Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[NH:12][C:11](S)=[N:10][C:9]=2[CH:14]=1.[CH2:15](Cl)/[CH:16]=[C:17](/[CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])\[CH3:18]>CN(C)C=O.C(Cl)Cl>[CH3:18]/[C:17](/[CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])=[CH:16]\[CH2:15][N:10]1[C:9]2[CH:14]=[C:5]([O:4][CH3:3])[CH:6]=[CH:7][C:8]=2[N:12]=[CH:11]1
Reactant: CC(C)=CCC/C(C)=C/CCl
Reactant: COc1ccc2[nH]c(S)nc2c1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc2ncn(C/C=C(\C)CCC=C(C)C)c2c1
Temperature: 25 °C
Yield: 76.7 %

Procedure:
To a suspension of sodium hydride (0.25 g, 11 mmol) in dimethylformamide (10 mL) at 0° C. under nitrogen was added 6-methoxy-2-mercaptobenzimidazole (1.98 g, 11 mmol) in dimethylformamide (20 mL). The solution was allowed to stir to ambient temperature, then geranyl chloride (1.9 g, 11 mmol) was added and the reaction mixture stirred at 90° C. overnight. Evaporation of the solvent gave a residue which was dissolved in CH2Cl2, washed with H2O and dried over Na2SO4. Evaporation and flash chromatography (Merck Kieselgel, 5% MeOH/CH2Cl2) gave 1-(3,7-dimethyl-2,6(E)-octadienyl)-6-methoxy-1H-1,3-benzimidazole (free base) (2.4 g, 77%) as a 1:1 mixture of 5- and 6-methoxy isomers. Conversion to the oxalate salt in diethyl ether filtration 10 minutes after addition of oxalic acid gave 500 mg of the title compound as a white solid (pure 6-methoxy by 400 MHz NMR with NOE). m.p. 90°-94° C. NMR (DMSO-d6)δ8.3(s,1H), 7.68(d,J=2 Hz,1H), 7.63(d,J=9 Hz,1H), 7.23(m,1H), 5.3 d,J=7 Hz, 1H), 5.0(m,1H), 4.90(d,J=8 Hz,2H), 2.0(m,4H), 1.70(s,3H), 1.58(s,3H), 1.55(s,3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:9]=[CH:10][C:3]=12.C([Li])(CC)C.[Br:26]C(Br)(Br)Br>C1COCC1>[Br:26][C:7]1[C:2]([F:1])=[C:3]2[CH:10]=[CH:9][N:8]([Si:11]([CH:15]([CH3:17])[CH3:16])([CH:18]([CH3:20])[CH3:19])[CH:12]([CH3:13])[CH3:14])[C:4]2=[N:5][CH:6]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(F)ccnc21
Reactant: BrC(Br)(Br)Br
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(F)c(Br)cnc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 84.4 %

Procedure:
4-Fluoro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (28.0 g, 95.7 mmol) in THF (600 mL) at −78° C. was treated dropwise with sec-butyllithium (150 mL, 211 mmol; 1.4M in cyclohexane). The reaction was stirred at −78° C. for 30 minutes. Perbromomethane (79.4 g, 239 mmol) in THF (100 mL) was then added dropwise. The reaction was stirred at −78° C. for 1 hour and then quenched with saturated aqueous NH4Cl. The aqueous phase was extracted with hexanes. The combined organic phases were dried (MgSO4) and concentrated in vacuo. The oil obtained was purified by flash chromatography on silica gel eluting with hexanes to provide 5-bromo-4-fluoro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (30 g, 84% yield) as an oil, which solidified upon standing. 1H NMR (400 MHz, CDCl3) δ 8.28 (d, 1H), 7.26 (s, 1H), 6.62 (d, 1H), 1.86-1.78 (m, 3H), 1.11 (d, 18H).
Reaction SMILES: I[C:2]1[C:10]2[C:9]([NH2:11])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH:12]([CH3:14])[CH3:13])[CH:3]=1.[CH3:15][NH:16][C:17]([NH:19][C:20]1[S:21][C:22]2[CH:28]=[C:27](B3OC(C)(C)C(C)(C)O3)[CH:26]=[CH:25][C:23]=2[N:24]=1)=[O:18].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:11][C:9]1[C:10]2[C:2]([C:27]3[CH:26]=[CH:25][C:23]4[N:24]=[C:20]([NH:19][C:17]([NH:16][CH3:15])=[O:18])[S:21][C:22]=4[CH:28]=3)=[CH:3][N:4]([CH:12]([CH3:14])[CH3:13])[C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: CC(C)n1cc(I)c2c(N)ncnc21
Reactant: CNC(=O)Nc1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CNC(=O)Nc1nc2ccc(-c3cn(C(C)C)c4ncnc(N)c34)cc2s1
Temperature: 25 °C
Yield: 58.4 %

