Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[NH2:8].Cl[C:10]1[C:19]2[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=2)[N:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>CN1CCCC1=O>[Cl:20][C:16]1[CH:15]=[C:14]2[C:19]([C:10]([NH:1][C@H:2]3[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]3[NH2:8])=[CH:11][CH:12]=[N:13]2)=[CH:18][CH:17]=1
Reactant: N[C@H]1CCCC[C@@H]1N
Reactant: Clc1ccc2c(Cl)ccnc2c1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: N[C@H]1CCCC[C@@H]1Nc1ccnc2cc(Cl)ccc12

Procedure:
13.6 g of (1S,2S)-(+)-1,2-diaminocyclohexane, 23.6 g of 4,7-dichloroquinoline and 16.6 ml of triethylamine were held at 150° C. in 150 ml of 1-methyl-2-pyrrolidone under argon for 16 hrs. The solvent was largely distilled off at 0.1 Torr/80° C. and the residue was triturated with 300 ml of 1.5N HCl. The resulting aqueous suspension was extracted three times with 300 ml of dichloromethane and then made basic with concentrated ammonia, with gum-like clumps separating. The supernatant solution was decanted off and extracted twice with 400 ml of dichloromethane. The crude product obtained from these extracts was purified by two-fold flash chromatography on neutral aluminium oxide (Brockmann activity II) with dichloromethane and dichloromethane/ethanol 30:1. Crystallization was effected from 40 ml of dichloromethane and 60 ml of ethyl acetate by distillation of the former. Yield: 4 g (12%) of (1S,2S)-N-(7-chloro-quinolin-4-yl)-cyclohexane-1,2-diamine; m.p. 160° C., [α]D =+129.30 (MeOH, c=1.0).
Reaction SMILES: [CH3:1][N:2]1[C:6]([O:7][CH:8]([F:10])[F:9])=[C:5]([Cl:11])[C:4]([C:12]2[CH:17]=[C:16]([N+:18]([O-])=O)[C:15]([Cl:21])=[CH:14][C:13]=2[F:22])=[N:3]1.O.C(OCC)(=O)C>C(O)(=O)C.[Fe]>[CH3:1][N:2]1[C:6]([O:7][CH:8]([F:10])[F:9])=[C:5]([Cl:11])[C:4]([C:12]2[CH:17]=[C:16]([NH2:18])[C:15]([Cl:21])=[CH:14][C:13]=2[F:22])=[N:3]1
Reactant: Cn1nc(-c2cc([N+](=O)[O-])c(Cl)cc2F)c(Cl)c1OC(F)F
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1nc(-c2cc(N)c(Cl)cc2F)c(Cl)c1OC(F)F
Temperature: 25 °C
Yield: 89.1 %

Procedure:
A stirred solution of 14.9 grams (0.042 mole) of 1-methyl-5-difluoromethoxy-4-chloro-3-(2-fluoro-4-chloro-5-nitrophenyl)pyrazole and 20 mL of water in 200 mL of acetic acid was warmed to 50° C., and 10.0 grams (0.179 mole) of iron powder was added portionwise. Upon completion of addition the reaction mixture was allowed to cool to ambient temperature. The reaction mixture was then poured into about 400 mL of a mixture of 1:1 ethyl acetate and water. The mixture was filtered through diatomaceous earth, and the organic layer in the filtrate was separated. The aqueous layer was washed with about 200 mL of ethyl acetate, and the wash was combined with the organic layer separated from the filtrate above. The combination was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel, using 5% methanol in methylene chloride as the eluant. The product-containing fractions were combined and concentrated under reduced pressure, yielding 12.2 grams of 1-methyl-5-difluoromethoxy-4-chloro-3-(2-fluoro-4-chloro-5-aminophenyl)pyrazole. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[N+](=[CH:13][Si](C)(C)C)=[N-].[BrH:18].CCOC(C)=O>C(#N)C.O>[Br:18][CH2:13][C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[CH3:1])=[O:5]
Reactant: Cc1ccccc1C(=O)Cl
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Br
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1ccccc1C(=O)CBr
Temperature: 25 °C
Reaction time: 15 h
Yield: 91 %

