Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:17]([OH:19])=O)=[N:8][C:9]=2[S:10]([CH2:13][CH:14]([CH3:16])[CH3:15])(=[O:12])=[O:11])[CH2:3][CH2:2]1.[CH3:20][NH:21][C:22]([CH3:25])([CH3:24])[CH3:23].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[C:22]([N:21]([CH3:20])[C:17]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([S:10]([CH2:13][CH:14]([CH3:15])[CH3:16])(=[O:11])=[O:12])[N:8]=1)=[O:19])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)CS(=O)(=O)c1nc(C(=O)O)ccc1C1CC1
Reactant: CNC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CS(=O)(=O)c1nc(C(=O)N(C)C(C)(C)C)ccc1C1CC1

Procedure:
In analogy to the procedure described in Example 47 b), 5-cyclopropyl-6-(isobutylsulfonyl)picolinic acid was reacted with N,2-dimethylpropan-2-amine (CAN 94896-77-2) in the presence of TBTU and DIEA to give the title compound as white solid; MS (EI): m/e=353.5 [MH+].
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[CH:12]([O:15][C:16]1[NH:20][N:19]=[C:18]([NH2:21])[CH:17]=1)([CH3:14])[CH3:13].C(N(CC)CC)C>C(#N)C>[Cl:11][C:4]1[N:3]=[C:2]([NH:21][C:18]2[CH:17]=[C:16]([O:15][CH:12]([CH3:14])[CH3:13])[NH:20][N:19]=2)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: CC(C)Oc1cc(N)n[nH]1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)Oc1cc(Nc2nc(Cl)ccc2[N+](=O)[O-])n[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 61 %

Procedure:
A mixture of 2,6-dichloro-3-nitropyridine (0.5 g) and 5-isopropoxy-1H-pyrazol-3-amine (Intermediate 6, 0.35 g) in acetonitrile (10 mL) with triethylamine (2 mL) was stirred at room temperature for 24 hours, The resulting mixture was concentrated, and the resulting residue was separated by silica gel column (Hexane/Ethyl acetate) to afford 0.45 g desired product. MS (electrospray): 298 (M+1) for C11H12ClN5O3.
Reaction SMILES: Cl.CN.[CH2:4]([N:6](CC)CC)C.Cl[CH2:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:28]3[CH:29]=[C:30]4[O:35][CH2:34][O:33][C:31]4=[CH:32][C:27]=3[CH2:26][CH:25]([CH3:36])[N:24]([C:37](=[O:39])[CH3:38])[N:23]=2)=[CH:18][CH:17]=1)=[O:14]>C(O)C>[CH3:4][NH:6][CH2:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:28]3[CH:29]=[C:30]4[O:35][CH2:34][O:33][C:31]4=[CH:32][C:27]=3[CH2:26][CH:25]([CH3:36])[N:24]([C:37](=[O:39])[CH3:38])[N:23]=2)=[CH:18][CH:17]=1)=[O:14]
Reactant: CCN(CC)CC
Reactant: CC(=O)N1N=C(c2ccc(NC(=O)CCl)cc2)c2cc3c(cc2CC1C)OCO3
Agent: CN
Agent: Cl
Solvent: CCO
Product: CNCC(=O)Nc1ccc(C2=NN(C(C)=O)C(C)Cc3cc4c(cc32)OCO4)cc1
Yield: 38.4 %

