Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:13][CH3:14])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[N:27]12[CH2:35][C:31]([CH2:36][NH2:37])([CH2:32][CH2:33][CH2:34]1)[CH2:30][CH2:29][CH2:28]2>O1CCCC1.CO>[N:27]12[CH2:35][C:31]([CH2:36][NH:37][C:7](=[O:9])[C:6]3[CH:10]=[C:2]([Cl:1])[C:3]([NH:13][CH3:14])=[CH:4][C:5]=3[O:11][CH3:12])([CH2:32][CH2:33][CH2:34]1)[CH2:30][CH2:29][CH2:28]2
Reactant: NCC12CCCN(CCC1)C2
Reactant: CNc1cc(OC)c(C(=O)O)cc1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CO
Product: CNc1cc(OC)c(C(=O)NCC23CCCN(CCC2)C3)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 73.3 %

Procedure:
A solution of 5-chloro-2-methoxy-4-(methylamino)benzoic acid (1.08 g, 5 mmol) in anhydrous tetrahydrofuran (7 mL) under nitrogen was treated with 1,1'-carbonyldiimidazole (0.90 g, 5.5 mmol), stirred one hour, degassed under a stream of nitrogen for 10 minutes, and cooled (0° C.). A solution of 1-azabicyclo[3.3.1]nonane-5-methanamine (0.82 g, 5.3 mmol) in tetrahydrofuran (3 mL) was added dropwise, and stirring was continued at room temperature for 18 hours. The suspension was diluted with enough methanol to dissolve the solid, then the solution was filtered through a short column of alumina (eluted with 20% methanol/tetrahydrofuran). The filtrate was concentrated in vacuo, triturated from cold ether, and recrystallized from acetonitrile to afford 1.29 g (73%) of colorless crystals; mp 188°-190° C. (second phase), first phase melting point 175° C.
Reaction SMILES: [Ga:1].[OH:2][S:3]([OH:6])(=[O:5])=[O:4]>C(O)C.O>[OH2:2].[S:3]([O-:6])([O-:5])(=[O:4])=[O:2].[Ga+3:1].[S:3]([O-:6])([O-:5])(=[O:4])=[O:2].[S:3]([O-:6])([O-:5])(=[O:4])=[O:2].[Ga+3:1]
Reactant: O=S(=O)(O)O
Reactant: [Ga]
Solvent: CCO
Solvent: O
Product: O=S(=O)([O-])[O-]
Product: [Ga+3]

Procedure:
4.1 g of gallium sulphate hydrate (the H2O/Ga2 (SO4)3 molar ratio is close to 25) are dissolved in 3.7 g of distilled water. The sulphate is obtained by dissolving gallium (Grade 1 from Johnson Matthey) in hot concentrated H2SO4, in excess, taking up the suspension obtained in ethanol at a concentration of 60% in water at normal temperature, reprecipitation, in this cooled solution, of gallium sulphate hydrate by adding ether followed by filtration and controlled drying. 1.15 g of 85% phosphoric acid (Prolabo) are added with stirring followed by 0.25 g of 40% hydrofluoric acid (Fluka) and, lastly, 4.55 g of di-n-propylamine (Fluka), abbreviated to DPA in what follows. Stirring is continued for approximately 15 minutes. The pH is then 6.
Reaction SMILES: [CH:1]1([C:4]2[NH:9][C:8]3[N:10]=[C:11]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)[S:12][C:7]=3[C:6](=[O:19])[N:5]=2)[CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[C:33]=1[CH3:42]>O1CCCC1>[CH:1]1([C:4]2[N:9]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:39])([F:40])[F:41])[C:33]=3[CH3:42])[C:8]3[N:10]=[C:11]([N:13]4[CH2:14][CH2:15][O:16][CH2:17][CH2:18]4)[S:12][C:7]=3[C:6](=[O:19])[N:5]=2)[CH2:3][CH2:2]1
Reactant: Cc1c(CBr)cccc1C(F)(F)F
Reactant: O=c1nc(C2CC2)[nH]c2nc(N3CCOCC3)sc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(Cn2c(C3CC3)nc(=O)c3sc(N4CCOCC4)nc32)cccc1C(F)(F)F
Reaction time: 0.5 h

