Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[C:5]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[N:6][C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=2[C:13]=1[NH:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)([O-])=O.[H][H]>C1(C)C=CC=CC=1.[Pt]>[O:27]([C:5]1[C:4]([NH2:1])=[C:13]([NH:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[N:6]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1c(Oc2ccccc2)nc2c(c1NCCOCCCc1cccnc1)CCCC2
Agent: [Pt]
Solvent: Cc1ccccc1
Product: Nc1c(Oc2ccccc2)nc2c(c1NCCOCCCc1cccnc1)CCCC2
Reaction time: 4 h
Yield: 74 %

Procedure:
A 500 mL Parr bottle was charged with a solution of 3-nitro-2-phenoxy-N-[2-(3-pyridin-3-ylpropoxy)ethyl]-5,6,7,8-tetrahydroquinolin-4-amine in toluene (150 mL) and 5% Pt/C catalyst (1.1 g), placed on Parr apparatus and charged with hydrogen (˜54 psi, 3.8 Kg/cm2). The reaction was allowed to shake for 4 hours, at which time the reaction was monitored by HPLC. The reaction was not complete. An additional 1.0 g 5% Pt/C catalyst was added to the Parr bottle, it was recharged with hydrogen and shaken overnight. The reaction was then complete. The mixture was filtered through Celite and washed with toluene (500 mL). The filtrate was concentrated to provide 2-phenoxy-N4-[2-(3-pyridin-3-ylpropoxy)ethyl]-5,6,7,8-tetrahydroquinoline-3,4-diamine as a yellow syrup (8.2 g, 74%). TLC (10% MeOH/CH2Cl2, Rf=0.48). Mass-spec M+1=419.2
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[Na].[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[CH2:15][C:16]([C:19]1([CH2:22][N:23]2[CH:27]=[N:26][CH:25]=[N:24]2)[CH2:21][O:20]1)([CH3:18])[CH3:17].O>C(O)CC>[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[CH2:15][C:16]([CH3:18])([CH3:17])[C:19]([CH2:22][N:23]1[CH:27]=[N:26][CH:25]=[N:24]1)([OH:20])[CH2:21][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: CC(C)(Cc1ccc(Cl)cc1Cl)C1(Cn2cncn2)CO1
Reactant: c1nc[nH]n1
Agent: [Na]
Solvent: CCCO
Solvent: O
Product: CC(C)(Cc1ccc(Cl)cc1Cl)C(O)(Cn1cncn1)Cn1cncn1
Yield: 18.8 %

Procedure:
3.7 g (52.6 mmol) of 1,2,4-triazole are added, with stirring, to a solution of 0.11 g (47 mmol) of sodium in 30 ml of n-propanol at room temperature. The mixture is heated to reflux temperature and a solution of 15.4 g (47 mmol) of 2-(2,4-dichlorophenyl-tert.-butyl)-2-(1,2,4-triazol-1-ylmethyl)oxirane in 20 ml of n-propanol is added. The reaction mixture is heated under reflux for 15 hours, then cooled and added to water. The mixture is extracted with methylenechloride, and the organic phase is dried over sodium sulphate and evaporated. The residue is purified by column chromatography (silica gel; ethyl acetate:cyclohexane=3:1). 3.5 g (18.8% of theory) of 4-(2,4-dichlorophenyl)-3,3-dimethyl-2-(1,2,4-triazol-1-ylmethyl)-1-(1,2,4-triazol-1-yl)-2-butanol of melting point 126° C. are obtained.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:10]([C:12]1[O:13][CH:14]=[CH:15][CH:16]=1)=O.Cl[Si](C)(C)C.CN([CH:25]=[O:26])C>>[CH3:5][C:4]1[N:1]=[C:2]2[S:6][C:5]3[CH2:7][CH2:8][CH2:9][C:4]=3[C:3]2=[C:10]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)[C:3]=1[CH2:10][C:12]([O:26][CH3:25])=[O:13]
Reactant: CN(C)C=O
Reactant: Nc1sc2c(c1C(=O)c1ccco1)CCC2
Agent: C[Si](C)(C)Cl
Product: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccco1)CCC3
Yield: 62 %

