Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][CH:6]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])N(C)C)(C)(C)C.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]C(O)=O)=[CH:18][CH:17]=1>C1(C)C=CC=CC=1.CCOC(C)=O>[C:11]([O:10][C:6](=[O:5])[CH2:22][C:19]1[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][CH:18]=1)([CH3:12])([CH3:13])[CH3:14]
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: CN(C)C(OC(C)(C)C)OC(C)(C)C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Cc1ccc(Cl)cc1
Temperature: 80 °C
Yield: 30.4 %

Procedure:
To a suspension of N,N-dimethyl-formamide-di-tert-butyl acetal (25 ml, 104.4 mmol) in dry toluene (90 ml) was added p-chlorophenyl acetic acid (5.94 g, 34.8 mmol) and the whole heated at 80° C. for 1 h. The mixture was diluted with EtOAc (50 ml) and washed with water (50 ml), 3% aqueous NaHCO3 solution (50 ml) and brine (20 ml) and then dried over MgSO4 and evaporated to give an oil. This oil was purified using 35%, then 50% DCM in pentane to give the title product (2.4 g, 30%); 1HNMR (400 MHz, CDCl3) δ: 1.42 (s, 9H), 3.44 (s, 2H), 7.20 (d, 2H), 7.28 (d, 2H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]=[C:8]1[O:12][C:10](=[O:11])[CH2:9]1>C(OC)(C)(C)C>[N:1]1([C:10](=[O:11])[CH2:9][C:8](=[O:12])[CH3:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=C1CC(=O)O1
Reactant: C1CCNCC1
Solvent: COC(C)(C)C
Product: CC(=O)CC(=O)N1CCCCC1
Temperature: -1 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
A solution of 25 g (0.294 mol) piperidin in 100 ml tert.-butyl-methylether was added dropwise to a solution of 26.25 g (0.310 mol) diketene in 200 ml tert.-butyl-methylether at −5 to 0° C. After stirring for 1 hour at −1° C., no starting material was detected anymore by thin-layer chromatography. The reaction mixture was spun off and the residue was distilled under vacuum. 49.55 g of product was obtained as a slightly yellow liquid.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>COC(C)(C)C>[CH3:22][S:23]([O:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COS(C)(=O)=O
Reaction time: 1.5 h

Procedure:
To a solution of (S)-tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate (201 mg, 1.00 mmol) and triethylamine (0.21 mL, 1.5 mmol) in tert-butyl methyl ether (4 mL) was added methanesulfonyl chloride (0.095 mL, 1.2 mmol). After 90 min., the mixture was filtered, washing the white solid with tert-butyl methyl ether (3×2 mL). The filtrate was concentrated in vacuo to provide the title compound as a colorless oil. 1H NMR (400 MHz, CDCl3,): δ 4.40-3.95 (m, 3H), 3.49-3.32 (m, 2H), 3.02 (s, 3H), 2.11-1.80 (m, 4H), 1.48 (s, 9H).
Reaction SMILES: CC(OC([N:8](C(OC(C)(C)C)=O)[N:9]([C:17]1[C:22]([F:23])=[C:21]([NH:24][CH2:25][C:26]2[N:27]=[CH:28][S:29][CH:30]=2)[N:20]=[C:19]([Cl:31])[N:18]=1)C(OC(C)(C)C)=O)=O)(C)C>CO.Cl>[Cl:31][C:19]1[NH:20][C:21]([NH:24][CH2:25][C:26]2[N:27]=[CH:28][S:29][CH:30]=2)=[C:22]([F:23])[C:17](=[N:9][NH2:8])[N:18]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)c1nc(Cl)nc(NCc2cscn2)c1F
Agent: Cl
Solvent: CO
Product: NN=c1nc(Cl)[nH]c(NCc2cscn2)c1F
Reaction time: 8 h
Yield: 43.1 %

Procedure:
Tris(1,1-dimethylethyl)2-{2-chloro-5-fluoro-6-[(1,3-thiazol-4-ylmethyl)amino]-4-pyrimidinyl}-1,1,2-hydrazinetricarboxylate (0.51 g, 0.8868 mmol) was dissolved in MeOH (5 mL) and HCl (4M in 1,4-dioxane) (5 mL). The reaction mixture was left to stir overnight, then evaporated and purified by RP-HPLC to provide 2-chloro-5-fluoro-6-[(1,3-thiazol-4-ylmethyl)amino]-4(1H)-pyrimidinone hydrazone as an orange oil (0.105 g). LCMS: (M+H)+=275.0.
Reaction SMILES: C(N(CC1C=CC=CC=1)[C:9]1([CH2:14][NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([CH3:26])[CH:24]=3)[N:19]=[C:18]([N:27]3[CH2:33][C:32]4[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=4[S:30](=[O:39])(=[O:38])[CH2:29][CH2:28]3)[CH:17]=2)[CH2:13]COC1)C1C=CC=CC=1.C(N)CC[CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][NH2:55]>>[O:38]=[S:30]1(=[O:39])[C:31]2[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=2[CH2:33][N:27]([C:18]2[CH:17]=[C:16]([NH:15][CH2:14][CH2:9][CH2:13][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][NH2:55])[C:25]3[C:24](=[C:23]([CH3:26])[CH:22]=[CH:21][CH:20]=3)[N:19]=2)[CH2:28][CH2:29]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC3(N(Cc4ccccc4)Cc4ccccc4)CCOC3)c2c1
Reactant: NCCCCCCCCN
Product: Cc1cccc2c(NCCCCCCCCN)cc(N3CCS(=O)(=O)c4ccccc4C3)nc12

