Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:8]([CH:9]=O)=[CH:7][CH:6]=[CH:5][C:4]=1[C:11]1[S:15][C:14]([C:16]2[CH:17]=[CH:18][C:19]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH:23]=2)[C:21]#[N:22])=[N:13][CH:12]=1)[CH3:2].C(O)(=O)C.C([O-])(=O)C.[Na+].[NH:37]1[CH2:42][CH2:41][CH:40]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:39][CH2:38]1>C(O)C>[C:21]([C:20]1[CH:23]=[C:16]([C:14]2[S:15][C:11]([C:4]3[C:3]([CH2:1][CH3:2])=[C:8]([CH2:9][N:37]4[CH2:42][CH2:41][CH:40]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:39][CH2:38]4)[CH:7]=[CH:6][CH:5]=3)=[CH:12][N:13]=2)[CH:17]=[CH:18][C:19]=1[O:24][CH:25]([CH3:27])[CH3:26])#[N:22]
Reactant: CCOC(=O)C1CCNCC1
Reactant: CCc1c(C=O)cccc1-c1cnc(-c2ccc(OC(C)C)c(C#N)c2)s1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C1CCN(Cc2cccc(-c3cnc(-c4ccc(OC(C)C)c(C#N)c4)s3)c2CC)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution of 5-[5-(2-ethyl-3-formylphenyl)-1,3-thiazol-2-yl]-2-[(1-methylethyl)oxy]benzonitrile (D73) (120 mg), acetic acid (0.036 mL) and sodium acetate (52.3 mg) in ethanol (20.00 mL) stirred under nitrogen at room temperature was added ethyl 4-piperidinecarboxylate (200 mg) in one charge. The reaction mixture was stirred at room temperature for 30 min, then the solvent was evaporated in vacuo. The residue was dissolved in dichloromethane (DCM) (20 mL), sodium triacetoxyborohydride (169 mg) was added to the mixture. The reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate (100 mL) and saturated brine (30 mL). The organic phase was dried over sodium sulphate and evaporated in vacuo to give the crude product ethyl 1-{[3-(2-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazol-5-yl)-2-ethylphenyl]methyl}-4-piperidinecarboxylate (D84) (165 mg). The crude product was used for next step without further purification. MS (ES): C30H35N3O3S requires 517. found 518.3 (M+H+).
Reaction SMILES: [CH3:1][N:2]([CH3:9])[CH2:3][C:4]([CH3:8])([CH3:7])[CH2:5][NH2:6].[C:10](O)(=[O:13])[CH:11]=[CH2:12]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.P(=O)(O)(O)O>[CH3:1][N:2]([CH3:9])[CH2:3][C:4]([CH3:8])([CH3:7])[CH2:5][NH:6][C:10](=[O:13])[CH:11]=[CH2:12]
Reactant: CN(C)CC(C)(C)CN
Reactant: C=CC(=O)O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=P(O)(O)O
Product: C=CC(=O)NCC(C)(C)CN(C)C
Yield: 70.9 %

Procedure:
Proceeding as in Example 1, 130 g 3-dimethylamino-2,2-dimethylpropylamine; 72 g acrylic acid; 3 g copper acetate; and 2 g 85% phosphoric acid were mixed. 130.5 g (71%) N-(3-dimethylamino-2,2-dimethylpropyl)acrylamide was isolated.
Reaction SMILES: [O:1]1[C:3]2[CH2:4][CH2:5][CH2:6][C:2]1=2.[CH3:7][C:8]1[C:9]([N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)=[N:10][C:11](=[O:14])[NH:12][CH:13]=1>O1CCCC1.CS(C)=O.[Pd]>[OH:1][CH:3]1[CH2:4][CH:5]([N:12]2[CH:13]=[C:8]([CH3:7])[C:9]([N:15]3[CH:19]=[N:18][CH:17]=[N:16]3)=[N:10][C:11]2=[O:14])[CH:6]=[CH:2]1
Reactant: Cc1c[nH]c(=O)nc1-n1cncn1
Reactant: C1CC2=C(C1)O2
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: Cc1cn(C2C=CC(O)C2)c(=O)nc1-n1cncn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 25.8 %

