Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:7][O:6][CH:5]([C:8]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[CH:15][C:9]=2/[C:10](/[NH:13][OH:14])=[N:11]/[H])[O:4][CH2:3]1.[CH2:24]1CCN2C(=NCCC2)C[CH2:25]1.C(OC(=O)C)(=O)C>CN(C=O)C>[CH3:1][C:2]1([CH3:23])[CH2:7][O:6][CH:5]([C:8]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[CH:15][C:9]=2[C:10]2[N:11]=[C:24]([CH3:25])[O:14][N:13]=2)[O:4][CH2:3]1
Reactant: C1CCC2=NCCCN2CC1
Reactant: [H]/N=C(\NO)c1cc(OC)c(OC)cc1C1OCC(C)(C)CO1
Solvent: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(-c2noc(C)n2)c(C2OCC(C)(C)CO2)cc1OC
Reaction time: 1 h

Procedure:
A mixture of 1.34 g of (E)- and/or (Z)-2-(5,5-dimethyl-[1,3]dioxan-2-yl)-N-hydroxy-4,5-dimethoxy-benzamidine, 1.20 ml of DBU and 0.61 ml of acetic anhydride in 50 ml of DMF was stirred for 1 hr. at room temperature and subsequently for 2 hrs. at 80° C. Subsequently, the DMF was removed in a vacuum and the residue was taken up in ethyl acetate. The ethyl acetate phase was washed with water and saturated NaCl solution and, after removal of the solvent, the residue was purified by column chromatography (CH2Cl2/ethyl acetate). There were obtained 0.43 g of 3-[2-(5,5-dimethyl-[1,3]dioxan-2-yl)-4,5-dimethoxy-phenyl]-5-methyl-[1,2,4]oxadiazole as a white solid; MS: 334 ([M]+).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][CH2:8][C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1.Cl.Cl[CH2:18][CH2:19][CH2:20][N:21]([CH3:23])[CH3:22].O>CN(C=O)C>[CH3:22][N:21]([CH3:23])[CH2:20][CH2:19][CH2:18][O:15][C:11]1[CH:10]=[C:9]([CH2:8][OH:7])[CH:14]=[CH:13][CH:12]=1
Reactant: OCc1cccc(O)c1
Reactant: CN(C)CCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCCOc1cccc(CO)c1
Temperature: 80 °C

