Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:11]3=[N:12][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:15]=[C:10]3[N:9]=[C:8]2[CH3:20])=[C:4]([Cl:23])[CH:3]=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>N1C=CC=CC=1>[Cl:23][C:4]1[CH:3]=[C:2]([NH:1][S:25]([CH3:24])(=[O:27])=[O:26])[CH:22]=[CH:21][C:5]=1[CH2:6][N:7]1[C:11]2=[N:12][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:15]=[C:10]2[N:9]=[C:8]1[CH3:20]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccc2nc(C)n(Cc3ccc(N)cc3Cl)c2n1
Solvent: c1ccncc1
Product: COC(=O)c1ccc2nc(C)n(Cc3ccc(NS(C)(=O)=O)cc3Cl)c2n1
Reaction time: 8 h
Yield: 54.5 %

Procedure:
Methyl 3-(4-amino-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (150 mg) was dissolved in pyridine (1.5 ml), and a solution of methanesulfonyl chloride (114 mg) in pyridine (0.5 ml) was added at room temperature. The mixture was refluxed under heating for 1 hr. Thereto was added a solution of methanesulfonyl chloride (114 mg) in pyridine (0.5 ml) at room temperature, and the mixture was left standing overnight at room temperature. The reaction mixture was concentrated under reduced pressure and ice water was added to the residue. The resulting product was extracted with chloroform. The organic layer was washed successively with a saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and filtrated. The filtrate was concentrated under reduced pressure. Ethanol was added to the residue, and the crystals were washed, filtrated and dried under reduced pressure to give the objective compound (101 mg) as pale-yellow crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[NH:8][N:7]=1)=[O:5])[CH3:2].[CH2:15]([O:22][C:23]1[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][C:24]=1[CH2:30]Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].Cl>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]([F:13])([F:14])[F:12])[N:8]([CH2:30][C:24]2[CH:25]=[C:26]([Br:29])[CH:27]=[CH:28][C:23]=2[O:22][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(C(F)(F)F)[nH]n1
Reactant: BrCc1cc(Br)ccc1OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(C(F)(F)F)n(Cc2cc(Br)ccc2OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.7 %

Procedure:
To a solution of 5-trifluoromethyl-1H-pyrazole-3-carboxylic acid ethyl ester (0.114 g, 0.55 mmol) and 1-benzyloxy-4-bromo-2-bromomethyl-benzene (0.196 g, 0.55 mmol) in DMF (2 ml) cooled at RT under N2 atmosphere was added K2CO3 (0.19 g, 1.375 mmol) The mixture was stirred at RT overnight, then acidified with HCl (2M, aq.) and extracted with EtOAc. The organic layer was separated, washed with brine, dried (MgSO4) and evaporated to dryness. The residue was purified by MPLC (10 g SiO2 cartridge, eluent 90% iso-hexane-10% EtOAc) yielding 0.18 g of title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[C:11]([O:16][CH2:17][C:18]([CH3:20])=[CH2:19])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SnH](CCCC)CCCC)CCC.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]2[C:18]([CH3:20])([CH3:19])[CH2:17][O:16][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(C)COc1cc(OCc2ccccc2)ccc1Br
Agent: CCCC[SnH](CCCC)CCCC
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: CC1(C)COc2cc(OCc3ccccc3)ccc21
Temperature: 100 °C
Yield: 90.6 %

