Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[CH:9]=[C:8]2[CH2:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][C:17]=1[O:25][CH3:26])=[O:4].[CH3:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34]([NH2:37])(=[O:36])=[O:35].CC(C)=O>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[CH:9]=[C:8]2[CH2:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH:37][S:34]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[CH3:27])(=[O:35])=[O:36])=[O:21])=[CH:18][C:17]=1[O:25][CH3:26])=[O:4]
Reactant: COC(=O)c1ccc2c(c1)c(Cc1ccc(C(=O)Cl)cc1OC)cn2C
Reactant: Cc1ccccc1S(N)(=O)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CC(C)=O
Product: COC(=O)c1ccc2c(c1)c(Cc1ccc(C(=O)NS(=O)(=O)c3ccccc3C)cc1OC)cn2C
Temperature: 15 °C
Yield: 96.4 %

Procedure:
A solution of 4-(dimethylamino)pyridine (8.17 g, 66.9 mmole) in dichloromethane (20 ml) was added over 15 minutes to a stirred suspension of the product of step c) (9.94 g, 26.8 mmole) and 2-methylbenzenesulfonamide (6.87 g, 40.1 mmole) in dichloromethane (30 ml). After 45 minutes the solution was heated to reflux and 20 ml distillate collected. Acetone (150 ml) was added and a further 80 ml distillate collected. The mixture was allowed to cool overnight and finally stirred at 15° C. before collection of the solid by filtration. This was then slurry-washed with methanol (3×30 ml) to afford 16.22 g (96.4%) of 4-(5-methoxycarbonyl-1-methylindol-3-ylmethyl)-3-methoxy-N-(2-methylphenylsulfonyl)benzamide, as its 4-(dimethylamino)pyridine salt; m.p. 185°-187° C. (with partial melting and resolidification at 138°-140° C.); NMR (250 MHz, DMSO-d6): 2.53 (s, 3H, ArCH3), 3.13 (s, 6H, N(CH3)2), 3.76, 3.83, 3.86 (each s, 3H, OCH3 plus NCH3 plus CO2CH3), 4.02 (s, 2H, ArCH2Ar'), 6.92 (d, 2H), 7.02 (d, 1H), 7.11-7.32 (m, 4H), 7.39-7.53 (m, 3H), 7.75 (dd, 1H), 7.88 (d, 1H), 8.20 (m, 3H).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:44]([O:46]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:45])[CH2:10][S:11][CH2:12][CH2:13][N:14]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:17][C@@H:16]([NH:31][C:32]([C:34]2[NH:35][C:36]3[C:41]([CH:42]=2)=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:33])[C:15]1=[O:43])=O)(C)(C)C.C(OC(N[C@H](C(OC(C1C=CC=CC=1)C1C=CC=CC=1)=O)CSCCN1C2C=CC=CC=2C(C2C=CC=CC=2)=N[C@H](NC(C2NC3C(C=2)=CC=CC=3)=O)C1=O)=O)(C)(C)C.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>ClCCl>[NH2:8][C@H:9]([C:44]([OH:46])=[O:45])[CH2:10][S:11][CH2:12][CH2:13][N:14]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:18]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[N:17][C@@H:16]([NH:31][C:32]([C:34]2[NH:35][C:36]3[C:41]([CH:42]=2)=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:33])[C:15]1=[O:43]
Reactant: CC(C)(C)OC(=O)N[C@@H](CSCCN1C(=O)[C@H](NC(=O)c2cc3ccccc3[nH]2)N=C(c2ccccc2)c2ccccc21)C(=O)OC(c1ccccc1)c1ccccc1
Agent: CC(C)(C)OC(=O)N[C@@H](CSCCN1C(=O)[C@@H](NC(=O)c2cc3ccccc3[nH]2)N=C(c2ccccc2)c2ccccc21)C(=O)OC(c1ccccc1)c1ccccc1
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](CSCCN1C(=O)[C@H](NC(=O)c2cc3ccccc3[nH]2)N=C(c2ccccc2)c2ccccc21)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.2 %