Procedure:
1.31 g (19.5 mmol) of methylamine hydrochloride and 3.24 ml (23.3 mmol) of triethylamine were added to a suspension containing 1.61 g (3.89 mmol) of 1-(4-chloroacetylaminophenyl)-3-acetyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine (see Example 106) in 100 ml of ethanol and the reaction mixture was refluxed for 10 hours, then evaporated under reduced pressure. The residue was purified by column chromatography (adsorbent: Kieselgel 60, eluent: chloroform--methanol 9:1). The crude product was triturated with 3 ml of 50% ethanol at 25° C. to give 0.61 g (38.6%) of the aimed product, m.p.: 220°-222° C. (weak decomp.).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:3].[BrH:11].[NH+]1C=CC=CC=1.Br>C(O)(=O)C>[Br:11][CH2:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(=O)c1ccc(O)cc1
Reactant: Br
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Product: O=C(CBr)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-hydroxyacetophenone (10 g) and pyridinium hydrobromide perbromide (23.5 g) in acetic acid (80 ml) was added hydrogenbromide (30% in acetic acid solution) (40 ml) and the mixture was stirred overnight at ambient temperature. The reaction mixture was added to ice water and extracted with ethyl acetate. The organic layer was taken and dried over magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to afford 2-bromo-1-(4-hydroxyphenyl)ethanone (1.72 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C@H:6]1[CH2:11][CH2:10][C@@H:9]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:8][C@H:7]1[CH2:17][OH:18])=[O:4].[F:19][C:20]([F:33])([F:32])[C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[N:27]=[CH:26][N:25]=[C:24]2N.C(N(CC)CC)C>C(O)C>[C:13]([NH:12][C@@H:9]1[CH2:10][CH2:11][C@H:6]([NH:5][C:3](=[O:4])[CH2:2][NH:1][C:24]2[C:23]3[C:28](=[CH:29][CH:30]=[C:21]([C:20]([F:32])([F:33])[F:19])[CH:22]=3)[N:27]=[CH:26][N:25]=2)[C@H:7]([CH2:17][OH:18])[CH2:8]1)([CH3:14])([CH3:15])[CH3:16]
Reactant: CC(C)(C)N[C@@H]1CC[C@H](NC(=O)CN)[C@H](CO)C1
Reactant: Nc1ncnc2ccc(C(F)(F)F)cc12
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)N[C@@H]1CC[C@H](NC(=O)CNc2ncnc3ccc(C(F)(F)F)cc23)[C@H](CO)C1
Yield: 22.1 %

Procedure:
A solution of 2-amino-N-((1S,2R,4R)-4-(tert-butylamino)-2-(hydroxymethyl)cyclohexyl)acetamide (54 mg, 0.21 mmol), 6-(trifluoromethyl)quinazolin-4-amine (52 mg, 0.25 mmol), and triethylamine (25 mg, 0.25 mmol) in 3 mL of ethanol was heated at 100° C. in the microwvae for 1 hr. The reaction mixture was concentrated and the residue chromatographed on silica gel (eluting with 2-8% NH4OH/MeOH/CH2Cl2) to give 21 mg of the title compound as a white solid.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[S:19](=[O:21])(=[O:20])[CH2:18][CH2:17][C:16]([C:22](O)=[O:23])=[CH:15][C:14]=3[CH:25]=2)=[CH:6][CH:5]=1)[CH2:2][CH3:3].S(Cl)(Cl)=O.CN(C=O)C.[CH3:35][N:36]([CH2:43][C:44]1[CH:50]=[CH:49][C:47]([NH2:48])=[CH:46][CH:45]=1)[CH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>C1COCC1.O.C(N(CC)CC)C>[CH3:35][N:36]([CH2:43][C:44]1[CH:45]=[CH:46][C:47]([NH:48][C:22]([C:16]2[CH2:17][CH2:18][S:19](=[O:21])(=[O:20])[C:13]3[CH:12]=[CH:11][C:10]([C:7]4[CH:8]=[CH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=4)=[CH:25][C:14]=3[CH:15]=2)=[O:23])=[CH:49][CH:50]=1)[CH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1
Reactant: CN(Cc1ccc(N)cc1)C1CCOCC1
Reactant: CCCc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCS3(=O)=O)cc1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 63.5 %

