Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]([CH2:8][C:9](=O)[CH3:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:12][NH:13][NH2:14].C(OCC)(=O)C.O>C(O)(=O)C>[CH2:6]([O:5][C:3]([C:2]1[CH:8]=[C:9]([CH3:10])[N:13]([CH3:12])[N:14]=1)=[O:4])[CH3:7]
Reactant: CNN
Reactant: CCOC(=O)C(=O)CC(C)=O
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(C)n(C)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Ethyl 2,4-dioxovalerate (5.6 ml, 40 mM) was dissolved in glacial acetic acid (35 ml) before cooling the reaction temperature to 8°-10° C. Methylhydrazine (2.0 ml, 38 mM) was added dropwise so that the reaction temperature did not rise above 15° C. After stirring at room temperature for 90 minutes the reaction was poured into ethyl acetate and water. The organic phase was washed with saturated sodium bicarbonate solution, water and brine before drying (MgSO4). Purification was accomplished was by chromatography on silica gel (10×4.5 cm) loading in dichloromethane and eluting with 50% ethyl acetate in hexane. Evaporation of solvent gave the title compound as a coloured oil which crystallised on standing (4.69 g); νmax (CH2Cl2) 1717 and 1223 cm-1 ; δH (CDCl3) 1.39 (3H, t, J 7.13 Hz), 2.30 (3H, s), 3.85 (3H, s), 4.39 (2H, q, J 7.21 Hz), 6.57 (1H, s); E.I m/e 168 (25% ).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH:11][CH2:12][CH:13]([OH:24])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[Cl:34][CH2:35][C:36](Cl)=[O:37]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:12][CH:13]([OH:24])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23])[C:36](=[O:37])[CH2:35][Cl:34])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)CCl
Reactant: COc1ccccc1OCC(O)CNCCNC(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccccc1OCC(O)CN(CCNC(=O)OC(C)(C)C)C(=O)CCl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Compound 11 (1.0 g, 3.0 mmol) was dissolved in 20 mL DCM and treated with diisopropylethyl amine (0.76 g, 4.5 mmol). The mixture was cooled to ° C. To the cold mixture was added dropwise chloroacetyl chloride in 5 mL DCM. The reaction mixture was allowed to stir at RT for 24 h. The mixture was diluted with 50 mL DCM and washed with 50 mL of water and 10% citric acid. The organic layer was dried over MgSO4 and filtered. The solvent was evaporated under reduced pressure and the residue was crystallized from ethylether to afford compound 12.
Reaction SMILES: [CH2:1](Br)C#C.CI.COC(N1CCC(N2CCC(N3C4C=CC=CC=4NC3=O)CC2)CC1)=O.[CH2:33]([O:35][C:36]([N:38]1[CH2:43][CH2:42][CH:41]([N:44]2[CH2:49][CH2:48][CH:47]([N:50]3[C:54]4[CH:55]=[CH:56][CH:57]=[CH:58][C:53]=4[NH:52][C:51]3=[O:59])[CH2:46][CH2:45]2)[CH2:40][CH2:39]1)=[O:37])[CH3:34]>>[CH2:33]([O:35][C:36]([N:38]1[CH2:43][CH2:42][CH:41]([N:44]2[CH2:45][CH2:46][CH:47]([N:50]3[C:54]4[CH:55]=[CH:56][CH:57]=[CH:58][C:53]=4[N:52]([CH3:1])[C:51]3=[O:59])[CH2:48][CH2:49]2)[CH2:40][CH2:39]1)=[O:37])[CH3:34]
Reactant: CCOC(=O)N1CCC(N2CCC(n3c(=O)[nH]c4ccccc43)CC2)CC1
Reactant: C#CCBr
Agent: COC(=O)N1CCC(N2CCC(n3c(=O)[nH]c4ccccc43)CC2)CC1
Solvent: CI
Product: CCOC(=O)N1CCC(N2CCC(n3c(=O)n(C)c4ccccc43)CC2)CC1

