Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:10]=[C:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[C:17](Br)[CH:16]=[CH:15][C:14]=2[O:20][CH2:21][CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[N:7]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:47][Si:48]([C:51]#[CH:52])([CH3:50])[CH3:49]>CN(C=O)C.[Cu]I>[CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:10]=[C:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[C:17]([C:52]#[C:51][Si:48]([CH3:50])([CH3:49])[CH3:47])[CH:16]=[CH:15][C:14]=2[O:20][CH2:21][CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[N:7]=1
Reactant: CCC(CC)COc1ccc(Br)cc1Cn1nc(CCC(=O)OC)cc1C
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCC(CC)COc1ccc(C#C[Si](C)(C)C)cc1Cn1nc(CCC(=O)OC)cc1C
Temperature: 120 °C
Yield: 48.4 %

Procedure:
A mixture of 3-{1-[5-Bromo-2-(2-ethyl-butoxy)-benzyl]-5-methyl-1H-pyrazol-3-yl}-propionic acid methyl ester (0.0774 g, 0.18 mmol), [PdCl2(PPh3)]2 (0.007 g, 0.01 mmol), PPh3 (0.0094 g, 0.018 mmol) mmol), CuI (2 mg, 0.01 mmol), trimethylsilylacetylene (0.0196 g, 0.2 mmol), Et2N (0.07314 g, 2.72 mmol in DMF (1 ml) heated at 120° C. in a microwave reactor under a N2 atmosphere for 50 min. The mixture was partitioned between 0.1M HCl and EtOAc. The organic layer was washed with brine, dried (MgSO4) and evaporated to dryness. The residue was purified by MPLC (20 g SiO2 cartridge, eluent 90% iso-hexane-10% EtOAc) yielding 3-{1-[5-trimethylsilanylethynyl-2-(2-ethyl-butoxy)-benzyl]-5-methyl-1H-pyrazol-3-yl}-propionic acid methyl ester (0.0396 g). This was dissolved in THF (20 ml), MeOH (20 ml), glacial acetic acid (8 ml) and Bu4NF solution (24 ml, 1M) was added. The mixture was stirred at RT overnight then heated at 60° C. for 3 hours, thereafter cooled to RT and partitioned between sat. NH4Cl solution and EtOAc, the organic layer was washed with brine, dried (MgSO4) and evaporated to dryness. The residue was purified by MPLC (20 g SiO2 cartridge, eluent 85% iso-hexane-15% EtOAc) yielding 3-{1-[5-Ethynyl-2-(2-ethyl-butoxy)-benzyl]-5-methyl-1H-pyrazol-3-yl}-propionic acid methyl ester (0.0078 g) which was converted to the title compound following the method in Example 1, Step 8.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][NH2:15])[CH:5]=[CH:6][CH:7]=1.C(=O)(O)[O-].[Na+].I[CH2:22][C:23]([NH2:25])=[O:24]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][NH:15][CH2:22][C:23]([NH2:25])=[O:24])[CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)CI
Reactant: NCc1ccccc1-c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: NC(=O)CNCc1ccccc1-c1cccc(Cl)c1

Procedure:
A reaction vessel was charged with 8.8 g (40 mmole) of [(3-chlorophenyl)phenyl]methylamine, 4.2 g (50 mmole) of sodium bicarbonate, 7.4 g (40 mmole) of iodoacetamide and 200 ml of absolute ethanol. The resulting suspension was brought to reflux and held at reflux for 18 hours. Solvent was evaporated and the residue was dissolved in dichloromethane. The organic phase was washed with water, dried over potassium carbonate and evaporated. The oil was dissolved in a minimum of ethanol, to which was added a solution of chlorhydric acid in ether. An oil was decanted which crystallized upon stirring. The white solid was then precipitated from ethanol by addition of ether.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([NH:14][CH3:15])=[O:13])[CH:3]=1.Cl.[F:20][C:21]1[CH:31]=[CH:30][C:24]([O:25][CH:26]2[CH2:29][NH:28][CH2:27]2)=[CH:23][CH:22]=1.C(N(CC)C(C)C)(C)C>CC(O)C>[F:20][C:21]1[CH:31]=[CH:30][C:24]([O:25][CH:26]2[CH2:27][N:28]([C:2]3[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]4[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=4)[C:12]([NH:14][CH3:15])=[O:13])[CH:3]=3)[CH2:29]2)=[CH:23][CH:22]=1
Reactant: CNC(=O)c1cccc(Nc2cc(Cl)ncn2)c1
Reactant: Fc1ccc(OC2CNC2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CNC(=O)c1cccc(Nc2cc(N3CC(Oc4ccc(F)cc4)C3)ncn2)c1
Temperature: 84 °C
Yield: 100 %

