Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1.[O-:9]Cl=O.[Na+]>CC(O)(C)C.CC(=CC)C>[Br:1][C:2]1[CH:3]=[C:4]([C:7]([OH:9])=[O:8])[S:5][CH:6]=1
Reactant: O=Cc1cc(Br)cs1
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: [Na+]
Solvent: CC(C)(C)O
Product: O=C(O)c1cc(Br)cs1
Temperature: 0 °C
Reaction time: 5 h
Yield: 85 %

Procedure:
4-Bromothiophene-2-carbaldehyde (1.9 g, 10 mmol) was dissolved in 40 mL of t-BuOH and 4 mL of 2-methyl-2-butene. The reaction mixture was cooled to 0° C. and NaClO2 (1.1 g, 12 mmol) dissolved in 12 mL of 1M NaH2PO4 was added. The reaction mixture was let warm to room temperature and stirred for 5 hours. The reaction mixture was concentrated to about half the volume, and poured into 20 mL 1N NaOH and 50 mL Et2O. The aqueous layer was made acidic with 6N HCl and extracted with EtOAc. This organic layer was dried over sodium sulfate and concentrated to obtain the product as a white solid, 1.75 g, 8.5 mmol, 85% yield. 1H NMR 500 MHz (DMSO-d6) 8.02 (1H, s), 7.78 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=[CH:14][CH:13]=3)[CH:9]=[N:10][C:5]2=[C:4](Cl)[CH:3]=1.[CH3:23][O-:24].[Na+]>CO.O>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=[CH:14][CH:13]=3)[CH:9]=[N:10][C:5]2=[C:4]([O:24][CH3:23])[CH:3]=1
Reactant: C[O-]
Reactant: Clc1cc(Cl)c2ncn(Cc3cccc4ccccc34)c2n1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cc(Cl)nc2c1ncn2Cc1cccc2ccccc12
Yield: 69.6 %

Procedure:
5,7-Dichloro-3-(1-naphthalenylmethyl)-3H-imidazo[4,5-b]pyridine (150 mg, 0.457 mmol) and sodium methoxide (0.157 mL, 0.686 mmol) in Methanol (1.5 mL) were irradiated in a microwave oven for 1 h at 110° C. The mixture was diluted with water, the precipitate was collected, washed with water, dried to give 5-chloro-7-(methyloxy)-3-(1-naphthalenylmethyl)-3H-imidazo[4,5-b]pyridine (143 mg, 0.318 mmol, 69.6% yield) which was used as is in the next step. MS (ES+) m/e 324 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 8.36 (s, 1H), 8.24 (d, J=7.83 Hz, 1H), 7.95-8.03 (m, 1H), 7.91 (d, J=8.08 Hz, 1H), 7.60 (qd, J=7.20, 5.43 Hz, 2H), 7.44 (dd, J=8.21, 7.20 Hz, 1H), 7.02 (d, J=7.07 Hz, 1H), 6.99 (s, 1H), 5.93 (s, 2H), 4.10 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH:7]2[CH2:12][NH:11][CH2:10][CH2:9][NH:8]2)=[CH:4][CH:3]=1.Cl[C:14]1[CH:23]=[C:22]2[C:17]([C:18](=[O:29])[C:19]([C:26]([OH:28])=[O:27])=[CH:20][N:21]2[CH2:24][CH3:25])=[CH:16][C:15]=1[F:30]>N1C=CC=CC=1>[Br:1][C:2]1[S:6][C:5]([CH:7]2[NH:8][CH2:9][CH2:10][N:11]([C:14]3[CH:23]=[C:22]4[C:17]([C:18](=[O:29])[C:19]([C:26]([OH:28])=[O:27])=[CH:20][N:21]4[CH2:24][CH3:25])=[CH:16][C:15]=3[F:30])[CH2:12]2)=[CH:4][CH:3]=1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Reactant: Brc1ccc(C2CNCCN2)s1
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(c4ccc(Br)s4)C3)cc21