Procedure:
A mixture of a mixture (0.66 g) of (3R)-1-[2-((2R)-2-tert-butoxycarbonylamino-2-benzhydryloxycarbonylethylthio)ethyl]-1,3-dihydro-3-(2-indolylcarbonylamino)-5-phenyl-2H-1,4-benzodiazepine-2-one and (3S)-1-[2-((2R)-2-tert-butoxycarbonylamino-2-benzhydryloxycarbonylethylthio)ethyl]-1,3-dihydro-3-(2-indolylcarbonylamino)-5-phenyl-2H-1,4-benzodiazepine-2-one, anisole (0.6 ml), trifluoroacetic acid (1.5 ml) and dichloromethane (15 ml) was stirred for 3.0 hours at room temperature. After removal of the solvent, the residue was mixed with ethyl acetate (50 ml) and water (50 ml). The mixture was adjusted to pH 6-7 with 5% aqueous solution of sodium bicarbonate under stirring. The organic layer was separated and concentrated. The resultant precipitate was collected by filtration, washed with water and dried to give a mixture (0.20 g) of (3R)-1-[2-((2R)-2-amino-2-carboxyethylthio)ethyl]-1,3-dihydro-3-(2-indolylcarbonylamino)-5-phenyl-2H-1,4-benzodiazepine-2-one and (3 S)-1-[2-((2R)-2-amino-2-carboxyethylthio)ethyl]-1,3-dihydro-3-(2-indolylcarbonylamino)-5-phenyl-2H-1,4-benzodiazepine-2-one.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([O:15][CH3:16])[C:9]=2[F:17])[N:5]=[C:4]([C:18]([O:20][CH3:21])=[O:19])[C:3]=1[Cl:22].Cl[C:24]1C=CC(B(O)O)=C(F)[C:25]=1[O:34]C>C(C(C)=O)C(C)C>[C:25]([NH:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([O:15][CH3:16])[C:9]=2[F:17])[N:5]=[C:4]([C:18]([O:20][CH3:21])=[O:19])[C:3]=1[Cl:22])(=[O:34])[CH3:24]
Reactant: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)cc(N)c1Cl
Reactant: COc1c(Cl)ccc(B(O)O)c1F
Solvent: CC(=O)CC(C)C
Product: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)cc(NC(C)=O)c1Cl

Procedure:
Another embodiment of the present disclosure includes a method of producing methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate. The method comprises producing an aqueous solution comprising 4-chloro-2-fluoro-3-methoxyphenylboronic acid. Methyl isobutyl ketone is added to the aqueous solution. The methyl isobutyl ketone and 4-chloro-2-fluoro-3-methoxyphenylboronic acid are separated from the water. The 4-chloro-2-fluoro-3-methoxyphenylboronic acid is reacted with methyl 4-(acetylamino)-3,6-dichloropyridine-2-carboxylate in methyl isobutyl ketone to produce methyl 4-(acetylamino)-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate, which is deacetylated to produce methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@@H:15]([OH:17])[CH3:16])[C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[Cl:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][C:29]=1[Cl:30])[C:23]([NH:25][NH2:26])=[O:24].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>C1COCC1>[Cl:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][C:29]=1[Cl:30])[C:23]([NH:25][NH:26][C:12](=[O:14])[C@H:11]([NH:10][C:4]1[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[C:3]=1[CH3:18])[C@@H:15]([OH:17])[CH3:16])=[O:24]
Reactant: Cc1c(N[C@@H](C(=O)O)[C@H](C)O)ccc(C#N)c1Cl
Reactant: NNC(=O)c1ccc(Cl)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(Cl)c(Cl)c2)[C@H](C)O)ccc(C#N)c1Cl
Temperature: -15 °C
Reaction time: 1 h