Procedure:
To 3-(6-chloropyrimidin-4-ylamino)-N-methylbenzamide (90.0 mg, 0.343 mmol) and 3-(4-fluorophenoxy)azetidine hydrochloride (73.3 mg, 0.360 mmol) in a disposable sealed tube at RT was added 2-propanol (2 mL) followed by N,N-diisopropylethylamine (0.179 mL, 1.028 mmol). The resulting reaction mixture was heated to 84° C. for 51 h, cooled to RT, concentrated, purified using MPLC (5 g cartridge, 12 g column, 0 to 65% 90/10 CH2Cl2-MeOH in CH2Cl2) giving 3-(6-(3-(4-fluorophenoxy)azetidin-1-yl)pyrimidin-4-ylamino)-N-methylbenzamide (135.0 mg).
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][CH:12]=[C:11]3[C:17]2[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH:22]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:26]=1[C:27](Cl)=[O:28]>>[CH:1]1([O:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[N:13]([C:27](=[O:28])[C:26]2[C:25]([Cl:24])=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:34])[CH:12]=[C:11]3[C:17]2[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH:22]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1CC=C(c2c[nH]c3ccc(OC4CCCCC4)cc23)CC1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Product: CN1CC=C(c2cn(C(=O)c3c(Cl)cccc3Cl)c3ccc(OC4CCCCC4)cc23)CC1

Procedure:
(40.1 mg, 100%); from 5-cyclohexyloxy-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (Example 4c, 25.7 mg, 0.083 mmol) and 2,6-dichlorobenzoyl chloride (30 uL, 0.21 mmol); HRMS-FAB+ for C27H28N2O2Cl2 : calculated MH+ : 483.16061; found: 483.15611.
Reaction SMILES: CO[CH:3]1[C:12]2C(=CC=C[CH:11]=2)C(C)[CH2:5][CH2:4]1.[CH:14]([C:17]1[CH:31]=[C:30]([CH3:32])[C:29](C=CC=CC)=[CH:28][C:18]=1[O:19][C:20]1[C:21]([NH2:27])=[N:22][C:23]([NH2:26])=[N:24][CH:25]=1)([CH3:16])[CH3:15]>>[CH:14]([C:17]1[CH:31]=[C:30]([CH3:32])[C:29]([C:12]([CH3:11])=[CH:3][CH:4]=[CH2:5])=[CH:28][C:18]=1[O:19][C:20]1[C:21]([NH2:27])=[N:22][C:23]([NH2:26])=[N:24][CH:25]=1)([CH3:16])[CH3:15]
Reactant: CC=CC=Cc1cc(Oc2cnc(N)nc2N)c(C(C)C)cc1C
Reactant: COC1CCC(C)c2ccccc21
Product: C=CC=C(C)c1cc(Oc2cnc(N)nc2N)c(C(C)C)cc1C

Procedure:
Similarly prepared, following the procedure of Example 2 but starting with 4-methoxy-1-methyl-1,2,3,4-tetrahydro-naphthalene instead of 7-methoxy-1-methyl-1,2,3,4-tetrahydro-naphthalene, was 5-(2-isopropyl-4-methyl-5-penta-1,3-dienyl-phenoxy)-pyrimidine-2,4-diamine, MP=148° C., MS (M+H)=309.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([O:14][CH3:15])[CH:6]=1.[CH2:16]([NH:18][CH2:19][CH3:20])[CH3:17].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.ClCCl>[CH2:16]([N:18]([CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([O:14][CH3:15])[CH:6]=1)[CH2:19][CH3:20])[CH3:17]
Reactant: CCNCC
Reactant: COc1cc(OCCCl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: CCN(CC)CCOc1ccc([N+](=O)[O-])c(OC)c1
Temperature: 80 °C