Procedure:
A solution of 5-cyclopropyl-2-(4-morpholinyl)[1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one (50 mg, 0.180 mmol) in Tetrahydrofuran (THF) (1000 μl) was stirred at 0° C. for 15 min, then lithium bis(trimethylsilyl)amide (359 μl, 0.359 mmol) in THF was added and stirring was continued for 30 min. 1-(bromomethyl)-2-methyl-3-(trifluoromethyl)benzene (54.6 mg, 0.216 mmol) in Tetrahydrofuran (THF) (300 μl) was added and the mixture was stirred at 65° C. overnight. The reaction mixture was concentrated and the residue purified by reversed-phase HPLC to provide the major regio-isomer, 5-cyclopropyl-4-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-2-(4-morpholinyl)[1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one (Example 70). (9 mg, 11%); LC/MS: MS (ES+) m/e 451 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 0.83-0.92 (m, 2H), 0.98-1.07 (m, 2H), 1.86-1.97 (m, 1H), 2.51 (s, 3H), 3.45-3.56 (m, 4H), 3.63-3.73 (m, 4H), 5.76 (s, 2H), 6.92 (d, J=7.83 Hz, 1H), 7.37 (m, 1H), 7.64 (d, J=7.8 Hz, 1H).
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Si:1]([O:8][CH:9]1[CH2:13][CH2:12][CH:11]([O:14][S:23]([CH3:22])(=[O:25])=[O:24])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(O)C1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1CCC(OS(C)(=O)=O)C1
Temperature: 0 °C
Reaction time: 16 h
Yield: 53.1 %

Procedure:
To a solution of 3-(tert-butyldimethylsilanyloxy)cyclopentanol (3.5 g, 16 mmol) in DCM (30 mL) was added triethylamine (2.65 mL, 19.4 mmol) and DMAP (20 mg, 0.16 mmol). The reaction mixture was cooled to 0° C. and methanesulfonyl chloride (1.34 mL, 16.5 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was washed with water and the organic layer was dried over sodium sulfate, filtered, and concentrated. Purification of the residue by column chromatography (20% diethyl ether:hexanes) afforded 2.5 g (53%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 5.19-5.3 (m, 1H), 4.4 (m, 1H), 3.0 (s, 3H), 1.8-2.3 (m, 4H), 1.5-1.7 (m, 2H), 0.86 (s, 9H), 0.05 (s, 6H).
Reaction SMILES: O=[C:2]([CH2:6][CH3:7])[CH2:3][C:4]#[N:5].[NH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)[NH2:9].C(O)(=O)C>C(O)C>[CH2:6]([C:2]1[CH:3]=[C:4]([NH2:5])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[N:9]=1)[CH3:7]
Reactant: NNc1ccccn1
Reactant: CCC(=O)CC#N
Solvent: CCO
Solvent: CC(=O)O
Product: CCc1cc(N)n(-c2ccccn2)n1
Temperature: 25 °C
Yield: 89.7 %