Procedure:
Example 1 was repeated except that the propargyl bromide was replaced with methyl iodide and 1-[1-(1-methoxycarbonylpiperidin-4-yl)-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one was replaced with 1-[1-(1-ethoxycarbonylpiperidin-4-yl-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one which was synthesized by the method of Referential Example 16, and the title compound was obtained as a colorless oil.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH:15][CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]([NH:8][CH2:9][C:10]([O:12]CC)=O)=[N:6][CH:7]=1.Br[C:25]1[C:26]([NH:32][CH2:33][C:34](OCC)=O)=[N:27][CH:28]=[C:29](Br)N=1.O1CCC(CCN)C[CH2:40]1>CS(C)=O>[NH:27]1[C:26]2=[N:32][CH:33]=[C:34]([C:2]3[N:3]=[C:4]4[N:15]([CH2:16][CH2:17][CH:18]5[CH2:19][CH2:20][O:21][CH2:22][CH2:23]5)[C:10](=[O:12])[CH2:9][NH:8][C:5]4=[N:6][CH:7]=3)[CH:40]=[C:25]2[CH:29]=[CH:28]1
Reactant: CCOC(=O)CNc1ncc(Br)nc1Br
Reactant: NCCC1CCOCC1
Reactant: CCOC(=O)CNc1ncc(Br)nc1NCCC1CCOCC1
Solvent: CS(C)=O
Product: O=C1CNc2ncc(-c3cnc4[nH]ccc4c3)nc2N1CCC1CCOCC1
Temperature: 150 °C
Yield: 44 %

Procedure:
Ethyl 2-(5-bromo-3-(2-(tetrahydro-2H-pyran-4-yl)ethylamino)pyrazin-2-ylamino)acetate. Ethyl 2-(3,5-dibromopyrazin-2-ylamino)acetate (See Example 6.B) (1.0 g, 2.95 mmol) and 2-(tetrahydro-2H-pyran-4-yl)ethanamine (0.381 g, 2.95 mmol) were placed in a microwave vial, dimethylsulfoxide (2 mL) was added and the resulting mixture was heated in a Biotage Emrys Optimizer microwave reactor at 150° C. for 3600 s. The crude reaction mixture was purified using silica gel chromatography (33% ethyl acetate in hexanes) to yield the title compound (0.5 g, 1.3 mmol, 44% yield). MS (ESI) m/z 387.1 [M]+, 389.1 [M+2]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]2[CH2:13][N:14]([C:16]3[C:17]([CH3:47])=[C:18]([CH3:46])[C:19]4[N:20]([C:22]([C:32]5[CH:37]=[CH:36][N:35]=[C:34]([NH:38]C(=O)OC(C)(C)C)[CH:33]=5)=[C:23]([C:25]5[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=5)[N:24]=4)[N:21]=3)[CH2:15][CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.O.N>ClCCl>[CH2:1]([N:8]1[CH2:9][CH:10]2[CH2:15][N:14]([C:16]3[C:17]([CH3:47])=[C:18]([CH3:46])[C:19]4[N:20]([C:22]([C:32]5[CH:37]=[CH:36][N:35]=[C:34]([NH2:38])[CH:33]=5)=[C:23]([C:25]5[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=5)[N:24]=4)[N:21]=3)[CH2:13][CH:11]2[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(N2CC3CN(Cc4ccccc4)CC3C2)nn2c(-c3ccnc(NC(=O)OC(C)(C)C)c3)c(-c3ccc(F)cc3)nc2c1C
Agent: N
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(N2CC3CN(Cc4ccccc4)CC3C2)nn2c(-c3ccnc(N)c3)c(-c3ccc(F)cc3)nc2c1C
Reaction time: 2 h