Procedure:
To a solution of 4-(benzyloxy)-1-bromo-2-(2-methylallyloxy)benzene (5.00 g, 15.1 mmol) in benzene (400 mL) was added tributyltin hydride (7.42 mL, 27.2 mmol) and benzoyl peroxide (0.70 g, 2.90 mmol) at 0° C. The resulting mixture was refluxed at 100° C. overnight. After cooling down to ambient temperature, the mixture was washed with water, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography (ethyl acetate/hexane, 1/20) to give the title compound (3.48 g, 91%): MS (ES+) m/z 255.6 (M+1).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].N1C=CN=C1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>O1CCCC1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: OCCCCCCBr
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCCCCCBr
Temperature: 0 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
6-Bromo-1-hexanol (20 g, 110.42 mmol) was dissolved in dry tetrahydrofuran (700 ml) and cooled to 0° C. under argon atmosphere, to which were added imidazole (15 g, 220.84 mmol) and t-butyldimethylsilyl chloride (33 g, 220.84 mmol) and the resulting solution was stirred overnight. After the reaction was completed, the mixture was poured in ice-water and extracted with ethyl acetate. The organic solvent was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. This crude product was purified by column chromatography on silica gel, eluting with ethyl acetate:n-hexane=1:40. After removal of the solvent, 30 g of the title compound was obtained as colorless oil. (yield: 92.4%)
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].F[C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15].O>C1(C)C=CC=CC=1>[CH3:5][C:3]1[O:4][C:12]2[C:13]([C:14](=[O:15])[C:2]=1[C:1]([O:7][CH3:8])=[O:6])=[CH:17][CH:18]=[CH:19][CH:20]=2
Reactant: COC(=O)CC(C)=O
Reactant: O=C(Cl)c1ccccc1F
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1c(C)oc2ccccc2c1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
In a dried flask, a solution of methyl acetoacetate (2.16 mL, 20.0 mmol) in toluene (100 mL) was treated with sodium hydride (60% mineral oil dispersion, 880 mg, 22.0 mmol). The resulting mixture was stirred at rt for 10 min, and then a solution of 2-fluorobenzoyl chloride (2.23 mL, 20.0 mmol) in toluene (50 mL) was added over about a 1 min. period. The resulting mixture was heated at reflux for 24.5 h, and then poured into water (200 mL). The mixture was extracted twice with ether (50 mL each). The combined organic phases were dried over sodium sulfate and concentrated under vacuum to provide a viscous yellow oil, which crystallized. The solid was recrystallized from a ethyl acetate/hexane solution to provide methyl 2-methyl-4-oxo-4H-chromene-3-carboxylate as off-white crystals in two crops (2.10 g, 48%). 1H NMR (400 MHz, CDCl3) δ ppm 2.53 (s, 3 H) 3.94 (s, 3 H) 7.42 (m, 2 H) 7.67 (ddd, J=8.5, 7.0, 1.8 Hz, 1 H) 8.21 (dd, J=7.9, 1.8 Hz, 1 H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][OH:21])[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.ClC(Cl)C.[C:26](Cl)(=[O:28])[CH3:27]>N1C=CC=CC=1>[C:26]([O:21][CH2:20][C:13]1[N:14]([CH2:15][C:16]([OH:18])([CH3:17])[CH3:19])[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:1])[C:11]=2[N:12]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)Cl
Reactant: CC(C)(O)Cn1c(CO)nc2c(N)nc3ccccc3c21
Solvent: CC(Cl)Cl
Solvent: c1ccncc1
Product: CC(=O)OCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)O

Procedure:
To a round-bottomed flask with stir bar was added 1-(4-amino-2-hydroxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol (1 g, 3.5 mmol) followed by dichloroethane (20 mL) and pyridine (3 mL). To the stirred suspension was added acetyl chloride (0.27 mL, 1.1 equivalents) and the reaction was stirred at ambient temperature for 30 min. The solvent was evaporated under reduced pressure to afford a solid. The product was isolated by two purifications by prep HPLC (ISCO Combiflash Separation System, Biotage Si 40+M column, eluted with a gradient of 0-7% methanol in dichloromethane with 1% ammonium hydroxide) to provide [4-amino-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-2-yl]methyl acetate as an off white solid (130 mg), mp 203-205° C.; MS (ESI) m/z 329 (M+H); Anal. Calcd for C17H20N4O3.0.25CH4O: C, 61.59; H, 6.29; N, 16.66. Found C, 61.24; H, 6.22; N, 16.97.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C([O-])([O-])=O.[K+].[K+].O>CC(C)=O>[N+:10]([C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:6]=1)([O-:12])=[O:11]
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(CCN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 80 h