Procedure:
Cesium carbonate (15.4 g) was added to a solution of 3-hydroxymethyl-phenol (3 g) in DMF (80 mL). To this mixture was added (3-chloro-propyl)-dimethyl-amine hydrochloride (4 g). The mixture was heated at 80° C. for 20 hours then allowed to cool. The reaction mixture was poured into water and extracted with ethyl acetate.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[CH2:12][C@H:11]([NH:13][C:14]2[C:15]([NH2:21])=[CH:16][CH:17]=[C:18]([F:20])[CH:19]=2)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([O:26][C:27]([NH:29][C@@H:30]([CH3:34])[C:31](O)=O)=[O:28])([CH3:25])([CH3:24])[CH3:23].C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:22]([O:26][C:27](=[O:28])[NH:29][C@H:30]([C:31]1[N:13]([C@H:11]2[CH2:12][C@@H:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:10]2)[C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[N:21]=1)[CH3:34])([CH3:25])([CH3:24])[CH3:23]
Reactant: Nc1ccc(F)cc1N[C@H]1C[C@@H](OCc2ccccc2)C1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2n1[C@H]1C[C@@H](OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of N2-(cis-3-benzyloxycyclobutyl)-4-fluorobenzene-1,2-diamine (1.13 g, 3.95 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (0.83 g, 4.35 mmol) and HOAt (0.59 g, 4.35 mmol) in DCM (20 mL) was cooled to 0° C. under nitrogen atmosphere. To this mixture N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (0.83 g, 4.35 mmol) was added portion wise and the reaction mixture stirred at RT for 1 h. The reaction mixture allowed to warm to RT then partitioned between DCM and a 10% aq. citric acid. The organic fraction was washed with brine (20 mL), dried (MgSO4), concentrated in vacuo and the resulting dark brown residue purified by column chromatography (Si—PCC, gradient 0-40% EtOAc in cyclohexane) to afford the title compound as a yellow gum, which solidified on standing (1.93 g, 93%). 1H NMR (CDCl3, 400 MHz): δ 7.46 (1H, s, br), 7.36-7.30 (5H, m), 7.11 (1H, q, J=14.8 Hz, 2.5 Hz), 6.37 (1H, dt, J=19.5 Hz, 2.8 Hz), 6.25 (1H, dd, J=14 Hz, 2.82 Hz), 4.94 (1H, d, J=5.83 Hz), 4.43 (2H, s), 4.23-4.07 (1H, m), 3.93-3.81 (1H, m), 3.47-3.35 (1H, m), 2.88-2.75 (1H, m), 2.03-1.85 (1H, m), 1.45 (3H, d, J=2.46 Hz), 1.43 (9H, s). LCMS (Method B): RT 3.88 min [M+H]+ 458. 110183151. The compound thus obtained (1 g, 2.19 mmol) was dissolved in AcOH (15 mL) and heated at 70° C. for 18 h. After cooling to RT, the volatiles were evaporated under reduced pressure and the residue partitioned between DCM (40 mL) and a saturated solution of NaHCO3 (20 mL). The organic fraction was washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo. The resulting dark yellow residue was purified by column chromatography (Si—PCC, gradient 0-50% EtOAc in cyclohexane) to afford the title compound as pale red gum (570 mg, 60%). LCMS (Method B): RT 3.61 min [M+H]+ 440.0. 1H NMR (CDCl3, 400 MHz): δ 7.70-7.60 (2H, m), 7.44-7.37 (5H, m), 7.05-6.96 (1H, m), 5.38-5.26 (1H, m), 5.20-5.05 (1H, m), 4.82-4.68 (1H, m), 4.55 (2H, s), 4.10-3.97 (1H, m), 3.02-2.77 (4H, m), 1.47 (3H, d, J=2.44 Hz), 1.44 (9H, s).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([F:22])=[C:16]2[C:21]=1[N:20]=[CH:19][CH:18]=[CH:17]2)(=[O:10])=[O:9].N(OC(C)(C)C)=O.CC(O)=O>C1COCC1>[F:22][C:15]1[CH:14]=[C:13]2[C:12](=[C:21]3[C:16]=1[CH:17]=[CH:18][CH:19]=[N:20]3)[NH:11][S:8](=[O:10])(=[O:9])[C:3]1[C:4]2=[CH:5][CH:6]=[CH:7][CH:2]=1
Reactant: Nc1ccccc1S(=O)(=O)Nc1ccc(F)c2cccnc12
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=S1(=O)Nc2c(cc(F)c3cccnc23)-c2ccccc21
Yield: 10 %

Procedure:
In a similar fashion using route 16 general procedure 61, 2-amino-N-(5-fluoro-quinolin-8-yl)-benzenesulfonamide (Intermediate 291) (350 mg, 1.1 mmol), t-butyl nitrite (0.2 ml, 1.65 mmol), AcOH (3.5 ml) and THF (3.5 ml) gave the title compound (33 mg, 10%) after purification by column chromatography with DCM/MeOH (99:1) as the eluent followed by recrystallisation with DCM/pentane.
Reaction SMILES: [C:1]1([CH:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[CH2:27][Cl:28].[ClH:34]>C(C(C)=O)C>[ClH:28].[ClH:34].[C:16]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][N:13]([CH2:27][C:26]3[CH:29]=[CH:30][C:31]([O:32][CH3:33])=[C:24]([O:23][CH3:22])[CH:25]=3)[CH2:14][CH2:15]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: c1ccc(C(CCN2CCNCC2)c2ccccc2)cc1
Reactant: COc1ccc(CCl)cc1OC
Agent: Cl
Solvent: CCC(C)=O
Product: COc1ccc(CN2CCN(CCC(c3ccccc3)c3ccccc3)CC2)cc1OC
Yield: 87.4 %

Procedure:
N-3,3-Diphenylpropylpiperazine in the amount of 2.8 g (0.01 mole) and 1.87 g (0.01 mole) of 3,4-dimethoxybenzyl chloride were dissolved in 20 ml of methyl ethyl ketone, and the resulting solution was heated at the refluxing temperature for 7.5 hours. After the reaction liquid was left to cool, dry hydrogen chloride gas was passed through the liquid while cooling the liquid to precipitate 1-(3,3-diphenylpropyl)-4-(3,4-dimethoxybenzyl)piperazine dihydrochloride. The crystals of this salt were recrystallized from an ethanol and ether mixed solvent to obtain 4.4 g (87.4% yield) of pure crystals with a melting point of 184°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])[CH2:14][CH:13]2[C:28](O)=[O:29])(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl.[C:32]([O:36][NH2:37])([CH3:35])([CH3:34])[CH3:33].CN(C1C=CC=CN=1)C>C(Cl)Cl>[C:32]([O:36][NH:37][C:28]([CH:13]1[CH2:14][N:15]([C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])[CH2:16][CH2:17][N:12]1[S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10])=[O:29])([CH3:35])([CH3:34])[CH3:33]
Reactant: COc1ccc(S(=O)(=O)N2CCN(C(=O)OCc3ccccc3)CC2C(=O)O)cc1
Reactant: CC(C)(C)ON
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N2CCN(C(=O)OCc3ccccc3)CC2C(=O)NOC(C)(C)C)cc1
Reaction time: 8 h

