Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Cl)=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([SH:26])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:26][C:23]2[CH:24]=[CH:25][C:20]([NH2:19])=[CH:21][CH:22]=2)=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cc(OCc2ccccc2)ccc1Cl
Reactant: Nc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1ccc(Sc2ccc(OCc3ccccc3)cc2[N+](=O)[O-])cc1
Temperature: 0 °C
Yield: 82.1 %

Procedure:
A solution of the compound prepared in Example 214A (1.0 g, 3.80 mmol), 4-aminothiophenol (0.5 g, 4.00 mmol), cesium carbonate (1.3 g, 4 mmol) in dimethylformamide (10 ml) was heated at 40° C. for 16 hours. Afterwards, ice water (50 mL) was added to the solution and the resultant slurry was treated with ethyl acetate (100 ml). The layers were separated and the organic layer was washed with 10% sodium bicarbonate and 10% sodium chloride, then dried over anhydrous sodium sulfate. The drying agent was filtered and solvent was removed under vacuum leaving an orange oil as the title compound, (1.1 g, 83%).
Reaction SMILES: [C:1]([CH:3]=[C:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:20][C@@H:19]([CH2:21][N:22]=[N+:23]=[N-:24])[O:18][C:17]3=[O:25])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)#[N:2].[C:26]([O:30]CC)(=[O:29])[C:27]#[CH:28].[C:33]1(C)C=CC=C[CH:34]=1>>[C:1]([CH:3]=[C:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:20][C@@H:19]([CH2:21][N:22]4[CH:34]=[C:33]([CH2:28][CH2:27][C:26]([OH:30])=[O:29])[N:24]=[N:23]4)[O:18][C:17]3=[O:25])=[CH:12][CH:11]=2)[CH2:8][CH2:9]1)#[N:2]
Reactant: N#CC=C1CCN(c2ccc(N3C[C@@H](CN=[N+]=[N-])OC3=O)cc2)CC1
Reactant: C#CC(=O)OCC
Reactant: Cc1ccccc1
Product: N#CC=C1CCN(c2ccc(N3C[C@@H](Cn4cc(CCC(=O)O)nn4)OC3=O)cc2)CC1
Yield: 70 %

Procedure:
The mixture of compound of Example 1 (2.05 mmol), ethyl propiolate (4.21 mmol), in toluene (10 ml) was heated under reflux for 4 hours. The solvent was removed under vacuum. The residue was triturated with the hexane and filtered to provide a isomeric mixture of two compounds. The column chromatographic purification on silica gel afforded the titled compound in 70% yield.
Reaction SMILES: [C:1](O)(=[O:4])[CH:2]=[CH2:3].C1(N=C=NC2CCCCC2)CCCCC1.[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([N:28]2[CH:36]([O:37][C:38]([N:40]3[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]3)=[O:39])[C:35]3[C:30](=[N:31][CH:32]=[CH:33][N:34]=3)[C:29]2=[O:46])=[N:26][CH:27]=1>C(Cl)Cl.C(OCC)(=O)C.CN(C)C=O>[OH2:4].[C:1]([N:43]1[CH2:42][CH2:41][N:40]([C:38]([O:37][CH:36]2[C:35]3[C:30](=[N:31][CH:32]=[CH:33][N:34]=3)[C:29](=[O:46])[N:28]2[C:25]2[CH:24]=[CH:23][C:22]([Cl:21])=[CH:27][N:26]=2)=[O:39])[CH2:45][CH2:44]1)(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)O
Reactant: O=C(OC1c2nccnc2C(=O)N1c1ccc(Cl)cn1)N1CCNCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C=CC(=O)N1CCN(C(=O)OC2c3nccnc3C(=O)N2c2ccc(Cl)cn2)CC1
Product: O
Temperature: 20 °C
Reaction time: 1 h
Yield: 56.4 %