Procedure:
To a solution of 2-methylbenzoyl chloride (169 μl, 1.29 mmol) in dry acetonitrile (5 ml) and cooled at 0° C., under nitrogen atmosphere, was added (diazomethyl)-trimethylsilane (1.94 ml, 3.88 mmol, 2M in hexane). The reaction was stirred at room temperature for 15 hours, then it was cooled at 0° C. and 48% HBr (512 μl, 4.53 mmol) was slowly added. The reaction was stirred at room temperature for 3 hours. EtOAc and water were added, the organic layer was separated and the aqueous phase was neutralized with 1M NaOH and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and evaporated to dryness to obtain 2-bromo-1-o-tolylethanone (250 mg, 91% yield). This intermediate was used in the next step without any further purification.
Reaction SMILES: [OH:1][C:2]([CH3:28])([CH3:27])[CH2:3][C@@:4]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Cl.[NH2:30][OH:31].CCN(CC)CC>CO>[OH:31][NH:30][C:17](=[NH:18])[C:16]1[CH:19]=[CH:20][C:13]([C@@H:11]([N:7]2[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:27])[CH3:28])([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[O:9][C:8]2=[O:10])[CH3:12])=[CH:14][CH:15]=1
Reactant: NO
Reactant: C[C@@H](c1ccc(C#N)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: C[C@@H](c1ccc(C(=N)NO)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 25 °C

Procedure:
A mixture of 4-{(S)-1-[(S)-6-(2-hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]ethyl}-benzonitrile (0.50 g), hydroxylamine hydrochloride (0.18 g), and NEt3 (0.43 mL), and methanol (10 mL) was stirred at reflux temperature for 5 h. After cooling to room temperature, the solvent was evaporated, mixture was concentrated, ethyl acetate was added to the residue, and the resulting mixture was washed with water and brine. The organic solution was dried Na2SO4) and concentrated and the residue was purified by chromatography on silica gel (CH2Cl2/MeOH 98:2->93:7) to afford the title compound as a foam-like solid.
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][S:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH:20]=3)[CH:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1.I([O-])(=O)(=O)=[O:40].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>CO.O>[CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][S:18]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([CH2:34][C:35]([CH3:37])([CH3:36])[CH3:38])[CH:20]=3)=[O:40])[CH:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1
Reactant: CCOC(=O)CC(c1cccc(CSc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)c1)C1CC1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCOC(=O)CC(c1cccc(CS(=O)c2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)c1)C1CC1
Temperature: 25 °C
Reaction time: 7 h
Yield: 87.9 %

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(3-(((2′-fluoro-5′-methoxy-2-neopentyl-[1,1′-biphenyl]-4-yl)thio)methyl)phenyl)propanoate (158 mg) in methanol (0.95 mL) was added a solution of sodium periodate (66 mg) in water (50 μL), and the mixture was stirred at room temperature for 7 hr. To the reaction mixture was added saturated aqueous sodium thiosulfate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (143 mg) as a colorless oil.
Reaction SMILES: [C:1](OC)([CH3:4])([CH3:3])[CH3:2].[CH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]=1[C:17]1[C:29]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:28][C:27]2[C:26]3[C:21](=[CH:22][C:23]([C:38]4[CH:47]=[CH:46][C:45]5[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=5)[CH:39]=4)=[C:24]([C:34]([CH3:37])([CH3:36])[CH3:35])[CH:25]=3)[CH2:20][C:19]=2[CH:18]=1.[CH2:48]([Li])[CH2:49][CH2:50][CH3:51].Cl>C(OCC)C.CCCCCC>[CH2:2]([C:51](=[C:28]1[C:27]2[C:19]([CH:20]=[C:21]3[C:26]=2[CH:25]=[C:24]([C:34]([CH3:37])([CH3:36])[CH3:35])[C:23]([C:38]2[CH:47]=[CH:46][C:45]4[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=4)[CH:39]=2)=[CH:22]3)=[C:18]([CH:21]2[CH:26]=[CH:27][CH:19]=[CH:20]2)[C:17]([C:8]2[CH:9]=[CH:10][C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:7]=2)=[C:29]1[C:30]([CH3:31])([CH3:32])[CH3:33])[CH2:50][C:49]1[CH:48]=[CH:16][CH:7]=[CH:8][CH:9]=1)[C:1]1[CH:4]=[CH:10][CH:11]=[CH:12][CH:3]=1
Reactant: COC(C)(C)C
Reactant: [Li]CCCC
Reactant: CC(C)(C)c1cc2c(cc1-c1ccc3ccccc3c1)Cc1cc(-c3ccc4ccccc4c3)c(C(C)(C)C)cc1-2
Agent: Cl
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(C)(C)c1cc2c(cc1-c1ccc3ccccc3c1)=Cc1c(C3C=CC=C3)c(-c3ccc4ccccc4c3)c(C(C)(C)C)c(=C(Cc3ccccc3)Cc3ccccc3)c1=2
Yield: 53 %

