Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([CH2:9][C@H:10]1[C@@H:15]([CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])[CH2:14][O:13][C@@H:12]([CH3:25])[O:11]1)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[C:26](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[O:1]([CH2:9][C@H:10]1[C@@H:15]([CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:26])=[O:23])[CH2:14][O:13][C@@H:12]([CH3:25])[O:11]1)[Si:2]([C:5]([CH3:8])([CH3:6])[CH3:7])([CH3:4])[CH3:3]
Reactant: C[C@@H]1OC[C@H](C/C=C\CCCC(=O)O)[C@H](CO[Si](C)(C)C(C)(C)C)O1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCC/C=C\C[C@H]1CO[C@@H](C)O[C@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 84.7 %

Procedure:
A solution of (2R,4R,5S)-4-t-butyldimethylsiloxymethyl-5-[(Z)-6-carboxy-2-hexenyl]-2-methyl-1,3-dioxane (4.75 g) in N,N-dimethylformamide (50 ml) were added potassium carbonate (1.76 g) and methyl iodide (1.62 ml) and the mixture was stirred at room temperature for 5 hours. The solution was poured into water and the resulting aqueous solution was extracted with ether. The organic layer was washed successively with water and brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was chromatographed on a silica gel column (75 g) with a mixture of n-hexane and ethyl acetate (20:1) as an eluent to give (2R,4R,5S) -4-t-butyldimethylsiloxymethyl-5-[(Z)-6-methoxycarbonyl-2-hexenyl]-2-methyl-1,3-dioxane (4.17 g) as an oil.
Reaction SMILES: [Br:1]Cl.[C:3]([Cl:11])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.BrBr.ClCl>[Fe]>[Br:1][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([Cl:11])=[O:10]
Reactant: O=C(Cl)c1ccccc1
Reactant: ClBr
Agent: [Fe]
Agent: BrBr
Agent: ClCl
Product: O=C(Cl)c1cccc(Br)c1

Procedure:
When using bromine chloride as the brominating agent, the bromine chloride can be preformed or formed in situ, and the latter is preferred. In accordance with this preferred procedure, benzoyl chloride, bromine and iron powder are charged to a reactor and the reactor contents are cooled to a temperature in the range of about 0 to about 60° C., preferably about 10° C., and chlorine is slowly fed into the reactor whereby bromine chloride is formed in situ. The bromine chloride reacts with the benzoyl chloride to form m-bromobenzoyl chloride (MBBC). Usually the reaction is performed at a temperature the range of about -10 to about 60° C., preferably at about 10° C. for a period in the range of about 1 to about 24 hours, and typically for about one hour after completion of the chlorine feed. The reaction mixture is then stripped with an inert gas, preferably nitrogen, for 1 to 24 hours at a temperature in the range of about 25 to about 120° C., preferably for two to three hours at about 60 to 90° C., followed by further stripping while cooling to ambient room temperature (ca. 25° C.). During the reaction and subsequent stripping operations, the exit gases are passed through suitable scrubbers to remove purged HCl, and unreacted bromine. The major residual byproducts of the bromination are m-chlorobenzoyl chloride, chlorobromobenzoyl chlorides, and dibromobenzoyl chlorides. The crude MBBC can be purified by distillation at reduced pressure, for example at 160° C. and 60 mm Hg pressure.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][C:9]([OH:11])=[O:10])[CH2:4][CH2:3]1.S(Cl)([Cl:14])=O.[CH3:16]O>>[ClH:14].[CH3:16][O:10][C:9](=[O:11])[CH2:8][CH:5]1[CH2:6][CH2:7][NH:2][CH2:3][CH2:4]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CC1CCNCC1
Reactant: CO
Agent: Cl
Product: COC(=O)CC1CCNCC1
Temperature: 40 °C

Procedure:
To a stirring suspension of piperidin-4-yl-acetic acid hydrochloride in MeOH (15 mL) at −5° C. was added thionyl chloride (1.12 mL, 15.3 mmol) dropwise. The reaction mixture was allowed to reach to RT then heated to 40° C. for 4 h. The reaction mixture was concentrated in vacuo and the resulting white solid was azeotroped with toluene twice. Washed with ether and filtered to give 2.7 g (quantitative yield). MS(ESI) 158.2 (M+H+).
Reaction SMILES: C([O:3][C:4](=[O:17])[CH2:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][C:7]=1[CH3:16])C.O.[Li+].[OH-].Cl>CO>[CH3:13][O:12][C:10]([C:9]1[CH:14]=[CH:15][C:6]([CH2:5][C:4]([OH:17])=[O:3])=[C:7]([CH3:16])[CH:8]=1)=[O:11]
Reactant: CCOC(=O)Cc1ccc(C(=O)OC)cc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(CC(=O)O)c(C)c1
Yield: 91.5 %