Procedure:
The equivalent amount of epoxycyclopentene is slowly added at 0° C. to 3.54 g (0.020 mol) of 5-methyl-4-(1,2,4-triazol-1-yl)pyrimidin-2(1H)-one (prepared by reaction of thymine with 1,2,4-triazole/POCl3 /triethylamine) in a mixture of 40 ml of dry tetrahydrofuran and 20 ml of dry dimethylsulfoxide with 5 mol % of the palladium(0) catalyst prepared in situ as above, and the reaction mixture is stirred at room temperature for 12 hours. The resulting suspension is filtered, the filtrate is concentrated and the residue is chromatographed over silica gel using methylene chloride/methanol 9/1. 1.34 g (25.8% of theory) of 1-[(1RS,4SR)-4-hydroxy-cyclopent-2-en-1-yl]-5-methyl-4-(1,2,4-triazol-1-yl)-pyrimidin-2(1H)-one (Example 1.18.1.) of melting point 198° to 204° C. are obtained. 1H NMR (270 KHz, d6 -DMSO), δ[ppm]: 9.31 (s, 1H), 8.38 (s, 1H), 8.07 (s, 1H), 6.25 (m, 1H), 5.92 (m, 1H), 5.52 (m, 1H), 5.28 (d, 1H), 4.71 (m, 1H), 2.87 (m, 1H), 2.30 (s, 3H), 1.47 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([F:7])=[C:4]([F:6])[F:5].[S:10](=[O:13])(=[O:12])=[O:11]>>[F:1][C:2]([F:9])([F:8])[C:3]1([F:7])[C:4]([F:6])([F:5])[O:13][S:10]1(=[O:12])=[O:11]
Reactant: O=S(=O)=O
Reactant: FC(F)=C(F)C(F)(F)F
Product: O=S1(=O)OC(F)(F)C1(F)C(F)(F)F
Reaction time: 96 h

Procedure:
A mixture of commercial liquid sulfur trioxide (10 ml) and hexafluoropropene (45 g, 0.30 mol) was sealed in a Carius tube at liquid nitrogen temperature, mixed well at 25° C., allowed to stand for 4 days at 25° C., and finally heated in a steam bath for 6 hours. From two such tubes, there was obtained by distillation, 3-(trifluoromethyl)-3,4,4-trifluoro-1-oxa-2-thiacyclobutane 2,2-dioxide (2-hydroxy-1-trifluoromethyl-1,2,2,-trifluoroethane sulfonic acid sultone, D. C. England, M. A. Dietrich and R. V. Lindsey, Jr., J. Amer. Chem. Soc., 82 6181 (1960)) (25 g, 22%) bp 44° C., and pentafluoro-2-propenyl fluorosulfate (hereinafter referred to as perfluoroallyl fluorosulfate) (73 g, 63%), bp 58°-60° C.
Reaction SMILES: [CH2:1]([C:3]1[S:4][CH:5]=[C:6](/[CH:8]=[CH:9]/[C:10]2[C:11]([O:21][CH2:22][C:23]3[CH:44]=[CH:43][C:26]([O:27][CH2:28][C:29]4[N:30]=[C:31]([C:35]5[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=5)[C:38]#[N:39])[O:32][C:33]=4[CH3:34])=[C:25]([O:45][CH3:46])[CH:24]=3)=[N:12][N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=2)[N:7]=1)[CH3:2].[N-:47]=[N+:48]=[N-:49].[Na+].[Cl-].[NH4+].CN(C)C=O>O>[CH2:1]([C:3]1[S:4][CH:5]=[C:6](/[CH:8]=[CH:9]/[C:10]2[C:11]([O:21][CH2:22][C:23]3[CH:44]=[CH:43][C:26]([O:27][CH2:28][C:29]4[N:30]=[C:31]([C:35]5[CH:36]=[C:37]([C:38]6[NH:49][N:48]=[N:47][N:39]=6)[CH:40]=[CH:41][CH:42]=5)[O:32][C:33]=4[CH3:34])=[C:25]([O:45][CH3:46])[CH:24]=3)=[N:12][N:13]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:14]=2)[N:7]=1)[CH3:2]
Reactant: CCc1nc(/C=C/c2cn(-c3ccccc3)nc2OCc2ccc(OCc3nc(-c4cccc(C#N)c4)oc3C)c(OC)c2)cs1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nc(/C=C/c2cn(-c3ccccc3)nc2OCc2ccc(OCc3nc(-c4cccc(-c5nnn[nH]5)c4)oc3C)c(OC)c2)cs1
Temperature: 120 °C
Reaction time: 6 h
Yield: 28.3 %