Procedure:
4-(2-Chloroethoxy)-2-methoxy-1-nitrobenzene (0.22 g, 0.9 mmol) was dissolved in acetonitrile (1 ml). Diethylamine (0.14 ml, 2.6 mmol) and potassium carbonate (0.31 g, 2.2 mmol) were added and the reaction was heated in a sealed pressure tube to 80° C. for 20 h. The reaction mixture was diluted with dichloromethane, then washed with 1M sodium hydroxide and brine, then dried over sodium sulfate. Evaporation of the solvent under reduced pressure gave the title compound as a brown oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH2:20][CH2:21][CH3:22])=[C:6]([C:8]2[NH:13][C:12](=[O:14])[C:11]([CH2:15][CH3:16])=[C:10]([CH2:17][CH3:18])[N:9]=2)[CH:7]=1.[CH2:23]([N:25]=[C:26]=[O:27])[CH3:24]>>[CH2:23]([NH:25][C:26]([O:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH2:20][CH2:21][CH3:22])=[C:6]([C:8]2[NH:13][C:12](=[O:14])[C:11]([CH2:15][CH3:16])=[C:10]([CH2:17][CH3:18])[N:9]=2)[CH:7]=1)=[O:27])[CH3:24]
Reactant: CCN=C=O
Reactant: CCCOc1ccc(O)cc1-c1nc(CC)c(CC)c(=O)[nH]1
Product: CCCOc1ccc(OC(=O)NCC)cc1-c1nc(CC)c(CC)c(=O)[nH]1

Procedure:
The title compound was prepared by reacting the compound of example 81 with ethyl isocyanate in the same manner as that of example 35. 1H NMR (CDCl3) δ: 8.20 (1H, d), 7.25 (1H, dd), 6.99 (1H, d), 5.06 (1H, br), 4.14 (2H, t), 3.32 (2H, m), 2.66 (2H, q), 2.58 (2H, q), 1.98 (2H, m), 1.28 (3H, t), 1.22 (3H, t), 1.14 (3H, t), 1.13 (3H, t).
Reaction SMILES: Br.Br.[C:3]1([CH3:21])[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[H-].[Na+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:3]1([CH3:21])[CH:4]=[CH:5][C:6]([S:9]([N:12]2[CH2:13][CH2:14][N:15]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:16][CH2:17][N:18]([CH2:21][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH2:19][CH2:20]2)(=[O:10])=[O:11])=[CH:7][CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCNCCNCC2)cc1
Reactant: BrCc1ccccc1
Agent: Br
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc(S(=O)(=O)N2CCN(Cc3ccccc3)CCN(Cc3ccccc3)CC2)cc1