Procedure:
Methyl 4-(2-ethoxy-2-oxoethyl)-3-methylbenzoate (366 mg) was suspended in MeOH(10 ml) and H2O (2 ml) and treated with LiOH (48 mg) over 3 days. After the reaction mixture was acidified with 1N HCl, the product was extracted with EtOAc. Evaporation and drying in vacuum afforded the desired product (295 mg).
Reaction SMILES: C(OC([N:8]([C@@H:10]1[CH2:14][CH2:13][N:12]([S:15]([C:18]2[C:19]3[C:20]([Br:29])=[CH:21][N:22]=[C:23]([Cl:28])[C:24]=3[CH:25]=[CH:26][CH:27]=2)(=[O:17])=[O:16])[CH2:11]1)[CH3:9])=O)(C)(C)C.C([O:34]C(N([C@@H]1CCNC1)C)=O)(C)(C)C.C(OC(N([C@H]1CCNC1)C)=O)(C)(C)C>>[OH:34][C:23]1[C:24]2[CH:25]=[CH:26][CH:27]=[C:18]([S:15]([N:12]3[CH2:13][CH2:14][C@@H:10]([NH:8][CH3:9])[CH2:11]3)(=[O:17])=[O:16])[C:19]=2[C:20]([Br:29])=[CH:21][N:22]=1.[ClH:28]
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CCNC1
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CCN(S(=O)(=O)c2cccc3c(Cl)ncc(Br)c23)C1
Agent: CN(C(=O)OC(C)(C)C)[C@H]1CCNC1
Product: CN[C@@H]1CCN(S(=O)(=O)c2cccc3c(O)ncc(Br)c23)C1
Product: Cl

Procedure:
(R)-3-[N-(tert-Butoxycarbonyl)-N-methylamino]-1-(1-chloro-4-bromo-5-isoquinolinesulfonyl)pyrrolidine (Intermediate 24b) can be prepared by using (R)-3-[N-(tert-butoxycarbonyl)-N-methylamino]pyrrolidine in the method of Example 35-1, Step A mentioned above instead of (S)-3-[N-(tert-butoxycarbonyl)-N-methyl-amino]pyrrolidine, and then used in the method of Example 35-1, Step B in a similar manner to obtain the title compound as hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([OH:15])=O)[S:10][C:11]=1[CH3:12].[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=1)[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].CC(OC(N[C@H](C(O)=O)CC1C=CC=CC=1C(F)(F)F)=O)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([NH:17][C@@H:18]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:39])[F:40])[CH:33]=2)[CH2:19][N:20]2[C:21](=[O:30])[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:28]2=[O:29])=[O:15])[S:10][C:11]=1[CH3:12]
Reactant: Cc1sc(C(=O)O)cc1-c1c(Cl)cnn1C
Reactant: N[C@@H](Cc1cccc(C(F)(F)F)c1)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Cc1sc(C(=O)N[C@@H](Cc2cccc(C(F)(F)F)c2)CN2C(=O)c3ccccc3C2=O)cc1-c1c(Cl)cnn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.9 %

Procedure:
To a 50 mL round-bottomed flask was added 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylic acid (181 mg, 0.70 mmol), 2-{(2S)-2-amino-3-[3-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (250 mg, 0.65 mmol) [Prepared according to the procedure of Preparation 6 except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-3-(trifluoromethyl)-L-phenylalanine (4.98 g, 15.0 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (399 mg, 0.85 mmol) in chloroform (8 mL). DIEA (620 μL, 3.55 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (319 mg, 0.50 mmol, 71%): LC-MS (ES) m/z=587 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[C:7]([C:9]([C:11]([F:14])([F:13])[F:12])=[CH2:10])[CH:6]=[C:5]([C:15]([F:18])([F:17])[F:16])[N:4]=1.[CH2:21]([N:28]([CH2:32][Si](C)(C)C)[CH2:29]OC)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>ClCCl.FC(F)(F)C(O)=O>[CH2:21]([N:28]1[CH2:32][CH2:10][C:9]([C:7]2[CH:8]=[C:3]([C:2]([F:1])([F:19])[F:20])[N:4]=[C:5]([C:15]([F:18])([F:16])[F:17])[CH:6]=2)([C:11]([F:14])([F:13])[F:12])[CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: C=C(c1cc(C(F)(F)F)nc(C(F)(F)F)c1)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)c1cc(C2(C(F)(F)F)CCN(Cc3ccccc3)C2)cc(C(F)(F)F)n1
Temperature: 25 °C
Yield: 85 %

