Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.C([Li])CCC.[CH2:15]1[O:17][CH2:16]1.[Cl-].[NH4+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:15][CH2:16][OH:17])=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(Cl)cc1
Reactant: C1CO1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: OCCC#Cc1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
Dissolve 14.2 g (0.104 mole) of 1-chloro-4-ethynylbenzene in 35 ml dry THF and cool to -78° C. Add 49 ml butyl lithium to cold reaction mixture and allow to warm to room temperature for 2 hours. After 2 hours, cool to -78° C. and the add 5.8 ml (0.114 mole) ethylene oxide in 20 ml THF. Allow to warm to room temperature. Monitor progress of reaction with thin-layer chromatography on silica gel (methylene chloride). After 18 hours, add 150 ml saturated aqueous ammonium chloride solution and extract with 150 ml diethyl ether. Wash organic layer with 2×100 ml saturated aqueous sodium chloride solution. Dry organic layer with magnesium sulfate and then filter, and evaporate solvent to obtain the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:20])[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.C([Si](C(C)C)(C(C)C)[O:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH2:42][C@@H:43]2[CH2:45][O:44]2)=[CH:37][C:36]=1[CH3:46])(C)C>>[CH2:22]([NH:21][C:19]([N:16]1[CH2:17][CH2:18][CH:13]([S:10]([C:7]2[CH:6]=[CH:5][C:4]([CH2:3][CH2:2][NH:1][CH2:45][C@H:43]([OH:44])[CH2:42][O:41][C:38]3[CH:39]=[CH:40][C:35]([OH:34])=[C:36]([CH3:46])[CH:37]=3)=[CH:9][CH:8]=2)(=[O:12])=[O:11])[CH2:14][CH2:15]1)=[O:20])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: Cc1cc(OC[C@@H]2CO2)ccc1O[Si](C(C)C)(C(C)C)C(C)C
Reactant: CCCCCCCCNC(=O)N1CCC(S(=O)(=O)c2ccc(CCN)cc2)CC1
Product: CCCCCCCCNC(=O)N1CCC(S(=O)(=O)c2ccc(CCNC[C@H](O)COc3ccc(O)c(C)c3)cc2)CC1
Yield: 16.8 %

Procedure:
4-{[4-(2-Aminoethyl)phenyl]sulfonyl}-N-octyl-1-piperidinecarboxamide (1.38 g, 3.258 mmol) was reacted with triisopropyl{2-methyl-4-[(2S)oxiranylmethoxy]phenoxy}silane (1.04 g, 3.095 mmol) according to Procedure G to give the title compound (eluant: 20:1 chloroform:methanol) (0.395 g, 0.520 mmol).
Reaction SMILES: [C:1]([NH:9][C:10](=[CH:15][N:16]([CH3:18])C)[C:11]([O:13][CH3:14])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N[C:20]1[CH:25]=[CH:24]C=[CH:22][CH:21]=1.Cl.O>C(O)(C)C>[C:1]([NH:9][C:10](=[CH:15][NH:16][C:18]1[CH:24]=[CH:25][CH:20]=[CH:21][CH:22]=1)[C:11]([O:13][CH3:14])=[O:12])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccccc1
Reactant: COC(=O)C(=CN(C)C)NC(=O)c1ccccc1
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: COC(=O)C(=CNc1ccccc1)NC(=O)c1ccccc1
Temperature: 10 °C
Reaction time: 0.17 h

Procedure:
10g (39.5 mmol) of methyl 2-benzoylamino-3-dimethylaminoacrylate and 11.1 g (118 mmol) of aniline were dissolved at 40° C. in 200 ml of isopropanol. The solution was admixed with 3.6 ml (43.5 mmol) of concentrated hydrochloric acid within 5 minutes (min) and stirred for a further 10 min. 200 ml of deionized water were added, the suspension was cooled to 10° C. and the crystallized product was filtered off. Yield: 11.5 g (92% of theory) 1H NMR: 3.62 (s, 3H); 6.90-7.00 (m, 1H); 7.19 (d, 2H); 7.25-7.30 (m, 2H); 7.48-7.61 (m, 3H); 7.93 (d, 1H); 8.02 (d, 2H); 8.90 (d, 1H); 9.15 (s, 1H)
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12]C)=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.B(Br)(Br)Br.CO>C(Cl)Cl.C1COCC1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COc1ccc2c(Cl)nccc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: Oc1ccc2c(Cl)nccc2c1
Temperature: 50 °C
Yield: 155.1 %