Procedure:
A mixture of 3-[4-({4-[({4-[(E)-2-(2-ethyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]benzonitrile (350 mg), sodium azide (55 mg), ammonium chloride (59 mg) and N,N-dimethylformamide (10 mL) was stirred at 120° C. for 6 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate-tetrahydrofuran. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:5-1:2-1:1, v/v) to give 5-{3-[4-({4-[({4-[(E)-2-(2-ethyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}-1H-tetrazole (106 mg, yield 28%) as colorless crystals. Recrystallization from ethyl acetate-diethyl ether gave colorless prism crystals. melting point: 144-147° C.
Reaction SMILES: [S:1]([O:5][CH2:6][CH:7]1[O:9][CH2:8]1)([CH3:4])(=[O:3])=[O:2].[ClH:10]>>[S:1]([O:5][CH2:6][CH:7]([OH:9])[CH2:8][Cl:10])([CH3:4])(=[O:3])=[O:2]
Reactant: CS(=O)(=O)OCC1CO1
Reactant: Cl
Product: CS(=O)(=O)OCC(O)CCl
Reaction time: 0.5 h
Yield: 85 %

Procedure:
Concentrated HCl (20 ml) was added to 3-mesyloxy-1,2-epoxypropane (5.0 g, 0.033 m) over 15-20 minutes. After stirring for an additional 30 minutes, the water was removed through the addition and subsequent evaporation of ethanol. Finally, residual ethanol was removed at room temperature and 0.1 mm to give 3-mesyloxy-2-hydroxy-1-chloropropane (5.4 g, 85%).
Reaction SMILES: C[Mg]Br.[CH3:4]COCC.[CH:9]12[O:14][CH:13]1[CH2:12][N:11]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH2:10]2>C1COCC1>[OH:14][CH:13]1[CH:9]([CH3:4])[CH2:10][N:11]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:12]1
Reactant: O=C(OCc1ccccc1)N1CC2OC2C1
Reactant: CCOCC
Agent: C[Mg]Br
Solvent: C1CCOC1
Product: CC1CN(C(=O)OCc2ccccc2)CC1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.4 %

