Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[C:22]([OH:23])=[C:21]([O:24][CH3:25])[C:20]([O:26][CH3:27])=[CH:19][C:18]=1[CH3:28])(=[O:3])[CH3:2].N(S([O-])(=O)=O)(S([O-])(=O)=[O:32])[O].[K+].[K+].O.P([O-])(O)(O)=O.[K+]>CN(C)C=O.CO>[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[C:22](=[O:23])[C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[C:19](=[O:32])[C:18]=1[CH3:28])(=[O:3])[CH3:2]
Reactant: [O]N(S(=O)(=O)[O-])S(=O)(=O)[O-]
Reactant: COc1cc(C)c(CCCCCCCCCCCCOC(C)=O)c(O)c1OC
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: COC1=C(OC)C(=O)C(CCCCCCCCCCCCOC(C)=O)=C(C)C1=O
Temperature: 25 °C
Reaction time: 720 h
Yield: 76 %

Procedure:
To a solution (300 ml) of 6-(12-acetoxydodecyl)-2,3-dimethoxy-5-methylphenol (6.1 g) in dimethylformamide are added potassium nitrosodisulfonate (18 g), water (300 ml), methanol (50 ml) and potassium dihydrogen phosphate (0.5 g), and the mixture is stirred at room temperature for 30 days. The product is extracted with dichloromethane, and the organic layer is washed with water and dried over anhydrous magnesium sulfate. The solvent is distilled off to give crude crystals. This product is recrystallized from hexane to give orange-yellow needles of 6-(12-acetoxydodecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (4.8 g). m.p. 47° C.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[CH:15](=O)[C:16]([CH3:19])([CH3:18])[CH3:17].C(O)(=O)C.C([BH3-])#N>ClCCl>[CH3:13][CH:12]([CH3:14])[CH2:11][C@H:3]([NH:2][CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:4]([O:6][C:7]([CH3:8])([CH3:9])[CH3:10])=[O:5]
Reactant: CC(C)C[C@H](N)C(=O)OC(C)(C)C
Reactant: CC(C)(C)C=O
Agent: Cl
Agent: [BH3-]C#N
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)C[C@H](NCC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
(S)-tert-Butyl 2-amino-4-methylpentanoate hydrochloride (1.022 g, 4.57 mmol) and pivalaldehyde (0.502 mL, 4.57 mmol) were combined in dichloromethane (25 mL). Acetic acid (1.0 mL) was added. The reaction was stirred at room temperature for 5 minutes, then PS-cyanoborohydride (3.90 g, 9.14 mmol) was added. The reaction was stirred at room temperature overnight, then filtered and the solvent was removed in vacuo. The crude material was diluted with dichloromethane and basified using saturated aqueous sodium bicarbonate to give (S)-tert-butyl 4-methyl-2-(neopentylamino)pentanoate: 1H NMR (300 MHz, CDCl3) δ ppm 3.04 (t, J=7.4, 1H), 2.40 (d, J=11.1, 1H), 2.09 (d, J=11.1, 1H), 1.86-1.70 (m, 1H), 1.46 (s, 10H), 1.40 (t, J=7.2, 3H), 0.95-0.89 (m, 6H), 0.89 (s, 9H). (S)-tert-butyl 4-methyl-2-(neopentylamino)pentanoate was dissolved in 10 mL of 4 N HCl in dioxane and stirred at room temperature overnight. The solvent was removed under a stream of nitrogen and under high vacuum to give (S)-4-methyl-2-(neopentylamino)pentanoic acid: 1H NMR (300 MHz, DMSO-d6) δ ppm 8.89-8.37 (m, 1H), 8.34-8.03 (m, 1H), 3.82 (t, J=6.5, 1H), 2.88 (d, J=12.3, 1H), 2.62 (d, J=12.2, 1H), 1.83-1.67 (m, 2H), 1.67-1.56 (m, 1H), 1.00 (s, 9H), 0.97-0.88 (m, 6H).
Reaction SMILES: [CH3:1][N:2]1[CH2:19][CH:18]2[CH:4]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=3[O:11][C:12]3[CH:13]=[CH:14][C:15]([Cl:20])=[CH:16][C:17]=32)[CH2:3]1.[C:21]([OH:33])(=[O:32])[CH2:22][C:23]([CH2:28][C:29]([OH:31])=[O:30])([C:25]([OH:27])=[O:26])[OH:24]>CC(C)=O.O>[CH3:1][N:2]1[CH2:19][CH:18]2[CH:4]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=3[O:11][C:12]3[CH:13]=[CH:14][C:15]([Cl:20])=[CH:16][C:17]=32)[CH2:3]1.[C:21]([O-:33])(=[O:32])[CH2:22][C:23]([CH2:28][C:29]([O-:31])=[O:30])([C:25]([O-:27])=[O:26])[OH:24]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: CN1CC2c3ccccc3Oc3ccc(Cl)cc3C2C1
Solvent: CC(C)=O
Solvent: O
Product: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Yield: 80 %