Procedure:
From N-(p-toluenesulfonyl-1,4,7-triazacyclononane (1.3.13.31), sodium hydride and benzyl bromide.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([O:16][CH3:17])=[CH:9][CH:10]=3)[C:5](=O)[C:4]=2[CH:3]=1.[CH2:19]1COC[CH2:20]1.C([Mg]Br)C.CC1C=CC(S(O)(=O)=O)=CC=1.N1C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([O:16][CH3:17])=[CH:9][CH:10]=3)[C:5](=[CH:19][CH3:20])[C:4]=2[CH:3]=1
Reactant: COc1ccc2oc3ccc(Br)cc3c(=O)c2c1
Reactant: C1CCOC1
Agent: CC[Mg]Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC=C1c2cc(Br)ccc2Oc2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A 250 mL RBF was charged with 2-bromo-7-methoxy-9H-xanthen-9-one (10.20 g, 33.4 mmol) and 100 mL dry THF. The mixture was stirred for 10 min at RT and the resulting suspension was placed in an ice-methanol bath for another 10 min. Ethylmagnesium bromide, 1.0 M in THF (43.5 mL, 43.5 mmol) was added to the mixture dropwise. After 30 min, the mixture was carefully quenched with saturated aqueous ammonium chloride (100 mL) at 0° C. and diluted with EtOAc. The organic layer was washed with brine, dried with sodium sulfate, and concentrated in vacuo. The crude material was dissolved in 100 mL of chloroform, treated with pyridine 4-methylbenzenesulfonate (0.115 g, 0.669 mmol), and heated to reflux for 4 hr then 50° C. overnight. The mixture was cooled to RT, diluted with DCM, and washed with saturated sodium bicarbonate and brine. The organic fraction was dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography using 5-40% Hexanes:EtOAc to afford 2-bromo-9-ethylidene-7-methoxy-9H-xanthene as a yellow oil, MH+=317.0/319.0@3.35 min.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[O:11][N:10]=[C:9]([C:12]([OH:14])=O)[CH:8]=2)[CH:4]=[N:3]1.C1C=CC2N(O)N=NC=2C=1.N=C=N.[NH2:28][C@@H:29]([CH3:45])[CH2:30][N:31]1[CH:35]=[CH:34][C:33]([C:36]2[CH:43]=[CH:42][C:39]([C:40]#[N:41])=[C:38]([CH3:44])[CH:37]=2)=[N:32]1.C(O)C(N)(CO)CO>CN(C=O)C.C(Cl)Cl>[C:40]([C:39]1[CH:42]=[CH:43][C:36]([C:33]2[CH:34]=[CH:35][N:31]([CH2:30][C@@H:29]([NH:28][C:12]([C:9]3[CH:8]=[C:7]([C:5]4[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=4)[O:11][N:10]=3)=[O:14])[CH3:45])[N:32]=2)=[CH:37][C:38]=1[CH3:44])#[N:41]
Reactant: Cn1cc(-c2cc(C(=O)O)no2)cn1
Reactant: Cc1cc(-c2ccn(C[C@H](C)N)n2)ccc1C#N
Agent: N=C=N
Agent: NC(CO)(CO)CO
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(-c2ccn(C[C@H](C)NC(=O)c3cc(-c4cnn(C)c4)on3)n2)ccc1C#N
Reaction time: 24 h
Yield: 18.1 %