Procedure:
To a solution of 1-(2-bromoethyl)-4-nitrobenzene (460 mg, 2.0 mmol) in acetone (15 mL) was added morpholine (610 mg, 7.0 mmol) and 680 mg of K2CO3. The mixture was stirred for 80 hours at ambient temperature, and then poured into water. The aqueous mixture was extracted with ether. The organic layer was washed with brine, dried over MgSO4, and evaporated in vacuo to give 456 mg (1.93 mmol; 97%) of the title compound, which was converted to the appropriate amine by the method disclosed in Preparation 16.
Reaction SMILES: C[C:2]1[CH:3]=[CH:4][C:5]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].BrC1C=CC=CC=1C(O)=O>>[N:12]1[N:11]([C:5]2[CH:4]=[CH:3][CH:2]=[CH:10][C:6]=2[C:7]([OH:9])=[O:8])[N:15]=[CH:14][CH:13]=1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)O)c1
Agent: O=C(O)c1ccccc1Br
Product: O=C(O)c1ccccc1-n1nccn1

Procedure:
The title compound was prepared following the same general protocol as described for 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid in Example A11 using 2-bromobenzoic acid. MS (ESI) 190 (M+H).
Reaction SMILES: [N+:1](/[CH:4]=[CH:5]/[C:6]1[CH:18]=[CH:17][C:9]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:8][CH:7]=1)([O-:3])=[O:2].C(O)(=O)C.[BH4-].[Na+]>CS(C)=O>[N+:1]([CH2:4][CH2:5][C:6]1[CH:18]=[CH:17][C:9]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:8][CH:7]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])/C=C/c1ccc(Oc2ccccn2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: O=[N+]([O-])CCc1ccc(Oc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 44.9 %

Procedure:
To a solution of 2-(4-((E)-2-nitro-vinyl)-phenoxy)-pyridine (9.9 g, 41 mmol) described in Manufacturing Example 209-1-2, acetic acid (2.5 g) and dimethyl sulfoxide (60 mL) was added sodium borohydride (770 mg, 20 mmol) while the temperature was held at 30° C. or lower, which was stirred for 15 minutes at room temperature. This reaction solution was partitioned into ethyl acetate and water while the temperature was held at 30° C. or lower. The organic layer was separated and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=3:1) to obtain the title compound (4.5 g, 45%).
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.OS(O)(=O)=O.[F:20][C:21]1[CH:22]=[C:23]([C:28]([CH3:43])([CH3:42])[C:29]([CH:31]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:32]([O:34]CC)=O)=[O:30])[CH:24]=[CH:25][C:26]=1[F:27]>CCOC(C)=O>[CH2:40]([O:39][C:37]([C:31]1[C:29](=[O:30])[C:28]([CH3:43])([CH3:42])[C:23]2[C:24]([C:32]=1[OH:34])=[CH:25][C:26]([F:27])=[C:21]([F:20])[CH:22]=2)=[O:38])[CH3:41]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)C(C)(C)c1ccc(F)c(F)c1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=C(O)c2cc(F)c(F)cc2C(C)(C)C1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
P2O5 (26.9 g, 189 mmol) was added to concentrated H2SO4 (50.5 mL) at 0° C. Diethyl 2-(2-(3,4-difluorophenyl)-2-methylpropanoyl)malonate (32.42 g, 94.7 mmol) was added at 0° C., and the reaction mixture was allowed to warm to ambient temperature and stirred for 16 hours. The resulting reaction mixture was then poured into ice, diluted with 400 mL of EtOAc, added to a separatory funnel, partitioned with water, washed 3 times with 75 mL of water, separated, dried over Na2SO4, and concentrated in vacuo to give the title compound as a beige yellow amorphous solid which was used without further purification. MS (m/z)=297 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]>CCOC(C)=O.[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:10][CH2:11][C@H:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:13][CH2:14]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCOC(=O)C1CC=C(c2ccc(F)c(Cl)c2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H]1CC[C@H](c2ccc(F)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 4-(3-chloro-4-fluorophenyl)cyclohex-3-ene-1-carboxylate (270 mg, 0.955-mmoL) in EtOAc (15 mL) was added 10% Pd/C (45 mg). The reaction was put under an atmosphere of H2 (balloon) and stirred vigorously at room temperature. After 30 min, the catalyst was removed by filtration, and the filtrate was concentrated to afford a mixture of cis and trans products. The desired trans isomer was separated by flash chromatography on silica gel (0 to 10% EtOAc/hexanes) to afford ethyl trans-4-(3-chloro-4-fluorophenyl)cyclohexanecarboxylate. Rf=0.25 (5% EtOAc/hexanes). 1H NMR (500 MHz, CDCl3): δ 7.21 (d, J=7.3 Hz, 1H), 7.02-7.06 (m, 2H), 4-14 (q, J=7.1 Hz, 2H), 2.48 (m, 1H), 2.32 (m, 1H), 2.08-2.12 (m, 2H), 1.91-1.98 (m, 2H), 1.53-1.67 (m, 2H), 1.37-1.46 (m, 2H), 1.27 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[C:13]([CH:14]=2)=[N:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])=[CH:17][CH:16]=2)[CH:10]=3)[CH2:3][CH2:2]1.[CH:32]([N-]C(C)C)(C)C.[Li+].CI.O>C1COCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[C:13]([CH:14]=2)=[N:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][Si:22]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:29]([CH3:31])[CH3:30])=[CH:17][CH:16]=2)[C:10]=3[CH3:32])[CH2:2][CH2:3]1
Reactant: CC(C)[N-]C(C)C
Reactant: CC(C)[Si](Oc1ccc(-n2cc3ccc(OCC4CC4)cc3n2)cc1)(C(C)C)C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CI
Product: Cc1c2ccc(OCC3CC3)cc2nn1-c1ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc1
Reaction time: 0.5 h