Procedure:
To a solution of 1-chloro-6-methoxy-isoquinoline (2 g, 10.3 mmol) in DCM (60 ml) was added BBr3 in (4.9 ml, 51.6 mmol) in 10 mL THF and the reaction was heated to 50° C. overnight. The reaction was cooled to 0° C. and 30 volumes of methanol was added as a quench. The solvent was removed to afford 2.87 g (>99%) of 1-chloro-isoquinolin-6-ol as a brown solid. LCMS found 180.36 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[S:25](=[O:27])(=[O:26])[N:24]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:23](=[O:32])[CH:22]=2)=[C:17]([Cl:33])[CH:16]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Li+].C(O)(=O)C>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[S:25](=[O:26])(=[O:27])[N:24]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:23](=[O:32])[CH2:22]2)=[C:17]([Cl:33])[CH:16]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@H](Cc1ccc(C2=CC(=O)N(C(C)(C)C)S2(=O)=O)c(Cl)c1)NC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1ccc(C2CC(=O)N(C(C)(C)C)S2(=O)=O)c(Cl)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.9 %

Procedure:
Methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-[4-(2-tert-butyl-1,1-dioxido-3-oxo-2,3-dihydroisothiazol-5-yl)-3-chlorophenyl]propanoate (300 mg, 0.598 mmol) in tetrahydrofuran (6.00 mL) was cooled to 0° C. and treated with lithium tetrahydroborate solution in tetrahydrofuran (2.0 M, 0.329 mL). The reaction was allowed to stir for 0.5 h at rt. After addition of acetic acid (0.5 mL), the solution was diluted with ethyl acetate (100 mL), washed with water (100 mL), separated, dried over sodium sulfate, filtered and was concentrated in vacuo. The crude material was purified by silica gel chromatography (5–30% ethyl acetate/hexanes) to afford the product as a white solid (162 mg, 54%). 1H NMR (400 MHz, CD3OD): δ 7.45–7.42 (m, 2H), 7.31–7.27 (m, 1H), 5.59 (t, J=8.0 Hz, 1H), 4.39–4.36 (m, 1H), 3.70 (s, 3H), 3.38–3.33 (m, 1H), 3.25–3.14 (m, 2H), 2.95–2.92 (m, 1H), 1.67 (s, 9H), 1.37 (s, 9H); LCMS found for C17H24ClN2O5S (M+H)+: m/z=403.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[F:24])[O:5][C:6]1[N:11]=[C:10]2[S:12][C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])=[N:14][C:9]2=[CH:8][CH:7]=1.[F:25][C:26]([F:38])([F:37])[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34](O)=[O:35])=[CH:29][CH:28]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>N1C=CC=CC=1.C(OCC)(=O)C>[F:24][C:23]1[CH:22]=[CH:21][C:4]([O:5][C:6]2[N:11]=[C:10]3[S:12][C:13]([NH:15][C:16]([CH:18]4[CH2:20][CH2:19]4)=[O:17])=[N:14][C:9]3=[CH:8][CH:7]=2)=[CH:3][C:2]=1[NH:1][C:34](=[O:35])[CH2:33][C:30]1[CH:29]=[CH:28][C:27]([C:26]([F:37])([F:25])[F:38])=[CH:32][CH:31]=1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C(Cc1ccc(C(F)(F)F)cc1)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Temperature: 80 °C
Reaction time: 12 h
Yield: 53.3 %