Procedure:
To a solution of (+)-1-(4-methoxybenzenesulfonyl)-4-benzyloxycarbonyl-2-piperazinecarboxylic acid (100 mg, 0.23 mmol) in methylene chloride (5 ml) is added O-t-butylhydroxylamine hydrochloride (35 mg, 0.28 mmol), dimethylaminopyridine (37 mg, 0.30 mmol), and dicyclohexycarbodiimide (57 mg, 0.28 mmol). After stirring overnight, the reaction is diluted with hexanes and the precipitated solid filtered off. The solution is concentrated and the crude product is purified by silica gel chromatography (elution with 2:1 ethyl acetate-hexanes with 1% acetic acid) to provide (+)-N-(t-butyloxy)-1-(4-methoxybenzenesulfonyl)-4-benzyloxycarbonyl-2-piperazinecarboxamide.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH:11]([CH3:13])[SH:12])=[CH:9][C:4]=2[O:3][CH2:2]1.[SH:14][CH2:15][CH2:16][OH:17]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH:11]([S:12][S:14][CH2:15][CH2:16][OH:17])[CH3:13])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: OCCS
Reactant: CC(S)Cc1ccc2c(c1)OCO2
Product: CC(Cc1ccc2c(c1)OCO2)SSCCO
Yield: 64 %

Procedure:
5.0 g of the title compound was prepared from 8.4 g of 2-(1,3-benzodioxol-5-yl)-1-methylethanethiol and 2.24 g of 2-mercaptoethanol as a colorless oil according to the same procedure as that described in Example 1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B1C2CCCC1CCC2.C1C=C[NH+]=CC=1.[O-:37][Cr](Cl)(=O)=O>C1COCC1.CCOCC>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]2([C:21]3[CH:16]([CH2:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:37])[CH2:14]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[Cr](=O)([O-])Cl
Reactant: CC(C)(C)OC(=O)N1CCC2(C=Cc3ccccc32)CC1
Agent: B1C2CCCC1CCC2
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)C1CC=CC=C12
Temperature: 70 °C
Yield: 46.5 %

Procedure:
To a solution of 661 mg (2.31 mmol) of 1'-(t-butyloxycarbonyl)spiro[1H-indene-1,4'-piperidine][prepared by the method of Chambers, et al, J. Med. Chem., 1992, 35, 2036] in 5.0 ml of THF was added 5.8 ml (1.0M THF, 2.9 mmol) of 9-BBN. The reaction mixture was heated at 70° C. until TLC analysis indicated that the starting material was consumed. The solution was concentrated and the residue was dissolved in dichloromethane. The solution was cooled to 0° C. and 4.1 g (19.2 mmol) of PCC was added slowly over 15 minutes. The reaction mixture was warmed to room temperature and then to reflux for 30 minutes. The solution was then diluted with ether and filtered through a pad of a mixture of celite and florisil. Purification by flash chromotgraphy (silica gel, hexane/ethyl acetate, 4:1) gave 326 mg (47%) of the title compound.
Reaction SMILES: Br.[CH2:2]([N:17]([CH2:19][CH:20]([OH:29])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])C)[CH2:3][N:4]([CH2:6][CH:7]([OH:16])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])C>>[CH2:3]([NH:4][CH2:6][CH:7]([OH:16])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:2][NH:17][CH2:19][CH:20]([OH:29])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCC(O)CN(C)CCN(C)CC(O)CCCCCCCC
Agent: Br
Product: CCCCCCCCC(O)CNCCNCC(O)CCCCCCCC