Procedure:
To a solution of 6-(cyclopropylmethoxy)-2-(4-{[tris(1-methylethyl)silyl]oxy}phenyl)-2H-indazole (218 mg) in THF (5 mL) was added dropwise a THF solution (1.11 M, 0.59 mL) of lithium diisopropylamide at −78° C. under an argon atmosphere, and the mixture was stirred for 30 min. To the reaction mixture was added methyl iodide (142 mg) at −78° C., and the mixture was stirred for 1.5 hr. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as a colorless oil (159 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([C:24]1[N:25]=[CH:26][N:27](S(C2C=CC(C)=CC=2)(=O)=O)[CH:28]=1)([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.ON1C2C=CC=CC=2N=N1>CO.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([C:24]1[N:25]=[CH:26][NH:27][CH:28]=1)([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)C(CCCCNC(=O)OC(C)(C)C)(C(=O)OCC)c1cn(S(=O)(=O)c2ccc(C)cc2)cn1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)C(CCCCNC(=O)OC(C)(C)C)(C(=O)OCC)c1c[nH]cn1

Procedure:
4.2 g (7.61 mmol) of diethyl 2-(4-tert-butoxycarbonylaminobutyl)-2-[1-(toluene-4-sulfonyl)-1H-imidazol-4-yl]malonate were dissolved in 190 ml of methanol and stirred with 4.66 g (30.45 mmol) of 1-hydroxybenzotriazole hydrate at RT for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue was chromatographed on silica gel (CH2Cl2:MeOH 9:1). The product-containing fractions were concentrated and the oil obtained was dissolved in ethyl acetate and washed with saturated NaHCO3 solution. The organic phase was dried over Na2SO4, filtered and concentrated. This gave 2.14 g (71%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([NH2:12])=[N:8][C:9]=2Cl)[N:4]([CH3:13])[N:3]=1.[N:14]1([CH2:20][CH2:21][NH2:22])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.CN(C=O)C>C(Cl)Cl.O>[Br:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([NH2:12])=[N:8][C:9]=2[NH:22][CH2:21][CH2:20][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:4]([CH3:13])[N:3]=1
Reactant: NCCN1CCOCC1
Reactant: Cn1nc(Br)c2c(Cl)nc(N)nc21
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1nc(Br)c2c(NCCN3CCOCC3)nc(N)nc21
Temperature: 50 °C