Procedure:
A mixture of 5-iodo-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (302) (200 mg, 0.66 mmol), 1-methyl-3-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)urea (J-2) (333 mg, 1.5 eq, 1.0 mmol), Pd(PPh3)4 (76 mg, 0.1 eq, 0.066 mmol) and Na2CO3 (2 N, 2 mL) in DME (10 mL) was stirred at reflux for 30 min under Ar. The mixture was cooled to room temperature, and then concentrated in vacuo. Brine (10 mL) was added to the residue and then extracted with ethyl acetate (3×30 mL). The combined organic layer was washed with brine (10 mL), dried over MgSO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography eluting with MeOH/DCM (1/30) to afford the desired product, 1-(6-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzo[d]thiazol-2-yl)-3-methylurea (303) (147 mg 58% yield) as a white solid ESI-MS m/z: 382.00 [M+H]+.
Reaction SMILES: [CH:1]([NH:3][CH2:4][C:5]1[N:6]=[CH:7][N:8]2[CH:12]=[C:11]([C:13]3[C@H:14]([CH3:27])[C@@H:15]4[C@@H:22]([C@H:23]([OH:25])[CH3:24])[C:21](=[O:26])[N:16]4[C:17]=3[C:18]([O-:20])=[O:19])[S:10][C:9]=12)=[O:2].[Na+].[C:29]([O:35][CH2:36]I)(=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31]>CN(C=O)C.ClCCl>[CH:1]([NH:3][CH2:4][C:5]1[N:6]=[CH:7][N:8]2[CH:12]=[C:11]([C:13]3[C@H:14]([CH3:27])[C@@H:15]4[C@@H:22]([C@H:23]([OH:25])[CH3:24])[C:21](=[O:26])[N:16]4[C:17]=3[C:18]([O:20][CH2:36][O:35][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])=[O:19])[S:10][C:9]=12)=[O:2]
Reactant: CC(C)(C)C(=O)OCI
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(c3cn4cnc(CNC=O)c4s3)[C@H](C)[C@H]12
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=C(c3cn4cnc(CNC=O)c4s3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 33 mg of sodium (1S,5R,6S)-2-(7-formylaminomethyl imidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate in 0.8 ml of DMF was added 29 mg of pivaloyloxymethyl iodide at −30° C., and the mixture was stirred for 1 hour during which the temperature was raised up to room temperature. The reaction mixture was diluted with 30 ml of dichloromethane, washed with semi-saturated aqueous saline, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue thus obtained was purified by column chromatography on silica gel (ethyl acetate:methanol=4:1) to give the title compound in a yield of 29 mg.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([NH:5][C@H:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:16])[CH:14]=2)[CH2:9][CH2:8][CH2:7]1)=[O:4].O.O.O.O.O.O.O.S([O-])([O-])(=O)=[O:27].[Mg+2].O.[K]>CC(C)=O>[F:18][C:2]([F:1])([F:17])[C:3]([NH:5][C@H:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:16])[CH:14]=2)[C:9](=[O:27])[CH2:8][CH2:7]1)=[O:4]
Reactant: O=S(=O)([O-])[O-]
Reactant: O=C(N[C@@H]1CCCc2ccc(F)cc21)C(F)(F)F
Agent: [K]
Agent: [Mg+2]
Solvent: CC(C)=O
Solvent: O
Product: O=C1CC[C@@H](NC(=O)C(F)(F)F)c2cc(F)ccc21
Yield: 96 %