Procedure:
A solution of acrylic acid (1.19 g.) in anhydrous methylene chloride (10 cc.) followed by a solution of N,N'-dicyclohexylcarbodiimide (3.4 g.) in anhydrous methylene chloride (30 cc.) are added successively, at a temperature of about 20° C., to a suspension of 6-(5-chloropyrid-2-yl)-7-oxo-5-(piperazin-1-yl)carbonyloxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine (5.6 g.) in anhydrous methylene chloride (100 cc.). The mixture is stirred for 1 hour at a temperature of about 20° C. The insoluble product (dicyclohexylurea) is filtered off and washed with methylene chloride (2×10 cc.). The filtrate is concentrated to dryness under reduced pressure and then the residue obtained is taken up in ethyl acetate (25 cc.) and a small amount of insoluble matter is filtered off. The filtrate is left to stand for 18 hours at a temperature of about 20° C. and the product which has crystallised is filtered off and washed with ethyl acetate (3×2 cc.). After drying, the product obtained (4.9 g.) is dissolved in methylene chloride (100 cc.). The solution is filtered through silica gel (100 g.) contained in a column of diameter 3 cm. Elution is carried out using pure methylene chloride (400 cc.), a mixture of methylene chloride and methanol (99-1 by volume; 300 cc.) and a mixture of methylene chloride and methanol (98-2 by volume; 300 cc.). These eluates are discarded. Elution is then carried out using a mixture of methylene chloride and methanol (98-2 by volume; 200 cc.) and the corresponding eluates are combined and concentrated to dryness under reduced pressure (20 mm.Hg). After recrystallisation from acetonitrile and drying, a product (2.3 g.), which is solvated with acetonitrile, is obtained. This product is dissolved in dimethylformamide (37 cc.) at a temperature of about 50° C. and the solution is poured into ice-water (370 cc.). The insoluble product is filtered off and washed with water (3×10 cc.). After drying, 5-(4-acryloylpiperazin-1-yl)carbonyloxy-6-(5-chloropyrid-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine hydrate (2.08 g.), which melts at about 202°-204° C., is obtained.
Reaction SMILES: [F:1][C:2]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[N:17][C:18]=3[NH2:20])[N:13]([C@@H:21]3[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]3)[N:12]=2)=[C:7]([F:27])[CH:6]=1.[C:33]([C:35](=[CH:39][CH:40]([CH3:42])[CH3:41])[C:36](O)=[O:37])#[N:34].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[NH2:20][C:18]1[N:17]=[CH:16][N:15]=[C:14]2[N:13]([C@@H:21]3[CH2:26][CH2:25][CH2:24][N:23]([C:36]([C:35](=[CH:39][CH:40]([CH3:42])[CH3:41])[C:33]#[N:34])=[O:37])[CH2:22]3)[N:12]=[C:11]([C:8]3[CH:9]=[CH:10][C:5]([O:4][C:3]4[CH:28]=[CH:29][CH:30]=[C:31]([F:32])[C:2]=4[F:1])=[CH:6][C:7]=3[F:27])[C:19]=12
Reactant: CC(C)C=C(C#N)C(=O)O
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3cccc(F)c3F)cc1F)nn2[C@@H]1CCCNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)C=C(C#N)C(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4cccc(F)c4F)cc3F)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of (R)-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.23 mmol, 1.0 eq), 2-cyano-4-methyl-pent-2-enoic acid (38 mg, 0.27 mmol, 1.2 eq) and DIEA (88 mg, 0.68 mmol, 3.0 eq) in 10 ml DCM was added HATU (130 mg, 0.34 mmol, 1.5 eq). The reaction mixture was stirred for 4 h at RT under N2. The mixture was purified by Pre-HPLC to give the title compound (25 mg40% yield). LCMS: m/z+ (562.2) (M+H)+ 1HNMR (400 MHz, CDCl3): δ 0.784˜1.186 (m, 7H), 1.765˜2.254 (m, 5H), 2.861˜4.937 (m, 4H), 6.218 (m, 0.4H), 6.857˜7.600 (m, 6H), 8.255 (s, 1H) and 9.888 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]2[C@@H:13]([CH2:21][NH:22][CH:23]2[CH2:26][CH:25]([CH2:27][CH2:28][C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:30])[CH2:24]2)[O:12]1.C=O.O.[C:42]([BH3-])#N.[Na+]>CO>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:19])([CH3:20])[O:18][C@@H:14]2[C@@H:13]([CH2:21][N:22]([CH3:42])[CH:23]2[CH2:26][CH:25]([CH2:27][CH2:28][C:29]([O:31][CH2:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[O:30])[CH2:24]2)[O:12]1
Reactant: [BH3-]C#N
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CNC1CC(CCC(=O)OCc3ccccc3)C1)O[C@H]2n1cnc2c(N)ncnc21
Agent: C=O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)C1CC(CCC(=O)OCc2ccccc2)C1
Reaction time: 0.75 h
Yield: 62.4 %