Procedure:
In a manner similar to that of Example 22, methylation of N,N'-ethylenebis[2-hydroxydecylamine] (15 g.) and treatment of the resulting product with hydrogen bromide gave N,N'ethylene-bis[N-methyl-2-hydroxydecylamine] (I: R= CH3 (CH2)7, R' = CH3, X= (CH2)2, Z= H) dihydrobromide (4.0 g., m.p. 152.0°-164.0° C.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.S(=O)(=O)(O)O.[Br:17]N1C(=O)CCC1=O>FC(F)(F)C(O)=O.C(OCC)(=O)C>[Br:17][C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]=1[CH3:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(F)cc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: Cc1c(Br)cc(F)cc1[N+](=O)[O-]
Reaction time: 24 h
Yield: 82.2 %

Procedure:
To a solution of 4-fluoro-2-nitrotoluene (2.0 g) in trifluroacetic acid (8 ml) was added concentrated sulfuric acid (2.5 ml) followed by N-bromosuccinimide (3.4 g). After stirring for 24 hours the reaction mixture was then diluted with ethyl acetate, washed with water, brine, dried (MgSO4) and the solvent removed in vacuo. The residue was purified by flash chromatography to give 1-bromo-5-fluoro-2-methyl-3-nitro-benzene (2.48 g).
Reaction SMILES: [H-].[Na+].[CH3:3][NH:4][C:5](=[O:9])[CH2:6][C:7]#[N:8].[F:10][C:11]([F:22])([F:21])[C:12]1[CH:17]=[CH:16][C:15]([N:18]=[C:19]=[O:20])=[CH:14][CH:13]=1>CCCCCC.C1COCC1>[CH3:3][NH:4][C:5](=[O:9])[CH:6]([C:19](=[O:20])[NH:18][C:15]1[CH:16]=[CH:17][C:12]([C:11]([F:10])([F:22])[F:21])=[CH:13][CH:14]=1)[C:7]#[N:8]
Reactant: CNC(=O)CC#N
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CNC(=O)C(C#N)C(=O)Nc1ccc(C(F)(F)F)cc1
Yield: 62.4 %

Procedure:
Sodium hydride (0.82 g, 20.4 mmoles), washed with Skellysolve B, was suspended in 20 ml of dry THF and treated at 15° C. with N-methylcyanoacetamide (2.0 g, 20.4 mmoles) [prepared in Step A]. The resultant suspension was further cooled to 5° C. and 4-trifluoromethylphenyl isocyanate (3.80 g, 20.4 mmoles) was added over several minutes. After 18 h at ambient temperature the solvent was removed and the residual syrup was poured into a cold mixture of water and 4 ml of 6N HCl. The precipitate was isolated by filtration and recrystallized from ethanol to give 3.63 g of the title compound, mp 184°-186° C.
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5](=[O:27])[CH2:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH2:25][CH3:26])[CH:12]=1.[C:28]1([CH2:34][C:35]([OH:37])=O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH3:3][O:4][C:5](=[O:27])[CH2:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][C:14]=2[CH2:23][N:24]([CH2:25][CH3:26])[C:35](=[O:37])[CH2:34][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:12]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cncc(CC(=O)OC)c1
Agent: Cl
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cncc(CC(=O)OC)c1)C(=O)Cc1ccccc1

Procedure:
[5-(2-Ethylaminomethyl-4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetic acid methyl ester, dihydrochloride and phenyl-acetic acid were reacted as described in Example 8, Step 6 to provide (5-{2-[(N-ethyl-N-phenylacetyl-amino)-methyl]-4-trifluoromethyl-phenyl}-pyridin-3-yl)-acetic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].F[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N+:17]([C:14]1[CH:15]=[CH:16][C:11]([O:9][C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=2)=[CH:12][CH:13]=1)([O-:19])=[O:18]
Reactant: Oc1ccc(F)c(Cl)c1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(Oc2ccc(F)c(Cl)c2)cc1
Yield: 92.7 %