Procedure:
3M methylmagnesium bromide in ether (99 ml, 296 mmol) was added dropwise over 1 hour to a suspension of benzyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (26 g, 119 mmol) and copper bromide-dimethyl sulfide complex (24.38 g, 119 mmol) in anhydrous THF (250 ml) at −40° C. under a nitrogen atmosphere. The reaction was allowed to stir at this temperature for an additional 1 hour before cautiously quenching of the reaction using 125 mL sat. ammonium chloride. The reaction was then allowed to warm to rt and diluted with water (125 mL), then extracted with ethyl acetate (3×150 mL). Ethyl acetate phases were combined, washed with brine, then dried with Na2SO4. After concentration, the crude material was purified by flash chromatography. (+/−)-Benzyl 3-hydroxy-4-methylpyrrolidine-1-carboxylate (24.5 g, 104 mmol, 88% yield) was obtained as light yellow oil. 1H NMR (400 MHz, chloroform-d) δ ppm 7.28-7.46 (5H, m), 5.14 (2H, s), 3.93-4.05 (1H, m), 3.63-3.78 (2H, m), 3.25-3.43 (1H, m), 3.12 (1H, ddd, J=13.26, 10. This material was resolved using the following chiral SFC conditions: column: CHIRALPAK® AD-H 5×25 cm, 5 μm, Column Temp. 40° C., Flow rate: 290 mL/min, Mobile Phase: CO2/MeOH=82/18, injection volume: 2.5 mL (Conc. 118 mg/mL), detector wavelength: 212 nm. The isolated isomers were named “Pk1” and “Pk2” in the elution order. Fractions containing Pk2 were concentrated to afford 10 g of (3R,4S)-benzyl 3-hydroxy-4-methylpyrrolidine-1-carboxylate as a yellow oil. 84, 5.17 Hz), 2.06-2.26 (1H, m), 1.90 (1H, d, J=8.36 Hz), 1.03 (3H, dd, J=6.71, 5.39 Hz); LCMS (CHROMOLITH® RP-18e 2.0×50 mm, 0.8 mL/min, Solvent A: 10% MeOH/water with 0.1% TFA, Solvent B: 90% MeOH/water with 0.1% TFA, gradient with 0-100% B over 4 minutes) retention time: 2.56 min; MS(ES+) m/z: 236.0 (M+H+); HPLC retention time: 3.028 min (analytical HPLC Method H). Chiral purity: 99.9% ee (chiral HPLC conditions: column: CHIRALPAK® AD-H (25×0.46 cm, 5 μm), 30% MeOH in CO2, 3 mL/min, 40° C., 200-400 nm, 100 bars).
Reaction SMILES: I[C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.[CH:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][C:31]=1B(O)O>>[CH:38]1[C:39]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:35]=[CH:36][C:37]=1[C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: Ic1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cccnc12
Product: c1ccc(C(c2ccccc2)(c2ccccc2)n2nc(-c3ccc4ccccc4c3)c3ncccc32)cc1
Yield: 28.7 %

Procedure:
By treating 731 mg of 3-iodo-1-trityl-1H-pyrazolo[4,3-b]pyridine obtained by Example 418 and 340 mg of 2-naphthalene boronic acid in the manner as described in Production example 194, 210 mg of the title compound was obtained as a colorless powder.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[C:9]([O:14][CH2:15][CH3:16])(=[O:13])[CH:10]([CH3:12])[CH3:11].Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][Br:24].[NH4+].[Cl-]>C1COCC1.CN1C(=O)N(C)CCC1>[Br:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][C:10]([CH3:12])([CH3:11])[C:9]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C(C)C
Reactant: BrCCCCCCBr
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: CCOC(=O)C(C)(C)CCCCCCBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.4 %