Procedure:
To the solution of 2,6-bis(trifluoromethyl)-4-(3,3,3-trifluoroprop-1-en-2-yl)pyridine (1.25 g) and N-benzyl-1-methoxy-N-[(trimethylsilyl)methyl]methanamine (5.0 g) in dichloromethane was added dropwise the solution of trifluoroacetic acid (0.038 g) in dichloromethane while cooling with ice. On completion of the dropwise addition, the mixture was warmed to room temperature and stirred over night. The mixture was washed with saturated sodium bicarbonate water and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the solvent was removed under reduced pressure, and the residue was then purified by silica gel chromatography to yield 4-[1-benzyl-3-(trifluoromethyl)pyrrolidin-3-yl]-2,6-bis(trifluoromethyl)pyridine (1.52 g).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([C:13]3([CH3:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:20][NH:21][C:22]1[CH:27]=[CH:26][C:25](B2OC(C)(C)C(C)(C)O2)=[CH:24][CH:23]=1>>[CH3:20][NH:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]2[N:3]=[C:4]3[C:10]([C:11]([C:13]4([CH3:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]4)=[O:12])=[CH:9][NH:8][C:5]3=[N:6][CH:7]=2)=[CH:24][CH:23]=1
Reactant: CC1(C(=O)c2c[nH]c3ncc(Br)nc23)CCCCC1
Reactant: CNc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CNc1ccc(-c2cnc3[nH]cc(C(=O)C4(C)CCCCC4)c3n2)cc1

Procedure:
[2-(4-Methylamino-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-(1-methyl-cyclohexyl)-methanone was prepared starting from (2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-(1-methyl-cyclohexyl)-methanone and methyl-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-amine following general procedures as described in these Examples. MP 273-275° C., M+H=349.
Reaction SMILES: Br[C:2]1[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][C:9](Br)=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:34]1(C)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>O>[C:19]1([C:2]2[C:15]3[C:16]4=[C:17]5[C:12](=[CH:13][CH:14]=3)[CH:11]=[CH:10][C:9]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[C:8]5[CH:7]=[CH:6][C:5]4=[CH:4][CH:3]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1ccccc1
Reactant: Brc1ccc2ccc3c(Br)ccc4ccc1c2c43
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: c1ccc(-c2ccc3ccc4c(-c5ccccc5)ccc5ccc2c3c54)cc1
Temperature: 100 °C
Yield: 99 %

Procedure:
In a stream of argon, 20 g (55.6 mmol) of 1,6-dibromopyrene, 16.3 g (133 mmol) of phenyl boronic acid, 2.5 g (4 mol %) of tetrakistriphenylphosphine palladium, an aqueous solution containing 26.5 g (65 mmol) of sodium carbonate in 125 mL of water, and 250 mL of toluene were added to a 1-L three-necked flask equipped with a cooling pipe, and the whole was refluxed under heat at 100° C. for 8 hours. After the completion of the reaction, 50 mL of water was added and then a crystal was filtered out, washed with 50 mL of water, 100 mL of ethanol, and 100 mL of toluene. As a result, 15.3 g of 1,6-diphenylpyrene (a white powder) was obtained (99% yield).
Reaction SMILES: [N:1]1[NH:2][C:3]2[CH:17]=[CH:16][CH:15]=[C:5]3[C:6](=[O:14])[C:7]4[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=4[C:9]=1[C:4]=23.[N-:18]=[N+]=[N-].[Na+].C(OCC)(=O)C.O1CCCC1>S(=O)(=O)(O)O>[N:1]1[NH:2][C:3]2[CH:17]=[CH:16][CH:15]=[C:5]3[C:6](=[O:14])[NH:18][C:7]4[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=4[C:9]=1[C:4]=23
Reactant: O=C1c2ccccc2-c2n[nH]c3cccc1c23
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1Nc2ccccc2-c2n[nH]c3cccc1c23
Temperature: 25 °C
Reaction time: 72 h
Yield: 25.3 %

