Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([CH2:13][C:14]1[O:15][CH:16]=[CH:17][N:18]=1)[C:8]([CH3:19])=[CH:7]2.[Br:20]N1C(=O)CCC1=O.C(OCC)C.C(OCC)(=O)C>CN(C)C=O>[Br:20][C:7]1[C:6]2[C:11](=[C:2]([F:1])[CH:3]=[CH:4][CH:5]=2)[C:10](=[O:12])[N:9]([CH2:13][C:14]2[O:15][CH:16]=[CH:17][N:18]=2)[C:8]=1[CH3:19]
Reactant: Cc1cc2cccc(F)c2c(=O)n1Cc1ncco1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cc1c(Br)c2cccc(F)c2c(=O)n1Cc1ncco1
Temperature: 50 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
A mixture of 8-fluoro-3-methyl-2-oxazol-2-ylmethyl-2H-isoquinolin-1-one (271 mg, 1.05 mmol) and N-bromosuccinimide (192 mg, 1.08 mmol) in N,N-dimethylformamide (4.8 mL) was stirred at 50° C. for 60 minutes. The reaction mixture was poured into diethyl ether (50 mL) and ethyl acetate (20 mL). A white solid precipitated, which was removed by filtration. The filtrate was washed with diluted brine (water:sat. NaCl(aq.)=1:1; 4×20 mL), dried over MgSO4 and evaporated to give a 321 mg of a solid (yield 90%), which was used in the next step without further purification. LC-MS (m/z) 337.3&339.4 (MH+), tR=1.1. 1H NMR (CDCl3, 500 MHz, TMS=0 ppm): 2.75 (s, 3H, Me), 5.52 (s, 2H, CH2), 7.07 (s (unres. d, J<1 Hz), 1H, oxazol), 7.16 (dd, J=8.1 Hz, J=11.1 Hz, 1H, C7-H), 7.62 (s (unres. d, J<1 Hz), 1H, oxazole), 7.66 (dt, J(t)=8.1 Hz, J(HF)=4.9 Hz, 1H, C6-H), 7.78 (d, J=8.2 Hz, 1H, C5-H).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:24])[NH:5][C:6]1[CH:16]=[C:15]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:9]([C:10]([O:12]CC)=[O:11])=[CH:8][N:7]=1)[CH3:2].[OH-].[Na+]>CO.O>[CH2:1]([NH:3][C:4](=[O:24])[NH:5][C:6]1[CH:16]=[C:15]([NH:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:9]([C:10]([OH:12])=[O:11])=[CH:8][N:7]=1)[CH3:2]
Reactant: CCNC(=O)Nc1cc(Nc2ccccc2)c(C(=O)OCC)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCNC(=O)Nc1cc(Nc2ccccc2)c(C(=O)O)cn1
Temperature: 70 °C
Yield: 85.1 %