Procedure:
To a solution of 2.9 g (4.58 mmol) of tert-butyl {4-[6-(5-benzylhexahydropyrrolo[3,4-c]pyrrol-2-yl)-2-(4-fluorophenyl)-7,8-dimethylimidazo[1,2-b]pyridazin-3-yl]pyrid-2-yl}carbamate in 30 mL of dichloromethane are added 6.8 mL of trifluoroacetic acid and the reaction is stirred for 2 hours. The medium is poured into 200 mL of water and the mixture is basified by addition of aqueous ammonia.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([CH3:10])[N:3]=1.[CH3:11][CH:12]1[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]1>CC(C)=O>[CH3:10][C:4]1[N:3]=[C:2]([N:14]2[CH2:15][CH2:16][CH2:17][CH:12]([CH3:11])[CH2:13]2)[N:7]=[C:6]([NH:8][CH3:9])[N:5]=1
Reactant: CNc1nc(C)nc(Cl)n1
Reactant: CC1CCCNC1
Solvent: CC(C)=O
Product: CNc1nc(C)nc(N2CCCC(C)C2)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 41.1 %

Procedure:
A mixture of 4-chloro-2-methyl-6-methylamino-1,3,5-triazine (1.06 g; 6.7 mM; described in J. Pharm. Soc. (Japan) 1975, 95, p.512) and 3-methylpiperidine (1.32 g, 13.3 mM) in acetone (10 ml) was stirred at ambient temperature for 6 hours. The mixture was filtered and the solid was partitioned between 3N aqueous ammonia solution (50 ml) and dichloromethane (50 ml). The organic solution was separated and dried (MgSO4) and the solvent was removed, and the residue was crystallised from elthanol. There was thus obtained 2-methyl-6-methylamino-4-(3-methylpiperidino)-1,3,5-triazine (608 mg, 41.3% yield) m.p. 155°-155.50° C.; microanalysis found: C,59.9; H,8.7; N,31.6%; C11H19N5 requires C,59.7; H,8.6; N,31.7%.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[CH3:15][C:16]1[O:17][C:18]2[C:24]([NH2:25])=[CH:23][CH:22]=[CH:21][C:19]=2[CH:20]=1.[NH:26]1[C:30]2[CH:31]=[CH:32][C:33]([CH:35]=O)=[CH:34][C:29]=2[N:28]=[CH:27]1>>[NH:26]1[C:30]2[CH:31]=[CH:32][C:33]([CH2:35][NH:1][C:4]3[C:5]4[CH:6]=[CH:7][C:8]([NH:25][C:24]5[C:18]6[O:17][C:16]([CH3:15])=[CH:20][C:19]=6[CH:21]=[CH:22][CH:23]=5)=[N:9][C:10]=4[CH:11]=[CH:12][CH:13]=3)=[CH:34][C:29]=2[N:28]=[CH:27]1
Reactant: O=Cc1ccc2[nH]cnc2c1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Reactant: Cc1cc2cccc(N)c2o1
Product: Cc1cc2cccc(Nc3ccc4c(NCc5ccc6[nH]cnc6c5)cccc4n3)c2o1

Procedure:
The title compound, MS: m/e=420.1 (M+H+), was prepared from 5-nitro-2-chloroquinoline, (2-methyl-1-benzofuran-7-yl) amine and 1H-benzimidazole-5-carboxaldehyde as described in example 26.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1.[C:19]1([CH2:25][CH2:26][C:27](Cl)=[O:28])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:27](=[O:28])[CH2:26][CH2:25][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[S:11][C:7]=2[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: COc1ccc(N2CCOCC2)c2sc(N)nc12
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)CCc3ccccc3)nc12

Procedure:
Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-amine and 3-phenylpropionyl chloride the title compound was obtained as a light yellow solid (3%), MS: m/e=398 (M+H+).
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3](Cl)=[O:4].[CH3:10][O:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([O:19][CH3:20])[C:13]=1[OH:21].C(N(CC)CC)C>ClCCl>[Br:1][CH:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]([O:21][C:13]1[C:14]([O:19][CH3:20])=[CH:15][C:16]([CH3:18])=[CH:17][C:12]=1[O:11][CH3:10])=[O:4]
Reactant: COc1cc(C)cc(OC)c1O
Reactant: CC(C)CC(Br)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C)cc(OC)c1OC(=O)C(Br)CC(C)C
Reaction time: 20 h
Yield: 76.1 %