Procedure:
Benzyl 3-[3-({[(3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyl-tetrahydro-2H-furo[3,4-d][1,3]dioxol-4-yl]methyl}amino)cyclobutyl]propanoate (3.2 g, 6.12 mmol) was dissolved in methanol (32 ml), Formaldehyde in water (37%) (0.92 ml, 12.3 mmol) was added and stirred for 45 min before adding sodium cyanoborohydride (0.54 g, 8.57 mmol) portionwise. The reaction was stirred for 2 h at r.t. before adding water (1 ml) and evaporating off the solvent at r.t. The residue was purified by chromatography with 7M ammonia in methanol/DCM to give the desired compound as a yellow oil (mix of diastereomers) (2.05 g, 62%, 82% pure): MS (ESI+) for C28H36N6O5 m/z 537.6 [M+H]+; LC purity 82% (ret. time, 1.60 min); 1H NMR (500 MHz, CDCl3) δH 8.32-8.38 (m, 1H), 7.91-7.97 (m, 1H), 7.32-7.39 (m, 5H), 6.05-6.10 (m, 1H), 5.61 (br. s., 2H), 5.53 (ddd, J=16.5, 6.4, 1.8 Hz, 1H), 5.11 (m, 2H), 4.93-5.00 (m, 1H), 4.32-4.40 (m, 1H), 2.50-2.88 (m, 1H), 2.37-2.49 (m, 2H), 2.21-2.30 (m, 2H), 2.10 (m, 3H), 1.91-2.04 (m, 1H), 1.73-1.79 (m, 2H), 1.64-1.72 (m, 2H), 1.56-1.63 (m, 4H), 1.41 (s, 3H), 1.15 (q, J=9.7 Hz, 1H).
Reaction SMILES: BrCCCCC[OH:7].CCN(CC)CC.[CH3:15][C:16]([Si:19](Cl)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:18])[CH3:17].[NH4+].[Cl-]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Si:19]([OH:7])([C:16]([CH3:18])([CH3:17])[CH3:15])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: OCCCCCBr
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](O)(c1ccccc1)c1ccccc1
Yield: 155.3 %

Procedure:
A solution of 5-bromo-pentanol (0.9889 g, 5.9 mmol, 1 eq) in anhydrous CH2Cl2 (20 mL) under N2 at 25° C. was treated with anhydrous Et3N (1.0 mL, 7.2 mmol, 1.2 eq), TBDPSCl (1.7 mL, 6.5 mmol, 1.1 eq) and DMAP (0.23 g, 1.9 mmol, 0.3 eq). The reaction mixture was stirred for 2 h before an aqueous solution of saturated NH4Cl (100 mL) was added. The aqueous layer was extracted with EtOAc (3×100 mL) and the organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was chromatographed (Sio2, 5×20 cm, 0-20% EtOAc/hexanes, gradient elution) to afford TBDPSOH (2.35 g, 98%) as a clear oil; 1H NMR (CDCl3, 400 MHz) δ7.66-7.60 (m, 4H) 7.44-7.33 (m, 6H), 3.64 (t, 2H, J=6.1 Hz), 3.37 (t, 2H, J=6.9 Hz), 1.82 (p, 2H, J=7.3 Hz), 1.59-1.45 (m, 4H), 1.03 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ135.6, 129.6, 127.6, 127.5, 63.5, 33.9, 32.5, 31.6, 26.8, 24.5, 19.2; IR (film) υmax 3069, 2930, 2856, 2359, 1470, 1427, 1389, 1106, 822, 738, 700 cm−1; FABHRMS (NBA-CsI) m/z 537.0235 (C21H29OSiBr+Cs+ requires 537.0225).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[CH:7]=[CH:6][C:5]2=[O:19]>C(O)(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[Cl:1][C:2]1[CH:11]=[C:10]2[C:9]3=[C:4]([C:5](=[O:19])[CH:6]=[CH:7][N:8]3[C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]2=3)[CH:3]=1
Reactant: O=c1ccn(-c2ccc(Cl)cc2)c2ccc(Cl)cc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: O=c1ccn2c3ccc(Cl)cc3c3cc(Cl)cc1c32
Yield: 2 %