Procedure:
(2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid (1.0 g, 3.7 mmol), 3,4-dichlorobenzohydrazide (CAS 28036-91-1, 763 mg, 3.7 mmol) and anhydrous THF (100 mL) were placed in a 500 mL round bottomed flask and the mixture was cooled to −15° C. 1-Hydroxybenzotriazole hydrate (502.8 mg, 3.7 mmol) was added to the mixture together with N-(3-Dimethylaminopropyl)-N′-ethylcarbodimide HCl (1.4 g, 7.4 mmol) and triethylamine (1.03 mL, 7.4 mmol) at −15° C. The reaction mixture was maintained at −15° C. and stirred for 1 h after which stirring continued overnight while the mixture slowly warmed to room temperature. After 18 h, the mixture was filtered under vacuum and the residue washed with THF (50 mL). The THF solution was concentrated to ca. 10 mL, whereupon ethyl acetate (200 mL) was added followed by water (100 mL). The phases were partitioned and the organic phase washed with water (50 mL), brine (50 mL), dried (Na2SO4), filtered and concentrated to furnish a light brown solid. 1H NMR (500 MHz, acetone-d6, δ in ppm) 8.10 (d, J=2.1 Hz, 1H), 7.90 (dd, J=2.2 Hz, 8.3 Hz, 1H), 7.74 (d, J=8.3 Hz, 1H), 7.55 (d, J=8.5 Hz, 1H), 6.71 (d, J=8.5 Hz, 1H), 5.57 (d, J=6.8 Hz, 1H), 4.44-4.36 (m, 1H), 4.16-4.10 (m, 1H), 2.88-2.80 (m, 1H), 2.37 (s, 3H), 1.37 (d, J=6.3 Hz, 3H).
Reaction SMILES: [CH2:1]1[CH2:11][C:9](=O)[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.C(O[CH:17]([N:21]([CH3:23])C)[N:18](C)C)(C)(C)C.Cl.[NH2:25]C(N)=N.[Na]>C(O)C>[N:25]1[C:9]2[C:8]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[CH2:2][CH2:1][C:11]=2[CH:23]=[N:21][C:17]=1[NH2:18]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: O=C1CCCc2ccccc21
Reactant: N=C(N)N
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: Nc1ncc2c(n1)-c1ccccc1CC2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
α-Tetralone (5.00 g, 34.2 mmol) was heated with t-butoxy bis(dimethylamino)methane (5.96 g, 34.2 mMol) at 90° C. overnight. The solvent was removed under vacuum to give a brown oil. The oil was dissolved in anhydrous ethanol (80 mL) and treated with guanidine hydrochloride (6.53 g, 68.4 mmol) and sodium metal (1.64 g, 71.3 mmol). After the sodium dissolved, the mixture was heated under reflux for 46 h. The mixture was cooled to ambient temperature and guanidine hydrochloride (1.00 g) and sodium metal (0.4 g) were added. Heating was then continued for 24 h. The solvent was removed under vacuum. The residue was partitioned between chloroform and water. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was crystallized from ethanol to give 5,6-dihydrobenzo[h]quinazolin-2-amine as brown needles, 3.07 g; 1H NMR (DMSO-d6, 300 MHz) 8.08 (m, 2H), 7.24-7.40 (m, 3H), 6.40 (s, 1H), 2.81 (m, 2H), 2.68 (m, 2H) ppm; 13C-NMR (DMSO-d6, 75 MHz) 163.60, 159.09, 157.54, 140.14, 133.22, 131.02, 128.80, 127.37, 125.16, 117.15, 28.46, 23.80; MS (ES) 198 (M+H).
Reaction SMILES: [OH:1][C:2]1[C:9]([O:10][CH2:11][C@@H:12]([CH3:15])[CH2:13][CH3:14])=[C:8]([O:16][CH2:17][C@@H:18]([CH3:21])[CH2:19][CH3:20])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].Br[CH2:23][CH2:24][CH2:25][CH:26]=[CH2:27].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C>[CH3:15][C@@H:12]([CH2:13][CH3:14])[CH2:11][O:10][C:9]1[C:2]([O:1][CH2:27][CH2:26][CH2:25][CH:24]=[CH2:23])=[C:3]([CH:6]=[CH:7][C:8]=1[O:16][CH2:17][C@@H:18]([CH3:21])[CH2:19][CH3:20])[CH:4]=[O:5]
Reactant: CC[C@H](C)COc1ccc(C=O)c(O)c1OC[C@@H](C)CC
Reactant: C=CCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCCCOc1c(C=O)ccc(OC[C@@H](C)CC)c1OC[C@@H](C)CC
Temperature: 80 °C
Reaction time: 3 h

Procedure:
Under nitrogen atmosphere, a mixture of 2-hydroxy-3,4-bis-[(S)-2-methyl-butoxy]-benzaldehyde (0.74 9, 2.51 mmol), 5-bromo-1-pentene (0.45 g, 3.02 mmol) and potassium carbonate (0.41 g, 3 mmol) in dry DMF (5 ml) was stirred at 80° C. for 3 h. The cooled reaction mixture was gently poured into HCl 3N (15 ml) and extracted with diethylether (3×20 ml). The combined organic extracts are washed with 30 ml of saturated NaCl solution, dried over magnesium sulphate and evaporated under reduced pressure. The obtained oily residue was chromatographed on silica (diethylether/petroleumether: 1/3) to give 3,4-bis-[(S)-2-methyl-butoxy]-2-(pent-4-enyloxy)-benzaldehyde as a slightly yellow oil (Yield: 0.82 g, 90%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Br[CH:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13])=[CH:3][CH:4]=1)=[O:7]
Reactant: COC(=O)C(C)Br
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1ccc(C=O)cc1
Yield: 71.5 %