Procedure:
A solution of sodium nitrite (31.55 g) in water (70 ml) was added dropwise to a stirred solution of D-leucine (20 g) in 47% aqueous hydrobromic acid (140 ml)/water (211 ml) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 20 hours, then diluted with diethyl ether (600 ml). The organic layer was separated and washed with aqueous sodium metabisulphite (200 ml), dried over sodium sulphate, filtered and the solvent removed under reduced pressure to give 2-bromo-4-methyl-pentanoic acid as a yellow oil (27.6 g) [1H NMR (CDCl3): δ0.93 (d, 3H), 0.98 (d, 3H), 1.75-1.85 (m, 1H), 1.91-1.95 (m, 2H), 4.30 (t, 1H)]. Oxalyl chloride (9.56 ml) was added dropwise to a stirred solution of the 2-bromo-4-methylpentanoic acid (10.7 g) and pyridine (0.1 ml) in dichloromethane (60 ml). The reaction mixture was stirred for 20 hours and the solvent was removed under reduced pressure to give 2-bromo-4-methylpentanoyl chloride (12 g) [1H NMR (CDCl3); δ0.95 (d, 3H), 1.01 (d, 3H), 1.80-2.07 (m, 3H), 4.52 (t, 1H)]. A solution of this 2-bromo-4-methylpentanoyl chloride (12 g) in dichloromethane (40 ml) was added dropwise to a stirred solution of 2,6-dimethoxy-4-methylphenol (9.41 g) and triethylamine (15.6 ml) in dichloromethane (20 ml). The reaction mixture was stirred for 20 hours and was then chromatographed on silica gel, eluting with dichloromethane, to give the title compound as a viscous yellow oil (14.7 g).
Reaction SMILES: C(O[C:6](=[O:20])[NH:7][C:8]1[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])=[N:10][O:11][CH:12]=1)(C)(C)C.Cl.C(N(C(C)C)CC)(C)C.[Cl:31][C:32]1[CH:37]=[CH:36][N:35]2[N:38]=[CH:39][C:40](C(Cl)=O)=[C:34]2[N:33]=1>O1CCOCC1.ClCCl>[C:14]1([CH3:19])[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:9]1[C:8]([NH:7][C:6]([C:40]2[CH:39]=[N:38][N:35]3[CH:36]=[CH:37][C:32]([Cl:31])=[N:33][C:34]=23)=[O:20])=[CH:12][O:11][N:10]=1
Reactant: O=C(Cl)c1cnn2ccc(Cl)nc12
Reactant: Cc1ccccc1-c1nocc1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1-c1nocc1NC(=O)c1cnn2ccc(Cl)nc12
Temperature: 40 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
A mixture of (3-o-tolyl-isoxazol-4-yl)-carbamic acid tert-butyl ester (500 mg, 1.82 mmol, 1.0 equiv), 4M HCl in dioxane (4 mL) in 1,4-dioxane (5 mL) was stirred at ambient temperature for 22 hours and at 40° C. for 1 hour. The mixture was concentrated under vacuum affording a residue which was dissolved in dichloromethane (15 mL) and treated with diisopropylethylamine (523 mg, 4.05 mmol, 2.2 equiv). The mixture was cooled with an ice-bath and a solution of 5-chloropyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (1.82 mmol, 1.0 equiv) in dichloromethane (10 mL) was added dropwise. The reaction mixture was warmed to room temperature after the addition. After 65 hours, the solution was sequentially washed with 1M HCl aqueous solution, saturated aqueous sodium bicarbonate solution, water, and saturated aqueous sodium chloride solution. The organic was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was triturated (methanol) to give 444 mg (70%) of 5-chloro-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (3-o-tolyl-isoxazol-4-yl)-amide. LCMS (ESI) m+H=354.2 (mono Cl); 1H NMR (300 MHz, DMSO-d6) δ: 9.47 (s, 1H), 9.36 (d, 1H), 9.11 (s, 1H), 8.72 (s, 1H), 7.53-7.40 (m, 4H), 7.37 (d, 1H), 2.31 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:16])=[C:11]([C:13]([OH:15])=O)[N:12]=2)=[C:4]([NH:17][CH:18]([CH3:20])[CH3:19])[CH:3]=1.[NH2:21][CH2:22][CH2:23][CH2:24][OH:25].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:16])=[C:11]([C:13]([NH:21][CH2:22][CH2:23][CH2:24][OH:25])=[O:15])[N:12]=2)=[C:4]([NH:17][CH:18]([CH3:20])[CH3:19])[CH:3]=1
Reactant: NCCCO
Reactant: Cc1oc(-c2cnc(Cl)cc2NC(C)C)nc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1oc(-c2cnc(Cl)cc2NC(C)C)nc1C(=O)NCCCO
Temperature: 25 °C