Procedure:
5-(1-methyl-1H-pyrazol-4-yl)isoxazole-3-carboxylic acid (57.9 mg, 0.3 mmol), HOBt (46 mg, 0.340 mmol) and PS-carbodiimide (364 mg), DCM (4 ml) and DMF (0.4 ml) were mixed in a glass vial. The mixture was shaken for 10 min. (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-methylbenzonitrile (48 mg, 0.2 mmol) was added and the mixture was stirred for 24 h. The solids were filtered off PS-Trisamine (333 mg, 1.0 mmol) was added to the filtrate. The mixture was shaken for 4 h and filtered. The filtrate was concentrated and purified by flash chromatography (gradient of DCM:MeOH) to give 15 mg of the title compound. 1H-NMR (400 MHz; CDCl3): δ 1.25 (d, 3H), 4.00 (s, 3H), 4.23-4.28 (m, 1H), 4.42-4.49 (m, 1H), 4.55-4.66 (m, 1H), 6.62 (d, 1H), 6.67 (s, 1H), 7.49 (d, 1H), 7.63 (d, 1H), 7.72-7.75 (m, 1H), 7.81 (m, 2H), 7.96 (s, 1H), 8.14 (m, 1H).
Reaction SMILES: C([O:3][C:4]([CH2:6][NH:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[CH:14]=[CH:13][C:12]([C:17]2[C:18]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:19][N:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=23)=[N:11]1)=[O:5])C.[OH-].[Na+]>C(O)C.O>[C:4]([CH2:6][NH:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[CH:14]=[CH:13][C:12]([C:17]2[C:18]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:19][N:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=23)=[N:11]1)([OH:5])=[O:3]
Reactant: CCOC(=O)CNCCn1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CNCCn1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
To a solution of 3-[2-{2-(ethoxycarbonylmethylamino)ethyl}-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (0.80 g) in ethanol (8 ml) was added a solution of sodium hydroxide (0.15 g) in water (4 ml) and the mixture was stirred for 0.5 hour at room temperature. The reaction mixture was concentrated and the residue was partitioned between water and ethyl acetate. The aqueous layer was separated, neutralized with 1N hydrochloric acid to give the precipitate, which was collected and purified by recrystallization from 50% aqueous ethanol to give 3-[2-{2-(carboxymethylamino)ethyl}-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (0.50 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH:4]([NH:13][C:14]([O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24]OCCOC)=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[CH2:31](OCCOCCO)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]CC.C(N(CC)CC)C>C(#N)C>[CH3:1][O:2][C:3](=[O:30])[CH:4]([NH:13][C:14]([O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[O:15])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([OH:12])=[CH:10][CH:11]=1
Reactant: COCCOCCOCCOCCOC(=O)NC(Cc1ccc(O)cc1)C(=O)OC
Reactant: CCCCCCCCCCCCOCCOCCO
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCCCCCCCCCOCCOCCOC(=O)NC(Cc1ccc(O)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Oligomer XXIV was prepared in an analogous manner to that described above for Oligomer XXII. Diethylene glycol monododecyl ether (2.712 g, 9.88 mmol) was dissolved in 100 mL dry acetonitrile. Triethylamine (2.06 mL, 14.8 mmol) and DSC (3.80 g, 14.8 mmol) were added. After stirring for 18 hours at room temperature under an inert atmosphere, the reaction mixture was concentrated in vacuo. The residual oil was taken up in concentrated sodium bicarbonate solution and extracted with EtOAc (2×200 mL). The combined EtOAc layers were washed with water (2×100 mL) and brine (2×100 mL). The organics were dried over Na2SO4, filtered and evaporated to dryness to give 3.58 g (87%) of XXIII.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([NH2:14])=[CH:7][CH:8]=[C:9]2[C:13]=1[NH:12][N:11]=[CH:10]2)=[O:4].[Cl:15]N1C(=O)CCC1=O>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[C:6]([NH2:14])=[C:7]([Cl:15])[CH:8]=[C:9]2[C:13]=1[NH:12][N:11]=[CH:10]2)=[O:4]
Reactant: COC(=O)c1c(N)ccc2cn[nH]c12
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: COC(=O)c1c(N)c(Cl)cc2cn[nH]c12
Temperature: 50 °C
Reaction time: 4 h
Yield: 36.8 %

Procedure:
To a mixture of 1.66 g (8.71 mmol) of 6-amino-1H-indazole-7-carboxylic acid methyl ester in 17 mL of N,N-dimethylformamide, is added 1.21 g (8.71 mmol) of N-chlorosuccinimide. The mixture is stirred during 4 hours at 50° C. and then the solvent is evaporated. The residue is precipitated in ethyl acetate and after filtration and washings with ethyl acetate, 927 mg of a pure white solid are obtained. The filtrate is evaporated and submitted to a flash chromatography which gives an additional 723 mg of the compound. In totality, 1.65 g (84%) of a product are obtained as a white solid; LC/MS:226/228 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:16]1[C:21]([CH:22]([CH2:27][CH2:28][CH3:29])[C:23]([O:25][CH3:26])=[O:24])=[C:20]([CH3:30])[N:19]=[C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:17]=1>O1CCCC1.C(=O)([O-])O.[Na+]>[N:1]1([C:16]2[C:21]([CH:22]([CH2:27][CH2:28][CH3:29])[C:23]([O:25][CH3:26])=[O:24])=[C:20]([CH3:30])[N:19]=[C:18]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:17]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1Cl
Reactant: C1CCCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1N1CCCCCC1
Temperature: 100 °C
Yield: 48.2 %