Procedure:
To a solution of 3-chloro-4-fluorophenol (1.46 g, 10 mmol) and 1-fluoro-4-nitrobenzene (1.41 g, 10 mmol) in acetonitrile (40 mL) was added potassium carbonate (2.76 g, 20 mmol). The reaction mixture was heated at reflux for 4 hours. After filtration, the solvent was removed to give a residue. The residue was washed with n-hexane (2 times 15 mL) and dried to afford the title compound (2.48 g) which was directly used in the next step.
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([O:15][C:16]2[C:21]([NH:22][C:23]3[C:24]4[C:31]([CH3:32])=[C:30]([C:33](O)=[O:34])[S:29][C:25]=4[N:26]=[CH:27][N:28]=3)=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:11][CH2:10]1)=O)(C)(C)C.[CH2:36]([NH2:39])[CH2:37][CH3:38]>C(Cl)Cl>[CH2:36]([NH:39][C:33]([C:30]1[S:29][C:25]2[N:26]=[CH:27][N:28]=[C:23]([NH:22][C:21]3[C:16]([O:15][CH:12]4[CH2:11][CH2:10][CH:9]([NH2:8])[CH2:14][CH2:13]4)=[N:17][CH:18]=[CH:19][CH:20]=3)[C:24]=2[C:31]=1[CH3:32])=[O:34])[CH2:37][CH3:38]
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3cccnc3OC3CCC(NC(=O)OC(C)(C)C)CC3)c12
Reactant: CCCN
Solvent: ClCCl
Product: CCCNC(=O)c1sc2ncnc(Nc3cccnc3OC3CCC(N)CC3)c2c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 0.1 g 4-[2-(4-tert-butoxycarbonylamino-cyclohexyloxy)-pyridin-3-ylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid, 39.689 μl chlor-trimethyl-propylenamine, 24 μl propylamine, 30.664 μl TEA and 5 ml DCM was stirred at rt overnight. The reaction mixture was washed successively with 0.1 M hydrochloric acid and 0.1 M sodium hydroxide solution, dried and filtered. The filtrate was concentrated. The residue was triturated with diethylether.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Br:11][C:12]1[CH:13]=[C:14]2[C:19](=[N:20][C:21]=1[CH:22]([O:25][CH3:26])[O:23][CH3:24])[N:18]([C:27]([O:29]C1C=CC=CC=1)=O)[CH2:17][CH2:16][CH2:15]2.[NH2:36][C:37]1[CH:44]=[C:43]([NH:45][CH2:46][CH2:47][O:48][CH3:49])[C:40]([C:41]#[N:42])=[CH:39][N:38]=1>C1COCC1>[Br:11][C:12]1[CH:13]=[C:14]2[C:19](=[N:20][C:21]=1[CH:22]([O:23][CH3:24])[O:25][CH3:26])[N:18]([C:27]([NH:36][C:37]1[CH:44]=[C:43]([NH:45][CH2:46][CH2:47][O:48][CH3:49])[C:40]([C:41]#[N:42])=[CH:39][N:38]=1)=[O:29])[CH2:17][CH2:16][CH2:15]2
Reactant: COC(OC)c1nc2c(cc1Br)CCCN2C(=O)Oc1ccccc1
Reactant: COCCNc1cc(N)ncc1C#N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COCCNc1cc(NC(=O)N2CCCc3cc(Br)c(C(OC)OC)nc32)ncc1C#N
Temperature: -25 °C
Reaction time: 0.58 h

Procedure:
LHMDS (1M in THF, 0.36 mL, 0.360 mmol) was added to a solution of phenyl 6-bromo-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (intermediate 11, 148 mg, 0.345 mmol) and 6-amino-4-((2-methoxyethyl)amino)nicotinonitrile (intermediate 75, 70 mg, 0.346 mmol) in THF (3 ml) at −70° C. and stirred for 35 min. The reaction mixture was allowed to warm to −25° C., stirred for 5 min and cooled to −70° C. while stirring for 30 min. The reaction mixture was allowed to warm to −15° C., stirred for 10 min, cooled to −70° C. and quenched with saturated aqueous NH4Cl. The reaction mixture was diluted with water and ethyl acetate, layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, dried using Na2SO4, filtered and evaporated. The crude product was purified by silica gel column chromatography eluting with a gradient ethyl acetate (90-100%) in heptane. Product fractions were combined, evaporated and dried to yield the title compound as a yellow solid. (UPLC-MS 3) tR 1.16 min, ESI-MS 505.1 [M+H]+. 1H NMR (600 MHz, CDCl3) δ 8.23 (s, 1H), 7.65 (s, 1H), 7.57 (s, 1H), 5.68 (s, 1H), 5.26-5.21 (m, 1H), 4.06-4.00 (m, 2H), 3.62 (t, 2H), 3.51-3.44 (m, 8H), 3.40 (s, 3H), 2.84 (t, 2H), 2.03-1.96 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].ClCCl.[C:14]12(O)[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2.S(=O)(=O)(O)O>O>[C:14]12([C:7]3[C:8]([OH:10])=[CH:9][C:2]([OH:1])=[C:3]([CH:6]=3)[CH:4]=[O:5])[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2
Reactant: OC12CC3CC(CC(C3)C1)C2
Reactant: O=Cc1ccc(O)cc1O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClCCl
Product: O=Cc1cc(C23CC4CC(CC(C4)C2)C3)c(O)cc1O
Temperature: 25 °C