Procedure:
This compound was prepared according to the procedure B from (2-amino-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)(furan-2-yl)methanone (0.440 g, 1.886 mmol), methyl levunilate (0.26 mL, 1.886 mmol), chlorotrimethylsilane (0.964 mL, 7.54 mmol) in DMF (3.7 mL) for 18 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2-50%) in heptane furnished 0.385 g (62%) of the title compound as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:13](Cl)(=O)[O:14]CC.C(Cl)(=O)C>CCCCCC>[CH2:11]([C:8]1[CH:9]=[CH:10][C:2]2[NH:1][C:13](=[O:14])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=1)[CH3:12]
Reactant: CCc1ccc(N)c(C(=O)O)c1
Reactant: CCOC(=O)Cl
Solvent: CCCCCC
Solvent: CC(=O)Cl
Product: CCc1ccc2[nH]c(=O)oc(=O)c2c1
Temperature: 100 °C
Reaction time: 0.83 h
Yield: 83.3 %

Procedure:
A mixture of 2-amino-5-ethylbenzoic acid (20.28 g) and ethyl chlorocarbonate (53.5 g) was stirred for 50 minutes at 100° C. and then cooled to 90° C. To the mixture was added dropwise acetyl chloride (13.81 g) in the course of 15 minutes and the reaction mixture was stirred for 2 hours at 100° C. After the resultant mixture was cooled to ambient temperature, to the mixture was added hexane and allowed to stand at ambient temperature to give crystals, which were separated by filtration, washed with hexane and dried under reduced pressure to give crystalline 6-ethyl-2H-3,1-benzoxazine-2,4(1H)-dione (19.55 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].C1C[O:15][CH2:14]C1>CCOC(C)=O>[N+:8]([C:7]1[C:2]2[NH:1][C:14](=[O:15])[O:11][C:3]=2[CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: C1CCOC1
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Solvent: CCOC(C)=O
Product: O=c1[nH]c2c([N+](=O)[O-])cccc2o1
Yield: 65 %

Procedure:
To 2-amino-3-nitrophenol 3b (2 g, 13.00 mmol) dissolved in THF (50 ml) was added in one portion DCI (1.5 equiv., 19.6 mmol, 3.176 g) and the reaction was refluxed for 4 hours. (TLC AcOEt 1/petroleum ether 1). The reaction was evaporated and the crude material was dissolved in HCL 2N and extracted 3 times with chloroform. The combined organic phases were washed with water, brine, dried over sodium sulfate and concentrated under vacuum. The crude solid was crystallized from ether giving 1.5 g of a beige solid. Yield=65% 1HNMR (DMSO, 200 MHz) δ 7.27 (1H, t, J=7.8 Hz), 7.72 (1H, dd, J=8.2 Hz, J′=1 Hz), 7.93 (1H, dd, J=8.4 Hz, J′=0.6 Hz), 12.64 (1H, bs)
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([CH:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:14][OH:15])=[CH:10][CH:11]=2)[C:6]([CH3:22])([CH3:21])[CH2:5][CH2:4]1)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C:43]1[CH:52]=[CH:51][C:46]([C:47]([O:49][CH3:50])=[O:48])=[CH:45][CH:44]=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.CCOCC>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([CH:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:14][O:15][C:43]3[CH:52]=[CH:51][C:46]([C:47]([O:49][CH3:50])=[O:48])=[CH:45][CH:44]=3)=[CH:10][CH:11]=2)[C:6]([CH3:21])([CH3:22])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCCCCC(CO)c1ccc2c(c1)C(C)(C)CCN2CC
Reactant: COC(=O)c1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCC(COc1ccc(C(=O)OC)cc1)c1ccc2c(c1)C(C)(C)CCN2CC
Yield: 46.5 %