Procedure:
To an ice-cold solution of 3-oxopentanenitrile (14.6 g, 150 mmol) and 2-hydrazinopyridine (13.6 g, 125 mmol) in ethanol (150 mL), acetic acid (14.3 mL, 250 mmol) was added and the resulting mixture was heated under reflux for 5 hours. The solution was allowed to cool to room temperature, and concentrated under reduced pressure, and water was added to the residue. The solution was made basic by the addition of an aqueous sodium hydroxide solution, and the organic matter was extracted with ethyl acetate. The extract was washed with saturated brine and water, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give the title compound (21.1 g, 90% yield). NMR (CDCl3) δ: 1.25 (3H, t, J=7.6 Hz), 2.59 (2H, q, J=7.6 Hz), 5.38 (1H, s), 5.90 (2H, br s), 7.04 (1H, ddd, J=1.2 Hz, 5.0 Hz, 7.4 Hz), 7.75 (1H, ddd, J=2.0 Hz, 7.4 Hz, 8.4 Hz), 7.94 (1H, ddd, J=0.8 Hz, 1.2 Hz, 8.4 Hz), 8.29 (1H, ddd, J=0.8 Hz, 2.0 Hz, 5.0 Hz).
Reaction SMILES: [CH2:1]([O:4][CH:5]1[NH:9][C:8](=[O:10])[CH2:7][CH2:6]1)[CH:2]=C.[C:11]1([S:17](Cl)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:21](OCC)(=O)C>CCOCC>[C:11]1([S:17]([N:9]2[CH:5]([O:4][C:1]([CH3:2])=[CH2:21])[CH2:6][CH2:7][C:8]2=[O:10])(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: C=CCOC1CCC(=O)N1
Reactant: CCOC(C)=O
Solvent: CCOCC
Product: C=C(C)OC1CCC(=O)N1S(=O)(=O)c1ccccc1
Temperature: -10 °C

Procedure:
The operation is done as in example 49, starting with 0.80 g of 5-(2-propenyloxy)pyrrolidin-2-one. After cooling to -10° C., a solution of 1.00 g of benzenesulphonyl chloride in 10 cm3 of anhydrous ether is added and the temperature is maintained at -10° C. 100 cm3 of ethyl acetate is added before filtering. Elution is done with a mixture of ethyl acetate and hexane (1-1) and by re-crystallizing from isopropyl ether, 0.20 g of product is obtained, m.p. 54°-56° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C1C=CC=CN=1)C.C(N(CC)CC)C.[F:34][C:35]([F:45])([F:44])[CH:36]([OH:43])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([O:43][CH:36]([C:35]([F:34])([F:44])[F:45])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(OCc2ccccc2)cc1
Reactant: CCCCCCC(O)C(F)(F)F
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCC(OC(=O)c1ccc(OCc2ccccc2)cc1)C(F)(F)F