Procedure:
3-Bromo-4-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine (Intermediate 14) (750 mg, 2.8 mmol), 2-(4-morpholinyl)ethylamine (0.44 ml, 3.3 mmol) and DMF (30 ml) are mixed together and heated to 50° C. overnight. After cooling to room temperature the reaction mixture is diluted with DCM (60 ml) and water (40 ml) and the aqueous portion is extracted with a further 40 ml DCM. The organic portions are combined, dried over MgSO4, filtered and concentrated in vacuo. The crude residue is dry loaded onto silica and purification by flash chromatography eluting with DCM then MeOH:DCM (5:95) affords the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH2:10][CH3:11].[Br:12]Br>>[Br:12][C:6]1[CH:5]=[CH:4][C:3]([O:9][CH2:10][CH3:11])=[C:2]([Cl:1])[C:7]=1[F:8]
Reactant: CCOc1cccc(F)c1Cl
Reactant: BrBr
Product: CCOc1ccc(Br)c(F)c1Cl
Reaction time: 0.5 h
Yield: 86.4 %

Procedure:
606 g of the compound (b43) was added to a reactor in a nitrogen atmosphere, to which 570 g of bromine was added dropwise over 1 hour in a temperature range of 20 to 40° C., followed by stirring for 30 minutes. The resulting reaction mixture was washed with a saturated sodium thiosulfate aqueous solution, a 10% sodium hydroxide aqueous solution, and water. The resulting reaction mixture having been washed was subjected to fractional distillation under reduced pressure to obtain 760 g of 1-bromo-3-chloro-4-ethoxy-2-fluorobenzene (C2). The resulting compound (C2) was white solid and had a melting point of 65.4 to 66.1° C. and a boiling point of 125 to 127° C./8 mmHg.
Reaction SMILES: CC([N:5]([CH2:9][C@H:10]1[C@H:14]([C:15]([NH2:17])=[O:16])[CH2:13][N:12]([CH2:18][CH2:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([O:30][CH3:31])[N:28]=3)[N:23]=[CH:22][C:21]=2[F:32])[CH2:11]1)C(=O)[O-])(C)C.Cl.O1CCOCC1>C(Cl)Cl>[NH2:5][CH2:9][C@@H:10]1[CH2:11][N:12]([CH2:18][CH2:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([O:30][CH3:31])[N:28]=3)[N:23]=[CH:22][C:21]=2[F:32])[CH2:13][C@@H:14]1[C:15]([NH2:17])=[O:16]
Reactant: COc1ccc2ncc(F)c(CCN3C[C@@H](CN(C(=O)[O-])C(C)(C)C)[C@H](C(N)=O)C3)c2n1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc2ncc(F)c(CCN3C[C@@H](CN)[C@@H](C(N)=O)C3)c2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1,1-dimethylethyl[((3S,4S)-4-(aminocarbonyl)-1-{2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)methyl]carbamate (0.51 g, 1.14 mmol) was dissolved in methylene chloride (5 mL). HCl in dioxane (2.87 mL, 11.14 mmol) was added and the solution stirred at ambient temperature for 2 hours. The solvent was removed under reduced pressure. (0.534 g, quant.) LCMS: m/z 348.4 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][CH:11]=[N:10][C:9]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][N:3]=1.[NH2:19][NH2:20]>>[C:13]1([C:9]2[N:10]=[CH:11][O:12][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([NH:19][NH2:20])=[N:3][CH:4]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Clc1ccc(-c2ocnc2-c2ccccc2)cn1
Reactant: NN
Product: NNc1ccc(-c2ocnc2-c2ccccc2)cn1
Temperature: 70 °C

