:46][N:45]2[C:49]([O:51][C:52]([CH3:53])([CH3:55])[CH3:54])=[O:50])=[C:18]([C:19]([O:21][CH3:22])=[O:20])[C:23]([N:26]([C:27]([O:29][C:30]([CH3:33])([CH3:31])[CH3:32])=[O:28])[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[CH:24][CH:25]=1
Reactant: COC(=O)c1c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc(Br)c1O
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc(Br)c1OC[C@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.8 %

Procedure:
Diisopropyl azodicarboxylate (1.21 g) was added to a solution of methyl 3-bromo-6-bis-(tert-butoxycarbonyl)amino-2-hydroxybenzoate (Intermediate 9, 2.23 g), tert-butyl (R)-2-hydroxymethylpyrrolidine-1-carboxylate (1.11 g) and triphenylphosphine (1.57 g) in anhydrous THF (25 mL) and the reaction mixture was stirred at room temperature for 30 minutes, then left to stand overnight. The mixture was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-30% to give tert-butyl (R)-2-[6-bromo-3-bis-(tert-butoxycarbonyl)amino-2-methoxycarbonyl-phenoxymethyl]pyrrolidine-1-carboxylate (3.17 g) as a colourless gum.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[OH:20])[N:7]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH3:29][O:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35]Cl)=[CH:33][CH:32]=1>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[O:20][CH2:35][C:34]2[CH:37]=[CH:38][C:31]([O:30][CH3:29])=[CH:32][CH:33]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: COc1ccc(CCl)cc1
Reactant: CCOC(=O)c1cc(C)n(Cc2cc(Cl)ccc2O)n1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(C)n(Cc2cc(Cl)ccc2OCc2ccc(OC)cc2)n1
Temperature: 100 °C

Procedure:
To a solution of 1-(5-chloro-2-hydroxy-benzyl)-5-methyl-1H-pyrazole-3-carboxylic acid ethyl ester 2 0.2 g (0.6 mmol) in DMF (5 mL) were added potassium carbonate (0.23 g, 1.7 mmol), potassium iodide (0.1 g, 0.6 mmol) and 4-methoxybenzyl chloride (0.1 ml, 0.7 mmol). The resulting mixture was heated at 100° C. in an Emrys microwave reactor for 30 minutes. The volatiles were removed in vacuo. The crude product was purified on silica to yield 1-[5-chloro-2-(4-methoxy-benzyloxy)-benzyl]-5-methyl-1H-pyrazole-3-carboxylic acid ethyl ester 13 as a white solid.
Reaction SMILES: C([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1)C1C=CC=CC=1.C[OH:23]>C(O)(=O)C.[C].[Pd]>[C:18]([OH:17])(=[O:23])[CH3:21].[NH2:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(NCc2ccccc2)CC1
Reactant: CO
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(N)CC1
Reaction time: 8 h
Yield: 57 %

Procedure:
In methanol (2 ml) and acetic acid (30 ml), 4-benzylamino-1-tert-butoxycarbonylpiperidine (4.04 g) was dissolved, followed by the addition of 10% palladium carbon (water content: about 50%, 3.06 g). The resulting mixture was subjected to catalytic hydrogenation overnight under medium pressure (3 atmospheric pressure). After the removal of the catalyst by filtration, the filtrate was distilled off under reduced pressure. The residue was solidified in ethyl acetate, whereby the title compound (2.23 g, 57%) was obtained.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[C:9]([Cl:10])=[CH:8][S:7][CH:6]=1.[CH2:11]1[O:19][CH:12]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[OH:19][CH:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:11][N:2]([CH3:1])[CH2:3][CH2:4][C:5]1[C:9]([Cl:10])=[CH:8][S:7][CH:6]=1
Reactant: c1ccc(C2CO2)cc1
Reactant: CNCCc1cscc1Cl
Product: CN(CCc1cscc1Cl)CC(O)c1ccccc1