Procedure:
N-[5-(3-Amino-4-fluorophenoxy)[1,3]thiazolo[5,4-b]pyridin-2-yl]cyclopropanecarboxamide (100 mg, 0.29 mmol) produced in Example 16(vi) was dissolved in pyridine (2.0 mL), [4-(trifluoromethyl)phenyl]acetic acid (120 mg, 0.58 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (220 mg, 0.58 mmol) were added, and the mixture was stirred at 80° C. for 12 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (10 mL), and washed successively with 5% aqueous ammonium chloride solution (10 mL), saturated aqueous sodium hydrogen carbonate solution (10 mL) and saturated brine (10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/hexane=40/60→100/0), and the obtained solution was concentrated under reduced pressure. The obtained residue was washed with ethyl acetate/heptane to give the title compound (82 mg, 53%) as a colorless powder.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]5([C:28]#[N:29])[CH2:27][CH2:26]5)[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:31]=1.[N:32]1[CH:37]=[CH:36][C:35]([C:38](O)=[O:39])=[CH:34][CH:33]=1.C(Cl)(=O)C(Cl)=O.O1CCCC1>CN(C)C=O.CN1CCCC1=O>[C:28]([C:25]1([C:21]2[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=2)[C:18]([NH:17][C:13]2[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=2)[O:10][C:7]2[CH:8]=[CH:9][C:4]3[N:5]([CH:31]=[C:2]([NH:1][C:38](=[O:39])[C:35]4[CH:36]=[CH:37][N:32]=[CH:33][CH:34]=4)[N:3]=3)[N:6]=2)=[O:30])[CH2:27][CH2:26]1)#[N:29]
Reactant: O=C(O)c1ccncc1
Reactant: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc5nc(N)cn5n4)c3)c2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc5nc(NC(=O)c6ccncc6)cn5n4)c3)c2)CC1
Yield: 59 %

Procedure:
Using N-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(1-cyanocyclopropyl)benzamide (150 mg, 0.365 mmol), pyridine-4-carboxylic acid (54 mg, 0.438 mmol), oxalyl chloride (63 μL, 0.734 mmol), N,N-dimethylformamide (1 drop), tetrahydrofuran (3 mL) and N-methylpyrrolidone (3 mL) as starting materials and in the same manner as in Example 412, the title compound (111 mg, 59%) was obtained as a pale-green powder.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[OH:7][CH2:8][C@H:9]1[N:19]2[C@@H:13]([S:14][CH2:15][CH2:16][C@H:17]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:18]2=[O:20])[CH2:12][CH2:11][CH2:10]1.IC>C1COCC1>[CH3:1][O:7][CH2:8][C@H:9]1[N:19]2[C@@H:13]([S:14][CH2:15][CH2:16][C@H:17]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:27])[CH3:26])[C:18]2=[O:20])[CH2:12][CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCS[C@H]2CCC[C@@H](CO)N2C1=O
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: COC[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)OC(C)(C)C)C(=O)N12
Reaction time: 0.25 h
Yield: 15.5 %

Procedure:
A solution of potassium tert-butoxide (1 M in THF, 1.55 mL, 1.55 mmol) was added dropwise to a 0° C. solution of tert-butyl (4S,7S,10aS)-7-(hydroxymethyl)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-ylcarbamate (513 mg, 1.55 mmol) in THF (5 mL). The reaction mixture turned yellow in color. After 15 min of stirring, iodomethane (441 mg, 3.10 mmol) was added. The ice bath was removed and the reaction mixture was stirred at rt overnight. Water was added to the reaction and the mixture was concentrated to remove most of the THF. The aqueous solution was then extracted with EtOAc. The organic phase was isolated, washed with saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. The crude product was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-60% EtOAc/Hex to give tert-butyl (4S,7S,10aS)-7-(methoxymethyl)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-ylcarbamate (83 mg, 0.24 mmol, 16% yield) as a colorless oil. Anal. Calcd. for C16H28N2O4S m/z 344.4. found: 345.1 (M+H)+.
Reaction SMILES: COC1C=CC(C[S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27]([OH:29])=O)[CH2:10]2)=CC=1.C(Cl)(=O)C(C)(C)C.[CH3:39][C@H:40]1[CH2:45][NH:44][C@H:43]([CH3:46])[CH2:42][N:41]1[C:47]([O:49][CH2:50][C:51]1[CH:56]=[CH:55][C:54]([N+:57]([O-:59])=[O:58])=[CH:53][CH:52]=1)=[O:48]>C(N(CC)CC)C>[CH3:46][C@H:43]1[CH2:42][N:41]([C:47]([O:49][CH2:50][C:51]2[CH:56]=[CH:55][C:54]([N+:57]([O-:59])=[O:58])=[CH:53][CH:52]=2)=[O:48])[C@H:40]([CH3:39])[CH2:45][N:44]1[C:27]([C@@H:11]1[CH2:10][C@H:9]([SH:8])[CH2:13][N:12]1[C:14]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=1)=[O:15])=[O:29]
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Reactant: C[C@@H]1CN(C(=O)OCc2ccc([N+](=O)[O-])cc2)[C@@H](C)CN1
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)[C@@H](C)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Yield: 23.9 %