Procedure:
1 g of (RS)-2-(N-ethyl-4,4-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)-heptanol dissolved in 20 ml THF were treated with 950 mg of triphenylphosphine, 550 mg of methyl 4-hydroxybenzoate and 0.57 ml of diethyl azodicarboxylate. The reaction mixture was heated to reflux for 6 hours. The mixture was diluted with 100 ml of ether and washed with two portions of 25 ml of water and one portion of 25 ml of sat. aq. sodium chloride solution. The organic phase was dried over MgSO4. The solvents were removed in vacuo and the resulting yellow oil was purified by flash chromatography (SiO2, 3% ethyl acetate/hexanes), giving 670 mg (RS)-methyl 4-[2-(N-ethyl-4,4-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)-heptyloxy]-benzoate as a pale yellow oil. The ester (670 mg), dissolved in 5 ml THF/5 ml H2O/5 ml methanol, was treated with 260 mg of lithium hydroxide hydrate. The mixture was stirred at 40° C. for 6 hours. The mixture was diluted with 5 ml water and acidified to pH 2 with 1N hydrochloric. The resulting suspension was taken in 20 ml ether and the phases were separated. The aqueous phase was extracted with three portions of 10 ml ether. The combined extracts were dried over MgSO4. The solvent was removed in vacuo and the crude product was purified by preparative tlc (10% methanol/methylene chloride), yielding 320 mg of a pale yellow oil. 1H NMR (CDCl3): 8.01 (d, J=9.0 HZ, 2H), 6.98 (d, J=2.1 Hz, 1H), 6.95-6.85 (m, 3H), 6.52 (d, J=8.4 Hz, 1H), 4.64 (quint, J=5.8 Hz, 1H), 3.32 (q, J=7.1 Hz, 2H), 3.25-3.15 (m, 2H), 2.88 (dd, J=14.1, 5.9 Hz, 1H), 2.78 (dd, J=14.1, 5.9 Hz, 1H), 1.80-1.65 (m, 4H), 1.55-1.25 (m, 6H), 1.24 (s, 3H), 1.18 (s, 3H), 1.11 (t, J=7.1 Hz, 3H), 0.86 (t, J=6.7 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]([CH3:9])([CH:6]([CH3:8])[CH3:7])[C:3]([NH2:5])=[O:4].[O:10]1[C:14]2=[N:15][C:16]3[C:22](=[O:23])[O:21][C:19](=[O:20])[C:17]=3[CH:18]=[C:13]2[CH:12]=[CH:11]1.CCOCC>O1CCCC1>[C:3]([C:2]([NH:1][C:22]([C:16]1[N:15]=[C:14]2[O:10][CH:11]=[CH:12][C:13]2=[CH:18][C:17]=1[C:19]([OH:21])=[O:20])=[O:23])([CH3:9])[CH:6]([CH3:8])[CH3:7])(=[O:4])[NH2:5]
Reactant: CC(C)C(C)(N)C(N)=O
Reactant: O=C1OC(=O)c2nc3occc3cc21
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)C(C)(NC(=O)c1nc2occc2cc1C(=O)O)C(N)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.9 %

Procedure:
2-Amino-2,3-dimethylbutyramide (2.1 g, 0.016 mol) is added to a stirred suspension of furo[2,3-b]pyridine-5,6-dicarboxylic acid anhydride (3.0 g, 0.016 mol) in tetrahydrofuran (7.5 mL) and the mixture allowed to stir at room temperature for 16 hours. The reaction mixture is then stirred at 60° C. for one hour, cooled to room temperature, ether added, and the solid filtered off and dried to give 5 g of 6-[(1-carbamoyl-1,2-dimethylpropyl)carbamoyl]furo[2,3-b]pyridine-5-carboxylic acid mp 192°-196° C. (dec).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:9])[CH2:6][NH:7][CH3:8])[CH3:3].Cl.CN(C)CCCN=C=NCC.[F:22][C:23]1[C:28]2[N:29]=[C:30]([CH2:32][CH2:33][C:34](O)=[O:35])[S:31][C:27]=2[C:26]([F:37])=[CH:25][C:24]=1[F:38].C(N(CC)CC)C>C(Cl)Cl>[CH2:2]([O:4][C:5](=[O:9])[CH2:6][N:7]([C:34](=[O:35])[CH2:33][CH2:32][C:30]1[S:31][C:27]2[C:26]([F:37])=[CH:25][C:24]([F:38])=[C:23]([F:22])[C:28]=2[N:29]=1)[CH3:8])[CH3:3]
Reactant: O=C(O)CCc1nc2c(F)c(F)cc(F)c2s1
Reactant: CCOC(=O)CNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CN(C)C(=O)CCc1nc2c(F)c(F)cc(F)c2s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 84.6 %