Procedure:
2-(6-chloro-4-(isopropylamino)pyridin-3-yl)-5-methyloxazole-4-carboxylic acid (30a) (100 mg, 0.338 mmol) was dissolved in DMF (5 mL). 3-aminopropan-1-ol (1.691 mmol, 5 equiv.) and DIPEA (1.353 mmol, 4 equiv.) were added to the reaction mixture and stirred at room temperature. HATU (1.014 mmol, 3 equiv.) was added to the reaction mixture and stirred for 3 h. The reaction mixture was concentrated under reduced pressure to remove excess of DMF. The residue obtained was partitioned between water and EtOAc. The organic layer was separated, dried over Na2SO4, filtered and concentrated. The crude material obtained was purified by flash column chromatography through silica gel and MeOH: CHCl3 as eluent to afford the title compound, 2-(6-chloro-4-(isopropylamino)pyridin-3-yl)-N-(3-hydroxypropyl)-5-methyloxazole-4-carboxamide (31).
Reaction SMILES: [H-].[Na+].[CH2:3]1[O:19][C:6]2([C:15]3[C:9]4[C:10](=[CH:16][NH:17][CH2:18][C:8]=4[CH2:7]2)[CH:11]=[CH:12][O:13][CH:14]=3)[O:5][CH2:4]1.[C:20]1([S:26](Cl)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O.C(Cl)(Cl)Cl.CCCCCC>[CH2:4]1[O:5][C:6]2([C:15]3[C:9]4[C:10](=[CH:16][N:17]([S:26]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)(=[O:28])=[O:27])[CH2:18][C:8]=4[CH2:7]2)[CH:11]=[CH:12][O:13][CH:14]=3)[O:19][CH2:3]1
Reactant: C1=CC2=CNCC3=C2C(=CO1)C1(C3)OCCO1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: O=S(=O)(c1ccccc1)N1C=C2C=COC=C3C2=C(C1)CC31OCCO1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 69 %

Procedure:
60% Sodium hydride 33 mg was added to a solution of compound (33) in dry dimethylformamide 2 ml with cooling in ice and the mixture was stirred for 10 min. Then, benzenesulfonyl chloride 152 mg was added. The mixture was heated at 60° C. for 14 h. Ice-water was added to the reaction mixtures, which was extracted with ethyl acetate. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was choromatographed on aluminum oxide in chloroform:hexane (1:1) to give the titled compound (34) as a pale yellow oil, 187 mg. Yield 69%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[CH2:7][NH:8][CH2:9][CH2:10][NH2:11].CS[C:14](=[NH:19])[NH:15][N+:16]([O-:18])=[O:17]>>[N+:16]([NH:15][C:14]([NH:11][CH2:10][CH2:9][NH:8][CH2:7][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][N:1]=1)=[NH:19])([O-:18])=[O:17]
Reactant: NCCNCc1cnccn1
Reactant: CSC(=N)N[N+](=O)[O-]
Product: N=C(NCCNCc1cnccn1)N[N+](=O)[O-]