Procedure:
A 3 g portion of 2-(5-bromo-2-thienyl)piperazine was suspended in 8 ml of dry pyridine. An 820 mg portion of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid was added and the mixture was heated in a pressure bottle, under argon, at 120°-130° C. for 18 hours, then cooled, filtered and evaporated to dryness. The residue was evaporated from toluene and this residue purified by chromatography, eluting with chloroform:water saturated methanol (9:1). The appropriate fractions were combined, evaporated and recrystallized from dimethylformamide-ether, giving 440 mg of the desired product, mp 233°-235° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13](=[O:20])[CH2:14][CH:15](O)[C:16]([OH:18])=[O:17])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].Cl>C(O)(=O)C>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([C:13](=[O:20])/[CH:14]=[CH:15]/[C:16]([OH:18])=[O:17])[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(C(=O)CC(O)C(=O)O)cc(OC)c1OC
Agent: Cl
Solvent: CC(=O)O
Product: COc1cc(C(=O)/C=C/C(=O)O)cc(OC)c1OC

Procedure:
15.8 g of 4-(3,4,5-trimethoxyphenyl)-4-oxo-2-hydroxy butanoic acid obtainedin Example 3, 20 cc of acetic acid and 20 cc of concentrated hydrochloric acid (d-1.18) are heated for 2.5 hours under reflux.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]([CH2:8][CH3:9])[CH2:6][CH3:7])=[O:4].[OH:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[N:17]=[CH:16][N:15]=[C:14]2[NH:23][C:24]1[CH:29]=[C:28]([NH:30][C:31]([C:33]2[CH:38]=[CH:37][N:36]=[C:35]([N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)[CH:34]=2)=[O:32])[CH:27]=[CH:26][C:25]=1[CH3:45].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O>[CH2:6]([N:5]([CH2:8][CH3:9])[C:3]([CH2:2][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[N:17]=[CH:16][N:15]=[C:14]2[NH:23][C:24]1[CH:29]=[C:28]([NH:30][C:31]([C:33]2[CH:38]=[CH:37][N:36]=[C:35]([N:39]3[CH2:40][CH2:41][O:42][CH2:43][CH2:44]3)[CH:34]=2)=[O:32])[CH:27]=[CH:26][C:25]=1[CH3:45])=[O:4])[CH3:7]
Reactant: COc1cc2ncnc(Nc3cc(NC(=O)c4ccnc(N5CCOCC5)c4)ccc3C)c2cc1O
Reactant: CCN(CC)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CCN(CC)C(=O)COc1cc2c(Nc3cc(NC(=O)c4ccnc(N5CCOCC5)c4)ccc3C)ncnc2cc1OC
Temperature: 100 °C
Yield: 21.6 %

Procedure:
2-Chloro-N,N-diethylacetamide (0.05 g) was added to a mixture of 6-hydroxy-7-methoxy-4-[2-methyl-5-(2-morpholinopyridine-4-carboxamido)anilino]quinazoline (0.15 g), cesium carbonate (0.3 g) and dimethylacetamide (2 ml) and the reaction mixture was stirred and heated to 100° C. for 18 hours. After cooling to ambient temperature the reaction mixture was partitioned between methylene chloride and water. The organic layer was dried with brine and sodium sulphate, filtered and evaporated. The residual gum was triturated under diethyl ether. There was thus obtained the title compound as a solid (0.04 g, 20%); NMR: 1.05 (t, 3H), 1.4 (t, 3H), 2.13 (s, 3H), 3.35 (m, 4H), 3.51 (m, 4H), 3.7 (m, 4H), 3.95 (s, 3H), 4.91 (s, 2H), 7.11 (m, 1H), 7.18 (s, 1H), 7.24 (s, 1H), 7.29 (m, 1H), 7.6 (m, 1H), 7.77 (m, 2H), 8.26 (m, 2H), 9.3 (broad s, 1H), 10.32 (broad s, 1H); m/s: M+H+ 600.
Reaction SMILES: [CH2:1](Br)[CH3:2].[NH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:12])=[C:9]([OH:11])[CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[CH2:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:12])=[C:9]([OH:11])[CH:10]=1)[CH3:2]
Reactant: Cc1ccc(N)cc1O
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCNc1ccc(C)c(O)c1