Procedure:
To a solution of (R)-2,2,2-trifluoro-N-(7-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)acetamide (3.51 g, 13.4 mmol, 1 equiv) in acetone (217 mL) was added magnesium sulfate heptahydrate (9.92 g, 40.3 mmol, 3 equiv) with water (167 mL). The mixture was stirred in ice bath. Potassium permangnate (6.37 g, 40.3 mmol, 3 equiv) was added in portions within 1 hour period. After addition, the reaction mixture was stirred at RT for 16 h. The resulting black solid was filtered off and washed with acetone. The combined filtrate and washings were diluted with CH2Cl2 (200 mL). The aqueous phase was separated and washed with CH2Cl2. The CH2Cl2 solution was washed with saturated Na2S2O7 solution (150 mL). The resulting black solid was filtered off The filtrate was evaporated to remove organic solvents. The concentrate was diluted with CH2Cl2 (400 mL). The aqueous phase was separated and washed with CH2Cl2. The combined CH2Cl2 phase was concentrated to give a white solid product (3.54 g, 96%). 1H NMR (400 MHz, DMSO-d6) δ 10.00 (s, 1H), 8.00 (q, 1H), 7.30-7.36 (m, 1H), 7.15 (dd, 1H), 5.32-5.38 (m, 1H), 2.60-2.85 (m, 2H), 2.16-2.30 (m, 2H).
Reaction SMILES: [CH3:1][C:2]([C:6]1[NH:7][C:8](=[O:12])[CH:9]=[CH:10][CH:11]=1)([CH3:5])[C:3]#[N:4].Cl[C:14]([F:20])([F:19])C(OC)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[F:19][CH:14]([F:20])[O:12][C:8]1[N:7]=[C:6]([C:2]([CH3:1])([CH3:5])[C:3]#[N:4])[CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C#N)c1cccc(=O)[nH]1
Reactant: COC(=O)C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C#N)c1cccc(OC(F)F)n1
Temperature: 95 °C
Reaction time: 3 h
Yield: 57.3 %