Procedure:
To methylene chloride (10 ml) was added sarcosine ethyl ester hydrochloride (307 mg, 2 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (WSC.HCl; 422 mg, 2.2 mmol), 3-(4,5,7-trifluorobenzothiazol-2-yl)propionic acid (522 mg, 2 mmol) and triethylamine (220 mg, 2.2 mmol), and the mixture was stirred at room temperature for 15 hours. The resulting mixture was washed with water, dried and evaporated to yield a residue, which was purified on a silica gel column to give N-[3-(4,5,7-trifluorobenzothiazol-2-yl)propionyl]-N-methylglycine ethyl ester (610 mg, 85%) as an oil.
Reaction SMILES: C([NH:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[CH2:11][CH2:12][C:13]([OH:15])=O)(=O)C.P(Cl)(Cl)Cl.[P:20]([OH:23])([OH:22])[OH:21]>Cl>[NH2:4][C@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[CH2:11][CH2:12][C:13]([OH:15])([P:20]([OH:23])(=[O:21])[OH:22])[P:20]([OH:23])(=[O:22])[OH:21]
Reactant: OP(O)O
Reactant: CC(=O)NC1CCCCC1CCC(=O)O
Agent: Cl
Solvent: ClP(Cl)Cl
Product: N[C@H]1CCCC[C@H]1CCC(O)(P(=O)(O)O)P(=O)(O)O
Yield: 32 %

Procedure:
From the cis-trans mixture of 3-(2-acetylaminocyclohexyl)-propionic acid described in Example 10, by recrystallisation from water there is obtained the pure cis-compound (yield 32% of theory; m.p. 131°-133° C.), the reaction of which with phosphorus trichloride/phosphorous acid takes place analogously to Example 1. The course of the splitting off of the acetyl radical by heating in hydrochloric acid is monitored by means of thin layer electrophoresis.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24](=[NH:26])[NH2:25])=[CH:20][CH:19]=2)[C:13](=[O:27])[CH2:12]1)=O)C1C=CC=CC=1.[H][H]>CO.CC(O)=O.[Pd]>[O:27]=[C:13]1[CH2:12][NH:11][CH2:16][CH2:15][N:14]1[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([NH2:26])=[NH:25])=[CH:20][CH:19]=1
Reactant: [H][H]
Reactant: N=C(N)c1ccc(CN2CCN(C(=O)OCc3ccccc3)CC2=O)cc1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: N=C(N)c1ccc(CN2CCNCC2=O)cc1
Reaction time: 4 h

Procedure:
To a solution of 4-(4-carbamimidoylbenzyl)-3-oxopiperazine-1-carboxylic acid benzyl ester (2.0 g, 5.0 mmol) in 40 mL of MeOH and 4 mL of AcOH is added 10% Pd/C (0.4 g). The atmosphere above the reaction is replaced by hydrogen. After 4 hours, the solution is filtered through a pad of Celite. The organic layer is concentrated. The resulting crude product is purified by RP-HPLC eluting in a gradient of 10% CH3CN/H2O (0.1%TFA) to 40% CH3CN/H2O (0.1% TFA). The title compound is obtained as a white foam. 1H NMR (d6-DMSO, 300 MHz) δ9.3 (bs, 4H), 9.1 (bs, 2H), 7.83 (d, 2H), 7.42 (d, 2H), 4.78 (s, 2H), 3.80 (s, 2H), 3.44 (m, 2H), 3.32 (m, 2H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[S:9][C:10]([C:14]([OH:16])=O)=[C:11]([CH3:13])[N:12]=1.Cl.[NH:18]1[CH2:21][CH2:20][CH2:19]1.C(N(CC)CC)C>C(Cl)Cl>[N:18]1([C:14]([C:10]2[S:9][C:8]([Br:7])=[N:12][C:11]=2[CH3:13])=[O:16])[CH2:21][CH2:20][CH2:19]1
Reactant: C1CNC1
Reactant: Cc1nc(Br)sc1C(=O)O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc(Br)sc1C(=O)N1CCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 41.7 %