Procedure:
4-Benzyloxy-benzoic acid chloride in an amount of 4.3 g was dissolved in 50 ml of methylene chloride, to which a solution of 2.9 g of optically active 1,1,1-trifluoro-2-octanol, 0.6 g of dimethylaminopyridine and 1.7 g of triethylamine in 50 ml of methlene chloride was gradually added under cooling with ice.
Reaction SMILES: S=C1N([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18](=[O:20])[CH3:19])=[C:13]([O:21][CH3:22])[CH:12]=2)=[O:8])CCS1.[CH2:23]([CH:25]([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:26][NH2:27])[CH3:24].C(N(CC)CC)C>C1COCC1.C(OCC)C>[C:18]([O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][O:9][C:7](=[O:8])[NH:27][CH2:26][CH:25]([CH2:23][CH3:24])[CH2:28][CH2:29][CH2:30][CH3:31])=[CH:12][C:13]=1[O:21][CH3:22])(=[O:20])[CH3:19]
Reactant: CCCCC(CC)CN
Reactant: COc1cc(COC(=O)N2CCSC2=S)ccc1OC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCC(CC)CNC(=O)OCc1ccc(OC(C)=O)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred yellow solution of VII (298.2 mg, 0.873 mmol) in anhydrous THF (10 mL) was added 2-ethylhexylamine (124 mg, 157 μL 1.1×0.873 mmol) and then, dropwise, triethylamine (97 mg, 135 μL, 1.1×0.873 mmol). The solution was stirred for 3 hours at room temperature. The colorless solution was then diluted with diethyl ether and washed with 1N HCl, distilled water, and saturated NaCl. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated. The crude product was purified by column chromatography on silica gel using hexanes/ethyl acetate (6:4, v/v) to give 9 as 207.2 mg (68%) of a clear, light yellow oil: Rf=0.60 (hexanes/ethyl acetate, 1:1, v/v); 1HNMR (CDCl3) δ 6.99 (d, 3J=8.0 Hz, 1H), 6.95 (d, 4J=1.75 Hz, 1H), 6.92 (dd, 3J=8.0 Hz, 4J=1.72 Hz, 1H), 5.04 (s, 2H), 4.67 (bs, 1H, NH), 3.82 (s, 3H), 3.16-3.08 (m, 2H), 2.29 (s, 3H), 1.43-1.35 (m, 1H), 1.33-1.119 (m, 8H) and 0.867 (apparent triplet, 3J=7.2 Hz, 6H). Exact mass (FAB+) calculated for C19H30NO5 [M+H] 352.2118. found 352.2101.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][CH3:14])[CH2:10][C@H:9]1[C:15]1[NH:16][CH:17]=[C:18]([C:20]2[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=2)[N:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:27][C:28]1[C:29]([NH:42][C:43](=[O:63])[C:44]2[CH:49]=[CH:48][C:47]([N:50]3[CH2:55][CH2:54][N:53]([C:56](=[O:61])[C:57]([CH3:60])([CH3:59])[CH3:58])[CH2:52][C@H:51]3[CH3:62])=[N:46][CH:45]=2)=[CH:30][C:31]([O:37][C:38]([F:41])([F:40])[F:39])=[C:32](B(O)O)[CH:33]=1.C(=O)([O-])[O-:65].[K+].[K+]>CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][CH3:14])[CH2:10][C@H:9]1[C:15]1[NH:16][CH:17]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([C:32]3[CH:33]=[C:28]([Cl:27])[C:29]([NH:42][C:43]([C:44]4[CH:45]=[N:46][C:47]([N:50]5[CH2:55][CH2:54][N:53]([C:56](=[O:61])[C:57]([CH3:60])([CH3:59])[CH2:58][OH:65])[CH2:52][C@H:51]5[CH3:62])=[CH:48][CH:49]=4)=[O:63])=[CH:30][C:31]=3[O:37][C:38]([F:41])([F:40])[F:39])=[CH:22][CH:21]=2)[N:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H]1CN(C(=O)C(C)(C)C)CCN1c1ccc(C(=O)Nc2cc(OC(F)(F)F)c(B(O)O)cc2Cl)cn1
Reactant: O=C([O-])[O-]
Reactant: CO[C@H]1C[C@@H](c2nc(-c3ccc(Br)cc3)c[nH]2)N(C(=O)OC(C)(C)C)C1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: [K+]
Solvent: CCOC(C)=O
Product: CO[C@H]1C[C@@H](c2nc(-c3ccc(-c4cc(Cl)c(NC(=O)c5ccc(N6CCN(C(=O)C(C)(C)CO)C[C@H]6C)nc5)cc4OC(F)(F)F)cc3)c[nH]2)N(C(=O)OC(C)(C)C)C1
Temperature: 65 °C
Yield: 41.6 %

Procedure:
To a round bottom flask was added (2S,4S)-2-[4-(4-bromo-phenyl)-1H-imidazol-2-yl]-4-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester (5.0 g, 11.8 mmol) and (R)-5-chloro-4-(6-(2-methyl-4-pivaloylpiperazin-1-yl)nicotinamido)-2-(trifluoromethoxy)phenylboronic acid (6.75 g, 12.4 mmol; Preparation 44), potassium carbonate (5.73 g, 41.4 mmol), and bis(di-tert-butyl(4-dimethylaminophenyl)-phosphine)dichloropalladium(II) (0.092 g, 0.130 mmol), followed by degassed tetrahydrofuran (50 mL) and water (1.28 mL). The reaction mixture was degassed with nitrogen for 5 min then heated at 65° C. for 4 h, and cooled to RT. Water (100 mL) was added and the reaction mixture was extracted with EtOAc (200 mL). The organic layer was washed with NaOH (2×100 mL), water (2×200 mL) and brine, dried over Na2SO4 and evaporated to give crude product (12.25 g). The crude product was purified by flash chromatography (150 g silica gel, 50-100% EtOAc (10 min), then 100% EtOAc (30 min)) to give the title intermediate (4.2 g; 41% yield) HPLC Method B: Retention time 15.29 min.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH2:8][C:9](=[O:13])[CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][CH:3]=1.[Cl:14][C:15]1[C:16]([CH3:25])=[C:17]([S:21](Cl)(=[O:23])=[O:22])[CH:18]=[CH:19][CH:20]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Cl:14][C:15]1[C:16]([CH3:25])=[C:17]([S:21]([NH:1][C:2]2[N:7]=[C:6](/[CH:8]=[C:9](\[O:13][S:21]([C:17]3[CH:18]=[CH:19][CH:20]=[C:15]([Cl:14])[C:16]=3[CH3:25])(=[O:22])=[O:23])/[CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][CH:3]=2)(=[O:23])=[O:22])[CH:18]=[CH:19][CH:20]=1.[CH:17]([S:21]([OH:23])(=[O:13])=[O:22])=[CH2:18]
Reactant: CCCC(=O)Cc1cccc(N)n1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=CS(=O)(=O)O
Product: CCC/C(=C/c1cccc(NS(=O)(=O)c2cccc(Cl)c2C)n1)OS(=O)(=O)c1cccc(Cl)c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 11.3 %