Procedure:
6-chloro-1-(4-chlorophenyl)-4(1H)-quinolinone (2 g) obtained in step 4 was dissolved in acetic acid (150 ml) and to the solution were added a boron tribromide-acetic acid complex (44 ml) and palladium diacetate (6.28 g). The mixture was heated under reflux for 1 hour in an argon atmosphere and allowed to cool. The insoluble content was removed by filtration and the solution was extracted with water and ethyl acetate. The ethyl acetate layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent:hexane/ethyl acetate=1:2) to obtain the title compound (40 mg, 2%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:16]([O-:18])=[O:17])=[C:6]([CH:15]=1)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.CC1(C)C(C)(C)OB([C:27]2[CH2:28][CH2:29][O:30][CH2:31][CH:32]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+].O>C(COC)OC>[O:30]1[CH2:29][CH:28]=[C:27]([C:2]2[CH:3]=[CH:4][C:5]([N+:16]([O-:18])=[O:17])=[C:6]([CH:15]=2)[NH:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH2:32][CH2:31]1
Reactant: O=[N+]([O-])c1ccc(Br)cc1NCc1ccccn1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: O=[N+]([O-])c1ccc(C2=CCOCC2)cc1NCc1ccccn1

Procedure:
5-bromo-2-nitro-N-(pyridin-2-ylmethyl)aniline E-1.9″ (145 mg; 0.47 mmol), 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyran (145 mg; 0.69 mmol), cesium carbonate (300 mg; 0.90 mmol) and [1,1′-Bis[diphenylphosphino]-ferrocene]dichloropalladium (30 mg; 0.04 mmol) are suspended in 2.5 ml dimethoxyethane and 0.8 ml water and heated for 1 h at 100° C. The solvent of the reaction mixture is removed under reduced pressure and the crude product is purified using reversed phase chromatography (Method: prep. HPLC1).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6](Br)=[CH:5][N:4]=1.[Li]C(CC)C.CNN(NC)[C:20](=[O:22])[CH3:21].O>CCOCC>[F:1][C:2]([F:11])([F:10])[C:3]1[N:4]=[CH:5][C:6]([C:20](=[O:22])[CH3:21])=[CH:7][CH:8]=1
Reactant: CNN(NC)C(C)=O
Reactant: FC(F)(F)c1ccc(Br)cn1
Agent: [Li]C(C)CC
Solvent: O
Solvent: CCOCC
Product: CC(=O)c1ccc(C(F)(F)F)nc1
Reaction time: 0.17 h
Yield: 54.5 %

Procedure:
To a solution of 2-trifluoromethyl-5-bromopyridine (5.0 g, 22 mmol) in Et2O (50 mL) was added sec-BuLi (0.91 M in cyclohexane, 24 mL, 22 mmol) at −78° C. After 10 minutes of stirring, N,N-dimethylaminoacetamide (2.3 mL, 24 mmol) dissolved in Et2O (10 mL) was added drop wise. Stirring was continued at −78° C. for 1 h and then at rt over night. The reaction mixture was poured into water (100 mL) and the water phase was extracted with Et2O (3×100 mL). Combined organics were washed with water and brine and dried (MgSO4). After careful evaporation of the solvent, the crude was purified by column chromotography (SiO2, pentane/ether 9/1) to give the title compound (2.3 g, 12 mmol, 54%) as a light yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([CH3:17])[C:13]2([CH2:15][CH2:14]2)[C:12](=[O:16])[NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCCCCC>CN(C)C=O.C(OCC)(=O)C>[CH2:20]([N:11]1[CH2:10][C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])([CH3:17])[C:13]2([CH2:14][CH2:15]2)[C:12]1=[O:16])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1(C)CNC(=O)C12CC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)NC1(C)CN(Cc2ccccc2)C(=O)C12CC2
Reaction time: 3 h
Yield: 89.2 %