Procedure:
500 mg Asenapine free base (˜1.7 mmol) were dissolved in 1.0 ml acetone and 320 mg of citric acid (Fluka #24788) which was dissolved in 1.0 ml water was added to the solution containing the free base. This solution was then seeded with a few mg of crystalline citrate salt according to example 1 and to the very thin suspension 2.0 ml water was added and stirred was performed while keeping the vial open letting some acetone evaporate. On the next day the obtained suspension was filtered and about 633 mg of solid product was obtained after drying under vacuum at r.t. for about 18 hours. Powder X-ray diffraction of the obtained solid product showed that the same crystalline form as in example 1 was obtained.
Reaction SMILES: [N+:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=O)([O-:3])=[O:2].C(Cl)(=O)C([Cl:15])=O>C(Cl)Cl.CN(C=O)C>[N+:1]([O-:3])([O:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([Cl:15])=[O:11])=[O:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)CCCCO[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)CCCCO[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 12 h
Yield: 82.6 %

Procedure:
5-(Nitrooxy)pentanoic acid (489 mg, 3.00 mmol; US Patent 2006/189603) was dissolved in anhydrous DCM (30 mL) under N2, cooled to 0° C., and added in succession anhydrous DMF (1 drop) and oxalyl chloride (262 uL, 3.00 mmol). Allowed to stir at ambient temperature for 12 h. 13CNMR displayed acid chloride (δ171 ppm) with small amount of carboxylic acid (˜δ173 ppm). Evaporated and dried in vacuo to yield 450 mg (80%) of 5-chloro-5-oxopentyl nitrate as light yellow oil, which was used without further purification.
Reaction SMILES: C([N:11]1[CH2:18][C:17]([OH:26])([CH2:19][C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])(OCC1C=CC=CC=1)=O.C(SC1(C(O)=O)C(C(=O)C)=CCN1CC1OC=CC=1)(=O)C>>[OH:26][C:17]1([CH2:19][C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[CH2:18][NH:11][C@H:12]([C:13]([OH:15])=[O:14])[CH2:16]1
Reactant: O=C(O)[C@@H]1CC(O)(Cc2ccncc2)CN1C(=O)OCc1ccccc1
Agent: CC(=O)SC1(C(=O)O)C(C(C)=O)=CCN1Cc1ccco1
Product: O=C(O)[C@@H]1CC(O)(Cc2ccncc2)CN1

Procedure:
The N-carbobenzyloxy-4-hydroxy-4-[(4-pyridyl)-methyl]-L-proline from part (a) is hydrogenated according to the procedure of Example 1 (b) to yield 4-hydroxy-4-[(4-pyridyl)methyl]-L-proline. This amino acid is reacted with D-3-acetylthio-2-methylpropionyl chloride according to the procedure of Example 1 (c) to yield [1(S)]-1-[3-(acetylthio)-2-methyl-1-oxopropyl]-4-hydroxy-4-[(4-pyridyl)methyl]-L-proline.
Reaction SMILES: [CH:1]([N:4]([CH:18]([CH3:20])[CH3:19])[CH2:5][CH2:6][NH:7][C:8]1[CH:13]=[C:12]([N+]([O-])=O)[CH:11]=[CH:10][N+:9]=1[O-:17])([CH3:3])[CH3:2].[CH3:21][O-:22].[Na+]>CO>[CH:1]([N:4]([CH:18]([CH3:20])[CH3:19])[CH2:5][CH2:6][NH:7][C:8]1[CH:13]=[C:12]([O:22][CH3:21])[CH:11]=[CH:10][N+:9]=1[O-:17])([CH3:3])[CH3:2]
Reactant: CC(C)N(CCNc1cc([N+](=O)[O-])cc[n+]1[O-])C(C)C
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc[n+]([O-])c(NCCN(C(C)C)C(C)C)c1