Procedure:
To a solution of 7-(4-propylphenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (200 mg) in THF (5 ml) were added at room temperature thionyl chloride (0.09 ml) and a drop of DMF, and the mixture was stirred for 1 hour. The solvent was evaporated under reduced pressure, and the residue was dissolved in THF (12 ml). The solution was added dropwise at 0° C. to a solution of 4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]aniline[122 mg (0.55 mmol)] and triethylamine (0.14 ml) in THF (2 ml), and the mixture was stirred at room temperature for 4 hours. To the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure to give pale yellow crystals, which were recrystallized from ethanol to give colorless crystals of N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-7-(4-propylphenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 27) (195.0 mg).
Reaction SMILES: CCN(CC)CC.[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl.[CH3:18][C:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:22])[CH2:20][NH2:21]>C(Cl)Cl>[CH3:22][C:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:18])[CH2:20][NH:21][C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(CN)c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(CNC(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
4.0 ml (30 mmol) of NEt3 and 4.22 g (30 mmol) of benzoylchloride were added in succession at 0° C. to a solution of 1.86 g (10.0 mmol) of 2-methyl-2-phenylpropylamine hydrochloride in DCM (30 ml) and the mixture was stirred for 1 h at RT. It was then diluted with DCM and washed with a 10% aqueous hydrochloric acid, a saturated aqueous Na2CO3 solution and brine. The organic phase was dried over Na2SO4, filtered and concentrated to small volume under vacuum. 2.48 g (9.8 mmol, 98%) of N-(2-methyl-2-phenylpropyl)benzamide were obtained as the residue, which was reacted further with no additional purification.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:9][C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[N:13]=2)=[O:11])=[N:5][CH:6]=[N:7][CH:8]=1)#[N:2].S(=O)(=O)(O)[OH:30]>>[C:1]([C:3]1[C:4]([NH:9][C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[N:13]=2)=[O:11])=[N:5][CH:6]=[N:7][CH:8]=1)(=[O:30])[NH2:2]
Reactant: N#Cc1cncnc1NC(=O)c1nn(Cc2ccccc2F)c2ncccc12
Reactant: O=S(=O)(O)O
Product: NC(=O)c1cncnc1NC(=O)c1nn(Cc2ccccc2F)c2ncccc12
Reaction time: 0.5 h

Procedure:
581 mg (1.56 mmol) of the compound from example 47A were introduced in portions at 0° C. into conc. sulfuric acid (2.0 ml) and the mixture was stirred for a further 30 min. Subsequently, the solution was added to ice and extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was stirred with ethyl acetate, and the solids were filtered off and dried under high vacuum. This gave 246 mg (40% of theory) of the title compound in solid form.
Reaction SMILES: [S:1]1[C:5]([NH:6][S:7](=[O:10])(=[O:9])[O-])=[N:4][CH:3]=[N:2]1.[Na+].P(Cl)(Cl)(Cl)(Cl)Cl.S(=O)(=O)(OC)N.Cl.[Br:25][C:26]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:27]=1[CH2:28][CH2:29][NH:30][CH2:31]2>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[Br:25][C:26]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:27]=1[CH2:28][CH2:29][N:30]([S:7]([NH:6][C:5]1[S:1][N:2]=[CH:3][N:4]=1)(=[O:9])=[O:10])[CH2:31]2
Reactant: Brc1cccc2c1CCNC2
Reactant: O=S(=O)([O-])Nc1ncns1
Agent: COS(N)(=O)=O
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=S(=O)(Nc1ncns1)N1CCc2c(Br)cccc2C1
Temperature: 50 °C
Reaction time: 0.08 h

Procedure:
To a 50 mL flask containing sodium 1,2,4-thiadiazol-5-ylsulfamate (Intermediate A, 96 mg, 0.472 mmol) and 10 mL of DCM was added PCl5 (Aldrich, St. Louis, Mo., 245 mg, 1.179 mmol). The resulting slurry was heated at 50° C. for 1.5 hours. LCMS showed conversion to the methyl sulfamate (following quench into methanol). The reaction was cooled to rt and was quenched with the addition of 5 drops of brine. The resulting slurry was stirred vigorously for 5 minutes before being filtered through a plug of diatomaceous earth, washing well with DCM. The mixture was concentrated under reduced pressure. The derived oil was taken up in 1 mL of DCM and was added to a solution of 5-bromo-1,2,3,4-tetrahydroisoquinoline hydrochloride (ASW Medchem, 50 mg, 0.236 mmol) and TEA (164 μl, 1.179 mmol) in 2 mL of DCM at 0° C. Another 0.164 mL of TEA was added and the reaction allowed to warm to room temperature where it was maintained for 2 hours. LCMS showed clean conversion to sulfonamide. The reaction was allowed to stir overnight before being diluted with saturated sodium bicarbonate (10 mL) and poured into a separatory funnel containing methylenechloride (10 mL). The layers were separated and the aqueous layer was extracted with methylenechloride (2×25 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under a vacuum to provide a yellow oil that was purified by silica gel chromatography (Redi-Sep pre-packed silica gel column (12 g), 0-10% methanol in methylenechloride) to provide 5-bromo-N-(1,2,4-thiadiazol-5-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide as an off white solid. [M+H]+=375.0 1H NMR (400 MHz, Acetone) δ ppm 8.28 (s, 1H), 7.96 (s, 1H), 7.45-7.50 (m, 1H), 7.09-7.20 (m, 2H), 4.32 (s, 2H), 3.48 (t, J=6.1 Hz, 2H), 2.86-2.92 (m, 2H)
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[OH-].[Na+].[CH2:10]([C:12]1([CH2:16]OS(C)(=O)=O)[CH2:15][O:14][CH2:13]1)[CH3:11]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:10]([C:12]1([CH2:16][O:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:7])[CH2:15][O:14][CH2:13]1)[CH3:11]
Reactant: CCC1(COS(C)(=O)=O)COC1
Reactant: OCCCCCO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Product: CCC1(COCCCCCO)COC1
Temperature: 70 °C