Procedure:
To a 100 mL round bottom flask was added 2-methyl-2-(6-oxo-1,6-dihydropyridin-2-yl)propanenitrile (8.2 g, 51 mmol, 1.0 equiv), methyl chlorodifluoroacetate (14.9 g, 103 mmol, 2.0 equiv), cesium carbonate (23.3 g, 71 mmol, 1.4 equiv), and DMF (100 mL). The reaction was heated to 95° C. and stirred for 3 hours. The reaction was then quenched with water (100 mL) and diluted with EtOAc (500 mL). The organic layer was separated from the aqueous layer. The aqueous layer was extracted with EtOAc (100 mL), and the combined organic phases were washed with saturated brine solution (3×200 mL), dried over Na2SO4, concentrated, and chromatographed with silica gel (2-5% EtOAc/hex) to give 2-(6-(difluoromethoxy)pyridin-2-yl)-2-methylpropanenitrile (6.2 g, 57%) as a clear oil.
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:14][C:13]=2[O:24][CH3:25])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:27])[N:6]2[CH3:26].[Cl:28][C:29]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:30]=1[S:36](Cl)(=[O:38])=[O:37]>N1C=CC=CC=1>[Cl:28][C:29]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:30]=1[S:36]([NH:1][C:2]1[C:10]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:14][C:13]=2[O:24][CH3:25])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:27])[N:6]2[CH3:26])(=[O:38])=[O:37]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Reactant: CCOC(=O)Cc1ccc(Oc2ccc3c(cc(C)n3C)c2N)c(OC)c1
Solvent: c1ccncc1
Product: CCOC(=O)Cc1ccc(Oc2ccc3c(cc(C)n3C)c2NS(=O)(=O)c2ccc(Cl)cc2Cl)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a room temperature solution of 3.3 (29 mg, 0.079 mmol) dissolved in pyridine (2 mL) was added 2,4-dichlorobenzenesulfonyl chloride (21 mg, 0.087 mmol). The resulting red solution was stirred at room temperature for 2 h, after which time HPLC indicated no 3.3 remained. The reaction solution was concentrated in vacuo on a rotary evaporator and the concentrate partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic separation was washed with water then brine. The organic extract was stirred over magnesium sulfate, filtered and the filtrate concentrated in vacuo on a rotary evaporator to afford an orange oil. The product was isolated by chromatography on silica gel, eluting with an ethyl acetate/hexane gradient, to afford a faint yellow oil. 1H NMR (500 MHz) (CDCl3) δ 7.71 (d, J=8.4 Hz, 1H); 7.48 (s, 1H); 7.04 (d, J=8.8 Hz, 1H); 6.88 (d, J=1.8 Hz, 1H); 6.70 (s, 1H); 6.59 (d, J=8.7 Hz, 1H); 6.53 (d, J=6.4 Hz, 1H); 6.52 (d, J=1.8 Hz, 1H); 6.16 (d, J=8.2 Hz, 1H); 4.19 (q, J=7.1 Hz, 2H); 3.86 (s, 3H); 3.64 (s, 3H); 3.59 (s, 2H); 2.48 (s, 3H) ppm.
Reaction SMILES: [NH:1]([C:3]1[N:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]3([NH:23]C(=O)OC(C)(C)C)[CH2:22][CH2:21][CH2:20]3)=[CH:15][CH:14]=1)[C:9]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[CH:8]2)[NH2:2].[N:37]#[C:38]Br>C(O)C.CCOC(C)=O>[NH2:23][C:19]1([C:16]2[CH:15]=[CH:14][C:13]([C:10]3[C:9]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:8][C:7]4[CH:6]=[CH:5][N:4]5[C:38]([NH2:37])=[N:2][N:1]=[C:3]5[C:12]=4[N:11]=3)=[CH:18][CH:17]=2)[CH2:22][CH2:21][CH2:20]1
Reactant: N#CBr
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(NN)nccc4cc3-c3ccccc3)cc2)CCC1
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1nnc2c3nc(-c4ccc(C5(N)CCC5)cc4)c(-c4ccccc4)cc3ccn12
Temperature: 60 °C
Reaction time: 72 h

Procedure:
A mixture of tert-butyl {1-[4-(8-hydrazino-3-phenyl-1,7-naphthyridin-2-yl)phenyl]cyclobutyl}carbamate (7-5) (30 mg, 0.0620 mmol), cyanogen bromide (19.8 mg, 0187 mmol) in ethanol (2 mL) was stirred at 60° C. for 72 hours. The mixture was diluted with AcOEt, washed with water, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel. The residue was treated with HCl in MeOH and the mixture was heated in a microwave reactor at 80° C. for 5 min. The solvent was evaporated and the residue was purified by reverse phase HPLC (H2O/0.1% TFA aq.-MeCN/0.1% TFA aq.) to give 9-[4-(1-aminocyclobutyl)phenyl]-8-phenyl[1,2,4]triazolo[4,3-h]-1,7-naphthyridin-3-amine (8-1) as a pale yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:14][C:15]1[N:16]=[C:17]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[S:18][C:19]=1[C:20](O)=[O:21].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:20]([C:19]2[S:18][C:17]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)=[N:16][C:15]=2[CH3:14])=[O:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1nc(-c2ccncc2)sc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccncc2)sc1C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.6 %