Procedure:
2-(2-Diisopropylaminoethylamino)-4-nitropyridine-N-oxide (10.0 g., 35.5 mmole) is added to a solution of sodium methoxide (3.0 g., 55 mmole) in dry methanol (100 ml.) and refluxed for 4 hours. The solvent is evaporated and the residue dissolved in chloroform, washed with water, dried over sodium sulfate and evaporated to give oily product.
Reaction SMILES: O1CCCCC1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:22]([NH:24][N:25]([C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])[CH2:26][CH:27]([CH3:29])[CH3:28])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[OH:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:22]([NH:24][N:25]([C:30](=[O:34])[CH:31]([CH3:32])[CH3:33])[CH2:26][CH:27]([CH3:28])[CH3:29])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:10]
Reactant: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)C(C)C)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)C(C)C)[C@H](C/C=C/c1ccccc1)C(=O)NO
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.7 %

Procedure:
A solution of 0.32 g of (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutryl-2′-isobutyl-4-methylvalerohydrazide in 10 ml of methanol was treated with 0.03 g of 4-toluenesulphonic acid. The mixture was stirred for 2 hours at room temperature and then the solvent was evaporated to leave a glass. This residue was triturated with diethyl ether to give 0.15 g of (E)-2(R)-[1(S)-(hydroxycarbamoyl)-4-phenyl-3-butenyl]-2′-isobutyryl-2′-isobutyl-4-methylvalerohydrazide in the form of a white solid.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([NH2:14])[CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2.[C:17]([C:19]1[N:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1)#[N:18].N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:16][C:2]([F:1])([F:15])[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([NH:14][S:25]([C:22]3[CH:23]=[N:24][C:19]([C:17]#[N:18])=[CH:20][CH:21]=3)(=[O:26])=[O:27])[CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cn1
Reactant: Nc1cc(OC(F)(F)F)cc2cccnc12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#Cc1ccc(S(=O)(=O)Nc2cc(OC(F)(F)F)cc3cccnc23)cn1
Yield: 35.2 %