Procedure:
1-(6-Amino-pyridin-2-yl)-pentan-2-one (0.15 g) in CH2Cl2 (5 mL) was treated at RT with 4-dimethylaminopyridine (0.103 g), 3-chloro-2-methyl-benzenesulfonyl chloride (0.208 g) and stirred at RT for 16 h. The mixture was partitioned between cold diluted aqueous HCl and AcOEt, the layers were separated, and the organic layer twice extracted with AcOEt. The combined organic layers were dried over Na2SO4, filtered and evaporated. From the residue was isolated by flash chromatography (heptane/EtOAc 1:1) the vinyl sulfonate 3-chloro-2-methyl-benzenesulfonic acid 1-[1-[6-(3-chloro-2-methyl-benzenesulfonylamino)-pyridin-2-yl]-meth-(Z)-ylidene]-butyl ester (23 mg) as an amorphous off-white solid (27 mg). MS (ESI−): 552.8 ([M−H]−).
Reaction SMILES: [CH2:1]([O:3][CH:4]=[CH:5][C:6](=[O:8])[CH3:7])[CH3:2].[Si:9](OS(C(F)(F)F)(=O)=O)([CH3:12])([CH3:11])[CH3:10]>C1COCC1>[CH2:1]([O:3][CH:4]=[CH:5][C:6](=[CH2:7])[O:8][Si:9]([CH3:12])([CH3:11])[CH3:10])[CH3:2]
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CCOC=CC(C)=O
Solvent: C1CCOC1
Product: C=C(C=COCC)O[Si](C)(C)C
Reaction time: 1 h
Yield: 77.5 %

Procedure:
In a 250 mL three-necked flask under N2 atomosphere, to a solution of 7.2 g of 4-ethoxy-but-3-en-2-one (63 mmol, 1 eq) and 12.7 g of TEA (126 mmol, 2 eq) in THF at −78° C., was added 21 g of TMSOTf (95 mmol, 1.5 eq) dropwise in 40 mins. Stirring was continued for 60 mins at 0˜−30° C. After the conversion was complete (check by NMR), the reaction was quenched with 5% NaHCO3, extract with Hexane and dried over Na2SO4. After remove the solvent the crude product was purified with redistillation (oil pump, <<1 mmbar: Bp, 40° C., Toluene; Bp, 115° C., product) to give 9.1 g pure product. Yield: 72.2%.
Reaction SMILES: [C:1]([C:3]1[CH:43]=[CH:42][C:6]2[N:7]([CH2:28][C:29]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[N:32]=[CH:31][C:30]=3[CH:39]3[CH2:41][CH2:40]3)[C:8](=[O:27])[C@@H:9]([NH:13][C:14](=[O:26])[C@@H:15]([N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH3:16])[C@H:10]([CH3:12])[NH:11][C:5]=2[CH:4]=1)#[N:2].N1C=CC=CC=1.[C:50](Cl)(=[O:52])[CH3:51]>C(Cl)Cl.O>[C:50]([N:11]1[C@@H:10]([CH3:12])[C@H:9]([NH:13][C:14](=[O:26])[C@@H:15]([N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:21])[CH3:22])[CH3:16])[C:8](=[O:27])[N:7]([CH2:28][C:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:32]=[CH:31][C:30]=2[CH:39]2[CH2:40][CH2:41]2)[C:6]2[CH:42]=[CH:43][C:3]([C:1]#[N:2])=[CH:4][C:5]1=2)(=[O:52])[CH3:51]
Reactant: CC(=O)Cl
Reactant: C[C@@H]1Nc2cc(C#N)ccc2N(Cc2c(C3CC3)cnc3ccccc23)C(=O)[C@H]1NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CC(=O)N1c2cc(C#N)ccc2N(Cc2c(C3CC3)cnc3ccccc23)C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@@H]1C
Temperature: 25 °C
Reaction time: 22 h
Yield: 35.7 %