Procedure:
Azepane (0.113 mL; 1.00 mmol) and triethylamine (0.277 mL; 2.00 mmol) were added to a solution of methyl 2-(4-chloro-6-methyl-2-phenylpyrimidin-5-yl)pentanoate (0.159 g; 0.5 mmol) in tetrahydrofuran (1.5 mL). The reaction vessel was sealed and heated at 100° C. for 18 h. The mixture was diluted with a saturated solution of sodium hydrogen carbonate and was extracted with ethyl acetate. The combined organics were washed with brine, dried over magnesium sulphate, filtered and concentrated under reduced pressure. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (2-40%) in heptane furnished 0.092 g (98%) of the title compound.
Reaction SMILES: [ClH:1].[NH:2]([CH2:6][CH2:7][CH2:8][CH2:9][C@H:10](O)[CH2:11][C:12]([NH2:14])=[O:13])[C:3]([NH2:5])=[NH:4].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O.[Cu](Cl)Cl>[ClH:1].[NH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH:11][C:12]([NH2:14])=[O:13])[C:3]([NH2:5])=[NH:4]
Reactant: N=C(N)NCCCC[C@H](O)CC(N)=O
Agent: Cl[Cu]Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CN(C)C=O
Product: N=C(N)NCCCCC=CC(N)=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 89.5 %

Procedure:
To a solution of 955 mg (4 mmoles) of (S)-7-guanidino-3-hydroxyheptanamide hydrochloride in 20 ml of anhydrous N,N-dimethylformamide were added 2.48 g (12 mmoles) of dicyclohexylcarbodiimide and 40 mg of copper(II) chloride. The mixture was stirred for 2 days at room temperature. The reaction mixture was filtered to remove the precipitate and the filtrate was concentrated under reduced pressure. The residue was dissolved in 10 ml of water and washed twice with 10 ml of ethyl acetate. The aqueous layer was evaporated to dryness, dissolved in 5 ml of water, passed through a column (20 mm inner diameter) packed with 50 ml of CM-Sephadex® C-25 (Na-type) and the column was eluted with 200 ml of 0.5M aqueous sodium chloride solution (10 ml fraction size). Fractions No. 17 to No. 30 were combined, evaporated to dryness and extracted 3 times with methanol. The methanol solution was passed through a column (20 mm inner diameter) packed with 150 ml of Sephadex® LH-20 and developed with methanol (5 ml fraction size). Fractions No. 9 to No. 16 were combined and evaporated to dryness. The residue, weighing 950 mg, was crystallized from ethanol-acetone to obtain 790 mg (89.5% yield) of 7-guanidino-2-heptenamide hydrochloride having a melting point of 162°-168° C.
Reaction SMILES: C.[NH2:2][C:3]1[C:8]([N+:9]([O-])=O)=[CH:7][C:6]([C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=2)=[CH:5][N:4]=1.O.NN>CO>[NH2:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([C:12]2[CH:13]=[CH:14][C:15]([Br:18])=[CH:16][CH:17]=2)=[CH:5][N:4]=1
Reactant: Nc1ncc(-c2ccc(Br)cc2)cc1[N+](=O)[O-]
Agent: NN
Solvent: O
Solvent: CO
Product: Nc1cc(-c2ccc(Br)cc2)cnc1N
Reaction time: 24 h
Yield: 51.1 %

Procedure:
0.145 g of ferric chloride and 0.12 g of activated charcoal are added to a suspension of 0.98 g of 2-amino-5-(4-bromphenyl)-3-nitropyridine (starting material H2) in 30 ml of methanol and the mixture is heated under reflux. 0.725 ml of hydrazine hydrate are added slowly and reflux is continued for 24 hours. After cooling the mixture is filtered and the filtrate is evaporated. The residue is partitioned between sodium-EDTA-solution (0.25M; pH 9–10) and dichloromethane. The organic phase is evaporated to give 0.45 g of the title compound as a yellowish solid of m.p. 187–188° C. The mass spectrum shows the molecular peak MH+ at 264.2 Da.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1.[C:23]1(=[O:29])[CH2:28][CH2:27][CH2:26][CH:25]=[CH:24]1.C1CCN2C(=NCCC2)CC1>C(#N)C>[CH3:20][Si:19]([CH3:22])([CH3:21])[CH2:18][CH2:17][O:16][CH2:15][N:12]1[C:8]2[N:9]=[CH:10][N:11]=[C:6]([C:4]3[CH:5]=[N:1][N:2]([CH:25]4[CH2:26][CH2:27][CH2:28][C:23](=[O:29])[CH2:24]4)[CH:3]=3)[C:7]=2[CH:14]=[CH:13]1
Reactant: O=C1C=CCCC1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4CCCC(=O)C4)c3)ncnc21
Reaction time: 1 h
Yield: 98 %