Procedure:
To a solution of iii (0.90 g, 2.74 mmol) in MeOH (25 mL) was added a solution of NaOH (0.55 g, 13.70 mmol) in H2O (5 mL). The resulting solution was heated at 70° C. for 3-4 h then cooled to RT and the solvent removed in vacuo. Water was added to the residue and this mixture extracted with EtOAc (2×50 mL). The organic layer was discarded, and the aqueous portion was carefully acidified (under ice-cooling) with 6N HCl till pH 5. The resulting precipitate was filtered, washed with ice-cold water and ether. The off-white solid thus obtained was dried under high vacuum to obtain compound iv (0.70 g, 85%). 1H-NMR (400 MHz, DMSO-d6): δ10.60 (br s, 1H), 9.07 (br s, 1H), 8.55 (s, 1H), 8.0 (br s, 1H), 7.13-7.42 (m, 6H), 3.12 (m, 2H), 1.05 (t, J=7.20 Hz, 3H); [M+H]+ m/z=301.21.
Reaction SMILES: I[C:2]1[NH:6][C:5]([CH2:7][O:8][CH3:9])=[N:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:16][C:17]1[CH:26]=[C:25]([CH3:27])[C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][C:18]=1[C:19]([O:21][CH3:22])=[O:20]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:9][O:8][CH2:7][C:5]1[NH:6][C:2]([C:24]2[C:25]([CH3:27])=[CH:26][C:17]([CH3:16])=[C:18]([CH:23]=2)[C:19]([O:21][CH3:22])=[O:20])=[CH:3][N:4]=1
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(C)cc1C
Reactant: COCc1ncc(I)[nH]1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COCc1ncc(-c2cc(C(=O)OC)c(C)cc2C)[nH]1
Temperature: 90 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
Into a 100-mL three neck round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 5-iodo-2-(methoxymethyl)-1H-imidazole (compound 230.4, 70 mg, 0.29 mmol) in dioxane (10 mL). Pd(dppf)Cl2 (22 mg, 0.029 mmol), a solution of potassium carbonate (160 mg, 1.16 mmol) in water (2 mL), methyl 2,4-dimethyl-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 160.1, 168 mg, 0.58 mmol) were added to the reaction. The reaction mixture was stirred overnight at 90° C., then quenched with 10 mL of H2O. The aqueous phase was extracted with 3×10 mL of ethyl acetate and the combined organic layers were washed with 1×10 mL of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:1) as eluent to furnish 70 mg (87%) of the title compound as a white solid.
Reaction SMILES: C(=O)(O)O.NNC(N)=N.FC(F)(F)C(O)=O.[NH2:17][C:18]1[N:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[NH:20][N:19]=1.[C:27]([CH2:35][C:36](=O)[CH3:37])(=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(Cl)Cl.C(O)(=O)C.C1(C)C=CC=CC=1>[NH2:17][C:18]1[N:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[NH:20][N:19]=1.[CH3:37][C:36]1[CH:35]=[C:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:19]2[N:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[N:22]=[C:18]2[N:17]=1
Reactant: CC(=O)CC(=O)c1ccccc1
Agent: N=C(N)NN
Agent: Nc1n[nH]c(C(F)(F)F)n1
Agent: O=C(O)O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2ccccc2)n2nc(C(F)(F)F)nc2n1
Yield: 112.7 %

Procedure:
By the procedure reported by V. A. Lopyrev Zh. Obshch. Khim. 53 p. 1684, 1983 (Chemical Abstracts 139865y, 1983) a crude sample of 3-amino-5-trifluoromethyl-1,2,4-triazole was prepared by the cyclocondensation of aminoguanidine bicarbonate with trifluoroacetic acid in refluxing toluene. This material was used effectively without further purification in subsequent ring condensation reactions. To 30 ml. of glacial acetic acid stirring, 3.0 g (19.7 mmol) of 3-amino-5-trifluoromethyl-1,2,4-triazole and 3.5 g (21.6 mmol) of benzoylacetone were added and the mixture heated at reflux for 3 h. A solution soon formed after heating. The solvent was evaporated in vacuo and excess water added to the residue followed by extraction with 200 ml of ethyl acetate. The extract was washed with water, saturated sodium bicarbonate, brine, dried over magnesium sulfate and evaporated in vacuo to give an oily residue. Silica gel column chromatography (methylene chloride) afforded 3.09 g of the title compound which was present as the major component, m.p. 106°-108° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[CH2:5][C:6]#[N:7].Br[CH2:13][CH2:14][CH2:15]Br.[H-].[Na+].CC(O)C>CS(C)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2([C:6]#[N:7])[CH2:15][CH2:14][CH2:13]2)[CH:8]=[CH:9][C:10]=1[Cl:11]
Reactant: BrCCCBr
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CC(C)O
Product: N#CC1(c2ccc(Cl)c(Cl)c2)CCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3,4-dichlorobenzyl cyanide (25 g) and 1,3-dibromopropane (15 ml) in dry dimethyl sulfoxide (150 ml) was added dropwise under nitrogen to a stirred mixture of sodium hydride (7.5 g), which was dispersed in mineral oil (7.5 g), and dimethyl sulfoxide (200 ml) at 30-35° C. The mixture was stirred at room temperature for 2 hours, and 2-propanol (8 ml) and then water (110 ml) were added dropwise. The mixture was filtered through diatomaceous earth which is marketed under the proprietary name CELITE, and the solid residue was washed with ether. The ether layer was separated off, washed with water, dried and evaporated. 1-(3,4-dichlorophenyl)-1-cyclobutane-carbonitrile was isolated by distillation (boiling point: 108 to 120° C. under 0.2 mbar. This procedure is a modification of the process described by Butler and Pllatz (J. Org. Chem. 36 No. 9 (1971) 1308).
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][C:7]2([CH2:17][C:16]3[C:11](=[CH:12][C:13]([N+:18]([O-:20])=[O:19])=[CH:14][CH:15]=3)[C:10]2=[O:21])[CH2:6][CH2:5]1)(=O)C.[ClH:22]>C(O)C>[ClH:22].[N+:18]([C:13]1[CH:12]=[C:11]2[C:16]([CH2:17][C:7]3([C:10]2=[O:21])[CH2:8][CH2:9][NH:4][CH2:5][CH2:6]3)=[CH:15][CH:14]=1)([O-:20])=[O:19]
Reactant: CC(=O)N1CCC2(CC1)Cc1ccc([N+](=O)[O-])cc1C2=O
Agent: Cl
Solvent: CCO
Product: O=C1c2cc([N+](=O)[O-])ccc2CC12CCNCC2
Temperature: 25 °C
Yield: 74.5 %