Procedure:
Following a procedure similar to that described in Preparation 8, but using 1.79 g of (2S,4S)-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)-2-pyrrolidinecarboxylic acid, 0.54 ml of pivaloyl chloride, 0.61 ml of triethylamine and 1.29 g of trans-2,5-dimethyl-1-(4-nitrobenzyloxycarbonyl)piperazine, 577 mg of the title compound were obtained as an amorphous solid.
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]([N:13]1[CH2:18][CH2:17][C:16]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)([C:19]#[N:20])[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-:29].[Na+]>O>[CH2:6]([N:13]1[CH2:14][CH2:15][C:16]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)([C:19]([NH2:20])=[O:29])[CH2:17][CH2:18]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: N#CC1(Nc2ccc(F)cc2)CCN(Cc2ccccc2)CC1
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: NC(=O)C1(Nc2ccc(F)cc2)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 500 ml 90% sulfuric acid were slowly added at 0° C. 152 g (493 mmol) 1-benzyl-4-(4-fluoro-phenylamino)-piperidine-4-carbonitrile. The mixture was stirred at ambient temperature for 16 h, then cooled to 0° C., diluted with 200 ml water, pH was adjusted to 9 by addition of 5N NaOH and the aqueous mixture extracted with dichloromethane. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and evaporated: 155 g 1-benzyl-4-(4-fluoro-phenylamino)-piperidine-4-carboxylic acid amide as light brown crystals: MS (ISP): 328.3 MH+.
Reaction SMILES: [CH3:1][N:2]([CH3:48])[CH2:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:46][CH3:47])=[C:13]([NH:16][C:17]3[N:30]4[C:21](=[N:22][C:23]5[C:28]([C:29]4=[O:31])=[C:27]([F:32])[CH:26]=[CH:25][CH:24]=5)[C:20]4[CH:33]=[CH:34][N:35]([S:36]([C:39]5[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=5)(=[O:38])=[O:37])[C:19]=4[N:18]=3)[CH:14]=2)[CH2:9][CH2:8][CH2:7]1)=[O:5].[CH3:49][NH2:50]>C1COCC1>[CH3:1][N:2]([CH3:48])[CH2:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:46][CH3:47])=[C:13]([NH:16][C:17]3[N:30]=[C:21]([NH:22][C:23]4[CH:24]=[CH:25][CH:26]=[C:27]([F:32])[C:28]=4[C:29]([NH:50][CH3:49])=[O:31])[C:20]4[CH:33]=[CH:34][N:35]([S:36]([C:39]5[CH:40]=[CH:41][C:42]([CH3:45])=[CH:43][CH:44]=5)(=[O:38])=[O:37])[C:19]=4[N:18]=3)[CH:14]=2)[CH2:9][CH2:8][CH2:7]1)=[O:5]
Reactant: CN
Reactant: COc1cc2c(cc1Nc1nc3c(ccn3S(=O)(=O)c3ccc(C)cc3)c3nc4cccc(F)c4c(=O)n13)N(C(=O)CN(C)C)CCC2
Solvent: C1CCOC1
Product: CNC(=O)c1c(F)cccc1Nc1nc(Nc2cc3c(cc2OC)CCCN3C(=O)CN(C)C)nc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
To a solution of 5-{[1-(N,N-dimethylglycyl)-6-(methyloxy)-1,2,3,4-tetrahydro-7-quinolinyl]amino}-8-fluoro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one (5.0 g, 7.47 mmol) in THF (200 ml) was added 2.0 M methylamine in THF (74.7 ml, 149 mmol) and the resulting reaction was stirred overnight at rt. The crude reaction was adsorbed to silica gel and purified by LC (DCM to 5% MeOH/DCM) to give 2-({2-{[1-(N,N-dimethylglycyl)-6-(methyloxy)-1,2,3,4-tetrahydro-7-quinolinyl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluoro-N-methylbenzamide (3.2 g, 61%). ESIMS (M+H)+=701.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH2:21][S:22]([NH:25][CH3:26])(=[O:24])=[O:23])[CH:19]=2)[NH:14][C:13]=1[Si:27]([CH3:30])([CH3:29])[CH3:28])(C(C)(C)C)(C)C.F>N1C=CC=CC=1.C(OCC)(=O)C>[OH:8][CH2:9][CH2:10][CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH2:21][S:22]([NH:25][CH3:26])(=[O:24])=[O:23])[CH:19]=2)[NH:14][C:13]=1[Si:27]([CH3:30])([CH3:28])[CH3:29]
Reactant: CNS(=O)(=O)Cc1ccc2[nH]c([Si](C)(C)C)c(CCCO[Si](C)(C)C(C)(C)C)c2c1
Agent: F
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CNS(=O)(=O)Cc1ccc2[nH]c([Si](C)(C)C)c(CCCO)c2c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 99 %