Procedure:
88.6 gm of ethyl bromide were added to a solution of 50 gm of 5-amino-2-methylphenol in 250 ml of ethanol; and the mixture was refluxed for four hours. After the solution had cooled, it was diluted with 1.2 liters of water and was made weakly alkaline with sodium carbonate. After repeated extraction with ether, the ether extracts were dried and concentrated. The residue was recrystallized from ethanol, and had a melting point of 128° C to 129° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]([C:14]#[N:15])([CH3:13])[CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C)C=O.[NH2:21][C:22]1[CH:23]=[C:24]([CH:39]=[CH:40][C:41]=1[F:42])[O:25][C:26]1[N:31]=[C:30]2[S:32][C:33]([NH:35][C:36](=[O:38])[CH3:37])=[N:34][C:29]2=[CH:28][CH:27]=1.O>C(Cl)(=O)C(Cl)=O.CN(C)C(=O)C>[C:36]([NH:35][C:33]1[S:32][C:30]2[C:29]([N:34]=1)=[CH:28][CH:27]=[C:26]([O:25][C:24]1[CH:39]=[CH:40][C:41]([F:42])=[C:22]([NH:21][C:4](=[O:6])[C:3]3[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([C:14]#[N:15])([CH3:13])[CH3:12])[C:2]=3[Cl:1])[CH:23]=1)[N:31]=2)(=[O:38])[CH3:37]
Reactant: CC(=O)Nc1nc2ccc(Oc3ccc(F)c(N)c3)nc2s1
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Product: CC(=O)Nc1nc2ccc(Oc3ccc(F)c(NC(=O)c4cccc(C(C)(C)C#N)c4Cl)c3)nc2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.1 %

Procedure:
To a solution of 2-chloro-3-(1-cyano-1-methylethyl)benzoic acid (0.33 g, 1.5 mmol) produced in Example C61(v) in oxalyl chloride (1.5 mL) was added N,N-dimethylformamide (100 μL), and the mixture was stirred at room temperature for 30 min, and concentrated to dryness under reduced pressure. This was dissolved in a mixture of N,N-dimethylacetamide (1.5 mL) and tetrahydrofuran (1.5 mL), and the solution was added dropwise to a solution of N-[5-(3-amino-4-fluorophenoxy)[1,3]thiazolo[5,4-b]pyridin-2-yl]acetamide (0.33 g, 1.00 mmol) in N,N-dimethylacetamide (3 mL) under ice-cooling. The reaction mixture was stirred at room temperature for 3 hr, and poured into water (100 mL), and the mixture was extracted with ethyl acetate (100 mL×2). The ethyl acetate layers were combined, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=0/100→100/0), and recrystallized from methanol to give the title compound (320 mg, 61%) as colorless crystals.
Reaction SMILES: C(OC(=O)C)(=O)C.[CH:8]([OH:10])=O.[Cl:11][C:12]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:13]=1[C:14]([NH:16][CH2:17][CH2:18][NH:19][OH:20])=[O:15]>N1C=CC=CC=1>[Cl:11][C:12]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:13]=1[C:14]([NH:16][CH2:17][CH2:18][N:19]([CH:8]=[O:10])[OH:20])=[O:15]
Reactant: O=C(NCCNO)c1cc(Cl)ccc1Cl
Reactant: O=CO
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: O=CN(O)CCNC(=O)c1cc(Cl)ccc1Cl
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 33 %