Procedure:
Under N2 atmosphere, a solution of LDA (2.0 M in heptane/tetrahydrofuran/ethylbenzene, 2.94 L, 5.9 mol) was added dropwise to a stirred solution of ethyl isobutyrate (720 g, 6.2 mol) in anhydrous THF (4.7 L) at −45° C. After 1 h, 1,6-dibromohexane (2400 g, 9.8 mol) was added dropwise, followed by the addition of DMPU (320 mL). The reaction mixture was stirred for 1 h and then allowed to warm to room temperature overnight. Saturated NH4Cl solution (3 L) was added and the mixture was extracted with ethyl acetate (3×6 L). The combined organic layers were washed with brine (4.5 L), 1 M aqueous HCl (6 L), saturated NaHCO3 solution (6 L), and brine (4.5 L). The solution was dried over MgSO4 and concentrated in vacuo. The residue was distilled under high vacuo to furnish ethyl 8-bromo-2,2-dimethyloctanoate (856 g, 52%) as a light yellowish oil. Bp 95-100° C./0.2 mm. 1H NMR (300 MHz, CDCl3/TMS): δ (ppm): 4.13 (q, J=7.1, 2 H), 3.39 (t, J=6.9, 2 H), 1.92-1.75 (m, 2 H), 1.58-1.25 (m, 8 H), 1.25 (t, J=7.1, 3 H), 1.12 (s, 6H). 13C NMR (75 MHz, CDCl3=77.52 ppm): δ (ppm): 177.62, 60.01, 42.08, 40.50, 33.63, 32.68, 29.13, 27.93, 25.00, 24.66, 14.22. HRMS (LSIMS, nba): Calcd for C12H24BrO2 (MH+): 279.0960, found: 279.0957.
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([NH2:16])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].[C:17]([C:19]1[N:24]=[CH:23][C:22]([NH:25][C:26]([CH2:28][CH:29]([CH3:34])[CH2:30][C:31](O)=[O:32])=[O:27])=[CH:21][CH:20]=1)#[N:18].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[C:17]([C:19]1[N:24]=[CH:23][C:22]([NH:25][C:26](=[O:27])[CH2:28][CH:29]([CH3:34])[CH2:30][C:31]([NH:16][C:12]2[CH:13]=[CH:14][C:15]3[N:3]([CH2:1][CH3:2])[C:4]4[C:9]([C:10]=3[CH:11]=2)=[CH:8][CH:7]=[CH:6][CH:5]=4)=[O:32])=[CH:21][CH:20]=1)#[N:18]
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Reactant: CC(CC(=O)O)CC(=O)Nc1ccc(C#N)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCn1c2ccccc2c2cc(NC(=O)CC(C)CC(=O)Nc3ccc(C#N)nc3)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.7 %

Procedure:
To a solution of 9-ethyl-9H-carbazol-3-ylamine (306.5 mg, 1.457 mmol) in DMF (7 mL) were added the compound obtained in Step 1 (300 mg, 1.215 mmol), HATU (554.14 mg, 1.457 mmol) and DIPEA (0.632 mL, 3.644 mmol) at room temperature, and the mixture was stirred at room temperature for 16 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate (2×50 mL). The organic layer was dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by preparative HPLC to give the title compound (260 mg, 48.71%) as a colorless powder.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Br:5][C:6]1[CH:16]=[CH:15][C:9]([CH:10]=[CH:11][C:12](Cl)=[O:13])=[CH:8][CH:7]=1>O.CC(C)=O>[Br:5][C:6]1[CH:7]=[CH:8][C:9]([CH:10]=[CH:11][C:12]([N:1]=[N+:2]=[N-:3])=[O:13])=[CH:15][CH:16]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(Cl)C=Cc1ccc(Br)cc1
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: [N-]=[N+]=NC(=O)C=Cc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.1 %