Procedure:
Reacting N-(2-pyrazinylmethyl)ethylenediamine with S-methyl-N-nitroisothiourea by the procedure of Example 2(ii) gives N-nitro-N'-[2-(2-pyrazinylmethylamino)ethyl]guanidine. Similarly, from the same starting material, according to the procedure of Example 2(iii), there is produced N-methyl-N'-nitro-N"-[2-(2-pyrazinylmethylamino)ethyl]guanidine.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[CH3:9][O:10][C:11](=[O:17])[CH2:12][CH2:13][C:14]([CH3:16])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl.CCOC(C)=O>[CH3:9][O:10][C:11](=[O:17])[CH2:12][CH2:13][CH:14]([NH:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[NH2:8])[CH3:16]
Reactant: Nc1ccccc1N
Reactant: COC(=O)CCC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: COC(=O)CCC(C)Nc1ccccc1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 21.7 %

Procedure:
To a mixture of 1,2-phenylenediamine (3.0 g, 27.7 mmol) and levulinic acid methyl ester (2.7 mL, 21.8 mmol) in 1,2-dichloroethane (25 mL) was added sodium triacetoxyborohydride (4.6 g, 21.7 mmol) and acetic acid (1.5 mL). The mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with EtOAc (100 mL) and washed with H2O (75 mL×3). The organic layer was dried over sodium sulfate and concentrated. The resulting residue was purified by CombiFlash with 40% EtOAc in Hexane as the eluent to afford the desired 4-(2-amino-phenylamino)-pentanoic acid methyl ester (1.05 g, 22%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[CH:12]([O:15][CH3:16])[O:13][CH3:14])[NH:8][CH2:7][CH2:6][CH2:5]2.[CH3:17][C:18]1[N:22]=[CH:21][NH:20][N:19]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C.O.[Cu]I>[CH3:14][O:13][CH:12]([O:15][CH3:16])[C:11]1[N:10]=[C:9]2[C:4]([CH2:5][CH2:6][CH2:7][NH:8]2)=[CH:3][C:2]=1[N:20]1[CH:21]=[N:22][C:18]([CH3:17])=[N:19]1
Reactant: Cc1nc[nH]n1
Reactant: COC(OC)c1nc2c(cc1Br)CCCN2
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(OC)c1nc2c(cc1-n1cnc(C)n1)CCCN2
Temperature: 120 °C

Procedure:
A suspension of 6-bromo-7-(dimethoxymethyl)-1,2,3,4-tetrahydro-1,8-naphthyridine (intermediate 12) (300 mg, 1.045 mmol), 3-methyl-1H-1,2,4-triazole (104 mg, 1.254 mmol), Cs2CO3 (720 mg, 2.210 mmol) and CuI (40 mg, 0.210 mmol) in DMF (2 ml) was heated to 120° C. for approximately 6 h. The reaction mixture was diluted with ethyl acetate and water, layers were separated and the aqueous layer was extracted with ethyl acetate (3×). Organic layers were combined, washed with water and brine, dried using Na2SO4, filtered, evaporated. The crude product was purified by silica gel column chromatography eluting with a gradient of MeOH (1-10%) in DCM. Product fractions were combined, evaporated and dried to yield the title compound as an orange resin. (UPLC-MS 3) tR 0.57 min; ESI-MS 290.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.21 (s, 1H), 7.21 (s, 1H), 5.35 (s, 1H), 4.95 (s, 1H), 3.51-3.41 (m, 2H), 3.36 (s, 6H), 2.75 (t, 2H), 2.47 (s, 3H), 1.97-1.86 (m, 2H).
Reaction SMILES: [CH2:1]([C:3]1([CH2:7][OH:8])[CH2:6][O:5][CH2:4]1)[CH3:2].C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH2:1]([C:3]1([CH2:7][O:8][S:17]([CH3:16])(=[O:19])=[O:18])[CH2:6][O:5][CH2:4]1)[CH3:2]
Reactant: CCC1(CO)COC1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCC1(COS(C)(=O)=O)COC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
After adding 465 g (4.0 mol) of 3-ethyl-3-hydroxymethyloxetane, 486 g (4.8 mol) of triethylamine, and 1840 ml of toluene in a glass flask having an internal volume of 5000 ml equipped with a stirrer, a thermometer, and a dropping funnel, 504 g (4.4 mol) of methanesulfonyl chloride was gently added while keeping the liquid temperature from 5° C. to 10° C. to carry out a reaction, while stirring, at the same temperature range for three hours and at room temperature for three hours. After completing the reaction, 930 ml of a saturated aqueous sodium hydrogen carbonate solution (concentration of 9.3 mass %) was added to the reaction solution to separate into a water layer and an organic layer. Then, after extracting the water layer with 930 ml of toluene, the extract was combined with the previous organic layer and washed with 465 ml of water. By concentrating the organic layer thus obtained under reduced pressure, 777 g of 3-ethyl-3-methanesulfonyloxymethyloxetane with a purity of 95 mass % (quantitative value determined by 1H-NMR) as a brown liquid was obtained (isolated yield based on 3-ethyl-3-hydroxymethyloxetane=95%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6]([CH3:13])=[CH:7][C:8]=2[CH3:12])[N:3]=1.[Br:14]Br.OS([O-])=O.[Na+].N>C(O)(=O)C.O>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6]([CH3:13])=[C:7]([Br:14])[C:8]=2[CH3:12])[N:3]=1
Reactant: BrBr
Reactant: Cc1cc(C)c2ccc(N)nc2n1
Agent: N
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1nc2nc(N)ccc2c(C)c1Br
Temperature: 60 °C
Yield: 52.4 %