Procedure:
In a similar fashion using route 14 general procedure 27, 6-(trifluoromethoxy)quinolin-8-ylamine (Intermediate 46) (125 mg, 0.54 mmol), 6-cyano-pyridine-3-sulfonyl chloride (Intermediate 19) (132 mg, 0.65 mmol), pyridine (0.09 ml, 1.09 mmol), DMAP (cat.) and DCM (10 ml) gave the title compound (75 mg, 35%) after purification by column chromatography with n-hexane/DCM (50:50) as the eluent.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[N:8]1[C:32](=[O:33])[C:11]2=[CH:12][N:13]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH:31]=[CH:30][CH:29]=[N:28]4)=[CH:23][CH:22]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:10]2=[N:9]1.[H-].[Na+].CI.[C:38](=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:38][O:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[N:8]1[C:32](=[O:33])[C:11]2=[CH:12][N:13]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH:31]=[CH:30][CH:29]=[N:28]4)=[CH:23][CH:22]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:10]2=[N:9]1
Reactant: O=c1c2cn(Cc3ccc(-n4cccn4)cc3)c3ccccc3c-2nn1[C@@H]1CCCC[C@H]1O
Reactant: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CO[C@@H]1CCCC[C@H]1n1nc2c3ccccc3n(Cc3ccc(-n4cccn4)cc3)cc-2c1=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
(±)-2-(trans-2-Hydroxycyclohexyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one (Example 508, 73 mg, 0.17 mmol) was dissolved in degassed N,N-dimethylformamide (3 mL), cooled to 0° C. and treated with sodium hydride (10 mg, 0.25 mmol, 1.5 equiv). After stirring for 15 minutes, the mixture was warmed to ambient temperature, stirred for 15 minutes and cooled to 0° C. The mixture was treated with methyl iodide (0.026 mL, 0.41 mmol, 2.5 equiv) and stirred at 0° C. for 1 hour. The mixture was treated with sodium bicarbonate (1.5 mL, aqueous saturated) and then poured into sodium bicarbonate (25 mL, aqueous saturated). The aqueous layer was extracted with ethyl acetate (2×100 mL), dried with sodium sulfate, filtered and concentrated in vacuo. The mixture was purified by silica gel gradient chromatography (100:0 to 90:10; dichloromethane:methanol), providing the titled compound: 1H-NMR (400 MHz, CDCl3) δ 8.40-8.37 (1H, m), 7.89 (1H, d, J=2.4 Hz), 7.72-7.68 (3H, m), 7.46-7.42 (2H, m), 7.40-736 (1H, m), 7.28 (2H, d, J=8.9 Hz), 6.46 (1H, m), 5.44 (2H, s), 4.39 (1H, td, J=10.2, 5.5 Hz), 3.83-3.77 (1H, m), 3.22 (3H, s), 2.27-2.23 (1H, m), 2.04-1.93 (2H, m), 1.86-1.77 (2H, m), 1.48-1.34 (4H, m) ppm; high resolution mass spectrometry (ES+) m/z 454.2250 [(M+H)+; calculated for C27H28N5O2: 454.2238].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[NH2:28])[C:5]([N:7]1[CH2:12][CH2:11][C:10]2([CH2:20][C:19](=[O:21])[C:18]3[N:17]([CH:22]([CH3:24])[CH3:23])[N:16]=[CH:15][C:14]=3[CH2:13]2)[CH2:9][CH2:8]1)=[O:6].[N:29]([CH3:32])=[C:30]=[S:31]>O1CCCC1>[NH2:1][C:2]1[CH:3]=[C:4]([C:5]([N:7]2[CH2:12][CH2:11][C:10]3([CH2:20][C:19](=[O:21])[C:18]4[N:17]([CH:22]([CH3:24])[CH3:23])[N:16]=[CH:15][C:14]=4[CH2:13]3)[CH2:9][CH2:8]2)=[O:6])[CH:25]=[CH:26][C:27]=1[NH:28][C:30]([NH:29][CH3:32])=[S:31]
Reactant: CN=C=S
Reactant: CC(C)n1ncc2c1C(=O)CC1(CCN(C(=O)c3ccc(N)c(N)c3)CC1)C2
Solvent: C1CCOC1
Product: CNC(=S)Nc1ccc(C(=O)N2CCC3(CC2)CC(=O)c2c(cnn2C(C)C)C3)cc1N
Reaction time: 6 h
Yield: 27.1 %

Procedure:
A mixture of 1′-(3,4-diaminobenzoyl)-1-isopropyl-4,6-dihydrospiro[indazole-5,4′-piperidin]-7(1H)-one (0.1 g, 0.3 mmol) and isothiocyanatomethane (19 mg, 0.3 mmol) was dissolved in tetrahydrofuran (3 mL). The reaction was heated to reflux and stirred for 6 hours. The reaction mixture was concentrated, and the residue was poured into cold water. The solution was extracted with ethyl acetate (3×20 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated to provide 1-(2-amino-4-(1-isopropyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-5,4′-piperidine]-1′-ylcarbonyl)phenyl)-3-methylthiourea (37 mg, 27%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:7][C:8]#[C:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])=[CH:12][N:11]=1)[C:3]([O:5][CH3:6])=[O:4]>C(#N)C.[O-]S(C(F)(F)F)(=O)=O.[Ag+]>[F:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]2[CH2:8][CH2:7][C@@H:2]([C:3]([O:5][CH3:6])=[O:4])[N:1]=2)=[N:11][CH:12]=1
Reactant: COC(=O)[C@@H](N)CC#Cc1ccc(OCc2ccccc2F)cn1
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CC#N
Product: COC(=O)[C@@H]1CCC(c2ccc(OCc3ccccc3F)cn2)=N1
Temperature: 25 °C
Reaction time: 60 h
Yield: 100.4 %