Procedure:
A mixture of acetic anhydride (2 mL) and formic acid (1 mL) was allowed to stand at 55° C. for 2.5 h. After cooling to 0° C., the resulting mixed anhydride (0.4 mL) was added to a solution of 2,5-dichloro-N-(2-hydroxyamino-ethyl)-benzamide (0.28 g, 1.1 mmol) in pyridine (10 mL) at 0° C. under an argon atmosphere. The reaction mixture was stirred for 2 h and the pyridine removed in vacuo. The residue was purified by preparative reverse-phase HPLC to provide the title compound (0.1 g, 33%) as a white solid. 1H NMR* (400 MHz, CD3OD): δ 8.35 (s, 0.5H); 7.95 (s, 0.5H); 7.45 (m, 3H); 3.78 (m, 1H); 3.73 (m, 1H); 3.62 (m, 2H). * 1:1 mixture of rotamers. ESMS: M+H=277.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:19])OC2C=CC=CC=2)[N:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:26][C:27]1[CH:28]=[C:29]([OH:34])[CH:30]=[CH:31][C:32]=1[F:33].C1CCN2C(=NCCC2)CC1>C(#N)C>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:26][C:27]2[CH:28]=[C:29]([OH:34])[CH:30]=[CH:31][C:32]=2[F:33])=[O:19])[N:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: Nc1cc(O)ccc1F
Reactant: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)n(-c2ccccc2)n1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(C)(C)c1cc(NC(=O)Nc2cc(O)ccc2F)n(-c2ccccc2)n1
Temperature: 50 °C
Yield: 58.9 %

Procedure:
To a stirred suspension of phenyl 3-tert-butyl-1-phenyl-1H-pyrazol-5-ylcarbamate (prepared as described in example 153A) (335 mg, 1 mmol) and 3-amino-4-fluorophenol (127 mg, 1 mmol) in acetonitrile (15 mL) at rt, was added DBU (0.3 mL, 2 mmol). The mixture was heated at 50° C. for 1 h. The reaction mixture was cooled to rt, concentrated under reduced pressure, and the residue purified via silica gel column chromatography to afford 1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(2-fluoro-5-hydroxyphenyl)urea (217 mg, 59%) as a solid. LC-MS (ESI) m/z 369 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH2:10]([O:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16])[CH3:11]>>[CH2:10]([O:12][C:13]1[CH:14]=[C:15]([NH:16][C:2]2[N:7]=[C:6]([NH:16][C:15]3[CH:17]=[CH:18][CH:19]=[C:13]([O:12][CH2:10][CH3:11])[CH:14]=3)[C:5]([F:9])=[CH:4][N:3]=2)[CH:17]=[CH:18][CH:19]=1)[CH3:11]
Reactant: CCOc1cccc(N)c1
Reactant: Fc1cnc(Cl)nc1Cl
Product: CCOc1cccc(Nc2ncc(F)c(Nc3cccc(OCC)c3)n2)c1

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 3-ethoxyaniline were reacted to yield N2,N4-bis(3-ethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 7.96 (1H, d, J=4.8 Hz), 7.22 (m, 6H), 7.07 (t, 1H, J=1.8 Hz), 6.95 (dt, 1H, J=1.2 and 7.2 Hz), 6.77 (m, 2H), 3.88, (q, 4H, J=6.3 Hz), 1.33 (two t, 6H, J=6.3 Hz); 19F NMR (CDCl3): −46175; LCMS: ret. time: 26.86 min.; purity: 97%; MS (m/e): 369 (MH+).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[CH2:13][CH2:12][N:11](C)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OC(Cl)C)=O>C1(C)C=CC=CC=1>[C:1]([NH:5][C:6]([C:8]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCC(C(=O)NC(C)(C)C)(c2ccccc2F)CC1
Agent: CC(Cl)OC(=O)Cl
Solvent: Cc1ccccc1
Product: CC(C)(C)NC(=O)C1(c2ccccc2F)CCNCC1