Procedure:
Oxalyl chloride (0.47 mL; 5.41 mmol) was added to a solution of 2-bromo-4-methyl-1,3-thiazole-5-carboxylic acid (1.0 g; 4.5 mmol) in DCM (25 mL). The mixture was stirred at RT for 18 hours, the DCM was evaporated in vacuo, the residue azeotroped with toluene (2×5 mL) and added to a solution of azetidine hydrochloride (503 mg; 5.41 mmol) and triethylamine (2.3 mL; 16.2 mmol) in DCM (50 mL). The mixture was stirred at RT for 18 hours, the DCM evaporated in vacuo, and the residue partitioned between water (75 mL) and ethyl acetate (150 mL). The organic layer was washed with brine, dried (MgSO4) and evaporated to a residue which was chromatographed on silica, eluting with 40% ethyl acetate in isohexane, to give a solid which was crystallised from ethyl acetate/isohexane to give the desired compound (490 mg). 1H NMR δ (CDCl3): 2.35 (m, 2H), 2.55 (s, 3H) and 4.1 (t, 4H).
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].C[O-].[Na+].[C:9](Cl)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CO>[C:3]([NH:5][C:9](=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[NH:2])[NH2:4]
Reactant: O=C(Cl)c1ccccc1
Reactant: N=C(N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: N=C(N)NC(=O)c1ccccc1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
A four neck flask (3 liters) equipped with a thermometer and a stirrer was charged with 573.2 g (6.0 mole) of guanidine hydrochloride and 1.5 liter of methanol and cooled to 20° C. Slowly dropwise added thereto was 324.1 g (6.0 mole) of sodium methoxide crystal at 20° C. or lower and stirred for 3 hours. Deposited crystals were filtered off. The mother liquor was charged to the four neck flask (3 liters) equipped with the above devices, and 337.4 g (2.4 mole) of benzoyl chloride was slowly dropwise added at 15° C. or lower and stirred for 12 hours. Deposited crystals were filtered off, and the mother liquor was concentrated under reduced pressure to obtain white crystals. The resulting crystals were sufficiently washed with 3 liters of deionized water and dried under reduced pressure, whereby the intended compound (white crystals) was obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:11]=[N:10][CH:9]=[CH:8][N:7]=1.[C:12]([N:20]=[C:21]=[S:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:12]([NH:20][C:21]([NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:11]=[N:10][CH:9]=[CH:8][N:7]=1)=[S:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCCSCc1cnccn1
Reactant: O=C(N=C=S)c1ccccc1
Product: O=C(NC(=S)NCCSCc1cnccn1)c1ccccc1