Procedure:
To a solution of 0.0738 g (0.157 mmol, 1.0 equiv.) of 3-(3-t-butyldimethysilyloxypropyl)-2-trimethylsilyl-N-methyl-1H-indole-5-methanesulfonamide in 2 mL of pyridine at 0° C. was added I mL of 48% aqueous hydrofluoric acid. The solution was stirred for 20 minutes at 0° C. The solution was diluted with 25 mL of ethyl acetate and washed with 10 mL of 10% aqueous sodium carbonate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield 0.0551 g (99%) of 3-(3-hydroxypropyl)-2-trimethylsilyl-N-methyl-1H-indole-5-methanesulfonamide, homogeneous by 1H NMR and TLC.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]=[N:7][OH:8])=[CH:4][CH:3]=1.[ClH:11]>>[Cl:11][C:6](=[N:7][OH:8])[C:5]1[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][CH:4]=1
Reactant: Cl
Reactant: Cc1ccc(C=NO)cc1
Product: Cc1ccc(C(Cl)=NO)cc1

Procedure:
27 g (0.2 mol) of 4-methylbenzaldoxime was chlorinated in the same manner as described in Example 9 (A) in 150 ml of 8N hydrochloric acid to give 28 g of the product as white crystals having a melting point of 60°-70°C. Yield, about 82%.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]2=[O:21].[OH:22][C:23]1[CH:28]=[CH:27][C:26](B(O)OC)=[CH:25][CH:24]=1.[C:33]([O-])([O-])=O.[Na+].[Na+]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:22][C:23]1[CH:28]=[CH:27][C:26]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]3=[O:21])=[C:25]([CH3:33])[CH:24]=1
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Reactant: O=C([O-])[O-]
Reactant: COB(O)c1ccc(O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(O)cc3C)ccn2c1=O
Temperature: 80 °C
Yield: 39.7 %