Procedure:
A solution of 0.216 g (0.75 mmol) 1'-acetyl-1,3-dihydro-1-oxo-6-nitrospiro[2H-indene-2,4'-piperidine] and 2 ml (6 mmol) 3N hydrochloric acid in 6 ml ethanol was heated at reflux for 18 hours. Another 0.2 ml (0.6 mmol) 3N hydrochloric acid was added and the solution was heated at reflux for 4 hours, then cooled to room temperature to give a white precipitate. The precipitate was filtered off, washed with ethanol, and dried to give 0.158 g (74%) product.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[N:16]=[N:17][C:18]([CH:34]3[CH2:37][CH2:36][CH2:35]3)=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:23][CH:22]=3)[CH:20]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:38]>C(Cl)Cl.O1CCOCC1>[ClH:38].[ClH:38].[CH:34]1([C:18]2[N:17]=[N:16][C:15]([O:14][CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[CH:20][C:19]=2[C:21]2[CH:22]=[CH:23][C:24]([O:27][CH:28]3[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]3)=[CH:25][CH:26]=2)[CH2:37][CH2:36][CH2:35]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(-c3ccc(OC4CCCCC4)cc3)c(C3CCC3)nn2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: c1cc(-c2cc(OC3CCNCC3)nnc2C2CCC2)ccc1OC1CCCCC1
Reaction time: 0.5 h

Procedure:
To a solution of 4-[6-cyclobutyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxy]-piperidine-1-carboxylic acid tert-butyl ester (0.35 mmol, 0.18 g) in DCM (1.0 mL) was added 4 N HCl in dioxane (1.0 mL) and the reaction was stirred for 30 min. The solvents were removed under reduced pressure and the residue was triturated with anhydrous ethyl ether and filtered to give 3-cyclobutyl-4-(4-cyclohexyloxy-phenyl)-6-(piperidin-4-yloxy)-pyridazine dihydrochloride (0.14 g).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH2:9])=[CH:6][CH:5]=1.C[O:15][C:16](=O)[C:17]1[C:22]([I:23])=[CH:21][C:20]([F:24])=[CH:19][C:18]=1[CH2:25]Br.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[F:24][C:20]1[CH:19]=[C:18]2[C:17](=[C:22]([I:23])[CH:21]=1)[C:16](=[O:15])[N:9]([CH2:8][C:7]1[CH:10]=[CH:11][C:4]([O:3][C:2]([F:12])([F:13])[F:1])=[CH:5][CH:6]=1)[CH2:25]2
Reactant: COC(=O)c1c(I)cc(F)cc1CBr
Reactant: NCc1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C1c2c(I)cc(F)cc2CN1Cc1ccc(OC(F)(F)F)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 36.2 %