Procedure:
To a mixture of 1-(tert-butoxycarbonyl)piperazine (3.72 g), 4-methyl-2-(4-pyridyl) -5-thiazolecarboxylic acid (4.4 g), triethylamine (2.5 g) and HOBt (2.7 g) in DMF (60 ml), was added WSC hydrochloride (4.217 g) under ice-cooling and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated, and to the residue were added dichloromethane and sodium bicarbonate aqueous solution. The organic layer was separated, washed with water and brine, dried and concentrated. The residue was purified with silica gel chromatography (dichloromethane:methanol=50:1) to give colorless crystals of the title compound (6.49 g).
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH3:4][N:5]1[C:12](=[O:13])[CH:11]([C:14](=[O:30])[NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[N:24]=[N:25][C:26](Cl)=[CH:27][CH:28]=3)=[CH:18][CH:17]=2)[C:9](=[O:10])[N:8]([CH3:31])[C:6]1=[O:7]>CO.O>[CH3:4][N:5]1[C:12](=[O:13])[CH:11]([C:14](=[O:30])[NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[N:24]=[N:25][C:26]([O:2][CH3:1])=[CH:27][CH:28]=3)=[CH:18][CH:17]=2)[C:9](=[O:10])[N:8]([CH3:31])[C:6]1=[O:7]
Reactant: C[O-]
Reactant: CN1C(=O)C(C(=O)Nc2ccc(Oc3ccc(Cl)nn3)cc2)C(=O)N(C)C1=O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc(Oc2ccc(NC(=O)C3C(=O)N(C)C(=O)N(C)C3=O)cc2)nn1

Procedure:
The equimolar amount of sodium methylate is added at room temperature to 1.0 g (0.0025 mole) of 1,3-dimethyl-5-[4-(6-chloropyridazin-3-yloxy)phenylcarbamoyl]barbituric acid in 20 ml of methanol. The mixture is heated under reflux for 5 hours, then cooled, diluted with water and filtered. The filtrate is washed with water and dried.
Reaction SMILES: [Br:1]Br.C([O-])(=O)C.[Na+].[F:8][C:9]1[CH:18]=[C:17]([C:19]2[CH:20]=[N:21][C:22]3[N:23]([CH:25]=[CH:26][N:27]=3)[CH:24]=2)[CH:16]=[CH:15][C:10]=1[C:11]([NH:13][CH3:14])=[O:12]>C(O)(=O)C>[Br:1][C:25]1[N:23]2[CH:24]=[C:19]([C:17]3[CH:16]=[CH:15][C:10]([C:11]([NH:13][CH3:14])=[O:12])=[C:9]([F:8])[CH:18]=3)[CH:20]=[N:21][C:22]2=[N:27][CH:26]=1
Reactant: BrBr
Reactant: CNC(=O)c1ccc(-c2cnc3nccn3c2)cc1F
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CNC(=O)c1ccc(-c2cnc3ncc(Br)n3c2)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.6 %

Procedure:
Bromine (17.4 μL, 0.338 mmol) was added to a mixture of sodium acetate (40.3 mg, 0.491 mmol) and 2-fluoro-4-imidazo[1,2-a]pyrimidin-6-yl-N-methylbenzamide (83.0 mg, 0.307 mmol) in acetic acid (2.6 mL) and the reaction mixture was stirred at ambient temperature for 30 min. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate and brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel with ethyl acetate in dichloromethane (0-50%) to afford the desired product (95 mg, 88.6%). LCMS: (M+H)=348.8/350.9.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[Cl:11])[N:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:3]=1[C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.N1C=CC=CC=1.Cl[C:32]([O:34][CH3:35])=[O:33].Cl>ClCCl>[C:17]([C:3]1[N:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:5]2[C:6]([C:2]=1[NH:1][C:32]([O:34][CH3:35])=[O:33])=[CH:7][CH:8]=[C:9]([Cl:11])[CH:10]=2)(=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)n1c(C(=O)c2ccccc2)c(N)c2c(Cl)cccc21
Reactant: COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)n1c(C(=O)c2ccccc2)c(NC(=O)OC)c2ccc(Cl)cc21
Reaction time: 3 h