Procedure:
To a solution of the product of step C (550 mg; 1.88 mmol) in toluene (10 mL) was added 1-chloroethyl chloroformate (15 mmol; 1.62 mL) and the reaction was heated to reflux for 36 h. The volatiles were removed in vacuo, the crude carbamate was then dissolved in methanol (10 mL) and the resultant solution was heated to reflux for 2 h. The volatiles were removed in vacuo, the crude amine was dissolved in methylene chloride (100 mL) and the solution was washed with a saturated solution of sodium bicarbonate, brine and the compound dried (Na2SO4). The drying agent was removed by filtration and the volatiles were removed in vacuo to furnish the crude product which was purified on silica gel using a gradient elution (95:5 then 90:10 methylene chloride/methanol (containing 10% v/v ammonium hydroxide) to afford the title compound.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([CH:27]=[CH:28][CH:29]=3)[CH2:19][S:20][CH2:21][CH2:22][C:23]([O:25]C)=[O:24])=[O:15])=[C:9]([C:30]3[CH:35]=[C:34]([NH:36][CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:47])([F:46])[F:45])[CH:39]=4)[CH:33]=[CH:32][N:31]=3)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].[OH-].Cl>O1CCCC1.O>[N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([CH:27]=[CH:28][CH:29]=3)[CH2:19][S:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:15])=[C:9]([C:30]3[CH:35]=[C:34]([NH:36][CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:46])([F:47])[F:45])[CH:39]=4)[CH:33]=[CH:32][N:31]=3)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(NCc3cccc(C(F)(F)F)c3)ccn2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 11.9 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of methyl 3-(3-(4-(piperidin-1-yl)-2-(4-(3-(trifluoromethyl)-benzylamino)pyridin-2-yl)phenylcarbamoyl)benzylthio)propanoate (300 mg, 0.35 mmol, 1.00 equiv, 78%) in tetrahydrofuran/H2O (20/5 mL), and LiOH (150 mg, 10.00 equiv, 40%). The resulting solution was stirred for 2 h at room temperature. The reaction progress was monitored by LCMS. The solution was adjusted to pH 6-7 with hydrochloric acid (1 N). The resulting solution was extracted with 3×50 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 1×20 mL of ethoxyethane. The resulting mixture was concentrated under vacuum. The crude product (250 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA to afford the product (27 mg, 10%) as a yellow oil. 1H-NMR (300 MHz, DMSO-d6, ppm) δ 13.49 (s, 1H), 10.05 (m, 1H), 8.89 (m, 1H), 8.02 (m, 1H), 7.68 (m, 4H), 7.37 (m, 5H), 7.08 (m, 1H), 6.91 (m, 2H), 6.28 (m, 1H), 3.80 (s, 2H), 3.23 (s, 4H), 2.27 (m, 2H), 1.63 (s, 6H). MS (ES, m/z): 649 [M+H]+.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[OH:18][CH2:19][C@H:20]([CH3:25])[C:21]([O:23][CH3:24])=[O:22].[CH:26]([O:28][CH2:29][CH:30]([CH3:32])[CH3:31])=[CH2:27]>C1(C)C=CC=CC=1>[CH3:25][C@@H:20]([CH2:19][O:18][CH:26]([O:28][CH2:29][CH:30]([CH3:32])[CH3:31])[CH3:27])[C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)[C@@H](C)CO
Reactant: C=COCC(C)C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H](C)COC(C)OCC(C)C
Reaction time: 4 h

Procedure:
A catalytic amount of pyridinium para-toluenesulfonate was added to 5.9 g (0.05 mole) of methyl (S)-(+)-3-hydroxy-2-methylpropionate. Thereto was dropwise added 5.5 g (0.055 mole) of isobutyl vinyl ether at room temperature. Then, stirring was conducted at room temperature for 4 hours to give rise to a reaction. Thereto was added 100 ml of toluene. The resulting mixture was washed with 50 ml of a 0.1% aqueous sodium hydroxide solution and 20 ml of water in this order. The washed material was subjected to vacuum distillation to remove the solvent, whereby was obtained 10.5 g (yield: 97.0.%) of an oily title compound (diastereomixture).
Reaction SMILES: [OH-:1].[Na+].Cl[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([F:12])[CH:6]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1C=CC=CC=1.O>[F:12][C:7]1[CH:6]=[C:5]([CH2:4][C:5]([CH3:10])([CH3:6])[CH:4]=[O:1])[CH:10]=[CH:9][C:8]=1[CH3:11]
Reactant: Cc1ccc(CCl)cc1F
Reactant: [OH-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: Cc1ccc(CC(C)(C)C=O)cc1F
Temperature: 70 °C