Procedure:
A mixture of 4-trifluoromethoxy-benzyl amine (0.092 mL, 0.6 mmol), 2-bromomethyl-4-fluoro-6-iodo-benzoic acid methyl ester (0.181 g, 0.49 mmol), and K2CO3 (0.138 g, 1 mmol) in toluene was heated with stirring at 100° C. for 2 h. The resulting mixture was filtered and concentrated. Silica gel column chromatography using 30% ethyl acetate in hexane afforded 5-fluoro-7-iodo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.080 g, 36%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.19 (s, 2H), 4.79 (s, 2H), 7.06-7.38 (m, 5H), 7.67 (d, 1H). GC-MS: m/z 451 (M)+, 382 (M−69)+.
Reaction SMILES: [N:1]1([CH2:6][C:7]([NH:9][C:10]2[N:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH2:14])=[O:13])=O)[CH:5]=[N:4][CH:3]=[N:2]1>N1C=CC=CC=1>[N:1]1([CH2:6][C:7]2[NH:14][C:12](=[O:13])[C:11]3[CH:15]=[CH:16][CH:17]=[N:18][C:10]=3[N:9]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: NC(=O)c1cccnc1NC(=O)Cn1cncn1
Solvent: c1ccncc1
Product: O=c1[nH]c(Cn2cncn2)nc2ncccc12
Yield: 9 %

Procedure:
2-(2-[1,2,4]Triazol-1-yl-acetylamino)-nicotinamide (206 mg, 0.8 mmol) was dissolved in pyridine (4 ml). The solution was microwaved for 15 min at 150° C. The solvent was removed in vacuo, and the residue purified by chromatography on silica (dichloromethane/methanol gradient) to yield 2-[1,2,4]triazol-1-ylmethyl-3H-pyrido[2,3-d]pyrimidin-4-one (18 mg, 72 μmol; 9%) as a yellow solid. MS (m/e): 229.1 [M+H+].
Reaction SMILES: [CH2:1]([OH:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[O:9]1[CH:14]=[CH:13][CH2:12][CH2:11][CH2:10]1.Cl>O>[O:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:8]
Reactant: C1=COCCC1
Reactant: OCCCCCCO
Agent: Cl
Solvent: O
Product: OCCCCCCOC1CCCCO1
Yield: 48.5 %

Procedure:
Hexane-1,6-diol (70.9 g) was melted in a water bath at ca. 60°, the melt cooled to 45° and dihydropyran (16.82 g) quickly added followed by 10 N hydrochloric acid (0.1 ml). The mixture was stirred and cold water added to maintain a reaction temperature of approximately 50°. When the exotherm had subsided, the mixture was stirred at room temperature for 0.5 h, then diluted with water (500 ml) and extracted with ER (2×250 ml). The ER solution was washed with water (3×500 ml), dried and concentrated to yield an oil which was purified by [FCS] elution with EA/hexane (1:1) affording the title compound (19.6 g). T.l.c. (EA/hexane 1:1) Rf 0.40.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[N:6]=[C:5]([CH3:16])[CH:4]=1.[C:17]([N:20]1[CH2:24][C:23](=O)[N:22]=[CH:21]1)(=[O:19])[CH3:18]>>[C:17]([N:20]1[CH2:24][CH2:23][N:22]=[C:21]1[NH:2][C:3]1[N:7]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=2)[N:6]=[C:5]([CH3:16])[CH:4]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)N1C=NC(=O)C1
Reactant: COc1ccc(-n2nc(C)cc2N)cc1
Agent: Cl
Product: COc1ccc(-n2nc(C)cc2NC2=NCCN2C(C)=O)cc1