Procedure:
Under a nitrogen atmosphere, 80 mL of dehydrated tert-butylmethylether was added to 0.82 g (1.54 mmol) of 2,7-di(2-naphthyl)-3,6-ditert-butyl-fluorene, and the mixture was stirred. This solution was cooled in an ice bath, and 1.10 mL (1.76 mmol) of a 1.60 mol/L hexane solution of n-butyllithium was added. The mixture was stirred at room temperature for 22 hours. To the yellow suspension thus obtained, 0.44 g (1.70 mmol) of 6,6-dibenzofulvene synthesized in Synthesis Example 1-1 (iii) was added, and the mixture was heated to reflux for 19 hours. Subsequently, 30 mL of 1N hydrochloric acid was added to the light orange-brown solution obtained to terminate the reaction. Then, 100 mL of diethylether was added to perform a liquid-liquid phase separation, and the soluble fraction was extracted. This organic layer was washed two times with a saturated aqueous solution of sodium hydrogen carbonate, two times with water, and once with saturated brine, and then dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography to obtain a target product as a pale yellow solid (yield 0.64 g (53%)). The target product was identified by 1H-NMR and FD-MS spectroscopy.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[N:8]=[C:9](SC)[N:10]=[CH:11][C:6]=2[CH:5]=[C:4]([C:14]2[CH:19]=[C:18]([C:20]3[O:24][N:23]=[C:22]([CH3:25])[CH:21]=3)[CH:17]=[CH:16][C:15]=2[CH3:26])[C:3]1=[O:27].OOS([O-])=O.[K+].[NH2:34][CH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>>[CH3:1][N:2]1[C:7]2[N:8]=[C:9]([NH:34][CH:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[N:10]=[CH:11][C:6]=2[CH:5]=[C:4]([C:14]2[CH:19]=[C:18]([C:20]3[O:24][N:23]=[C:22]([CH3:25])[CH:21]=3)[CH:17]=[CH:16][C:15]=2[CH3:26])[C:3]1=[O:27]
Reactant: NC1CCOCC1
Reactant: CSc1ncc2cc(-c3cc(-c4cc(C)no4)ccc3C)c(=O)n(C)c2n1
Agent: O=S([O-])OO
Agent: [K+]
Product: Cc1cc(-c2ccc(C)c(-c3cc4cnc(NC5CCOCC5)nc4n(C)c3=O)c2)on1

Procedure:
8-Methyl-6-[2-methyl-5-(3-methyl-isoxazol-5-yl)-phenyl]-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one was treated with OXONE™ following the procedure of step 3 of Example 1, and the resulting sulfonyl compound was treated with 4-amino-tetrahydropyran using the procedure of step 4 of Example 1, to give 8-Methyl-6-[2-methyl-5-(3-methyl-isoxazol-5-yl)-phenyl]-2-(tetrahydro-pyran-4-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one: MS (M+H)=432.
Reaction SMILES: [F-].[K+].[Br:3][C:4]1[N:8]2[N:9]=[C:10](Cl)[CH:11]=[CH:12][C:7]2=[N:6][CH:5]=1.[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=1[CH:22]1[CH2:26][CH2:25][CH2:24][NH:23]1>CS(C)=O>[Br:3][C:4]1[N:8]2[N:9]=[C:10]([N:23]3[CH2:24][CH2:25][CH2:26][CH:22]3[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[CH3:14])[CH:11]=[CH:12][C:7]2=[N:6][CH:5]=1
Reactant: Cc1ccc(C)c(C2CCCN2)c1
Reactant: Clc1ccc2ncc(Br)n2n1
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1ccc(C)c(C2CCCN2c2ccc3ncc(Br)n3n2)c1
Temperature: 130 °C
Reaction time: 6 h