Procedure:
A solution of NaN3 (2.2 g, 33.8 mmol) in water (7.5 mL) was added dropwise over 5 min to a stirred solution of 4-bromocinnamoyl chloride (22 mmol) in acetone (22 mL) at -10° C. The heterogeneous mixture was stirred at 0° C. for 1 h and diluted with water (25 mL). The precipitate was collected by filtration and dried in vacuo over P2O5 to give 4-bromocinnamoyl azide (5.22 g, 20.7 mmol) as a golden-coloured solid.
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]([NH:31][C:32]([C:34]2[C:35](=[O:48])[N:36]([C:41]3[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=3)[C:37]([CH3:40])=[CH:38][CH:39]=2)=[O:33])[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14]1[CH:15]=[N:16][N:17](C(OC(C)(C)C)=O)[CH:18]=1)[N:10]([CH3:26])[N:9]=[CH:8]2.[ClH:49]>C(Cl)Cl.CO>[F:1][C:2]1[CH:30]=[C:29]([NH:31][C:32]([C:34]2[C:35](=[O:48])[N:36]([C:41]3[CH:42]=[CH:43][C:44]([F:47])=[CH:45][CH:46]=3)[C:37]([CH3:40])=[CH:38][CH:39]=2)=[O:33])[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14]1[CH:15]=[N:16][NH:17][CH:18]=1)[N:10]([CH3:26])[N:9]=[CH:8]2.[ClH:49].[F:1][C:2]1[CH:30]=[C:29]([NH:31][C:32]([C:34]2[C:35](=[O:48])[N:36]([C:41]3[CH:42]=[CH:43][C:44]([F:47])=[CH:45][CH:46]=3)[C:37]([CH3:40])=[CH:38][CH:39]=2)=[O:33])[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14]1[CH:15]=[N:16][NH:17][CH:18]=1)[N:10]([CH3:26])[N:9]=[CH:8]2
Reactant: Cc1ccc(C(=O)Nc2ccc(Oc3cc4cnn(C)c4cc3-c3cnn(C(=O)OC(C)(C)C)c3)c(F)c2)c(=O)n1-c1ccc(F)cc1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: Cc1ccc(C(=O)Nc2ccc(Oc3cc4cnn(C)c4cc3-c3cn[nH]c3)c(F)c2)c(=O)n1-c1ccc(F)cc1
Temperature: 30 °C
Reaction time: 2 h

Procedure:
tert-Butyl 4-(5-(2-fluoro-4-(1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamido)phenoxy)-1-methyl-1H-indazol-6-yl)-1H-pyrazole-1-carboxylate (423.9 g, 649.50 mmol) is dissolved in DCM (4.24 L). HCl in MeOH (5.74 N, 799.99 mL, 4.59 mol) is added and the solution is heated at 30° C. for 1 hour. Then the reaction mixture is heated to 45° C. and DCM (1.5 L) is added. After two hours, the solution is heated to 50° C. and DCM (2 L) is added. After 3 hours, DCM (2 L) is added followed by HCl in MeOH (4.5 N, 721.67 mL, 3.25 mol). After another 45 min, DCM (1 L), HCl in MeOH (4.5 N, 288.67 mL, 1.30 mol), and MeOH (1.5 L) are added. The reaction solution is then heated to 60° C. After 4 hours, MeOH (2 L) is added and 10 min later DCM (1 L) is added followed by HCl in MeOH (4.5 N, 200 mL). After 5 hours, the reaction is complete. The reaction mixture is concentrated to about ⅓ volume. MeOH (2 L) is added and the solution is concentrated to a thick slurry. Again, MeOH (2 L) is added and the mixture is concentrated to a thick slurry. The slurry is cooled to about 10-15° C. and then filtered. The solids are washed with MeOH. The solids are placed in a 55° C. vacuum oven for 2 days to give the desired product N-(3-fluoro-4-(1-methyl-6-(1H-pyrazol-4-yl)-1H-indazol-5-yloxy)phenyl)-1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide hydrochloride (377 g, 92.8%). MS (m/z): 551.0 (M−H).
Reaction SMILES: [OH:1][C:2]1[C:3]([I:9])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.I[CH3:11]>>[I:9][C:3]1[C:2]([O:1][CH3:11])=[CH:7][CH:6]=[C:5]([CH3:8])[N:4]=1
Reactant: Cc1ccc(O)c(I)n1
Reactant: CI
Product: COc1ccc(C)nc1I