Procedure:
To a solution of 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidine (309 mg, 0.980 mmol) in ACN (6 mL) was added 2-cyclohexen-1-one (190 μL, 01.96 mmol), followed by DBU (40 μL, 0.3 mmol). The resulting mixture was stirred for one hour at which point LCMS indicated complete addition. The mixture was reduced in vacuo and the crude product was purified by column chromatography to obtain the product (397 mg, 98%). 1H NMR (400 MHz, CDCl3): δ 8.84 (s, 1H), 8.27 (s, 1H), 8.25 (s, 1H), 7.45 (d, 1H), 6.79 (d, 1H), 5.67 (s, 2H), 4.61 (m, 1H), 3.55 (m, 2H), 3.05-2.90 (m, 2H), 2.45-2.30 (m, 4H), 2.05 (m, 1H), 1.90 (m, 1H), 0.92 (m, 2H), −0.06 (s, 9H). MS (EI) m/z=412.2 (M+H).
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1)[CH2:3][OH:4].ClCCl.[C:17]([N:21]=[C:22]=[S:23])([CH3:20])([CH3:19])[CH3:18]>C(O)C>[C:17]([NH:21][C:22]([NH:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1)[CH2:3][OH:4])=[S:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: NC(CO)c1cccc([N+](=O)[O-])c1
Reactant: CC(C)(C)N=C=S
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(C)NC(=S)NC(CO)c1cccc([N+](=O)[O-])c1
Reaction time: 7 h

Procedure:
The process is performed as in Example 2, starting with 5.1 g of 2-amino-2-(3-nitrophenyl)-1-ethanol in 170 cm3 of ethanol containing 85 cm3 of dichloromethane and 4.6 cm3 of tert-butyl isothiocyanate, at a temperature in the region of 20° C. for 3 days and then at a temperature in the region of 60° C. for 7 hours. After addition of a further 0.35 cm3 of tert-butyl isothiocyanate and 16 hours at a temperature in the region of 60° C., an identical work-up gives 5.7 g of N-(tert-butyl)-N′-[2-hydroxy-1-(3-nitrophenyl)ethyl]thiourea in the form of an ocher-colored solid melting at 162° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10].[CH2:11]([NH:18][CH3:19])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:11]([N:18]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10])[CH3:19])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CNCc1ccccc1
Reactant: OCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(CCCCCCCCO)Cc1ccccc1
Temperature: 35 °C
Reaction time: 7 h
Yield: 100 %

Procedure:
8-Bromo-1-octanol (25 g, 119.6 mmol) in acetonitrile (50 mL) was added to a stirred solution of N-benzyl-N-methylamine (43.49 g, 358.9 mmol) and potassium carbonate (49.52 g, 358.9 mmol) in acetonitrile (250 mL) at 35° C. The reaction mixture was then stirred at 35° C. for 7 h and then cooled to ambient temperature. The potassium carbonate was filtered and the filtrate was concentrated under reduced pressure. The crude residue was dissolved in MTBE (400 mL) and the organic phase was washed with water, brine and dried over magnesium sulfate. N-methyl-2-pyrrolidone was added and the mixture was concentrated under reduced pressure to remove excess N-benzyl-N-methylamine. MTBE (400 mL) was added and the organic phase was washed with water, brine, and dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford the title intermediate as an oil (˜100% conversion).