Procedure:
By the method of Example 1, Step F, 10.0 g (0.0819 mole) of 4-hydroxybenzaldehyde and 16.4 g (0.0983 mole) of methyl 2-bromopropionate were reacted in the presence of 13.6 g (0.0983 mole) of anhydrous potassium carbonate in N,N-dimethylformamide, yielding 12.2 g of methyl 2-(4-formylphenoxy)propionate as a yellow liquid. The NMR and IR spectra were consistent with the proposed structure.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([F:24])=[N:19][CH:20]=[CH:21][C:22]=3[F:23])[CH:12]=2)[CH:10]=1)=[O:5])C.[OH-].[K+]>C(O)C>[F:24][C:18]1[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[C:22]([F:23])[CH:21]=[CH:20][N:19]=1
Reactant: CCOC(=O)c1cn(-c2cccc(-c3c(F)ccnc3F)c2)cn1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cn(-c2cccc(-c3c(F)ccnc3F)c2)cn1

Procedure:
This compound is prepared by hydrolysis of 9j using a 1:1 mixture of aqueous potassium hydroxide (2M) and ethanol.
Reaction SMILES: [CH3:1][O:2][C:3]([O:6][CH3:7])([CH3:5])[CH3:4].[C:8]1(C)[CH:13]=CC(S(O)(=O)=O)=C[CH:9]=1.[CH2:19](O)[CH2:20][CH2:21]C>>[CH2:1]([O:2][C:3]([O:6][CH2:7][CH2:19][CH2:20][CH3:21])([CH3:5])[CH3:4])[CH2:9][CH2:8][CH3:13]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COC(C)(C)OC
Reactant: CCCCO
Product: CCCCOC(C)(C)OCCCC
Temperature: 110 °C
Reaction time: 2 h

Procedure:
A mixture of 2,2-dimethoxypropane (31.2 g, 0.3M), n-butanol (48.9 g, 0.66M) and toluene-p-sulphonic acid (0.05 g) is heated at 110° C., removing a fraction boiling below 60° C. over 2 hours. The mixture is cooled, brought to pH 9 with sodium methoxide in methanol, then distilled to give acetone di-n-butylketal b.p. 80° C./15 mm Hg, (33.8 g 60%). A sample of this ketal (18.8 g 0.1 m) and hypophosphorous acid (2.2 g, 0.033M) are stirred at room temperature for 7 days. Fractional distillation gives n-butyl (1-hydroxy-1-methylethyl)phosphinate (b.p. 84° C./0.3 mm Hg).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:17]C(OCC)=O.[CH2:23]([NH2:26])[CH2:24][NH2:25]>C(Cl)(Cl)Cl>[ClH:17].[NH2:25][CH2:24][CH2:23][NH:26][C:1](=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCN
Reactant: O=C(O)c1ccccc1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cl
Product: NCCNC(=O)c1ccccc1