Procedure:
To a solution of ethyl 3-amino-2-benzoyl-6-chloro-1H-indole-1-caboxylate (step 2, 1.5 g, 4.4 mmol) and pyridine (0.50 ml, 6.6 mmol) in dichloromethane (20 ml) was added methyl chloroformate (0.40 ml, 5.3 mmol) at room temperature. After stirring for 3 h, the mixture was poured into 2N aqueous HCl (20 ml) and extracted with dichloromethane (30 ml×2). The combined organic layers were dried (MgSO4) and concentrated to give 1.7 g (quant.) of the title compound as yellow amorphous solids.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:18])=[C:4]([NH2:17])[CH:5]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:7]=1.C(OC(=O)C)(=O)C.C([O-])(=O)C.[K+].[N+:31]([O-])(OCCC(C)C)=O>C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[C:4]2[C:3]=1[CH:18]=[N:31][NH:17]2
Reactant: CC(C)CCO[N+](=O)[O-]
Reactant: Cc1c(N)cc(Oc2ccc(F)cc2F)cc1Br
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: c1ccccc1
Product: Fc1ccc(Oc2cc(Br)c3cn[nH]c3c2)c(F)c1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 57.9 %

Procedure:
3-Bromo-5-(2,4-difluoro-phenoxy)-2-methyl-phenylamine (5.31 g, 16.9 mmol) was dissolved in 50 mL dry benzene, and acetic anhydride (5.17 g, 50.7 mmol) and potassium acetate (1.69 g, 17.2 mmol) were added. The reaction mixture was placed under nitrogen atmosphere and heated to 80° C. with stirring for 10 minutes. Isoamyl nitrate (3.39 mL, 25.4 mmol) was added dropwise over 30 minutes, after which the reaction mixture was stirred at 80° C. under nitrogen for 17 hours. The reaction mixture was cooled and filtered, and the filtrate was concentrated under reduced pressure. Water (8 mL) and concentrated HCl (16 mL of 6N aqueous solution) were added, and the mixture was heated to 55° C. Methanol (100 mL) was added, and the mixture was heated to 80° C. The mixture was cooled and concentrated under reduced pressure, and the residue was partitioned between water and ethyl acetate. The organic layer was separated and concentrated under reduced pressure. The residue was partitioned betwee methylene chloride and saturated sodium bicarbonate. The organic layer was separated, washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was chromatographed through silica (0%-25% EtOAc in hexanes) to give 3.18 g of 4-bromo-6-(2,4-difluoro-phenoxy)-1H-indazole.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][C:12](=[O:47])[O:13][CH2:14][C@@H:15]([N:33]([CH3:46])[C:34]([NH:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[C:39]=2F)=[O:35])[CH2:16][C@@H:17]([OH:32])[CH2:18][O:19][P:20]([O:27]C(C)(C)C)([O:22]C(C)(C)C)=[O:21])[N:2]=1.[ClH:48]>CO>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][C:12](=[O:47])[O:13][CH2:14][C@@H:15]([N:33]([CH3:46])[C:34]([NH:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[C:39]=2[Cl:48])=[O:35])[CH2:16][C@@H:17]([OH:32])[CH2:18][O:19][P:20]([OH:27])([OH:22])=[O:21])[N:2]=1
Reactant: Cl
Reactant: CN(C(=O)NCc1cccc(F)c1F)[C@H](COC(=O)Nc1cc2ccccc2cn1)C[C@@H](O)COP(=O)(OC(C)(C)C)OC(C)(C)C
Solvent: CO
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@H](COC(=O)Nc1cc2ccccc2cn1)C[C@@H](O)COP(=O)(O)O
Reaction time: 0.5 h