Procedure:
173 g (1 mol) of 2-amino-5,7-dimethyl-1,8-naphthyridine is suspended in 500 ml of glacial acetic acid. At 60° C. and with stirring, 160 g (1 mol) of bromine is dripped in, the solid going into solution. After all has been added, the mixture is stirred overnight at room temperature (20° C.) and then poured into 1 liter of water. Excess bromine is reduced by adding a small amount of NaHSO3. The pH is brought to 4 with concentrated NH3 solution. The mixture is stirred for about 30 minutes and the precipitate is filtered off and dried under reduced pressure to give 132 g of a pale brown solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]3[S:20][CH:21]=[CH:22][N:23]=3)(=[O:17])=[O:16])=[CH:11][C:10]=2[C:24]#[N:25])=[C:4]([C:26]2[N:30]([CH3:31])[N:29]=[CH:28][CH:27]=2)[CH:3]=1.[F:32][C:33]1[C:38](B(O)O)=[CH:37][CH:36]=[CH:35][N:34]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:24]([C:10]1[CH:11]=[C:12]([S:15]([NH:18][C:19]2[S:20][CH:21]=[CH:22][N:23]=2)(=[O:17])=[O:16])[CH:13]=[CH:14][C:9]=1[O:8][C:5]1[C:4]([C:26]2[N:30]([CH3:31])[N:29]=[CH:28][CH:27]=2)=[CH:3][C:2]([C:38]2[C:33]([F:32])=[N:34][CH:35]=[CH:36][CH:37]=2)=[N:7][CH:6]=1)#[N:25]
Reactant: Cn1nccc1-c1cc(Cl)ncc1Oc1ccc(S(=O)(=O)Nc2nccs2)cc1C#N
Reactant: OB(O)c1cccnc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nccc1-c1cc(-c2cccnc2F)ncc1Oc1ccc(S(=O)(=O)Nc2nccs2)cc1C#N
Reaction time: 0.08 h
Yield: 28.4 %

Procedure:
10 mg of 4-((6-chloro-4-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl)oxy)-3-cyano-N-(thiazol-2-yl)benzenesulfonamide was dissolved in DMF/H2O=1:1 (0.46 mL), and 3.2 mg of (2-fluoropyridin-3-yl)boronic acid, 0.8 mg of Pd(PPh3)4 and 7.4 mg of Na2CO3 were added thereto. After reacting with microwave reactor at 120° C. for 5 minutes, DMF was removed by concentrating under reduced pressure. After extracting with EA, the extract was treated with MgSO4 and concentrated under reduced pressure. The residue was separated by PLC (developing solvent, EA) to obtain 3.2 mg (28% yield) of the title compound.