Procedure:
24.4 g (0.02 mol) of benzoic acid are reacted with triethylamine and ethyl chloroformate in a manner analogous to that described in Example 5 and added dropwise at 10° to a solution of 53.5 ml (0.8 mol) of ethylenediamine in 750 ml of chloroform. After removing the difficulty soluble neutral constituents by filtration, the chloroform solution is concentrated and excess ethylenediamine is removed in a high vacuum. The oily residue (36.3 g) is taken up in 200 ml of 2N sodium hydroxide solution, saturated with solid sodium chloride and extracted several times with ethyl acetate. The ethyl acetate extracts are dried over magnesium sulfate and concentrated. The product is converted into the hydrochloride which is purified by recrystallization from ethanol, there being obtained 5.2 g of N-(2- aminoethyl)benzamide hydrochloride [J. Amer. Chem. Soc. 61, 822 (1939)], m.p. 163°-165°.
Reaction SMILES: O[N:2]1[C:6]2C=CC=CC=2N=N1.CCN=C=N[CH2:16][CH2:17][CH2:18][N:19]([CH3:21])[CH3:20].CNC.C1C[O:28]CC1.[ClH:30].O1CCOCC1>CN(C=O)C.O>[ClH:30].[CH3:21][N:19]([CH3:20])[C:18](=[O:28])[C@@H:17]([NH:2][CH3:6])[CH3:16]
Reactant: CCN=C=NCCCN(C)C
Reactant: On1nnc2ccccc21
Reactant: C1CCOC1
Agent: CNC
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CN[C@@H](C)C(=O)N(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (S)-Boc-N-Me-Ala-OH (9.8 mmol, 2.00 g, from Bachem) in DMF (10 mL) were added 1-Hydroxy-1H-benzotriazole (10.8 mmol, 1.46 g) and EDCI (10.8 mmol, 2.08 g). The reaction mixture was stirred for 10 min before a 2M solution of dimethylamine in THF (11.8 mmol, 5.9 mL) was added. After stirring for 18 h at room temperature, water was added and the mixture was extracted several times with ethyl acetate. The combined organic layers were washed with 1N aqueous hydrochloric acid, aqueous sodium bicarbonate solution and water. After drying over magnesium sulfate, the volatiles were removed in vacuo. Yield: 1.86 g of a colorless oil (82%). The Boc-protected coupling product was dissolved in MeOH (19 mL) and treated with a 4N solution of HCl in dioxane (32.3 mmol, 8.1 mL). After stirring for 18 h at room temperature, the reaction mixture was evaporated to dryness to leave 1.41 g of a white solid (quantitative yield).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:21]=[CH:20][C:15]([C:16]([NH:18][NH2:19])=[O:17])=[CH:14][CH:13]=1)[CH:6]=[CH:5]2.C1N=CN([C:27](N2C=NC=C2)=[O:28])C=1.CCOC(C)=O>C(Cl)Cl>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:13]=[CH:14][C:15]([C:16]3[O:17][C:27](=[O:28])[NH:19][N:18]=3)=[CH:20][CH:21]=1)[CH:6]=[CH:5]2
Reactant: NNC(=O)c1ccc(-c2ccc3cc(O)ccc3n2)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=c1[nH]nc(-c2ccc(-c3ccc4cc(O)ccc4n3)cc2)o1
Temperature: 25 °C
Yield: 11 %

Procedure:
A mixture of 4-(6-hydroxyquinolin-2-yl)benzohydrazide (90 mg, 0.322 mmol) and CDI (454 mg, 3.22 mmol) in DCM (20 mL) was refluxed overnight. The resulting mixture was cooled to room temperature, followed by an aqueous/EtOAc workup. The crude was purified by prep-HPLC (0.1% TFA as additive) to give Compound IV-24 (18 mg, yield 11%). 1H NMR (CD3OD, 400 MHz): δ 8.64-8.48 (m, 1H), 8.38-7.96 (m, 6H), 7.66-7.24 (m, 2H). MS (ESI): m/z 305.7 [M+H]+.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:14]=3)[N:6]2[N:5]=1)=O.[O:23]=[S:24]1(=[O:38])[CH2:29][CH2:28][N:27]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)[CH2:26][CH2:25]1.C(N(CC)C(C)C)(C)C>COCC(O)C>[O:38]=[S:24]1(=[O:23])[CH2:25][CH2:26][N:27]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([NH:37][C:4]3[N:9]=[CH:8][C:7]4=[CH:10][CH:11]=[C:12]([C:13]5[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH3:22])(=[O:20])=[O:21])[CH:14]=5)[N:6]4[N:5]=3)=[CH:33][CH:32]=2)[CH2:28][CH2:29]1
Reactant: Nc1ccc(CN2CCS(=O)(=O)CC2)cc1
Reactant: CS(=O)c1ncc2ccc(-c3cccc(S(C)(=O)=O)c3)n2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCC(C)O
Product: CS(=O)(=O)c1cccc(-c2ccc3cnc(Nc4ccc(CN5CCS(=O)(=O)CC5)cc4)nn23)c1
Yield: 11.8 %