Procedure:
In step 4-1, potassium fluoride (58 mg, 1.0 mmol), and (3-bromo-6-chloroimidazo[1,2-b]pyridazine (12-1) (100 mg, 0.43 mmol) was added to a solution of 2-(2,5-dimethylphenyl)pyrrolidine (100 mg, 0.57 mmol) in 3 mL of DMSO. The reaction mixture was heated to 130° C. and stirred for 6 hours at 130° C. The reaction mixture was cooled to room temperature and purified using normal phase flash chromatography with ethyl acetate and hexanes (1:1) as a mobile phase to yield 3-bromo-6-(2-(2,5-dimethylphenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazine (4-1) as its racemic mixture. 1H NMR (400 MHz, D3 acetonitrile) δ ppm 7.50 (app d, J=9.5 Hz, 1H), 7.40 (br s, 1H), 7.08 (d, J=6.5 Hz, 1H), 6.92 (d, J=6.6 Hz, 1H), 6.82 (br s, 1H), 6.58 (br d, J=9.5 Hz, 1H), 5.28 (br d, J=5.0 Hz, 1H), 4.08-3.95 (m, 1H), 3.62 (app q, J=6.4 Hz, 1H), 3.30 (s, 1H), 2.51-2.42 (m, 1H), 2.24 (br s, 6H), 2.17-2.04 (m, 2H). LCMS observed m/z 371.1, 373.1 major ion.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]([CH2:28][CH:29](OC)OC)[C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]([CH2:25][CH2:26][OH:27])[CH3:24])=[CH:19][CH:18]=3)=[O:15])=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>CN(C)C=O.O>[CH:1]1([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:28]=[CH:29][N:16]([C:17]4[CH:22]=[CH:21][C:20]([N:23]([CH2:25][CH2:26][OH:27])[CH3:24])=[CH:19][CH:18]=4)[C:14]3=[O:15])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(CN(C(=O)Nc1ccc(N(C)CCO)cc1)c1ccc(OC2CCCC2)cc1)OC
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CN(CCO)c1ccc(-n2ccn(-c3ccc(OC4CCCC4)cc3)c2=O)cc1
Reaction time: 48 h

Procedure:
A solution of 1-(4-cyclopentyloxyphenyl)-1-(2,2-dimethoxyethyl)-3-{4-[(2-hydroxyethyl)methylamino]phenyl}urea (0.4 g) in dimethyl-formamide (6 mL) was mixed with trifluoroacetic acid (2 mL) and left to stand for 48 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and sodium carbonate solution, dried and concentrated. The product with the molecular weight of 393.49 (C23H27N3O3); MS (ESI): 394 ([M+H]+), was obtained in this way.
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl.[CH3:5][NH:6]C.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].Cl.[C-]#N.[K+]>CO.O>[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][C:18]([C:5]#[N:6])([N:2]([CH3:3])[CH3:1])[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: CNC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: Cl
Agent: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CO
Product: CN(C)C1(C#N)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 5 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
500 ml (10 eq.) dimethylamine solution and 109.9 g (5 eq.) dimethylamine hydrochloride were added to a solution of 50 g (1 eq.) tert-butyloxycarbonyl-4-oxopiperidine in 100 ml methanol and the mixture was cooled to 5° C. 5 ml (0.1 eq.) hydrochloric acid were then added dropwise to the reaction mixture over a period of 10 min and the mixture was stirred for 60 min at room temperature. 48.9 g (3 eq.) potassium cyanide were added in portions to this reaction mixture and the mixture was stirred for 24 h at room temperature. Once the conversion was complete, 150 ml water were added to the reaction mixture and it was extracted 3 times with 100 ml ethyl acetate. The combined organic phases were dried with Na2SO4. Following removal of the solvent under reduced pressure, crude product was obtained which was recrystallized out of hexane. 57 g (90%) of product were obtained in the form of a colorless solid.
Reaction SMILES: [CH3:1][CH2:2][O:3]/[C:4](/[O-:8])=[CH:5]/[N+]#N.[O:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1>>[O:9]1[CH2:13][CH2:12][CH2:11][CH:10]1[CH2:5][C:4]([O:3][CH2:2][CH3:1])=[O:8]
Reactant: C1CCOC1
Reactant: CCO/C([O-])=C/[N+]#N
Product: CCOC(=O)CC1CCCO1

Procedure:
Following the procedure of Preparative Example 14, 2.0 g (17.5 mmol) of ethyl diazo acetate was reacted with tetrahydrofuran to give 1.7 g of the product as a colorless oil, bp 84°-86° C. at 20 mm Hg.
Reaction SMILES: [CH3:1][C@:2]1(O)[CH2:6][C@@H:5](O)[CH:4]=[CH:3]1.[C:9]([O:12][C:13](=O)[CH3:14])(=[O:11])[CH3:10]>C1COCC1.CN(C1C=CN=CC=1)C>[C:9]([O:12][CH2:13][CH3:14])(=[O:11])[CH3:10].[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C[C@@]1(O)C=C[C@H](O)C1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CCCCCC
Product: CCOC(C)=O
Reaction time: 3 h
Yield: 52.5 %