Procedure:
To a rt solution of tert-butyl(S)-1-((3S,4S)-7-cyano-1-((3-cyclopropylquinolin-4-yl)methyl)-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (70 mg, 120 μmol) in CH2Cl2 (801 μl) was added pyridine (29.4 μl, 360 μmol), followed by acetyl chloride (12.8 μl, 180 μmol), dropwise. The reaction was stirred at rt for 22 h, then diluted with H2O and extracted with CH2Cl2. The combined organic layers were washed with sat. aq. NaHCO3 and sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated. The crude material was purified by reverse phase preparative HPLC then flash chromatography to provide tert-butyl(S)-1-((3S,4S)-5-acetyl-7-cyano-1-((3-cyclopropylquinolin-4-yl)methyl)-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (26.8 mg, 36%) as a white solid. MS m/z 625 (MH)+.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[CH:14]=[C:13]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)(=[O:18])=[O:17])[O:12][N:11]=1>C(Cl)(Cl)Cl.ClCCl>[Cl:1][C:14]1[C:10]([CH3:9])=[N:11][O:12][C:13]=1[NH:15][S:16]([C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)=[CH:23][CH:24]=1)(=[O:18])=[O:17]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1ccc(-c2ccc(S(=O)(=O)Nc3cc(C)no3)cc2)cc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cc1ccc(-c2ccc(S(=O)(=O)Nc3onc(C)c3Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.9 %