Procedure:
2-Methanesulfinyl-7-(3-methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (100 mg, 0.298 mmol), 4-(1,1-dioxo-1$1(6)-thiomorpholin-4-ylmethyl)-phenylamine (158 mg, 0.656 mmol), and N,N-diisopropylethylamine (114 μL, 0.656 mmol) were placed in 1-methoxy-2-propanol (728 μL). The reaction was microwaved on 300 watts, 170° C. for 8 hours. Purification by prep-HPLC using a gradient of 10-70% AcN/water both containing 0.1% TFA as the eluting solvent. The product was then free based to obtain the title compound as an orange foam (18 mg, 12%). LCMS (m/e) 512 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.76 (s, 1H), 8.71 (s, 1H), 8.34 (d, 1H, J=7.9 Hz), 7.94 (d, 1H, J=7.8 Hz), 7.73-7.66 (m, 1H), 7.58 (d, 2H, J=8.3 Hz), 7.31 (d, 2H, J=8.3 Hz), 7.05 (d, 1H, J=4.8 Hz), 6.99 (s, 1H), 6.87 (d, 1H, J=4.8 Hz), 3.63 (s, 2H), 3.09 (s, 3H), 3.09-3.03 (m, 4H), 3.03-2.94 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:5]2=[N:4][C:3]=1[CH2:12][CH2:13][C:14]1[CH:26]=[CH:25][C:17]2[N:18]=[C:19](S([O-])(=O)=O)[O:20][C:16]=2[CH:15]=1.[K+].Cl.[NH2:29][C:30]([NH2:32])=[NH:31].[OH-].[K+].O>CN(C)C=O.C(OCC)(=O)C>[CH3:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:5]2=[N:4][C:3]=1[CH2:12][CH2:13][C:14]1[CH:26]=[CH:25][C:17]2[N:18]=[C:19]([NH:31][C:30]([NH2:32])=[NH:29])[O:20][C:16]=2[CH:15]=1
Reactant: N=C(N)N
Reactant: Cc1ccn2c(C)c(CCc3ccc4nc(S(=O)(=O)[O-])oc4c3)nc2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccn2c(C)c(CCc3ccc4nc(NC(=N)N)oc4c3)nc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 33.1 %

Procedure:
Potassium 6-[2-(3,7-dimethylimidazo[1,2-a]pyridin-2-yl)ethyl]-2-benzoxazolesulfonate (1.10 g) was added to a mixture of guanidine hydrochloride (257 mg) and potassium hydroxide (150 mg) in N,N-dimethylformamide (12 ml). After being stirred for 4 hours at ambient temperature, the reaction mixture was mixed with water (110 ml) and ethyl acetate (20 ml). The resulting precipitate was collected, washed with water and recrystallized from ethanol to give 6-[2-(3,7-dimethylimidazo[1,2-a]-pyridin-2-yl)ethyl]-2-guanidinobenzoxazole (0.31 g).
Reaction SMILES: [CH2:1]([O:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][O:14][CH2:15][CH3:16])[CH:9]=[CH:8][C:7]=1[O:17][CH:18]([CH3:20])[CH3:19])[CH3:2].[Li][CH2:22]CCC.CI>C1COCC1>[CH2:15]([O:14][CH2:13][O:12][C:10]1[CH:9]=[CH:8][C:7]([O:17][CH:18]([CH3:20])[CH3:19])=[C:6]([O:5][CH2:4][O:3][CH2:1][CH3:2])[C:11]=1[CH3:22])[CH3:16]
Reactant: [Li]CCCC
Reactant: CCOCOc1ccc(OC(C)C)c(OCOCC)c1
Solvent: C1CCOC1
Solvent: CI
Product: CCOCOc1ccc(OC(C)C)c(OCOCC)c1C
Temperature: -78 °C
Reaction time: 1 h
Yield: 78.5 %