Procedure:
A suspension of 2-Chloro-5-(4-phenyl-oxazol-5-yl)-pyridine (2.55 g, 9.9 mmol) in hydrazine (8 mL) was heated at 70° C. until a solution formed (approximately 20 minutes). The hydrazine product was removed from the heat and concentrated in vacuo affording the above named compound as a dark solid (2.5 g, 100%).
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH3:26])[C@H:3]([NH:7][C:8]([C:10]1[N:11]=[C:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][C:14]=12)=[O:9])[C:4](O)=[O:5].C(Cl)(=O)C([Cl:31])=O.CN(C=O)C>C(Cl)Cl>[CH3:1][C:2]([CH3:27])([CH3:26])[C@H:3]([NH:7][C:8]([C:10]1[N:11]=[C:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][C:14]=12)=[O:9])[C:4]([Cl:31])=[O:5]
Reactant: CN1CCn2c(-c3ccccc3)nc(C(=O)N[C@H](C(=O)O)C(C)(C)C)c2C1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN1CCn2c(-c3ccccc3)nc(C(=O)N[C@H](C(=O)Cl)C(C)(C)C)c2C1
Reaction time: 2 h

Procedure:
To a solution (S)-3,3-dimethyl-2-(7-methyl-3-phenyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxamido)butanoic acid (Compound 281) (0.11 g, 0.30 mmol) in DCM was added oxalyl chloride (0.08 g, 0.60 mmol) followed by a catalytic amount of DMF. The resulting mixture was stirred for 2 h and the solvent was evaporated, toluene (2 mL) was added and the mixture was concentrated again. The resulting product (Intermediate 23A) was dried under vacuum and then used in the next step without further purification.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[C:9]([Cl:15])[CH:8]=1.C([O:19][B:20](OC(C)C)[O:21]C(C)C)(C)C.Cl>C1COCC1>[Cl:15][C:9]1[CH:8]=[C:7]([B:20]([OH:21])[OH:19])[CH:12]=[CH:11][C:10]=1[S:13][CH3:14]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CSc1ccc(Br)cc1Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1ccc(B(O)O)cc1Cl
Temperature: 20 °C
Reaction time: 1 h

Procedure:
Butyl lithium (15 ml, 1.9M in hexanes) was added over 40 min to a solution of the product from step b) (6.82 g) and triisopropylborate (8.0 ml) in THF (30 ml) at −78° C. and stirred for a further 1 h. 2M HCl (20 ml) was added, the mixture was warmed to 20° C. and extracted with ether (three times). The organic extracts were dried (MgSO4), evaporated and purified by chromatography (silica, petrol-ether as eluent) to give the sub-title compound (1.82 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N:15]2[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16]2)[CH:12]=[CH:11][C:10]=1[N:22]1[CH:27]=[C:26]([O:28][CH3:29])[C:25](=[O:30])[C:24]([C:31]([O:33]C)=[O:32])=[N:23]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C1COCC1.Cl>CO>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N:15]2[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16]2)[CH:12]=[CH:11][C:10]=1[N:22]1[CH:27]=[C:26]([O:28][CH3:29])[C:25](=[O:30])[C:24]([C:31]([OH:33])=[O:32])=[N:23]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1nn(-c2ccc(-n3cc(F)c(F)c3)cc2OCc2ccccc2)cc(OC)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cn(-c2ccc(-n3cc(F)c(F)c3)cc2OCc2ccccc2)nc(C(=O)O)c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of methyl 1-[2-(benzyloxy)-4-(3,4-difluoro-1H-pyrrol-1-yl)phenyl]-5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylate (4.54 g), 1M aqueous sodium hydroxide solution (15 mL), THF (30 mL) and methanol (30 mL) was stirred at room temperature for 30 min. The reaction mixture was neutralized with 1M hydrochloric acid, and the precipitate was collected by filtration, and washed with water to give the title compound (0.5 THF solvate, 4.70 g).