Procedure:
1,5-Pentanediol (1,171 g (11.2 mol)), tetrabutylammonium bromide (24.1 g (75 mmol)) and 96% sodium hydroxide (90 g (2.2 mol)) were added to a glass flask having an inner volume of 2,000 ml equipped with a stirrer, a thermometer, a dropping funnel and a reflux condenser, and the mixture was warmed to 70° C. with stirring. Subsequently 3-ethyl-3-methanesulfonyloxymethyloxetane (324 g (1.5 mol)) having a purity of 90% (a value measured by 1H-NMR) was dropwise added while keeping the liquid temperature at 75-85° C. to perform the reaction at the same temperature for 3 hours. After the completion of the reaction, the reaction solution was washed with heptane (200 ml), and then water (583 ml) was added and a liquid separation was performed. Water (1,166 ml) and toluene (500 ml) were added to a resultant organic layer, and a liquid separation was performed. Subsequently toluene (500 ml) was added to a resultant aqueous layer to perform the extraction, an extract (a toluene layer) and an organic layer were mixed, and a resultant mixture was washed at water (300 ml). Subsequently a resultant aqueous layer and an aqueous layer separated earlier were mixed, and a resultant mixture was extracted with toluene (500 ml). After washing an extract (a toluene layer) with water (300 ml), the extract was mixed with the previously obtained organic layer, and a resultant mixture was concentrated under reduced pressure. A resultant concentrate (a bisoxetane ether compound generated in the amount of only 14% (an analysis value by a gas chromatography)) was distilled under reduced pressure (136-140° C., 533 Pa) to give, as a colorless liquid, 3-ethyl-3-(5-hydroxypentyl)oxymethyloxetane having a purity of 93% (an analysis value by a gas chromatography) (109 g) (an isolated yield based on 3-ethyl-3-methanesulfonyloxymethyloxetane: 33%).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C(/N=N/C(N(C)C)=O)=O)C.[Br:40][C:41]1[CH:42]=[C:43](O)[CH:44]=[C:45]2[C:50]=1[CH:49]=[N:48][CH:47]=[CH:46]2>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:43]1[CH:44]=[C:45]2[C:50](=[C:41]([Br:40])[CH:42]=1)[CH:49]=[N:48][CH:47]=[CH:46]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1cc(Br)c2cnccc2c1
Reactant: OCc1ccccc1
Agent: CN(C)C(=O)/N=N/C(=O)N(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Brc1cc(OCc2ccccc2)cc2ccncc12
Temperature: 25 °C
Reaction time: 13 h

Procedure:
Benzyl alcohol (0.25 mL; Ald), triphenylphosphine (1.29 g), and TMAD (850 mg; Ald) were added to a toluene (30 mL) solution of Intermediate 7 (500 mg) and the resulting mixture was stirred at room temperature for 13 hours. The reaction mixture solution was filtrated, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (Yamazen; n-hexane/ethyl acetate) to give the title compound (186 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=2)[N:3]=1.[Cl:20][C:21]1[CH:37]=[CH:36][CH:35]=[CH:34][C:22]=1[CH2:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O>>[Cl:20][C:21]1[CH:37]=[CH:36][CH:35]=[CH:34][C:22]=1[CH2:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=2)[N:3]=1
Reactant: OB(O)c1ccccc1OCc1ccccc1Cl
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Product: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccccc3OCc3ccccc3Cl)n2)c1