Procedure:
To a solution of methyl (2S)-2-amino-5-(5-{[(2-fluorophenyl)methyl]oxy}-2-pyridinyl)-4-pentynoate (D84, 300 mg, 0.91 mmol) in acetonitrile was added silver triflate (24 mg, 0.091 mmol) and the mixture was stirred for 60 hours at room temperature. The solvent was evaporated and the residue diluted with water and extracted with ethyl acetate. The organic layer was dried (Na2SO4), filtered and evaporated affording the title compound as a yellow solid (300 mg, quantitative). Rt (HPLC): 3.58 min; MS: (ES/+) m/z: 329 [MH]+ C18H17FN2O3 requires 328.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([NH:12][C:13]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)=[O:14])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:27][NH:28][CH3:29]>C(O)C>[CH3:27][N:28]([CH3:29])[C:2]1[C:11]2[C:6](=[C:7]([NH:12][C:13]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)=[O:14])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=C(NCc1ccc(C(F)(F)F)cc1)Nc1cccc2c(Cl)nccc12
Reactant: CNC
Solvent: CCO
Product: CN(C)c1nccc2c(NC(=O)NCc3ccc(C(F)(F)F)cc3)cccc12
Temperature: 100 °C

Procedure:
N-(1-Chloroisoquinolin-5-yl)-N′-(4-trifluoromethylbenzyl)urea (Example 69; 60 mg) was suspended in ethanol (5 ml). Ethanolic dimethylamine (33%, 2 ml) was added and the mixture heated to 100° C. in a sealed tube for 16 hours after which time TLC indicated complete reaction. The reaction mixture was evaporated and the residue purified by preparative thin layer chromatography (5% methanol-dichloromethane eluant) to give the title compound (20 mg). m/z (ES+) 389 (M+H)+.
Reaction SMILES: [CH2:1]1[N:8]([CH2:9][CH2:10][NH+:11]([CH2:22][C:23]([O-:25])=[O:24])[CH2:12][CH2:13][N:14]2[CH2:21][C:19](=[O:20])[O:18][C:16](=[O:17])[CH2:15]2)[CH2:7][C:5](=[O:6])[O:4][C:2]1=[O:3].[NH2:26][CH2:27][CH2:28][CH2:29][NH2:30].C1CN2C(=NCCC2)C1.Cl>CN(C=O)C.CN(C=O)C.C1CN2C(=NCCC2)C1>[C:2]([CH2:1][N:8]1[CH2:7][C:5](=[O:6])[NH:30][CH2:29][CH2:28][CH2:27][NH:26][C:16](=[O:17])[CH2:15][N:14]([CH2:21][C:19]([OH:18])=[O:20])[CH2:13][CH2:12][N:11]([CH2:22][C:23]([OH:25])=[O:24])[CH2:10][CH2:9]1)([OH:4])=[O:3]
Reactant: NCCCN
Reactant: O=C([O-])C[NH+](CCN1CC(=O)OC(=O)C1)CCN1CC(=O)OC(=O)C1
Agent: C1CN=C2CCCN2C1
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(O)CN1CCN(CC(=O)O)CC(=O)NCCCNC(=O)CN(CC(=O)O)CC1
Reaction time: 8 h
Yield: 17.7 %