Procedure:
N-methyl 4-chloro-thiophene-3-ethylamine was reacted with styrene oxide as described in Example 20(b) to give the title product as an oil.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[C@H:9]2[O:10][C:11]([CH3:14])([CH3:13])[O:12][C@H:8]2[C@H:7]([N:15]2[CH:23]=[N:22][C:21]3[C:16]2=[N:17][CH:18]=[N:19][C:20]=3Cl)[CH2:6]1)=[N+:2]=[N-:3].[CH3:25][O:26][C:27]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:28]=1[CH2:35][NH2:36].C(N(CC)C(C)C)(C)C>C(O)CCC>[N:1]([CH2:4][C@@H:5]1[C@H:9]2[O:10][C:11]([CH3:14])([CH3:13])[O:12][C@H:8]2[C@H:7]([N:15]2[CH:23]=[N:22][C:21]3[C:16]2=[N:17][CH:18]=[N:19][C:20]=3[NH:36][CH2:35][C:28]2[CH:29]=[CH:30][C:31]([O:33][CH3:34])=[CH:32][C:27]=2[O:26][CH3:25])[CH2:6]1)=[N+:2]=[N-:3]
Reactant: CC1(C)O[C@@H]2[C@@H](CN=[N+]=[N-])C[C@@H](n3cnc4c(Cl)ncnc43)[C@@H]2O1
Reactant: COc1ccc(CN)c(OC)c1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNc2ncnc3c2ncn3[C@@H]2C[C@H](CN=[N+]=[N-])[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Temperature: 80 °C

Procedure:
A solution of 9-((3aS,4R,6R,6aR)-6-(azidomethyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-6-chloro-9H-purine (1.29 g, 3.69 mmol) and (2,4-dimethoxyphenyl)methanamine (0.71 mL, 4.7 mmol) in 1-butanol (10 mL) was treated with N,N-diisopropylethylamine (0.93 mL, 5.3 mmol) and heated at 80° C. for 16.5 h; HPLC/LC MS indicated conversion to the desired product. The reaction mixture was allowed to cool to rt and the volatiles were removed under the flow of air to afford a brown-orange paste. Purification by column chromatography (2×8 cm silica; 0-10% acetone/CH2Cl2) afforded the title compound (1.72 g, 97%) as a yellow-orange foam/oil: MS (ESI+) for C22H28N8O4 m/z 481.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:5]=[C:6]2[CH:12]=[C:11]([C:13]([OH:15])=O)[S:10][C:7]2=[N:8][CH:9]=1)[CH3:2].S(Cl)([Cl:18])=O>>[CH2:1]([O:3][C:4]1[N:5]=[C:6]2[CH:12]=[C:11]([C:13]([Cl:18])=[O:15])[S:10][C:7]2=[N:8][CH:9]=1)[CH3:2]
Reactant: CCOc1cnc2sc(C(=O)O)cc2n1
Reactant: O=S(Cl)Cl
Product: CCOc1cnc2sc(C(=O)Cl)cc2n1
Yield: 100 %

Procedure:
A solution of 2-ethoxythieno[2,3-b]pyrazine-6-carboxylic acid (30 mg, 0.134 mmol) in thionyl chloride (1 mL) was stirred at 80° C. for 2 h. Evaporated to dryness and co-evaporated with toluene to give 2-ethoxythieno[2,3-b]pyrazine-6-carbonyl chloride (32 mg, 100%).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]2([NH:11][C:12]([C:14]3[C:15]4[CH:22]=[N:21][N:20]([C:23]5[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=5)[C:16]=4[CH:17]=[N:18][CH:19]=3)=[O:13])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>CS(C)=O.CCOC(C)=O>[N:30]1([C:2]2[N:7]=[CH:6][C:5]([C:8]3([NH:11][C:12]([C:14]4[C:15]5[CH:22]=[N:21][N:20]([C:23]6[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=6)[C:16]=5[CH:17]=[N:18][CH:19]=4)=[O:13])[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1
Reactant: O=C(NC1(c2ccc(Br)nc2)CC1)c1cncc2c1cnn2-c1ccc(F)cc1
Reactant: C1COCCN1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=C(NC1(c2ccc(N3CCOCC3)nc2)CC1)c1cncc2c1cnn2-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
A solution of 1-(4-fluoro-phenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid [1-(6-bromo-pyridin-3-yl)-cyclopropyl]-amide (35 mg, 0.077 mmol) and morpholine (68 μL, 0.77 mmol) in DMSO (1 mL) is heated in a pressure tube at 160° C. After 40 hours, the mixture is cooled to room temperature, diluted with EtOAc (50 mL) and washed with saturated aqueous ammonium chloride (2×50 mL), saturated aqueous sodium bicarbonate (50 mL), brine (50 mL), dried over MgSO4, filtered and concentrated. The resulting solid is purified by silica gel chromatography eluting with a gradient of 0-5% methanol in dichloromethane to give a solid, which is triturated with ether (5 mL), filtered and dried to afford the title compound.