Procedure:
A mixture of ethyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (120 mg, 0.400 mmol), 4-hydroxy-methyl-phenyl boronic acid (73 mg, 0.48 mmol), (Ph3P)2PdCl2 (28 mg, 0.040 mmol), and Na2CO3 (190 mg in 0.8 mL of water, 1.80 mmol) in THF (5 mL) was degassed 3 times under N2 and heated to 80° C. overnight. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (2×20 mL). The organic phase was separated, dried, and concentrated. The residue was purified by flash silica column chromatography (hexane:ethyl acetate, 1:3 to pure ethyl acetate) to afford the title compound as a yellow solid (60 mg, 40%).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][C:6](=[O:9])[NH:5][C:4]1=[O:10].CC(O)=O.[NH2:15][C:16]1[C:24]([OH:25])=[CH:23][CH:22]=[C:18]([C:19](O)=[O:20])[C:17]=1[C:26](O)=[O:27]>C(N(CC)CC)C>[NH2:15][C:16]1[C:24]([OH:25])=[CH:23][CH:22]=[C:18]2[C:17]=1[C:26](=[O:27])[N:2]([CH:3]1[CH2:8][CH2:7][C:6](=[O:9])[NH:5][C:4]1=[O:10])[C:19]2=[O:20]
Reactant: NC1CCC(=O)NC1=O
Reactant: Nc1c(O)ccc(C(=O)O)c1C(=O)O
Agent: Cl
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: Nc1c(O)ccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 51 %

Procedure:
3-Aminopiperidine-2,6-dione hydrochloride (9.58 g, 58.4 mmol) was dissolved in triethylamine (TEA) (14.7 g) and the mixture was stirred at room temperature for 4 hrs. HOAc (150 mL) and 3-amino-4-hydroxyphthalic acid C1-5 (9.6 g, 48.7 mmol) were added. The mixture was stirred at 120° C. for 20 mins. TEA was added until the white solid was dissolved completely. The mixture was stirred at 120° C. for 2 hrs. After cooling, the solution was extracted with ethyl acetate (500 mL×4). The combined organic layers were dried over Na2SO4, filtered, and concentrated to a dark solid. The dark solid was washed with EA (300 mL) and dried to give compound 1 as a dark solid (7.2 g, yield: 51%). 1H NMR (DMSO-d6, 400 MHz) δ: 11.05 (s, 1H), 10.82 (s, 1H), 6.98 (d, J=8 Hz, 1H), 6.92 (d, J=7.6 Hz, 1H), 5.95 (s, 2H), 5.03-4.98 (m, 1H), 2.91-2.83 (m, 1H), 2.60-2.44 (m, 2H), 2.01-1.98 (m, 1H); MS (ESI+): m/z 290 (M+1); Elem. Anal. Calcd. for C13H11N3O5: C, 53.98; H, 3.83; N, 14.53. Found: C, 53.67; H, 3.80; N, 14.44.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH3:12])=[CH:7][CH:6]=1)=[O:4].[CH3:13][N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1>C(OCC)C>[Br-:1].[CH3:13][NH+:14]1[CH:18]=[CH:17][N:16]([CH2:2][C:3]([C:5]2[CH:10]=[CH:9][C:8]([CH2:11][CH3:12])=[CH:7][CH:6]=2)=[O:4])[CH2:15]1
Reactant: CCc1ccc(C(=O)CBr)cc1
Reactant: Cn1ccnc1
Solvent: CCOCC
Product: CCc1ccc(C(=O)CN2C=C[NH+](C)C2)cc1
Product: [Br-]
Yield: 38.2 %