Procedure:
To a solution of 9 (100 mg, 0.877 mmol) in dry THF (10 ml) at room temperature was added acetic anhydride (89 mg, 0.877 mmol), and catalytic amount of DMAP. The reaction was allowed to stir for 3 h and then concentrated. The residue was taken in ethyl acetate (40 ml) and was treated twice with saturated sodium bicarbonate solution (20 ml), followed by brine (10 ml). The organic layer was dried over sodium sulfate and the resulting product 13 was purified by column chromatography using ethyl acetate/hexane (1:2) (80.25 mg, yield=58.77%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[O:19]([CH2:21][C:22]([OH:24])=[O:23])[NH2:20]>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:20][O:19][CH2:21][C:22]([OH:24])=[O:23])=[O:14]
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Reactant: NOCC(=O)O
Product: O=C(O)CONC(=O)c1ccncc1Nc1ccc(I)cc1F

Procedure:
[({3-[(2-fluoro-4-iodophenyl)amino]isonicotinoyl}amino)oxy]acetic acid was synthesized according to the procedure for General Method 1, outlined above, starting with 0.3 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.51 mmol of aminoxy-acetic acid. LC/MS [5.21 min; 432 (M+1)]
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[N:3]=1.[NH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21]>CO>[Cl:1][C:2]1[N:11]=[C:10]([NH:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[N:3]=1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: Cc1ccc2nc(Cl)nc(Cl)c2c1
Solvent: CO
Product: Cc1ccc2nc(Cl)nc(NCCNC(=O)OC(C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
A mixture of 2,4-dichloro-6-methylquinazoline (700 mg, 3.29 mmol), tert-butyl N-(2-aminoethyl)carbamate (2.6 g, 16.4 mmol) and methanol (35 mL) was stirred at room temperature for 1 hour. The resulting mixture was concentrated in vacuo and the residue was purified by flash column chromatography to afford 1.0 g of the product as a white solid (yield was 91%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH:11]1[CH:15]=[N:14][N:13]=[N:12]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[N:11]1[N:12]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[N:13]=[N:14][CH:15]=1
Reactant: c1nnn[nH]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(-n2ncnn2)cc1
Temperature: 90 °C
Reaction time: 24 h
Yield: 31.1 %

Procedure:
4-Fluoronitrobenzene (2 g, 0.014 mol), tetrazole (1 g, 0.014 mol), potassium carbonate (1.96 g, 0.014 mol) were dissolved in DMSO (50 ml) and stirred at 90° C. for 24 h under dry conditions. The yellow suspension was poured into water (150 ml), the resulting yellow solid filtered of and dried in vacuo to afford the title compound (831 mg, 31%).
Reaction SMILES: S(O[CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)(C1C=CC(C)=CC=1)(=O)=O.BrCC1CCCCO1.[F:34][C:35]1[C:36]([F:53])=[CH:37][C:38]2[O:52][CH2:51][C:41]3([C:49]4[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=4)[NH:43][C:42]3=[O:50])[C:39]=2[CH:40]=1.N1C2C(=CC=CC=2)C2(COC3C=C4C(=CC2=3)CCO4)C1=O>>[F:34][C:35]1[C:36]([F:53])=[CH:37][C:38]2[O:52][CH2:51][C:41]3([C:49]4[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=4)[N:43]([CH2:12][CH:13]4[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:17][CH2:18]4)[C:42]3=[O:50])[C:39]=2[CH:40]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: O=C1Nc2ccccc2C12COc1cc(F)c(F)cc12
Agent: BrCC1CCCCO1
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Product: CC(C)(C)OC(=O)N1CCC(CN2C(=O)C3(COc4cc(F)c(F)cc43)c3ccccc32)CC1