Procedure:
7-t-Butoxycarbonylamino-4-oxo-7-methyl-5-azaspiro[2.4]heptane (42.63 g) was suspended in dimethylformamide (850 mL) under a nitrogen gas atmosphere, and the suspension was cooled with ice. To the suspension, 60% sodium hydride (6.93 g) was added, and the mixture was returned to room temperature. Subsequently, benzyl bromide (22.64 mL) was added to the reaction mixture, followed by stirring. After three hours, insoluble material was removed through filtration, and water was added to the filtrate. Ethyl acetate was further added thereto for extraction. The organic layer obtained through extraction was dried with sodium sulfate, followed by filtration. The filtrate was concentrated under reduced pressure, to thereby yield an oily residue. The residue was subjected to silica gel chromatography (hexane:ethyl acetate), to thereby yield the title product as pale yellow oil (51.0 g, yield: 89.2%).
Reaction SMILES: [Cl-:1].[CH3:2][P+:3]1([CH3:8])[CH2:7][CH:6]=[CH:5][CH2:4]1.[Cl:9]Cl>C(Cl)(Cl)Cl>[Cl-:1].[Cl:1][CH:5]1[CH:6]([Cl:9])[CH2:7][P+:3]([CH3:8])([CH3:2])[CH2:4]1
Reactant: ClCl
Reactant: C[P+]1(C)CC=CC1
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: C[P+]1(C)CC(Cl)C(Cl)C1

Procedure:
44.3 g (0.2 mole) of 1,1-dimethyl-3-phospholenium chloride were suspended in 250 ml of chloroform and reacted with 14.2 g (0.2 mole) of chlorine at 20° C. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. This gave 3,4-dichloro-1,1-dimethyl-phospholanium chloride in the form of colourless crystals of melting point 90°-100° C. (decomp.).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[F:9][C:10]1[C:15]([CH:16]=[O:17])=[C:14]([OH:18])[C:13]([O:19][CH3:20])=[CH:12][CH:11]=1.O.C(OCC)(=O)C>C(#N)C>[Br:1][C:11]1[CH:12]=[C:13]([O:19][CH3:20])[C:14]([OH:18])=[C:15]([C:10]=1[F:9])[CH:16]=[O:17]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(F)c(C=O)c1O
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: COc1cc(Br)c(F)c(C=O)c1O
Yield: 71.9 %

Procedure:
After adding 3.11 g of N-bromosuccinimide to a solution of 2.98 g of 6-fluoro-2-hydroxy-3-methoxybenzaldehyde [CAS No. 457628-15-8] in 15 ml of acetonitrile, the mixture was stirred overnight at room temperature. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off, and the filtrate was concentrated under reduced pressure to give 3.13 g of 5-bromo-6-fluoro-2-hydroxy-3-methoxybenzaldehyde (crude product).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH:16]=1.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23](Cl)=[O:24]>>[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH:16]=1)=[O:24]
Reactant: CN1CC=C(c2c[nH]c3ccc(N)cc23)CC1
Reactant: O=C(Cl)c1cccs1
Product: CN1CC=C(c2c[nH]c3ccc(NC(=O)c4cccs4)cc23)CC1
Yield: 32.9 %

Procedure:
Beginning with 1.0 gm (4.4 mMol) 5-amino-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole and 0.494 mL (4.6 mMol) 2-thiophenecarbonyl chloride, 0.489 gm (33.0%) of the title compound were recovered as a bright yellow solid.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:15]=[CH:16][C:17]3[O:22][CH2:21][CH2:20][N:19]([S:23]([C:26]4[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=4[O:33][CH3:34])(=[O:25])=[O:24])[C:18]=3[CH:35]=2)=[O:13])=[CH:7][CH:6]=1)=[NH:4].N1C=CC=CC=1.C(C(CCCC)[CH2:45][O:46]C(Cl)=O)C>CN(C)C=O.O>[O:46]=[C:45]1[O:1][N:2]=[C:3]([C:5]2[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]3[CH:15]=[CH:16][C:17]4[O:22][CH2:21][CH2:20][N:19]([S:23]([C:26]5[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=5[O:33][CH3:34])(=[O:24])=[O:25])[C:18]=4[CH:35]=3)=[O:13])=[CH:7][CH:6]=2)[NH:4]1
Reactant: CCCCC(CC)COC(=O)Cl
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1CCOc2ccc(C(=O)Nc3ccc(C(=N)NO)cc3)cc21
Solvent: CN(C)C=O
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(Cl)cc1S(=O)(=O)N1CCOc2ccc(C(=O)Nc3ccc(-c4noc(=O)[nH]4)cc3)cc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid [4-(N-hydroxycarbamimidoyl)-phenyl]-amide (97 mg, 0.19 mmol) in dimethylformamide (2.0 mL) was treated with pyridine (0.020 mL, 0.20 mmol) and the mixture was cooled at 0° C. Chloroformic acid 2-ethylhexyl ester (36 mg, 0.19 mmol) was added dropwise and the mixture was stirred at 0° C. for 30 min. The mixture was diluted with water and extracted three times with ethyl acetate. The combined organic extracts were dried over sodium sulfate and evaporated. The residue was suspended in xylene (8.0 mL) and refluxed for 2 hours. Upon cooling to room temperature a solid precipitated, which was filtered and dried under high vacuum. 4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid [4-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenyl]-amide was obtained as a white solid, 74 mg (73%), MS (ISP): m/e=541.1, 542.7 (M−H).
Reaction SMILES: [F:1][CH:2]([F:26])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][C:13]([NH:16][C:17]3[CH:18]=[N:19][CH:20]=[C:21]([CH:25]=3)[C:22]([OH:24])=O)=[N:14][CH:15]=2)=[CH:6][CH:5]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:60]([N:67]1[CH2:72][CH2:71][NH:70][CH2:69][CH2:68]1)([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61]>CN(C=O)C>[F:26][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][C:13]([NH:16][C:17]3[CH:18]=[N:19][CH:20]=[C:21]([CH:25]=3)[C:22]([N:70]3[CH2:69][CH2:68][N:67]([C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])[CH2:72][CH2:71]3)=[O:24])=[N:14][CH:15]=2)=[CH:6][CH:5]=1
Reactant: O=C(O)c1cncc(Nc2ncc(-c3ccc(OC(F)F)cc3)cn2)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cncc(Nc3ncc(-c4ccc(OC(F)F)cc4)cn3)c2)CC1
Reaction time: 0.03 h