Procedure:
Under the conditions of example 1 D, 10 g of 3-hydroxy-2-iodo-6-methylpyridine is reacted with 2.7 ml of iodomethane and worked up. 10.5 g of 2-iodo-3-methoxy-6-methylpyridine of melting point 45°-50° C. is obtained.
Reaction SMILES: [S:1]([OH:5])([OH:4])(=[O:3])=[O:2].NOCCN(C)C[C@H]1O[C@@H](N2C3N=CN=C(N)C=3N=C2C)[C@H](O)[C@@H]1O.C(OC(=[N:36][O:37][CH2:38][CH2:39][CH2:40][CH2:41][N:42]([CH3:62])[CH2:43][C@H:44]1[O:48][C@@H:47]([N:49]2[C:58]3[C:52]([C:53]([N:55]=[CH:56][N:57]=3)=[NH:54])=[N:51][C:50]2=[O:59])[C@H:46]([OH:60])[C@@H:45]1[OH:61])C)C.OS(O)(=O)=O>>[S:1]([OH:5])([OH:4])(=[O:3])=[O:2].[NH2:36][O:37][CH2:38][CH2:39][CH2:40][CH2:41][N:42]([CH3:62])[CH2:43][C@H:44]1[O:48][C@@H:47]([N:49]2[C:58]3[C:52]([C:53]([N:55]=[CH:56][N:57]=3)=[NH:54])=[N:51][C:50]2=[O:59])[C@H:46]([OH:60])[C@@H:45]1[OH:61]
Reactant: CCOC(C)=NOCCCCN(C)C[C@H]1O[C@@H](N2C(=O)N=C3C(=N)N=CN=C32)[C@H](O)[C@@H]1O
Agent: Cc1nc2c(N)ncnc2n1[C@@H]1O[C@H](CN(C)CCON)[C@@H](O)[C@H]1O
Agent: O=S(=O)(O)O
Product: CN(CCCCON)C[C@H]1O[C@@H](N2C(=O)N=C3C(=N)N=CN=C32)[C@H](O)[C@@H]1O

Procedure:
The procedure was the same as reported above for 7a using 8c (190 mg, 0.41 mmol) and 2N H2SO4 (3 mL). The compound was purified by column chromatography (elution with 4:1:0.5 chloroform:methanol:NH4OH): yield 208 mg (82%), MS: m/z 384 (M+H)+; 1HNMR (DMSO-d6) δ 10.45 (bs, 1H, 8-OH), 8.05 (s, 1H, H-2), 6.58 (bs, 2H, 6-NH2), 5.77 (d, 1H, H-1′, J1′,2′=5.0 Hz), 5.37-5.71 (bm, 2H, O—NH2), 4.83 (t, 1H, H-2′, J2′,3′=4.2 Hz), 4.18-4.29 (m, 2H, H-3′, H-4′), 3.88 (t, 2H, NH2O—CH2), 3.34-3.54 (m, 2H, 5′-CH2), 3.06 (bt, 2H, N(CH3)—CH2), 2.73 (s, 3H, N—CH3), 1.46-1.74 (bm, 4H, NH2OCH2—CH2CH2); UV λmax, nm, pH 1, 263.3 (∈ 12,200), pH 7, 268.9 (∈ 13,600), pH 13, 279.9 (∈ 15,600). Anal. (C15H25N7O5.1.9H2SO4.0.1C2H5OH.2H2O) C, H, N, S.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=[O:5].[CH3:12][O:13][C:14](=[O:19])[CH2:15][C:16]([CH3:18])=[O:17].[H-].[Na+]>O.[Cu]Br>[Cl:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:2]([CH:15]([C:14]([O:13][CH3:12])=[O:19])[C:16](=[O:17])[CH3:18])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1c(Cl)cccc1Br
Reactant: COC(=O)CC(C)=O
Agent: [Cu]Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COC(=O)C(C(C)=O)c1cccc(Cl)c1C(=O)O
Temperature: 70 °C
Yield: 34 %