Procedure:
5-Amino-3-methyl-1-(4-methoxyphenyl) pyrazole HCl (Farmaco 17, 443, 1962) (23.9 g.) and 1-acetyl-2-imidazolinone (15.4 g.) were reacted as described in Example I to give 14.6 g. of product, mp 129°-131°.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[OH:11].[NH:12]1[CH2:17][CH2:16][CH2:15][C@@H:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=3[CH2:24][C@H:13]12.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:12]2[CH2:17][CH2:16][CH2:15][C@@H:14]3[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=4[CH2:24][C@H:13]23)=[O:8])=[CH:4][C:3]=1[OH:11]
Reactant: O=C(O)c1ccc(Cl)c(O)c1
Reactant: c1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(c1ccc(Cl)c(O)c1)N1CCC[C@@H]2c3ccccc3C[C@@H]21
Yield: 44 %

Procedure:
The title compound is prepared from 4-chloro-3-hydroxy-benzoic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 44% of theory; LC (method 4): tR=1.97 min; Mass spectrum (ESI+): m/z=328 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][N:9]([C@H:22]1[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@H:25]([C:35](=[S:37])[NH2:36])[CH2:24][CH2:23]1)[S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])(=[O:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[CH:40](OC)[N:41]([CH3:43])[CH3:42]>O1CCOCC1>[CH2:1]([O:8][N:9]([C@H:22]1[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:29])[C@H:25]([C:35](=[S:37])/[N:36]=[CH:40]/[N:41]([CH3:43])[CH3:42])[CH2:24][CH2:23]1)[S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])(=[O:11])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(OC)N(C)C
Reactant: CC(C)(C)OC(=O)N1C[C@H](N(OCc2ccccc2)S(=O)(=O)c2ccccc2[N+](=O)[O-])CC[C@H]1C(N)=S
Solvent: C1COCCO1
Product: CN(C)/C=N/C(=S)[C@@H]1CC[C@@H](N(OCc2ccccc2)S(=O)(=O)c2ccccc2[N+](=O)[O-])CN1C(=O)OC(C)(C)C
Temperature: 45 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
A mixture of (2S,5R)-tert-butyl 5-(N-(benzyloxy)-2-nitrophenylsulfonamido)-2-carbamothioylpiperidine-1-carboxylate (1.65 g, 3 mmol) and 1,1-dimethoxy-N,N-dimethylmethanamine (1.08 g, 9.0 mmol) in dry dioxane (20 mL) was stirred at 45° C. overnight. The reaction mixture was concentrated under vacuum and the residue was purified by silica gel column chromatography (1:1 petroleum ether/EtOAc) to give (2S,5R)-tert-butyl 5-(N-(benzyloxy)-2-nitrophenylsulfonamido)-2-((E)-(dimethylamino)methylenecarbamothioyl)piperidine-1-carboxylate (1.3 g, 72%) as a yellow solid. ESI-MS (EI+, m/z): 606 [M+H]+.
Reaction SMILES: [ClH:1].C(OC([N:9]=[C:10]([NH:40]C(OC(C)(C)C)=O)[NH:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26]([NH:28][C:29]([C:31]2[C:36]([NH2:37])=[N:35][C:34]([NH2:38])=[C:33]([Cl:39])[N:32]=2)=[O:30])=[NH:27])=[CH:17][CH:16]=1)=O)(C)(C)C>CO>[ClH:39].[ClH:1].[NH2:37][C:36]1[C:31]([C:29]([NH:28][C:26]([NH:25][CH2:24][CH2:23][CH2:22][CH2:21][C:18]2[CH:19]=[CH:20][C:15]([O:14][CH2:13][CH2:12][NH:11][C:10]([NH2:40])=[NH:9])=[CH:16][CH:17]=2)=[NH:27])=[O:30])=[N:32][C:33]([Cl:39])=[C:34]([NH2:38])[N:35]=1
Reactant: CC(C)(C)OC(=O)N=C(NCCOc1ccc(CCCCNC(=N)NC(=O)c2nc(Cl)c(N)nc2N)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: N=C(N)NCCOc1ccc(CCCCNC(=N)NC(=O)c2nc(Cl)c(N)nc2N)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
12N HCl (15 mL) was added dropwise to an ice cooled solution of N-(4-{4-[2-(N′,N″-di-tert-butoxycarbonylguanidino)ethoxy]phenyl}butyl)-1-(3,5-diamino-6-chloropyrazine-2-carbonyl)-guanidine 5 (370 mg, 0.56 mmole) in methanol (15 mL) over 1 min. After the addition, the cooling bath was removed, and the reaction was allowed to stir for 30 min. TLC (silica gel, methylene chloride/methanol/concentrated ammonium hydroxide, 3:3:1) indicated slow reaction progression. An additional 15 mL of 12N HCl was added dropwise at room temperature, and after 2 h, TLC indicated reaction completion. The solvent was evaporated and methanol (100 mL) was added and then evaporated below 30° C., this process was repeated a further three times and then the residue was placed under vacuum at 40° C. for 2 days to afford 300 mg (96%) of the pure product as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 1.57 (m, 4H), 2.56 (m, 2H), 3.52 (m, 2H), 4.02 (t, 2H), 4.60 (br s, 2H), 6.88 (d, 2H), 7.14 (d, 2H), 7.41 (m, 8H), 7.91 (t, 1H), 8.93 (m, 2H), 9.33 (t, 1H), 10.55 (s, 1H). mp 223-230. m/z (ESI)=463 [C19H27ClN10O2+H]+.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[C:4]#[C:5][CH3:6].Cl[C:9]1[CH:14]=[C:13]([O:15][CH:16]([CH3:22])[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[N:12]=[CH:11][N:10]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:3]([O:7][C:9]1[CH:14]=[C:13]([O:15][CH:16]([CH3:22])[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[N:12]=[CH:11][N:10]=1)[C:4]#[C:5][CH3:6]
Reactant: CC#CCO
Reactant: CC(CC(C)(C)C)Oc1cc(Cl)ncn1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CCOc1cc(OC(C)CC(C)(C)C)ncn1
Reaction time: 0.17 h