Procedure:
To a solution of 5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)nicotinic acid 19 (0.028 mmol) in DMF (1 mL) is added HATU (0.033 mmol) and DIEA (0.084 mmol) at rt. The resulting mixture is stirred for 2 min then N-boc-piperazine (0.03 mmol) is added. The reaction mixture is stirred at it for 12 h and directly purified by preparative LCMS to give tert-butyl 4-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)nicotinoyl)piperazine-1-carboxylate. The residue is treated with TFA (1 mL) at rt for 1 h, concentrated under vacuum, and directly purified by preparative LCMS to afford (5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)pyridin-3-yl)(piperazin-1-yl)methanone B3. NMR (400 MHz, d3-CH3CN) δ 9.32 (bs, 1H), 8.86 (s, 2H), 8.67 (bs, 1H), 8.41 (bs, 1H), 7.75 (d, J=12.0 Hz, 2H), 7.33 (d, J=12.0 Hz, 2H), 6.87 (t, J=73 Hz, 1H), 4.20 (bs, 4H), 3.30 (bs, 4H). MS (m/z) (M+1)+: 427.1.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[C:16]([C:17]#[N:18])=[CH:15][N:14]=[C:13](S(C)(=O)=O)[N:12]=3)=[CH:9][N:8]([S:23]([C:26]3[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[C:5]2=[N:6][CH:7]=1.[NH2:33][C@H:34]([CH:37]([CH3:39])[CH3:38])[CH2:35][OH:36].C(N(C(C)C)CC)(C)C>C1COCC1>[OH:36][CH2:35][C@H:34]([NH:33][C:13]1[N:12]=[C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([CH3:1])[CH:3]=3)[N:8]([S:23]([C:26]3[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH:9]=2)[C:16]([C:17]#[N:18])=[CH:15][N:14]=1)[CH:37]([CH3:39])[CH3:38]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nc(S(C)(=O)=O)ncc3C#N)c3cc(C)cnc32)cc1
Reactant: CC(C)[C@@H](N)CO
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3nc(N[C@@H](CO)C(C)C)ncc3C#N)c3cc(C)cnc32)cc1
Yield: 76.9 %

Procedure:
A mixture of 4-(5-methyl-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-(methylsulfonyl)pyrimidine-5-carbonitrile (120 mg, 0.257 mmol), (R)-(−)-2-amino-3-methyl-1-butanol (57 μl, 0.515 mmol) and diisopropylethylamine (90 μl, 0.515 mmol) in THF (4 mL) was heated at reflux for 1 hour. The reaction mixture was concentrated in vacuo and the residue was purified on silica gel by flash column chromatography to give the title compound as a colourless glassy solid (97 mg, 77% yield).