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using tert-butyl 4-(tosyloxymethyl)piperidine-1-carboxylate to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 5,6-difluorospiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, tert-butyl 4-[(5,6-difluoro-2′-oxospiro[1-benzofuran-3,3′-indol]-1′(2′H)-yl)methyl]piperidine-1-carboxylate was obtained (57%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 7.34 (ddd, J=9.0, 7.6, 1.5 Hz, 1H), 7.16-7.06 (m, 2H), 6.92 (d, J=7.8 Hz, 1H), 6.78 (dd, J=10.3, 6.3 Hz, 1H), 6.49 (dd, J=10.3, 6.3 Hz, 1H), 4.95 (d, J=9.0 Hz, 1H), 4.70 (d, J=9.0 Hz, 1H), 4.13 (br s, 2H), 3.74-3.56 (m, 2H), 2.69 (t, J=12.4 Hz, 2H), 2.07-1.96 (m, 1H), 1.68-1.63 (m, 2H), 1.45 (s, 9H), 1.32-1.26 (m, 2H); MS (ES+) m/z 493.3 (M+23).
Reaction SMILES: NC1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1.[OH-].[K+].C(O)(=O)C>O.C(O)CO>[NH2:6][C:5]1[CH:7]=[CH:8][C:9]([O:11][C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)=[CH:10][C:4]=1[SH:3]
Reactant: Nc1nc2ccc(Oc3ccc(F)cc3)cc2s1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: OCCO
Product: Nc1ccc(Oc2ccc(F)cc2)cc1S
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.5 %

Procedure:
22 g of 2-amino-6-(4-fluorophenoxy)benzothiazole (prepared as described in preparation 7) were added to a mixture of a solution of 90 g of potassium hydroxide in 100 ml of water and 28 ml of ethylene glycol, and the mixture was stirred for 2 hours on an oil bath kept at 130° C under an atmosphere of nitrogen. After the mixture had been cooled to room temperature, 90 ml of acetic acid was added dropwise to the resulting homogenous solution to deposit a precipitate: this was extracted with toluene. The toluene extract was dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure, to afford 16 g of the title compound as a pale yellow solid.
Reaction SMILES: [S:1]([OH:5])([OH:4])(=[O:3])=[O:2].[NH:6]([C:8]([CH2:10][CH2:11][N:12]([CH3:32])[CH2:13][C@H:14]1[O:18][C@@H:17]([N:19]2[C:28]3[N:27]=[CH:26][N:25]=[C:23]([NH2:24])[C:22]=3[N:21]=[C:20]2C)[C@H:16]([OH:30])[C@@H:15]1[OH:31])=[O:9])[NH2:7].C(CCN(C)C[C@H]1O[C@@H](N2C3N=CN=C(N)C=3N=C2)[C@H](O)[C@@H]1O)(OCC)=O.O.NN>>[S:1]([OH:5])([OH:4])(=[O:3])=[O:2].[NH:6]([C:8]([CH2:10][CH2:11][N:12]([CH3:32])[CH2:13][C@H:14]1[O:18][C@@H:17]([N:19]2[C:28]3[N:27]=[CH:26][N:25]=[C:23]([NH2:24])[C:22]=3[N:21]=[CH:20]2)[C@H:16]([OH:30])[C@@H:15]1[OH:31])=[O:9])[NH2:7]
Reactant: Cc1nc2c(N)ncnc2n1[C@@H]1O[C@H](CN(C)CCC(=O)NN)[C@@H](O)[C@H]1O
Agent: CCOC(=O)CCN(C)C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1O
Agent: NN
Agent: O=S(=O)(O)O
Solvent: O
Product: CN(CCC(=O)NN)C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1O

Procedure:
The procedure was the same as reported above for 13k using 13g (95 mg, 0.25 mmol) and hydrazine monohydrate (63 mg, 0.06 mL, 1.25 mmol): yield 39 mg (43%), MS: m/z 367 (M+H)+; 1HNMR (D2O) δ 8.47 (s, 1H, H-8), 8.45 (s, 1H, H-2), 6.17 (d, 1H, H-1′, J1′,2′=4.7 Hz), 4.90 (dd, 1H, H-2′, J2′,3′=5.2 Hz), 4.56-4.60 (bm, 1H, H-4′), 4.48 (dd, 1H, H-3′, J3′,4′=5.0 Hz), 3.82 (dd, 1H, 5′-CH2), 3.66 (dd, 1H, 5′-CH2), 3.59 (bt, 2H, N(CH3)—CH2), 2.97 (s, 3H, N—CH3), 2.86 (t, 2H, NHCO—CH2); UV λmax, nm, pH 1, 256.8 (∈ 16,600), pH 7, 258.5 (∈ 16,800), pH 13, 259.5 (∈ 17,600). Anal. (C14H22N8O4.2.0H2SO4.2.0H2O) C, H, N.