Procedure:
To a solution of 100 mg of 2,6-dihydrodibenzo[cd,g]indazol-6-one [CAS No. 129-56-6] in 0.6 ml concentrated sulfuric acid was added 78 mg of sodium azide [CAS No. 26628-22-8], followed by stirring at room temperature for 3 days. After adding ice, the reaction mixture was poured into a mixture solution of 100 ml of ethyl acetate and 10 ml of tetrahydrofuran and washed with saturated sodium hydrogen carbonate solution. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran, adsorbed by 3.5 g of silica gel and subjected to silica gel chromatography [Wako Gel C-200, 2 g]. The fractions of tetrahydrofuran-toluene [19:1 to 9:1] were concentrated, and the resulting powder was suspended in tetrahydrofuran-toluene. A powder was collected by filtration, and recrystallized from dimethylformamide-water, to give 27 mg of 6,7-dihydro-2H-benzo[6,7]azepino[5,4,3-cd]indazol-6-one as green needles.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([NH:18][C:19](=[O:25])[C:20]([O:23][CH3:24])([CH3:22])[CH3:21])=[O:17])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH2:26]([N:28]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[N:29]1)[CH3:27].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[CH2:26]([N:28]1[CH:32]=[C:31]([C:2]2[CH:7]=[C:6]([O:8][C:9]3[CH:10]=[CH:11][C:12]([NH:15][C:16]([NH:18][C:19](=[O:25])[C:20]([O:23][CH3:24])([CH3:22])[CH3:21])=[O:17])=[N:13][CH:14]=3)[CH:5]=[CH:4][N:3]=2)[CH:30]=[N:29]1)[CH3:27]
Reactant: COC(C)(C)C(=O)NC(=O)Nc1ccc(Oc2ccnc(Cl)c2)cn1
Reactant: CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCn1cc(-c2cc(Oc3ccc(NC(=O)NC(=O)C(C)(C)OC)nc3)ccn2)cn1
Temperature: 90 °C
Yield: 28.6 %