Procedure:
A solution of 4.41 g (0.019 mol) of 1-bromo-2-(4-ethylphenyl)-2-oxoethane and 1.65 g (0.02 mol) of 1-methylimidazole in 40 ml of diethyl ether was stirred at room temperature for approximately 18 hours. The reaction solvent was decanted, and the residue was washed with diethyl ether and dissolved in a small amount of acetonitrile. The resulting solution was diluted with a small amount of ethyl acetate, whereupon a brown precipitate formed. The solid was collected and recrystallized from acetonitrile/ethyl acetate to provide 2.26 g of 1-methyl-3-[2-(4-ethylphenyl)-2-oxoethyl]-1H-imidazolium bromide as fine yellow brown needles. (38% yield) mp=177°-179° C.
Reaction SMILES: [Br:1][C:2]1[NH:6][C:5]([C:7]([OH:9])=O)=[C:4](/[CH:10]=[CH:11]/[O:12][CH3:13])[N:3]=1.CN(C(ON1N=N[C:24]2[CH:25]=CC=[CH:28][C:23]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:36][C:37]1[N:38]=[C:39]([CH2:47][NH2:48])[C:40]2[C:45]([CH:46]=1)=[CH:44][CH:43]=[CH:42][CH:41]=2.O>C(N(CC)CC)C.CN(C)C=O>[CH3:36][C:37]1[N:38]=[C:39]([CH2:47][NH:48][C:7]([C:5]2[N:6]([CH2:28][C:23]#[C:24][CH3:25])[C:2]([Br:1])=[N:3][C:4]=2/[CH:10]=[CH:11]/[O:12][CH3:13])=[O:9])[C:40]2[C:45]([CH:46]=1)=[CH:44][CH:43]=[CH:42][CH:41]=2
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CO/C=C/c1nc(Br)[nH]c1C(=O)O
Reactant: Cc1cc2ccccc2c(CN)n1
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC#CCn1c(Br)nc(/C=C/OC)c1C(=O)NCc1nc(C)cc2ccccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 3.50 g 2-bromo-5-(trans-2-methoxy-vinyl)-3H-imidazole-4-carboxylic acid and 1.30 g TBTU in 1.20 ml triethylamine and 30 ml of dimethylformamide is stirred for 15 min at ambient temperature. Then 1.09 g 3-methyl-isoquinolin-1-ylmethylamine are added, and the resulting suspension is stirred for 4 h at ambient temperature. Then ice-cooled water is added and the precipitate is separated off. The precipitate is dissolved in dichloromethane, the solution is dried over sodium sulphate and the solvent is removed.
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[C:9](/[CH:11]=[CH:12]/[C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[N:10]=[C:6]2[C:5]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:4][CH:3]=1.COC1C=CC(C[N:36]2[C:41](=[O:42])[N:40]([CH3:43])[C:39]3[CH:44]=[CH:45][C:46](B4OC(C)(C)C(C)(C)O4)=[CH:47][C:38]=3[S:37]2(=[O:58])=[O:57])=CC=1.[C:61]([OH:67])([C:63]([F:66])([F:65])[F:64])=[O:62]>>[F:64][C:63]([F:66])([F:65])[C:61]([OH:67])=[O:62].[CH3:43][N:40]1[C:39]2[CH:44]=[CH:45][C:46]([C:2]3[N:7]4[CH:8]=[C:9](/[CH:11]=[CH:12]/[C:13]5[CH:22]=[CH:21][C:20]6[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=6)[N:14]=5)[N:10]=[C:6]4[C:5]([N:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)=[N:4][CH:3]=3)=[CH:47][C:38]=2[S:37](=[O:58])(=[O:57])[NH:36][C:41]1=[O:42]
Reactant: COc1ccc(CN2C(=O)N(C)c3ccc(B4OC(C)(C)C(C)(C)O4)cc3S2(=O)=O)cc1
Reactant: Brc1cnc(N2CCOCC2)c2nc(/C=C/c3ccc4ccccc4n3)cn12
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)NS(=O)(=O)c2cc(-c3cnc(N4CCOCC4)c4nc(/C=C/c5ccc6ccccc6n5)cn34)ccc21
Temperature: 25 °C

Procedure:
Compound 2b was subjected to Suzuki coupling conditions using the methods described in Example 1, Step G, with compound 40b and the resulting product was deprotected with TFA at 70° C. for 30 min. The reaction mixture was allowed to cool to rt and concentrated. The residue obtained was dried under reduced pressure overnight, suspended in ETOAc (10 mL) and sonicated for 10 min. The solid formed was collected by suction filtration and dried under reduced pressure to obtain the title compound 24. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.67-8.78 (m, 1H), 8.04-8.23 (m, 7H), 7.88-7.98 (m, 1H), 7.65-7.78 (m, 3H), 7.51 (s, 1H), 4.33 (br. s., 4H), 3.78-3.91 (m, 4H), 3.51 (s, 3H).