Procedure:
To a stirred mixture of 2-bromo-6-chlorobenzoic acid (20 g, 85 mmol), methylacetoacetate (310 ml, excess), and copper (I) bromide 12.2 g, 85 mmol) sodium hydride (8.5 g, 212 mmol, 60% in oil) was added by portions and then heated at 70° C. for 16 hours. The resulting mixture was diluted with water (600 ml) and extracted with diethyl ether (3×500 ml). Aqueous phase was acidified with 2M HCl and extracted with ethyl acetate (2×800 ml). The combined organic solution was washed with brine (100 ml), dried (Na2SO4) and evaporated. The obtained oil was treated with a hot mixture of ethyl acetate (20 ml) and heptane (200 ml) and decanted for 2 times, dried in vacuo to give 8 g of yellow-brown solid, yield 34%. 1H NMR (500 MHz, DMSO-d6): 1.73 (s, 3H), 3.6 (s, 3H), 7.24 (d, 1H), 7.44 (t, 2H), 7.5 (d, 1H), 12.85 (s, 1H, OH of enol form), 13.4 (br, 1H, CO2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[C:5]([Cl:8])=[N:6][CH:7]=1.[NH:13]1[CH2:17][CH2:16][C@H:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:14]1>>[Br:1][C:2]1[CH:3]=[C:4]([S:9]([N:13]2[CH2:17][CH2:16][C@H:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])[CH2:14]2)(=[O:11])=[O:10])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: O=S(=O)(Cl)c1cc(Br)cnc1Cl
Product: CC(C)(C)OC(=O)N[C@H]1CCN(S(=O)(=O)c2cc(Br)cnc2Cl)C1

Procedure:
Prepared according to the methods described in reagent preparation 25 using 5-bromo-2-chloropyridine-3-sulfonyl chloride and (S)-tert-butyl pyrrolidin-3-ylcarbamate in step 1. 1H NMR (400 MHz, CDCl3) δ 8.61 (d, 1H), 8.52 (d, 1H), 4.67 (s, 1H), 4.25 (s, 1H), 3.57 (m, 4H), 3.34 (m, 1H), 2.22 (m, 1H), 1.92 (m, 1H), 1.45 (s, 9H); MS (ES) for C14H19BrClN3O4S: 440, 442 (Br isotopes, MH+).
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[N:10]=[CH:11][NH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.I[CH2:15][CH2:16][CH2:17][CH3:18]>CN(C=O)C>[CH2:15]([N:12]1[CH:13]=[C:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:10]=[CH:11]1)[CH2:16][CH2:17][CH3:18]
Reactant: CCCCI
Reactant: c1ccc(-c2c[nH]cn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCn1cnc(-c2ccccc2)c1
Temperature: 70 °C
Yield: 90.7 %

Procedure:
To the suspension of sodium hydride (2.40 g, 60% mineral oil suspension, 60 mmol) in 30 ml of anhydrous DMF is added a solution of 4-phenylimidazole (7.21 g, 50 mmol) in 30 ml of DMF at room temperature, the resulting mixture is stirred at 70° C. 1h, and then cooled to room temperature followed by the dropwise addition of iodobutane (9.66 g 52.5 mmol, 1.05 eq.). The mixture is stirred at room temperature for 1 h, heated to 70° C. and stirred for an additional 8 h. The reaction mixture is cooled to room temperature, poured into 200 ml of ice-water, extracted with ethyl acetate (100 ml×3). The combined organics are washed with water, brine, dried over anhydrous sodium sulfate, filtered, evaporated at reduced pressure and purified by flash chromatography on silica gel to obtain 9.08 g of 1-butyl-4-phenylimidazole. 1H NMR (400 MHz, CDCl3) δ 7.77 (2H, d, J=7.6 Hz), 7.49 (1H, s), 7.36 (2H, t, J=7.6 Hz), 7.23 (1H, m), 7.20 (1H, s), 3.95 (2H, t, 17.2 Hz), 1.80 (2H, m), 1.36 (2H, m), 0.96 (3H, t, J=7.2 Hz); MS (+VE) m/z 201 (M+1).