Procedure:
A mixture of Example C5 (0.12 g, 0.33 mmol), 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (80 mg, 0.36 mmol) and K2CO3 (0.14 g, 0.99 mmol) in dioxane (4 mL) and H2O (1 mL) was sparged with Ar, treated with Pd(PPh3)4 (0.040 g, 0.034 mmol), sparged again with Ar and heated at 90° C. overnight. The mixture was cooled to RT, treated with satd. NaHCO3, extracted with EtOAc (3×) and the combined organics were dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to obtain N-((5-((2-(1-ethyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)-2-methoxy-2-methylpropanamide (40 mg, 28%). 1H NMR (400 MHz, DMSO-d6): δ 10.82 (s, 1H), 10.20 (br s, 1H), 8.38 (d, J=5.7 Hz, 1H), 8.31 (s, 1H), 8.27 (d, J=2.9 Hz, 1H), 8.02 (br s, 1H), 7.98 (s, 1H), 7.75 (dd, J=9.0, 2.9 Hz, 1H), 7.24 (d, J=2.4 Hz, 1H), 6.71 (dd, J=5.7, 2.4 Hz, 1H), 4.14 (q, J=7.3 Hz, 2H), 3.21 (s, 3H), 1.37 (t, J=7.3 Hz, 3H), 1.36 (s, 6H); MS (ESI) m/z: 425.2 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]2[C:17](Br)=[CH:16][C:15]([F:19])=[CH:14][N:13]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:20]1[CH2:25][CH2:24][CH:23]([CH2:26][OH:27])[CH2:22][CH2:21]1.CCN(CC)CC>CS(C)=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]2[C:17]([N:20]3[CH2:25][CH2:24][CH:23]([CH2:26][OH:27])[CH2:22][CH2:21]3)=[CH:16][C:15]([F:19])=[CH:14][N:13]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OCC1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CC(c2ncc(F)cc2Br)C1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(c2ncc(F)cc2N2CCC(CO)CC2)C1
Temperature: 100 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
To a solution of 3-(3-bromo-5-fluoro-pyridin-2-yl)-azetidine-1-carboxylic acid tert-butyl ester (58) (660 mg, 2 mmol, Preparation 17) and piperidin-4-yl-methanol (35) (230 mg, 2 mmol) in DMSO (20 mL) was added Et3N (404 mg, 4 mmol). The reaction mixture was stirred at 100° C. overnight. The reaction mixture was diluted with water, extracted with EtOAc (50 mL×3). The combined organic extracts were washed with water (30 mL) and brine (30 mL), dried over Na2SO4 and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography (EtOAc:PE=3:1) on silica gel to give (76) (490 mg, 1.34 mmol, yield 67%). ESI-MS (M+1): 366 calc. for C19H28FN3O3 365.
Reaction SMILES: [NH2:1][C:2]([C:9]1[CH:14]=[C:13]([Br:15])[CH:12]=[CH:11][C:10]=1[F:16])([CH3:8])[C:3]([F:7])([F:6])[CH2:4][OH:5].C([O-])([O-])=O.[Na+].[Na+].[Cl:23][CH2:24][C:25](Cl)=[O:26].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.CO>[Br:15][C:13]1[CH:12]=[CH:11][C:10]([F:16])=[C:9]([C:2]([NH:1][C:25](=[O:26])[CH2:24][Cl:23])([C:3]([F:6])([F:7])[CH2:4][OH:5])[CH3:8])[CH:14]=1
Reactant: O=C(Cl)CCl
Reactant: CC(N)(c1cc(Br)ccc1F)C(F)(F)CO
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(NC(=O)CCl)(c1cc(Br)ccc1F)C(F)(F)CO
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To an ice cooled solution of 3-amino-3-(5-bromo-2-fluorophenyl)-2,2-difluorobutan-1-ol (3.1 g, 10.4 mmol), in DCM (60 ml) was added aqueous Na2CO3 (2.74 g, 25.8 mmol in 7.0 mL H2O) and stirred for 10 min. Chloroacetyl chloride (0.986 ml, 11.4 mmol) was then added to the resultant reaction mixture and stirring continued for 30 min at 0° C. Upon formation of the new product by TLC analysis, K2CO3 (1.5 g, 10.4 mmol) in MeOH (17 mL) was added to the reaction mixture and stirred at rt for 30 min. The reaction mixture was diluted with DCM, separated the organic layer and washed successively with water and brine solution, dried over anhydrous Na2SO4 and concentrated under reduced pressure to furnish title compound as a colorless gum. Yield=3.3 g (78.5%).
Reaction SMILES: [CH:1]1([C:4]#[CH:5])[CH2:3][CH2:2]1.[NH2:6][C:7]1[C:17](Br)=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][N:8]=1>CCOC(C)=O>[NH2:6][C:7]1[C:17]([C:5]#[C:4][CH:1]2[CH2:3][CH2:2]2)=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][N:8]=1
Reactant: CCOC(=O)c1cnc(N)c(Br)c1
Reactant: C#CC1CC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc(N)c(C#CC2CC2)c1
Yield: 78.2 %