Procedure:
By the procedure of Example 18, 2-[(2-aminoethyl)thiomethyl]pyrazine is reacted with benzoyl isothiocyanate to give N-benzoyl-N'-[2-(2-pyrazinylmethylthio)ethyl]thiourea. Removing the benzoyl group by the procedure of Example 18 gives N-[2-(2-pyrazinylmethylthio)ethyl]thiourea.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[N:22]=[C:12]3[CH:13]([C:17]([O:19]CC)=[O:18])[CH2:14][CH2:15][CH2:16][N:11]3[N:10]=2)[CH:6]=[CH:5][C:4]=1[N:23]1[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]1.Cl>C1COCC1.CO.[OH-].[Na+]>[CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[N:22]=[C:12]3[CH:13]([C:17]([OH:19])=[O:18])[CH2:14][CH2:15][CH2:16][N:11]3[N:10]=2)[CH:6]=[CH:5][C:4]=1[N:23]1[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]1
Reactant: CCOC(=O)C1CCCn2nc(-c3ccc(-n4cnc(C)c4)c(OC)n3)nc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1nc(-c2nc3n(n2)CCCC3C(=O)O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Ethyl 2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine-8-carboxylate (331 mg) was dissolved in a mixed solvent of THF (5 mL) and methanol (5 mL) A 5 N sodium hydroxide aqueous solution (693 μL) was added and the mixture was stirred at room temperature for two days. The reaction solution was neutralized with 5 N hydrochloric acid (693 μl), and then concentrated under reduced pressure to remove the organic solvent. Methanol (2 mL) was added to the residue, and the precipitated salt was separated by filtration. Thereafter, the filtrate was concentrated under reduced pressure to obtain the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:16][C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[C:9]=2[CH3:17])=[CH:4][CH:3]=1.[CH2:18](Br)[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:20]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]=[C:11]3[N:12]([CH2:18][C:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[O:20])[CH:13]=[CH:14][CH:15]=[C:10]3[C:9]=2[CH3:17])=[CH:6][CH:7]=1
Reactant: Cc1c(-c2ccc(Br)cc2)[nH]c2ncccc12
Reactant: O=C(CBr)c1ccccc1
Product: Cc1c2cccn(CC(=O)c3ccccc3)c-2nc1-c1ccc(Br)cc1

Procedure:
The title compound was prepared from 2-(p-bromophenyl)-3-methyl-pyrrolo-[2,3-b]pyridine and phenacylbromide on a 1.7 mmol scale according to the procedure described in example 8 yielding 620 mg (74%).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([NH:12][C:13]2[CH:14]=[N:15][CH:16]=[N:17][CH:18]=2)[CH:11]=1)[C:7]#[N:8].[CH3:19]I>C1COCC1.CCOC(C)=O>[F:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([N:12]([CH3:19])[C:13]2[CH:18]=[N:17][CH:16]=[N:15][CH:14]=2)[CH:11]=1)[C:7]#[N:8]
Reactant: N#Cc1cc(F)cc(Nc2cncnc2)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(c1cncnc1)c1cc(F)cc(C#N)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 82.7 %

Procedure:
NaH (23 mg, 0.96 mmol, 1.1 eq) was added to a flame-dried round-bottom flask and anhydrous THF (2.1 mL) was added. The slurry was cooled to 0° C. and compound 11 (185 mg, 0.864 mmol, 1.00 eq) was added as a solution in THF (2.1 mL). After stirring at 0° C. for 30 minutes methyl iodide (59.3 μL, 0.958 mmol, 1.10 eq) was added and the reaction was allowed to warm to room temperature while stirring overnight. The reaction was diluted with EtOAc and washed with water (1×). The aqueous layer was back extracted (1×) with EtOAc and the combined organics were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 163 mg (83%) of the title compound as a tan solid: 1H NMR (400 MHz, CDCl3) δ 8.93 (s, 1H), 8.71 (s, 2H), 7.32-7.27 (m, 2H), 7.19 (dt, J=11.7, 2.3 Hz, 1H), 3.35 (s, 3H); [M+1]+: 229.2.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[C:8]=2[N+:14]([O-:16])=[O:15])=[C:4]([CH3:19])[C:3]=1[CH3:20].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][C:23]=1[C:31]([F:34])([F:33])[F:32]>>[NH2:13][C:9]1[C:8]([N+:14]([O-:16])=[O:15])=[C:7]([O:6][C:5]2[CH:17]=[CH:18][C:2]([NH:1][C:29]([NH:28][C:25]3[CH:26]=[CH:27][C:22]([Cl:21])=[C:23]([C:31]([F:33])([F:32])[F:34])[CH:24]=3)=[O:30])=[C:3]([CH3:20])[C:4]=2[CH3:19])[CH:12]=[CH:11][N:10]=1
Reactant: Cc1c(N)ccc(Oc2ccnc(N)c2[N+](=O)[O-])c1C
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Product: Cc1c(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)ccc(Oc2ccnc(N)c2[N+](=O)[O-])c1C
Yield: 86 %