Procedure:
Example 27 was prepared under similar conditions as described in the preparation of Example 1 using crude 4-chloro-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine and {2-[(2-chlorobenzyl)oxy]phenyl}boronic acid (Aldrich Chemical Company Inc.). The batch was purified by preparative HPLC.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C@H:8]([CH2:14][OH:15])[CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[S:24](Cl)([CH3:27])(=[O:26])=[O:25]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:7][C@@H:8]([CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:14][O:15][S:24]([CH3:27])(=[O:26])=[O:25])=[O:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)C[C@@H](CO)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C[C@@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of ((S)-1-hydroxymethyl-3,3-dimethyl-butyl)-carbamic acid tert-butyl ester (250 mg, 0.756 mmol) and triethylamine (0.116 mL, 0.832 mmol) in CH2Cl2 (4 mL) cooled at −10° C. was added under nitrogen atmosphere mesylchloride (0.065 mL, 0.832 mmol) and the reaction mixture was stirred at 0° C. for 1.5 h. The reaction mixture was quenched with ice and water then extracted twice with EtOAc. The combined organic layers were washed with water, dried (Na2SO4), filtered and concentrated. The crude material (colorless oil) was used without purification in the next step. TLC, Rf (c-hexane/EtOAc 1:1): 0.46.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([O:14]N2C3C=CC=CC=3N=N2)=O)=[C:5]2[N:6]=[CH:7][C:8]([F:10])=[CH:9][N:4]2[N:3]=1.[O:24]1[CH2:27][CH:26]([N:28]2[CH2:33][CH2:32][N:31]([C:34]3[CH:39]=[CH:38][N:37]=[CH:36][C:35]=3[NH2:40])[CH2:30][CH2:29]2)[CH2:25]1>CN1C(=O)CCC1>[NH2:1][C:2]1[C:11]([C:12]([NH:40][C:35]2[CH:36]=[N:37][CH:38]=[CH:39][C:34]=2[N:31]2[CH2:30][CH2:29][N:28]([CH:26]3[CH2:25][O:24][CH2:27]3)[CH2:33][CH2:32]2)=[O:14])=[C:5]2[N:6]=[CH:7][C:8]([F:10])=[CH:9][N:4]2[N:3]=1
Reactant: Nc1cnccc1N1CCN(C2COC2)CC1
Reactant: Nc1nn2cc(F)cnc2c1C(=O)On1nnc2ccccc21
Solvent: CN1CCCC1=O
Product: Nc1nn2cc(F)cnc2c1C(=O)Nc1cnccc1N1CCN(C2COC2)CC1
Temperature: 100 °C

Procedure:
To a suspension of benzotriazol-1-yl 2-amino-6-fluoro-pyrazolo[1,5-a]pyrimidine-3-carboxylate 6a (prepared according to methods similar to the one depicted in Preparation 2a) (5 g, 15.62 mmol) in NMP (78.27 mL) was added 4-[4-(oxetan-3-yl)piperazin-1-yl]pyridin-3-amine (prepared according to methods similar to the one depicted in Preparation N-1, described below) (3.660 g, 15.62 mmol) and the resulting mixture heated at 100° C. for 18 hours. The reaction mixture was cooled to RT and then passed through a pre-wetted SCX cartridge (2×50 g cartridge) and the cartridge was washed with methanol. The product was eluted with 2M ammonia in methanol and the eluent was concentrated in vacuo to leave a dark solid that was purified by column chromatography on silica using the ISCO column companion, eluting with DCM and 90:10:1 DCM:MeOH:NH3 (0-100% gradient, 40 g column) Product fractions were combined and concentrated in vacuo to leave the product as a yellow solid which was then recrystallised from methanol to leave pure product as a yellow solid. MS (ES+) 413.2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][CH:15]=[C:16](Br)[N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:19][O:20][C:21](=[O:62])[NH:22][C@H:23]([C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C:34]1[NH:35][CH:36]=[C:37]([C:39]2[CH:44]=[CH:43][C:42]([C:45]3[C:46]4[S:52][CH:51]=[C:50](B5OC(C)(C)C(C)(C)O5)[C:47]=4[S:48][CH:49]=3)=[CH:41][CH:40]=2)[N:38]=1)=[O:28])[CH:24]([CH3:26])[CH3:25].C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>CN(C=O)C.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>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[NH:17][C:16]([C:50]2[C:47]3[S:48][CH:49]=[C:45]([C:42]4[CH:41]=[CH:40][C:39]([C:37]5[N:38]=[C:34]([C@@H:30]6[CH2:31][CH2:32][CH2:33][N:29]6[C:27](=[O:28])[C@@H:23]([NH:22][C:21]([O:20][CH3:19])=[O:62])[CH:24]([CH3:25])[CH3:26])[NH:35][CH:36]=5)=[CH:44][CH:43]=4)[C:46]=3[S:52][CH:51]=2)=[CH:15][N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3csc4c(B5OC(C)(C)C(C)(C)O5)csc34)cc2)c[nH]1)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCCC1c1nc(Br)c[nH]1
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: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3csc4c(-c5cnc([C@@H]6CCCN6C(=O)OC(C)(C)C)[nH]5)csc34)cc2)c[nH]1)C(C)C
Temperature: 80 °C
Yield: 59 %