Procedure:
N-chlorosuccinimide (0.266 g, 2 mmol) was added, in one lot, to a stirred suspension of N-(3-methyl-5-isoxazolyl)-4-(4-methylphenyl)benzenesulfonamide (0.327 g, 1 mmol, Example 14nb) in chloroform (10 ml) and stirred at room temperature for 2 h. The reaction mixture was diluted with dichloromethane (50 ml) and washed with water (2×50 ml). The organic layer was dried over MgSO4 and concentrated. The crude product was purified by column chromatography using ethyl acetate as eluent to give N-(4-chloro-3-methyl-5-isoxazolyl)-4-(4-methylphenyl)benzensulfonamide [210 mg, 58% yield, m.p. 260° C. (de coup)].
Reaction SMILES: [ClH:1].[Cl-:2].[NH2:3][C:4]([CH3:10])([CH3:9])[CH2:5][S+:6]([CH3:8])[CH3:7].C(O[Cl:16])(C)(C)C>CO.O>[Cl-:16].[Cl:1][N:3]([Cl:2])[C:4]([CH3:10])([CH3:9])[CH2:5][S+:6]([CH3:8])[CH3:7]
Reactant: CC(C)(C)OCl
Reactant: C[S+](C)CC(C)(C)N
Reactant: Cl
Agent: [Cl-]
Solvent: CO
Solvent: O
Product: C[S+](C)CC(C)(C)N(Cl)Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of (2-amino-2-methylpropyl)dimethylsulfonium chloride hydrochloride (0.42 g, 2.0 mmol) in a mixture of methanol (10 mL) and water (10 mL) was cooled in an ice bath for 15 min. t-BuOCl (0.72 mL, 3.0 equiv, 6.1 mmol) was added in one portion via syringe to the colorless solution to give a deep yellow solution. The reaction mixture was stirred for 30 min at 0° C., then room temperature for 30 min. The methanol was removed under reduced pressure and the crude solid was purified via reverse phase chromatography on a Shimadzu Prep-LC utilizing water/methanol and 0.05% acetic acid as modifier. Fractions were collected monitoring UV absorbance at 215 nm. Fractions were pooled frozen and lyophilized to give a white solid, (0.26 g, 53.5%). 1H NMR (D2O, 400 MHz): δ 1.41 (s, 6H), 2.51 (s, 2H), 2.98 (s, 2 H). LRMS (ESI−) for C6H14Cl2NS+ (202.0); Found: 203, 204 (M+, M2H+).
Reaction SMILES: O=S(Cl)[Cl:3].[N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[CH2:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]O.CO>C(Cl)(Cl)Cl>[N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[CH2:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][Cl:3]
Reactant: O=S(Cl)Cl
Reactant: OCc1cccc(OCc2ccc3ccccc3n2)c1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: ClCc1cccc(OCc2ccc3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
SOCl2 (2 ml) was added to a solution of 3.58 g (13.5 mmol) of 3-(2-quinolinylmethoxy)benzyl alcohol in 100 ml of CHCl3, followed by stirring at room temperature for 24 hours. A small amount of MeOH was added to the reaction mixture and the solvents were distilled off under reduced pressure, whereby the title compound was obtained as white powder.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:34][N:35](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN>>[CH:1]1([N:7]2[CH2:13][C:12]([F:14])([F:15])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:35][CH3:34])=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Product: CNC(=O)c1ccc(Nc2ncc3c(n2)N(C2CCCCC2)CC(F)(F)C(=O)N3C)c(OC)c1

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and methylamine. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.13-1.42 (m, 2 H) 1.52-1.91 (m, 8 H) 2.80 (d, 3 H) 3.94 (s, 3 H) 4.16 (t, 2 H) 4.49 (quin, 1 H) 7.50 (d, 1 H) 7.55 (s, 1 H) 8.14 (d, J=8.1 Hz, 1 H) 8.24 (d, J=2.0 Hz, 1 H) 8.42 (d, J=4.3 Hz, 1 H) 8.58 (br. s., 1 H). [M+H] calc'd for C23H28F2N6O3 475; found 475.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:36]1[CH:41]=[CH:40][N:39]=[CH:38][N:37]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:17][C@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:24]2[N:28](C3CCCCO3)[N:27]=[CH:26][CH:25]=2)=[CH:12][C:11]=1[F:35])(=[O:9])=[O:8].C([SiH](CC)CC)C.CO>ClCCl.FC(F)(F)C(O)=O>[F:35][C:11]1[CH:12]=[C:13]([O:17][C@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:24]2[NH:28][N:27]=[CH:26][CH:25]=2)[C:14]([F:16])=[CH:15][C:10]=1[S:7]([NH:6][C:36]1[CH:41]=[CH:40][N:39]=[CH:38][N:37]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@H]3CCCC[C@@H]3c3ccnn3C3CCCCO3)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: O=S(=O)(Nc1ccncn1)c1cc(F)c(O[C@H]2CCCC[C@@H]2c2ccn[nH]2)cc1F
Reaction time: 1 h
Yield: 76.4 %

Procedure:
To a solution of the N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(pyrimidin-4-yl)-4-({(1S*,2R*)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]cyclohexyl}oxy)benzenesulfonamide (366 mg, 0.547 mmol) prepared in Example 22b and triethylsilane (0.40 mL) in dichloromethane (4.0 mL), trifluoroacetic acid (4.0 mL) was added at room temperature, and the reaction solution was stirred for 1 hour. To the reaction solution, methanol (4.0 mL) was added, and the mixture was further stirred at room temperature for 1 hour. The reaction solution was concentrated, and the residue was purified with silica gel chromatography (dichloromethane/methanol=95:5) to yield the title compound (182 mg, 61%) as a colorless solid.