Procedure:
To a solution of the crude (2S,4R)-5-(di-tert-butoxyphosphoryloxy)-2-(3-(2,3-difluorobenzyl)-1-methylureido)-4-hydroxypentyl isoquinolin-3-ylcarbamate in MeOH (15 mL) at 0° C. was added conc. HCl (12 N, 16 mL, 192.4 mmol) dropwise. The mixture was stirred for 30 min and concentrated. The residue was dissolved in 50 mL H2O. Aqueous NaOH solution (1 N) was added to adjusted the PH to 3˜4. EtOAc (50 mL) was then added. The mixture was stirred at RT for 1 h. The white solid was then filtered and washed with H2O and EtOAc and dried under high vacuum to give (2S,4R)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-4-hydroxy-5-(phosphonooxy)pentyl isoquinolin-3-ylcarbamate (2.85 g) as a white powder (4.95 g, 89% for 2 steps). LRMS (M−H+) m/z 567.5
Reaction SMILES: [CH2:1]([C:6]12[CH2:17][CH2:16][CH2:15][C:13]3[C:14]1=[C:9]([CH:10]=[CH:11][CH:12]=3)[NH:8][C:7]2=[O:18])[CH2:2][CH2:3][CH:4]=C.C[N+]1([O-])CC[O:23]CC1.O1CCOCC1.I([O-])(=O)(=O)=O.[Na+]>[Os](=O)(=O)(=O)=O.O>[CH:4]([CH2:3][CH2:2][CH2:1][C:6]12[CH2:17][CH2:16][CH2:15][C:13]3[C:14]1=[C:9]([CH:10]=[CH:11][CH:12]=3)[NH:8][C:7]2=[O:18])=[O:23]
Reactant: C=CCCCC12CCCc3cccc(c31)NC2=O
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: O=CCCCC12CCCc3cccc(c31)NC2=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a shaded container, 2a-(4-pentenyl)-2a,3,4,5-tetrahydro-1H-benz[cd]indol-2-one (1.3 g, 5.3 mmol) and N-methylmorpholine oxide (1.9 g, 16 mmol) were dissolved in a mixed solvent of 1,4-dioxane (20 ml) with water (10 ml), and the solution was mixed with osmium tetroxide (4% aqueous solution 3.4 ml, 0.53 mmol) and stirred at room temperature for 2 hours. The reaction solution was mixed with rater (80 ml), the reaction product was extracted with ethyl acetate, washed with saturated brine and dried with anhydrous sodium sulfate, and then the solvent was removed by evaporation under a reduced pressure. The residue was dissolved in a mixed solvent of 1,4-dioxane (20 ml) with water (10 ml), and the solution was mixed with sodium periodate (2.6 g, 12 mmol) and stirred as such for 2.5 hours. The reaction solution was mixed with water (100 ml), and the reaction product was extracted with ethyl acetate, washed with saturated brine and dried with anhydrous sodium sulfate. By evaporating the solvent from the extract under a reduced pressure, 1.3 g (5.3 mmol 100% in yield) of the title compound was obtained.
Reaction SMILES: [C:1]([C:4]([CH3:26])=[CH:5][CH2:6][CH2:7][C:8]([CH3:25])=[CH:9][CH2:10][C:11]1[C:16]([OH:17])=[C:15]([O:18][CH3:19])[C:14]([O:20][CH3:21])=[C:13]([O:22]C)[C:12]=1[CH3:24])([OH:3])=[O:2].CCOCC>C(OCC)(=O)C>[C:1]([C:4]([CH3:26])=[CH:5][CH2:6][CH2:7][C:8]([CH3:25])=[CH:9][CH2:10][C:11]1[C:16](=[O:17])[C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[C:13](=[O:22])[C:12]=1[CH3:24])([OH:3])=[O:2]
Reactant: COc1c(C)c(CC=C(C)CCC=C(C)C(=O)O)c(O)c(OC)c1OC
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COC1=C(OC)C(=O)C(CC=C(C)CCC=C(C)C(=O)O)=C(C)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.1 %

Procedure:
2 g of 6-(7-carboxy-3-methyl-2,6-octadienyl)-2,3,4-trimethoxy-5-methylphenol as prepared in Example 1 was dissolved in 20 ml of ethyl acetate and 5 g of ferric chloride hexahydrate was added thereto. The reaction mixture was stirred at room temperature for 30 min. After adding 100 ml of ether, it was washed with water, dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by means of silica gel chromatography with the use of ethyl acetate/benzene as the eluent to give 1.8 g of the title compound as an orange oil.