Procedure:
Method H3 was used with 4-(4-amino-2,3-dimethylphenoxy)-3-nitropyridin-2-amine and 4-chloro-3-trifluoromethyl-phenyl isocyanate to afford the title compound (625 mg, 86%) as a yellow powder. 1H-NMR (δ, ppm, DMSO-d6): 2.07 (s, 3H, CH3), 2.19 (s, 3H, CH3), 5.77 (d, 1H, HPy,5, J=5.7 Hz), 6.98 (d, 1H, Harom, J=8.7 Hz), 7.14 (s, 2H, NH2,Py), 7.57 (d, 1H, Harom, J=8.7 Hz), 7.62 (m, 1H, Harom), 7.96 (d, 1H, HPy,6, J=5.7 Hz), 8.12 (m, 1H, Harom), 8.21 (s, 1H, NHurea1), 9.38 (s, 1H, NHurea3). LC-MS (m/z): 496 (M+H, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH:13]([OH:15])[CH2:12][N:11]([N:16]=[C:17]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)SC)[C:10]1=O.[N-:35]=[N+]=[N-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH:13]([OH:15])[CH2:12][N:11]2[N:16]=[C:17]([NH:20][CH:21]3[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[CH2:25][CH2:26]3)[N:35]=[C:10]12
Reactant: CSC(=NN1CC(O)CC(c2ccc(F)cc2Cl)C1=O)NC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2nc3n(n2)CC(O)CC3c2ccc(F)cc2Cl)CC1
Temperature: 100 °C

Procedure:
To a solution of tert-butyl 4-(((3SR,5SR)-3-(2-chloro-4-fluorophenyl)-5-hydroxy-2-oxopiperidin-1-ylimino)(methylthio)methylamino)piperidine-1-carboxylate (1.1 g, 2.1 mmol) in DMF (5.5 mL) was added sodium azide (0.2 g, 3.2 mmol) and the reaction heated to 100° C. for 48 hours. The reaction was then concentrated to dryness, redissolved in ethyl acetate, washed with water, brine, dried with sodium sulfate and the solvent was evaporated. The residue was redissolved in THF, trimethylphosphine added (2.1 mL, 1 M in toluene, 2.1 mmol) and the reaction heated to 160° C. in a micowave for 12 hours. The reaction was then concentrated in vacuo and the residue was purified by column chromatography on silica gel using ethyl acetate/MeOH (v/v 1:0 to 9:1) as eluent. The title compound was obtained as a light yellow foam (0.2 g, 20%), an inseparable 1:1 mixture of diasteriomers.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].Cl.Cl.[NH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]1[CH2:29][CH2:28][C:27]2[C:30]3[CH:20]1[CH2:21][C:22](=[O:35])[C:23]=3[C:24]([O:33][CH3:34])=[C:25]([O:31][CH3:32])[CH:26]=2>C(Cl)Cl>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]1[CH2:29][CH2:28][C:27]2[C:30]3[CH:20]1[CH2:21][C:22](=[O:35])[C:23]=3[C:24]([O:33][CH3:34])=[C:25]([O:31][CH3:32])[CH:26]=2)(=[O:10])=[O:9]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: COc1cc2c3c(c1OC)C(=O)CC3N(CCCCN)CC2
Agent: Cl
Solvent: ClCCl
Product: COc1cc2c3c(c1OC)C(=O)CC3N(CCCCNS(=O)(=O)c1ccccc1Cl)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 119 %

Procedure:
2-Chlorobenzenesulfonyl chloride (92.4 mg, 0.44 mmol) was added to a solution of 3-(4-Amino-butyl)-7,8-dimethoxy-2a,3,4,5-tetrahydro-2H-3-aza-acenaphthylen-1-one dihydro-chloride (150 mg, 0.40 mmol) and NN′-diisopropylethylamine (0.400 ml) in CH2Cl2 (20 mL) and the mixture was stirred overnight at room temperature. The resulting solution was washed with water (3×20 mL), dried over Na2SO4 and evaporated to dryness. The free base was dissolved in ethyl acetate (2 ml) and A 2.8 M solution of hydrogen chloride in ethanol was then added. The product was crystallized and collected by filtration, and vacuum dried to give a pale brown solid (135 mg, 66%).