Procedure:
In 2 ml of tetrahydrofuran was suspended 0.03 g of sodium hydride (60% in oil), to which 0.5 ml of a solution containing 0.05 g of 2-butyn-1-ol in tetrahydrofuran was added dropwise at room temperature, followed by stirring for 10 minutes. To this was added dropwise 0.5 ml of a solution containing the above 4-chloro-6-(1,3,3-trimethylbutoxy)pyrimidine in tetrahydrofuran, followed by stirring at room temperature for 4 hour. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution, which was extracted three times with t-butyl methyl ether. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.14 g of 4-(2-butynyloxy)-6-(1,3,3-trimethylbutyloxy)pyrimidine (the present compound (7)).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:13]([OH:15])=O)[CH:10]([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1CCC(N=C=NC2CCCCC2)CC1.Cl.Cl.[NH2:33][C:34]1[NH:35][C:36]2[NH:37][CH2:38][CH:39]([CH:45]([OH:49])[CH:46]([OH:48])[CH3:47])[NH:40][C:41]=2[C:42](=[O:44])[N:43]=1>C(Cl)Cl.N1C=CC=CC=1>[C:4]([O:3][C:1](=[O:2])[NH:8][CH:9]([C:13]([N:40]1[CH:39]([CH:45]([OH:49])[CH:46]([OH:48])[CH3:47])[CH2:38][NH:37][C:36]2[NH:35][C:34]([NH2:33])=[N:43][C:42](=[O:44])[C:41]1=2)=[O:15])[CH:10]([CH3:11])[CH3:12])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(O)C(O)C1CNc2[nH]c(N)nc(=O)c2N1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)C(NC(=O)OC(C)(C)C)C(=O)N1c2c([nH]c(N)nc2=O)NCC1C(O)C(C)O
Reaction time: 1 h
Yield: 76.1 %