Procedure:
Under argon, a mixture of sodium hydroxide (2.8 g, 70 mmol) and tetrabutylammonium iodide (0.6 g, 1.6 mmol) in 8 ml benzene and 2.8 ml H2O was heated at 70° C. to form a homogeneous mixture. A mixture of the product of STEP 2 (10.5 g, 60.1 mmol) and isobutylaldehyde (5.76 g, 80 mmol) in 20 ml benzene was added to the above solution dropwise. The resulting reaction mixture was heated at 70-75° C. for 6 h. The product was extracted with ethyl acetate and washed with H2O. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried with MgSO4, and concentrated. The residue was purified by chromatography (on silica gel, ethyl acetate/hexane=5/95) to yield a colorless oil in 7.3 g (58%). NMR spectra of the product were consistent for the proposed structure.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([OH:16])=[C:14]([C:17](=O)[CH3:18])[C:13]([CH3:20])=[N:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:21][O:22][C:23]([C:25]1[S:29][C:28]([C:30]([NH:32][NH2:33])=[O:31])=[CH:27][CH:26]=1)=[O:24]>CN(C=O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14](=[C:17]([NH:33][NH:32][C:30]([C:28]3[S:29][C:25]([C:23]([O:22][CH3:21])=[O:24])=[CH:26][CH:27]=3)=[O:31])[CH3:18])[C:13]([CH3:20])=[N:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)c1c(C)nn(-c2ccc(C(C)(C)C)cc2)c1O
Reactant: COC(=O)c1ccc(C(=O)NN)s1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(=O)NNC(C)=C2C(=O)N(c3ccc(C(C)(C)C)cc3)N=C2C)s1
Temperature: 110 °C
Reaction time: 12 h
Yield: 35.2 %

Procedure:
54.5 mg (0.20 mmol) of 1-(1-(4-tert-butylphenyl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl)-ethanone and 40.0 mg (0.20 mmol) of 5-methoxycarbonyl-2-thiophenecarboxylic acid hydrazide were dissolved in 2.0 mL of DMF and stirred at 110° C. for 12 hours. After cooling, the solvent was removed by evaporation, and the crude product was washed with ethyl acetate and collected by filtration to obtain 32.0 mg of the desired product as a yellow solid (yield 35%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:12][C:13]([C:15]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]([CH3:11])([CH3:10])[CH3:9].[CH3:26]I>CC#N>[OH:1][C:2]1[CH:3]=[C:4]([NH:12][C:13]([C:15]2[CH:16]=[N:17][C:18]3[C:23]([C:24]=2[O:25][CH3:26])=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]([CH3:9])([CH3:11])[CH3:10]
Reactant: CC(C)(C)c1ccc(NC(=O)c2c[nH]c3ccccc3c2=O)cc1O
Reactant: CI
Solvent: CC#N
Product: COc1c(C(=O)Nc2ccc(C(C)(C)C)c(O)c2)cnc2ccccc12

Procedure:
N-(3-Hydroxy-4-tert-butyl-phenyl)-4-methoxy-quinoline-3-carboxamide (415) was synthesized following the general scheme above reacting N-(3-hydroxy-4-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (428) with methyl iodide. 1H NMR (400 MHz, DMSO-d6) δ 12.26 (s, 1H), 9.46 (s, 1H), 8.99 (s, 1H), 8.42 (t, J=4.2 Hz, 1H), 7.95-7.88 (m, 2H), 7.61-7.69 (m, 1H), 7.38 (d, J=2.1 Hz, 1H), 7.10 (d, J=8.4 Hz, 1H), 6.96 (dd, J=8.4, 2.1 Hz, 1H), 4.08 (s, 3H), 1.35 (s, 9H); HPLC ret. time 3.46 min, 10-99% CH3CN, 5 min run; ESI-MS 351.5 m/z (MH+).
Reaction SMILES: C[Zn]C.I[C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[N+:14]([O-:16])=[O:15])[NH:7][N:6]=1.[CH3:17]O.Cl>O1CCOCC1.C(Cl)Cl>[CH3:17][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[N+:14]([O-:16])=[O:15])[NH:7][N:6]=1
Reactant: CO
Reactant: O=[N+]([O-])c1cccc2[nH]nc(I)c12
Agent: C[Zn]C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1n[nH]c2cccc([N+](=O)[O-])c12
Reaction time: 0.5 h
Yield: 27 %