Procedure:
A solution of 4c (190 mg, 0.67 mmol) in anhydrous THF (530 μL) was added dropwise to a solution of nBuLi (2.5 M in hexanes, 410 μL, 1.00 mmol) in anhydrous THF (440 μL) at room temperature. After 1 hour, the solution was cooled to −78° C. and methyl iodide (170 μL, 2.67 mmol) was added. The resulting solution was warmed to room temperature over 12 hours, and the reaction was quenched by the addition of saturated aqueous NH4Cl. Water (5 mL) was added and the solution was extracted with CH2Cl2 (3×10 mL). Combined organic fractions were dried (Na2SO4), filtered, and concentrated. The residue was purified via column chromatography (SiO2, 6:1 Hexane:EtOAc) to afford 5c as a yellow oil (157 mg, 79%): 1H NMR (CDCl3, 500 MHz) 6.70 (d, J=9.0 Hz, 1H), 6.61 (d, J=9.0 Hz, 1H), 5.10 (s, 2H), 5.08 (s, 2H), 4.34 (quintet, J=6.1 Hz, 1H), 3.78 (q, J=7.1 Hz, 2H), 3.67 (q, J=7.1 Hz, 2H), 2.13 (s, 3H), 1.23 (d, J=6.1 Hz, 6H), 1.24-1.15 (m, 6H); 13C NMR (CDCl3, 125 MHz) δ 150.3, 146.6, 145.3, 122.7, 113.7, 110.1, 97.3, 94.0, 71.5, 65.4, 64.2, 29.4, 22.2, 15.2, 15.2, 9.9; IR (film) νmax 2924, 2853, 2359, 2339, 1591, 1483, 1113, 1057, 974 cm−1; HRMS (ESI+) m/z: [M+H]+ calcd for C16H26O5, 299.1858. found, 299.1909.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:23]([O:25][CH3:26])=[O:24])#[N:2].C(Cl)(=O)C(Cl)=O.[CH2:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:36][CH2:35][CH:34]1[NH2:43].CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[CH2:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:36][CH2:35][CH:34]1[NH:43][C:18]([C:17]1[CH:16]=[CH:15][C:14]([O:13][C:12]2[CH:11]=[C:10]3[C:5]([CH:6]([C:23]([O:25][CH3:26])=[O:24])[CH2:7][CH2:8][O:9]3)=[CH:4][C:3]=2[C:1]#[N:2])=[CH:22][CH:21]=1)=[O:20]
Reactant: NC1CCc2ccccc2C1
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(C#N)cc21
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)NC4CCc5ccccc5C4)cc3)c(C#N)cc21
Reaction time: 0.5 h
Yield: 74 %

Procedure:
4-(6-Cyano-4-(methoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation 2) (10 mg, 0.028 mmol) was diluted with DCM (500 uL) followed by the addition of oxalyl chloride in DCM (2M) (0.017 ml, 0.034 mmol) and 1 drop of DMF. After stirring for 30 minutes, 1,2,3,4-tetrahydro-naphthalen-2-ylamine (8.3 mg, 0.057 mmol) and DIEA (0.020 mL, 0.11 mmol) were added. After stirring for 2 hours, the reaction was loaded directly onto a biotage 12i cartridge and eluted with 5% ethyl acetate/hexanes to 100% ethyl acetate to yield methyl 7-(4-((1,2,3,4-tetrahydronaphthalen-2-yl)carbamoyl)phenoxy)-6-cyanochroman-4-carboxylate (10 mg, 73% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13]([N:15]4[C:19]([CH3:21])([CH3:20])[C:18](=[O:22])[N:17]([CH3:23])[C:16]4=[O:24])[S:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:25]=1.[CH3:26][C:27]([OH:44])([CH3:43])[CH2:28][N:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30]1>[Pd]>[OH:44][C:27]([CH3:43])([CH3:26])[CH2:28][N:29]1[CH:33]=[C:32]([C:2]2[CH:3]=[CH:4][C:5]3[C:11]4[N:12]=[C:13]([N:15]5[C:19]([CH3:20])([CH3:21])[C:18](=[O:22])[N:17]([CH3:23])[C:16]5=[O:24])[S:14][C:10]=4[CH2:9][CH2:8][O:7][C:6]=3[CH:25]=2)[CH:31]=[N:30]1
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CN1C(=O)N(c2nc3c(s2)CCOc2cc(Br)ccc2-3)C(C)(C)C1=O
Agent: [Pd]
Product: CN1C(=O)N(c2nc3c(s2)CCOc2cc(-c4cnn(CC(C)(C)O)c4)ccc2-3)C(C)(C)C1=O
Yield: 12 %

Procedure:
1-(8-Bromo-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepin-2-yl)-3,5,5-trimethylimidazolidin-2,4-dione was coupled with 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol under Suzuki palladium conditions to give 492. Yield 12%. MS (ESI+): 482.2. 1H NMR (400 MHz, DMSO) δ 8.18 (d, J=8.3, 1H), 8.12 (s, 1H), 7.91 (s, 1H), 7.39 (dd, J=8.3, 1.8, 1H), 7.24 (t, J=4.4, 1H), 4.73 (s, 1H), 4.34 (t, J=4.9, 2H), 4.03 (s, 2H), 3.26 (t, J=5.0, 2H), 3.02 (s, 3H), 1.81 (s, 6H), 1.09 (s, 6H)