Procedure:
To a stirred solution of N-Boc-L-Valine (4.56 g, 21 mmol) in DCM (15 ml) at 0° C. was added a solution of DCC (2.17 g, 10.5 mmol) in DCM (10 ml). The resulting solution was stirred for 1 h after which a white precipitate formed. The white solid was filtered and filtrate added to a stirred solution of 2-amino-6-(1,2-dihydroxy-propyl)-5,6,7,8-tetrahydro-1H-pteridin-4-one dihydrochloride (3.0 g, 9.55 mmol) dissolved in pyridine (80 mL). The mixture was stirred at room temperature under an atmosphere of nitrogen for 1.5 h. The reaction mixture was quenched by addition of methanol (20 ml). The solvent was evaporated in vacuo and the residue purified by preparative RP-HPLC to give the sub-title product as a tan solid (3.2 g, 76%). MS: ESI (positive): 441 (M+H).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[N:16]1[CH:20]([C:21]2[S:22][C:23]([C:26]3[CH2:27][CH2:28][NH:29][CH2:30][CH:31]=3)=[CH:24][CH:25]=2)[CH2:19][C:18]([C:32]([F:38])([F:37])[C:33]([F:36])([F:35])[F:34])=[N:17]1.[CH3:39][N:40]([CH3:45])[S:41](Cl)(=[O:43])=[O:42]>>[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[N:16]1[CH:20]([C:21]2[S:22][C:23]([C:26]3[CH2:27][CH2:28][N:29]([S:41](=[O:43])(=[O:42])[N:40]([CH3:45])[CH3:39])[CH2:30][CH:31]=3)=[CH:24][CH:25]=2)[CH2:19][C:18]([C:32]([F:37])([F:38])[C:33]([F:35])([F:36])[F:34])=[N:17]1
Reactant: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2ccc(C3=CCNCC3)s2)c(F)c1
Reactant: CN(C)S(=O)(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)S(=O)(=O)N1CC=C(c2ccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)s2)CC1

Procedure:
The titled compound was prepared in accordance with the same procedures as in Step 2 of Example 200, except for using 1-(2,4-difluoro-phenyl)-5-[5-(1,2,3,6-tetrahydropyridin-4-yl)-thiophen-2-yl]-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole trifluoroacetate Prepared in Step 1 of Example 200; and using dimethylsulfamoyl chloride instead of methanesulfonyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(O)(C(F)(F)F)=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccc(-c2c[nH]c3ccccc23)c1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: Clc1cccc(C2CNc3ccccc32)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
3-(3-Chlorophenyl)indole (5.30 g, 23.3 mmol) was dissolved in 50 mL of 1 M BH3 in THF. The mixture was cooled to about 0° C. To the solution was added slowly TFA (50 mL). After addition, the solution was stirred for about 10 minutes. To the solution was added slowly 1M BH3 in THF (40 mL). The mixture was stirred for about 5 minutes and then concentrated in vacuo. The residue was purified by column chromatography on silica, eluting with EtOAc/hexane 1:6. The title compound was obtained as an oil (Yield; 3.93 g, 74%). Rf=0.20 (Silica, EtOAc/hexane 1:4) MS (ES): 229.1; Calc. MW=229.7.)
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[CH3:16][NH2:17]>CO>[CH3:10][CH:9]([CH3:11])[C:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:17][CH3:16])=[C:3]([N+:13]([O-:15])=[O:14])[CH:4]=1)=[O:12]
Reactant: CC(C)C(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CN
Solvent: CO
Product: CNc1ccc(C(=O)C(C)C)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 12 h
Yield: 100 %

Procedure:
To a stirred solution of 30 parts of 1-(4-chloro-3-nitrophenyl)-2-methyl-1-propanone in 240 parts of methanol was added a solution of 20 parts of methanamine in 160 parts of methanol. After stirring for 12 hours at 60° C., the reaction mixture was evaporated to dry, yielding 30 parts (100%) of 2-methyl-1-[4-(methylamino)-3-nitrophenyl]-1-propanone as a residue (interm. 45).