Procedure:
To a degassed mixture of compounds 48 (1.10 mmol), 50 (1.10 mmol), and sodium carbonate (4.42 mmol) in a mixture of DMF and water (33 mL/3 mL) was added Pd(PPh3)4 (0.11 mmol). The reaction mixture was heated at 80° C. for 2 hrs. Ethyl acetate and water were added. The dried organic layers were evaporated in vacuo and the residue was purified by silica gel chromatography (eluent: DCM first; then DCM/MeOH 9/1) to give compound 51 as a beige solid in 59% yield. MS (ESI, EI+) m/z=744 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]3[CH:13]=[CH:14][C:15]([CH:17]=O)=[N:16][C:11]3=[N:10][CH:9]=2)=[CH:4][C:3]=1[C:19]1[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=1.[NH2:27][OH:28]>CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]3[CH:13]=[CH:14][C:15]([CH:17]=[N:27][OH:28])=[N:16][C:11]3=[N:10][CH:9]=2)=[CH:4][C:3]=1[C:19]1[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: N#Cc1ccccc1-c1cc(-c2cnc3nc(C=O)ccn23)ccc1F
Reactant: NO
Solvent: O
Solvent: CO
Product: N#Cc1ccccc1-c1cc(-c2cnc3nc(C=NO)ccn23)ccc1F
Temperature: 60 °C

Procedure:
A suspension of 2′-fluoro-5′-(7-formylimidazo[1,2-α]pyrimidin-3-yl)biphenyl-2-carbonitrile (260 mg, 0.8 mmol) in methanol (3 ml) was treated with hydroxylamine (0.13 ml of a 50 wt. % solution in water) then heated at 60° C. for 3 h. The reaction was cooled to 0° C., the solid collected by filtration and washed with a little cold methanol to afford 2′-fluoro-5′-[7-(hydroxyiminomethyl)imidazo[1,2-α]pyrimidin-3-yl]biphenyl-2-carbonitrile as a yellow solid. This solid was suspended in dichloromethane (5 ml), treated with 1,1′-carbonyldiimidazole (180 mg, 1.1 mmol) and triethylamine (0.31 ml, 2.3 mmol) then heated at reflux for 2 h. The reaction was cooled, diluted with dichloromethane then washed with water, brine, dried over anhydrous sodium sulfate, filtered and pre-adsorbed onto silica. Purification by chromatography on silica gel eluting with dichloromethane/methanol/conc. ammonia (99:0.9:0.1) afforded a solid which was recrystallised from acetonitrile to furnish 3-(2′-cyano-6-fluorobiphenyl-3-yl)imidazo[1,2-α]pyrimidine-7-carbonitrile as a yellow powder (160 mg, 63% over 2 steps): δH (400 MHz, DMSO) 7.64-7.72 (3H, m), 7.78-7.81 (1H, m), 7.89 (1H, ddd, J 7, 7 and 1), 7.94-7.99 (2H, m), 8.05 (1H dd, J 8 and 2), 8.43 (1H, s), 9.36 (1H, d, J 7); m/z (ES+) 340 (M++H).