Procedure:
A solution of dimethyl zinc (1.73 ml, 3.46 mmol) was added dropwise to a mixture of 3-iodo-4-nitro-1H-indazole (0.500 g, 1.73 mmol) and (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium (0.427 g, 0.519 mmol) in dioxane (0.2M, 9 mL) under argon. The mixture was heated under reflux for 2 hours. After cooling, MeOH (<1 mL) was added, followed by 2N HCl (1 mL) and DCM (5 mL). After stirring mixture for 30 minutes, the organic layer was separated, washed with saturated aqueous sodium bicarbonate, water, and brine. The combined organic extracts were dried (phase separator silicone treated filter paper), concentrated and purified on silica gel (1-10% EtOAc in DCM to provide 3-methyl-4-nitro-1H-indazole (0.082 g, 27% yield) as a brown residue.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](O)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:34]=[CH:33][C:23]3[N:24]=[C:25]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[S:26][C:22]=3[CH:21]=1)=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].C(OC(C1N=C(O)C2C(C=1O)=CC=C(OC1C=CC3N=C(N4CCOCC4)SC=3C=1)C=2)=O)CCC.P(Cl)(Cl)([Cl:73])=O.C(=O)(O)[O-].[Na+]>ClC(Cl)C>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([Cl:73])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:34]=[CH:33][C:23]3[N:24]=[C:25]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[S:26][C:22]=3[CH:21]=1)=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(O)c2ccc(Oc3ccc4nc(N5CCOCC5)sc4c3)cc2c1O
Reactant: O=P(Cl)(Cl)Cl
Agent: CCCCOC(=O)c1nc(O)c2cc(Oc3ccc4nc(N5CCOCC5)sc4c3)ccc2c1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCCCOC(=O)c1nc(Cl)c2ccc(Oc3ccc4nc(N5CCOCC5)sc4c3)cc2c1O
Temperature: 120 °C

Procedure:
A solution of the regioisomeric mixture of 1,4-dihydroxy-6-(2-morpholin-4-yl-benzothiazol-6-yloxy)-isoquinoline-3-carboxylic acid butyl ester and 1,4-dihydroxy-7-(2-morpholin-4-yl-benzothiazol-6-yloxy)-isoquinoline-3-carboxylic acid butyl ester synthesized as described above (1.51 g, 3.04 mmol), and phosphorus oxychloride (417 μL, 4.56 mmol) in dichloroethane (23 mL) was stirred at 120° C. in a CEM microwave apparatus for thirty minutes. The mixture was then stirred at ambient temperature with saturated sodium bicarbonate solution for one hour. The organic layer was washed with brine, dried over anhydrous sodium sulfate, concentrated in vacuo and the residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and dichloromethane to give a solid (1.05 g). It was recrystallized from ethyl acetate to give the title compound as a white solid (484 mg): MS: (+) m/z 514.17 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:6](=[N:7][O:8][N:9]=2)[CH:5]=[CH:4][C:3]=1[OH:11].[O:12](S(C(F)(F)F)(=O)=O)[S:13]([C:16]([F:19])([F:18])[F:17])(=O)=[O:14].CCN(CC)CC>C(Cl)Cl>[F:17][C:16]([F:19])([F:18])[S:13]([O:11][C:3]1[CH:4]=[CH:5][C:6]2=[N:7][O:8][N:9]=[C:10]2[C:2]=1[CH3:1])(=[O:14])=[O:12]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1c(O)ccc2nonc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(OS(=O)(=O)C(F)(F)F)ccc2nonc12
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of 4-methyl-2,1,3-benzoxadiazol-5-ol (2.10 g, 17.9 mmol) in 40 mL of dry DCM was added Tf2O (7.61 g, 26.9 mmol) dropwise at −78° C. under Ar and stirred for 5 minutes, then Et3N (2.73 g, 26.9 mmol) was added dropwise to the mixture and the reaction was stirred at 0° C. for 4 hours. Then the reaction was poured into 200 mL of ice water and extracted with DCM (50 mL×3). The combined organic layers were washed with brine, dried and concentrated, the residue was purified by silica gel column to give the title compound.