Procedure:
40 g (0.29 mol) of 2,4-dihydroxybenzaldehyde, 600 ml of dichloromethane and 46.4 g (0.34 mol) of 1-adamantanol were introduced into a round-bottomed flask and 24 ml of concentrated sulfuric acid were added. The reaction medium was stirred at room temperature for twelve hours and was then poured into water. The organic phase was separated out after settling had taken place, dried over magnesium sulfate and evaporated. The residue obtained was purified by chromatography on a column of silica, eluted with dichloromethane. 50.8 g (64%) of the expected aldehyde, having a melting point of 259°-61° C., were recovered.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[N+:9]([C:12]1[N:13]=[CH:14][NH:15][CH:16]=1)([O-:11])=[O:10].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:15]2[CH:16]=[C:12]([N+:9]([O-:11])=[O:10])[N:13]=[CH:14]2)[CH:7]=1
Reactant: O=[N+]([O-])c1c[nH]cn1
Reactant: Cc1ccnc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccnc(-n2cnc([N+](=O)[O-])c2)c1
Temperature: 130 °C
Reaction time: 21 h
Yield: 34.2 %

Procedure:
A suspension of 2-fluoro-4-methylpyridine (1.11 g), 4-nitroimidazole (1.24 g) and potassium carbonate (1.65 g) in N,N-dimethylformamide (10 ml) was stirred at 130° C. for 21 hours. After cooling, the mixture was poured into water and stirred for 30 minutes. The precipitate was collected by filtration and dried to give 1-(4-methylpyridin-2-yl)-4-nitroimidazole (698 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[NH:21][CH:22]=[CH:23][C:16]=34)=[CH:13][N:12]([CH2:24][C:25]([OH:27])=[O:26])[N:11]=2)=[CH:6][CH:5]=1)([O-])=O.[Sn].Cl.[C:30]1([N:36]=[C:37]=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(O)C>[C:30]1([NH:36][C:37]([NH:1][C:4]2[CH:9]=[CH:8][C:7]([C:10]3[C:14]([C:15]4[CH:20]=[CH:19][N:18]=[C:17]5[NH:21][CH:22]=[CH:23][C:16]=45)=[CH:13][N:12]([CH2:24][C:25]([OH:27])=[O:26])[N:11]=3)=[CH:6][CH:5]=2)=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C=Nc1ccccc1
Reactant: O=C(O)Cn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc([N+](=O)[O-])cc2)n1
Agent: Cl
Agent: [Sn]
Solvent: CCO
Product: O=C(O)Cn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc(NC(=O)Nc3ccccc3)cc2)n1
Temperature: 70 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
A heterogeneous mixture of [3-(4-nitrophenyl)-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]acetic acid (31.0 mmol), elemental tin dust (5.30 mmol), 6.0N aqueous hydrochloric acid (5.3 mL) and absolute ethanol (5.3 mL) was stirred at 70° C. for 1 h. The solution was filtered through Celite and concentrated in vacuo. The resulting aniline was dissolved in anhydrous pyridine (10 mL) and phenyl isocyanate (11.17 mmol) added dropwise. The reaction mixture was stirred at room temperature for 4 h. After concentration in vacuo, purification by Gilson reverse phase HPLC afforded the title compound as a white solid (93%). ESMS [M+H]+: 453.2
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[C:4]([NH2:6])=[S:5].[CH:14]1(N)[CH2:16][CH2:15]1>O>[CH:14]1([NH:6][C:4](=[S:5])[CH:3]([N:2]([CH3:13])[CH3:1])[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:16][CH2:15]1
Reactant: NC1CC1
Reactant: CN(C)C(C(N)=S)c1ccccn1
Solvent: O
Product: CN(C)C(C(=S)NC1CC1)c1ccccn1

Procedure:
A mixture of 2-dimethylamino-2-(2-pyridyl)thioacetamide and 40% aqueous solution of cyclopropylamine is heated at reflux for 45 minutes. The mixture is cooled and water is added. The mixture is then extracted with chloroform and the extracts are dried, concentrated and the residue is recrystallized to give N-cyclopropyl-2-dimethylamino-2-(2-pyridyl)thioacetamide.