Procedure:
Cyclopropyl acetylene (3 mmol) was reacted with ethyl 6-amino-5-bromonicotinate (245 mg, 1 mmol) as described in procedure A of Example 1. Ethyl 6-amino-5-(2-cyclopropylethynyl)nicotinate (180 mg) was obtained as a solid after silica gel column chromatography (EtOAc:hexanes, 1:1). LC/MS; (M+H)+=231.
Reaction SMILES: C(O[CH:5]1[O:18][C@H:17]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[C@H:12]([O:13][C:14](=[O:16])[CH3:15])[C@H:11]([NH:24][C:25](=[O:36])[C:26]2[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([O:34][CH3:35])[CH:27]=2)[C@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=O)C.C(OC(=O)C)(=O)C.[BrH:44]>ClCCl>[C:8]([O:7][C@@H:6]1[C@@H:11]([NH:24][C:25](=[O:36])[C:26]2[CH:27]=[C:28]([O:34][CH3:35])[CH:29]=[C:30]([O:32][CH3:33])[CH:31]=2)[C@@H:12]([O:13][C:14](=[O:16])[CH3:15])[C@@H:17]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:18][C@@H:5]1[Br:44])(=[O:10])[CH3:9]
Reactant: COc1cc(OC)cc(C(=O)N[C@H]2[C@@H](OC(C)=O)[C@@H](COC(C)=O)OC(OC(C)=O)[C@@H]2OC(C)=O)c1
Reactant: Br
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: COc1cc(OC)cc(C(=O)N[C@@H]2[C@@H](OC(C)=O)[C@@H](Br)O[C@H](COC(C)=O)[C@@H]2OC(C)=O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1,2,4,6-Tetra-O-acetyl-3-deoxy-3-(3,5-dimethoxybenzamido)-D-galactopyranose 4 (50 mg, 0.098 mmol) was dissolved in dichloromethane (1 ml) which had been dried over 4 Å molecular sieves. Acetic anhydride (18 μl, 0.20 mmol) and HBr (0.2 ml, 33% in AcOH) were added, and the mixture was stirred under N2 at room temperature. After 2 h 30 min, the reaction mixture was diluted with dichloromethane (30 ml) and poured into ice-water (30 ml). The organic phase was washed with NaHCO3 (30 ml of a saturated aqueous solution), dried (MgSO4), filtered and concentrated in vacuo to give 2,4,6-tri-O-acetyl-3-deoxy-3-(3,5-dimethoxybenzamido)-α-D-galactopyranosyl bromide 9, which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10]([N:26]3[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]3)=[N:9]2)=[CH:5][CH:4]=1.[F:41][C:42]1[CH:47]=[CH:46][C:45]([N:48]2[C:53](=[O:54])[C:52]([C:55](O)=[O:56])=[CH:51][CH:50]=[N:49]2)=[CH:44][CH:43]=1.Cl.C(N=C=NCCCN(C)C)C.N1(O)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[F:25][C:19]1[CH:20]=[C:21]([NH:24][C:55]([C:52]2[C:53](=[O:54])[N:48]([C:45]3[CH:46]=[CH:47][C:42]([F:41])=[CH:43][CH:44]=3)[N:49]=[CH:50][CH:51]=2)=[O:56])[CH:22]=[CH:23][C:18]=1[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=3)[N:9]=[C:10]([N:26]3[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[CH2:28][CH2:27]3)[C:11]=12
Reactant: O=C(O)c1ccnn(-c2ccc(F)cc2)c1=O
Reactant: COc1ccc(Cn2nc(N3CCN(C(=O)OC(C)(C)C)CC3)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Cn2nc(N3CCN(C(=O)OC(C)(C)C)CC3)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.2 %

Procedure:
A 50 mL round-bottomed flask was charged with tert-butyl 4-(1-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-1H-pyrazolo[3,4-b]pyridin-3-yl)piperazine-1-carboxylate (63.5 mg, 0.1157 mmol), 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (54.21 mg, 0.2315 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (110.9 mg, 0.5787 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (78.20 mg, 0.5787 mmol), N-ethyl-N-isopropylpropan-2-amine (0.2066 ml, 1.157 mmol) and DMF (10 mL). The reaction mixture was stirred at ambient temperature overnight. The reaction was partitioned between EtOAc and H2O. The phases were separated and the aqueous phase was re-extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 100/1 to 10/1, v/v) to afford product (56.8 mg, 64.17%). LRMS (APCI pos) m/e 765 (M+1).
Reaction SMILES: [OH:1][CH:2]([C:6]1[O:10][N:9]=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:7]=1[CH3:16])[CH2:3][CH:4]=[CH2:5].[CH:17](=O)[CH3:18].[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.[Cl-].[NH4+]>C(Cl)Cl>[CH3:16][C:7]1[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:9][O:10][C:6]=1[CH:2]1[CH2:3][CH:4]=[CH:5][CH:17]([CH3:18])[O:1]1
Reactant: CC=O
Reactant: C=CCC(O)c1onc(C(=O)OCC)c1C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: CCOC(=O)c1noc(C2CC=CC(C)O2)c1C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of ethyl 5-(1-hydroxybut-3-en-1-yl)-4-methylisoxazole-3-carboxylate (35 mg, 0.155 mmol) in DCM (1 mL) was treated with acetaldehyde (8.72 μl, 0.155 mmol) and the reaction mixture was cooled to 0° C. A solution of TMSOTf (80.4 μL, 0.465 mmol) in DCM (1.5 mL) cooled to 0° C. was added and the reaction mixture was stirred at 0° C. for 30 minutes and at room temperature overnight. To the resulting mixture was added a saturated solution of ammonium chloride (aq) (2 mL) and this was extracted with DCM (×3). The combined organic extracts were passed through a phase separating cartridge and the eluent was concentrated under reduced pressure. The crude material was adsorbed onto silica and purification by chromatography eluting with 0-100% EtOAc in iso-hexane afforded the title compound;