Procedure:
A 500 mL three-neck round bottom flask was charged with 100 mL of dry DMF and the flask flushed with nitrogen. Two syringes were charged separately with solutions of diethylenetriaminepentaacetic acid dianhydride (2.00 g, 5.60 mmol) in 175 mL of DMF and 1,3-diaminopropane (0.415 g, 5.60 mmol) in DMF/DBN (172 mL/3 mL). The two syringes, mounted on a syringe pump were connected to the flask via two long needles passing through rubber septa. These solutions were added dropwise at ambient temperature at a rate of 40 mL/hour to a vigorously stirred solution. A syringe filled with DBN remained positioned in the flask such that additional DBN could be added dropwise to the reaction mixture when cloudiness was seen. A total of 2.5 mL of additional DBN was required to maintain a homogeneous reaction mixture. After the addition was complete, the reaction mixture was allowed to stir overnight, stripped to dryness, and 1N HCl added to adjust the pH to 10.5. This solution was then applied to AG1-X8 (100-200 MESH, OAc-) resin and eluted with 0.5N acetic acid to yield 0.428 g (18%) of the title product, as a white solid after removal of acetic acid followed by lyophilization.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([O:7][C:8]2[CH:9]=[C:10]([CH3:24])[C:11]3[CH:15]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[O:14][B:13]([OH:22])[C:12]=3[CH:23]=2)=[N:4][N:3]=1.CCN(CC)CC.[C:32](OC(=O)C)(=[O:34])[CH3:33]>C(Cl)Cl>[C:32]([NH:1][C:2]1[S:6][C:5]([O:7][C:8]2[CH:9]=[C:10]([CH3:24])[C:11]3[CH:15]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[O:14][B:13]([OH:22])[C:12]=3[CH:23]=2)=[N:4][N:3]=1)(=[O:34])[CH3:33]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3nnc(N)s3)cc(C)c21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CC1OB(O)c2cc(Oc3nnc(NC(C)=O)s3)cc(C)c21
Reaction time: 8 h

Procedure:
To a solution of ethyl 2-(6-(5-amino-1,3,4-thiadiazol-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (70 mg, 0.2 mmol) in DCM (10 mL) was added Et3N (0.11 ml) and acetic anhydride (0.08 mL). The mixture was stirred at room overnight. The mixture was concentrated and precipitate was filtered and washed with a mixture of hexane and ethyl acetate to afford the product as a light yellow solid (59 mg). 1H NMR (DMSO-d6) δ 12.44 (s, 1H), 9.28 (s, 1H), 7.4 (s, 1H), 7.26 (s, 1H), 5.54 (d, 1H), 4.03 (q, H) 3.14 (dd, 1H), 2.48 (d, 1H), 2.35 (s, 3H), 2.13 (s, 3H), 1.11 (t, 3H); MS found: (M+H)+=392.1.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Cl.[CH3:6][C:7]1[CH:14]=[C:13](O)[CH:12]=[CH:11][C:8]=1[CH:9]=[O:10]>[OH-].[Na+]>[CH3:6][C:7]1[CH:14]=[C:13]([CH2:1][CH:3]2[O:5][CH2:4]2)[CH:12]=[CH:11][C:8]=1[CH:9]=[O:10]
Reactant: ClCC1CO1
Reactant: Cc1cc(O)ccc1C=O
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(CC2CO2)ccc1C=O
Temperature: 55 °C
Reaction time: 3 h
Yield: 71.4 %

Procedure:
To epichlorohydrin (20 g., 0.216 mole) heated at 55° C. is added dropwise a solution of 2-methyl-4-hydroxybenzaldehyde (9.0 g., 0.066 mole) in 2.5N sodium hydroxide solution (40 ml.). After the addition, the solution is allowed to stir an additional 3 hours at 55° C. and then at room temperature overnight. The oil is distilled to give 8.3 g of 2-methyl-4-(2,3-epoxypropyl)benzaldehyde, m.p. 160°-170° C. at 1 mm. Hg.
Reaction SMILES: CC1C=CC=C(C)C=1NC(NC(=N)NOC)=[O:11].CN(C(OC)OC)C.[NH4+].[OH-].[CH3:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[C:30]=1[N:36]1[CH:41]=[N:40][C:39]([NH:42][O:43][CH3:44])=[N:38][C:37]1=[O:45]>CC#N.CCOCC.CN(C=O)C>[OH2:11].[CH3:35][C:31]1[CH:32]=[CH:33][CH:34]=[C:29]([CH3:28])[C:30]=1[N:36]1[CH:41]=[N:40][C:39]([NH:42][O:43][CH3:44])=[N:38][C:37]1=[O:45]
Reactant: CONC(=N)NC(=O)Nc1c(C)cccc1C
Agent: COC(OC)N(C)C
Agent: CONc1ncn(-c2c(C)cccc2C)c(=O)n1
Agent: [NH4+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CC#N
Product: O

Procedure:
To a suspension of 10.9 g. (40.0 mmol) of 1-(2',6'-dimethylphenyl)-3-methoxyamidinourea in CH3CN (50 ml.) is added 9.5 g. (80.0 mmol) of DMF-DMA and the mixture heated at 105°-110° C. in a closed bomb for 1-1/2 hours. The reaction mixture is cooled and poured into a round bottom flask and the CH3CN removed under reduced pressure. The residue is partitioned between CHCl3 and H2O and the layer separated. The aqueous layer is extracted with CHCl3 (1×75 ml.). The combined organic layers are washed with H2O (1×50 ml.), dried (MgSO4) and concentrated under reduced pressure to give an oily residue. The residue is taken up in Et2O and washed with H2O (2×50 ml.). The Et2O layer is dried (MgSO4) and concentrated under reduced pressure to give a viscous oil. NMR shows that DMF has been removed. The oil is taken up in hot CH3CN cooled and a small amount of CHCl3, H2O and DMSO insoluble material filtered off. The filtrate is concentrated to give a viscous oil. TLC of the oil (Silicagel; 3% NH4OH, iPA) versus starting material shows one spot moves slower than starting material. Upon addition of MEOH and warming on a steam bath the oil solidifies. The solid is crystallized from MeOH to give 4.6 g. (43%) of 1-(2',6'-dimethylphenyl)-4-methoxyamino-1,2-dihydro-1,3,5-triazin-2-one as a white solid, melting point 78°-80° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.Br[C:14]1[CH:19]=[CH:18][CH:17]=[C:16](Br)[N:15]=1>[Cl-].[Zn+2].[Cl-].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.C1COCC1.CCCCCC>[Br:1][C:2]1[N:3]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Brc1ccccn1
Reactant: Brc1cccc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Brc1cccc(-c2ccccn2)n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 67.2 %

Procedure:
In a nitrogen atmosphere, a THF (5 ml) solution of bromopyridine (0.5 g) was cooled to −78° C., then a hexane solution of n-butyllithium (1.57 M, 2 ml) was added dropwise thereto, after dropwise, the mixture was stirred at 0° C. for 3 hours. Thereafter, a THF solution of zinc chloride (3.15 g) was added dropwise to the mixture, after dropwise, the mixture was stirred for 3 hours. Next, 2,6-dibromopyridine (0.75 g) and tetrakis(triphenylphosphine)palladium (146 mg) were added to the mixture at room temperature, and the mixture was refluxed for 1 day. After the reaction mixture was allowed to cool, to which was then added water, the mixture was extracted with toluene, the solvent was distilled off, and the residue was purified by silica gel column chromatography, thereby obtaining desired compound as white crystal (0.5 g).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:29])[NH:5][C:6]1[CH:27]=[CH:26][C:9]([O:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:24][CH3:25])=[C:18]([C:21](O)=[O:22])[CH:19]=3)[N:14]=[CH:13][CH:12]=2)=[CH:8][C:7]=1[F:28])[CH3:2].[O:30]([NH2:32])[CH3:31].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(N(CC)CC)C>[CH3:31][O:30][NH:32][C:21]([C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][C:17]=1[O:24][CH3:25])[N:14]=[CH:13][CH:12]=[C:11]2[O:10][C:9]1[CH:26]=[CH:27][C:6]([NH:5][C:4]([NH:3][CH2:1][CH3:2])=[O:29])=[C:7]([F:28])[CH:8]=1)=[O:22]
Reactant: CON
Reactant: CCNC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(C(=O)O)cc23)cc1F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: CCNC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(C(=O)NOC)cc23)cc1F

Procedure:
4-(4-(3-Ethylureido)-3-fluorophenoxy)-7-methoxyquinoline-6-carboxylic acid (65 mg) was treated with methoxylamine, triethylamine and benzotriazol-1-yloxytris(dimethylamino) phosphonium hexafluorophosphate in the same manner as Example 634, to obtain the title compound (21 mg) as a solid.