Procedure:
The title compound was prepared in analogy to Example 12-1 in Scheme 5 by using 4-(4-chloro-8-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 2-1 by using 2,4-dichloro-8-methylquinoline and 2,3,4,5-tetrahydro-1,4-benzothiazepine) and octane-1,8-diamine. MS obsd. (ESI+) [(M+H)+] 481, 1H NMR (400 MHz, CD3OD) δ ppm 8.09-8.07 (d, J=7.6 Hz, 1 H), 7.96-7.94 (d, J=8.4 Hz, 1 H), 7.85-7.83 (d, J=7.6 Hz, 1 H), 7.73-7.70 (m, 2 H), 7.36-7.32 (m, 2 H), 5.90 (s, 1 H), 5.33 (s, 2 H), 4.52-4.51 (m, 2 H), 3.81-3.78 (t, 2 H), 3.47-3.42 (t, 2 H), 2.91-2.89 (t, 2 H), 2.64 (s, 3 H), 1.67-1.63 (m, 4 H), 1.50-1.37 (m, 8 H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N:9]2[C:13]3[N:14]=[C:15]([CH3:26])[N:16]=[C:17]([N:18]4[CH2:23][CH2:22][CH:21]([CH2:24][OH:25])[CH2:20][CH2:19]4)[C:12]=3[C:11]([CH3:27])=[CH:10]2)=[C:4]([CH3:28])[CH:3]=1.[H-].[Na+].Cl[C:32]([O:34][CH2:35][CH3:36])=[O:33]>O1CCCC1>[CH2:35]([O:34][C:32](=[O:33])[O:25][CH2:24][CH:21]1[CH2:22][CH2:23][N:18]([C:17]2[C:12]3[C:11]([CH3:27])=[CH:10][N:9]([C:5]4[C:6]([CH3:8])=[CH:7][C:2]([Br:1])=[CH:3][C:4]=4[CH3:28])[C:13]=3[N:14]=[C:15]([CH3:26])[N:16]=2)[CH2:19][CH2:20]1)[CH3:36]
Reactant: Cc1nc(N2CCC(CO)CC2)c2c(C)cn(-c3c(C)cc(Br)cc3C)c2n1
Reactant: CCOC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)OCC1CCN(c2nc(C)nc3c2c(C)cn3-c2c(C)cc(Br)cc2C)CC1
Temperature: 0 °C
Yield: 27.5 %

Procedure:
{1-[7-(4-Bromo-2,6-dimethylphenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]piperidin-4-yl}methanol (1.15 g) synthesized in the similar manner as example 1 in tetrahydrofuran (25 mL) was stirred, then NaH (60% in paraffin, 0.10 g) was added and the mixture was healed at reflux for 3 hours. After cooling to 0° C., ethyl chloroformate (0.28 g) in a small amount of tetrahydrofuran was added and the reaction mixture was allowed to reach room temperature and evaporated. The residue was purified over a silica gel on a glass filter (eluent: CH2Cl2/CH3CN=95:5 then 90:10) to give the title product (366 mg).
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]([CH:7]=[CH:8][C:9]=1[I:10])[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH3:18][C:19]([SH:22])([CH3:21])[CH3:20].O>CN(C=O)C>[Br:1][C:2]1[C:3]([S:22][C:19]([CH3:21])([CH3:20])[CH3:18])=[C:4]([CH:7]=[CH:8][C:9]=1[I:10])[CH:5]=[O:6]
Reactant: O=Cc1ccc(I)c(Br)c1F
Reactant: CC(C)(C)S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)Sc1c(C=O)ccc(I)c1Br
Temperature: 80 °C
Yield: 62.6 %

Procedure:
A mixture of 3-bromo-2-fluoro-4-iodo-benzaldehyde (1.3 g, 4.0 mmol), potassium carbonate (0.66 g, 4.7 mmol), and 2-methylpropane-2-thiol (0.53 mL, 4.7 mmol) in dry DMF (2 mL) was heated at 80° C. in a sealed tube for 16 h. The reaction mixture was cooled to RT, water was added, and the mixture was extracted with dichloromethane (2×30 mL). The combined organic fractions were washed with water (60 mL), dried over sodium sulfate, filtered, and concentrated. Purification of the residue by column chromatography (5% ethyl acetate:hexanes) afforded 1.0 g (64%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 1.30 (s, 9H), 7.54 (d, J=8.1 Hz, 1H), 7.87 (d, J=8.1 Hz, 1H), 10.29 (s, 1H).
Reaction SMILES: Cl.[OH:2][CH:3]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:10]=1)[C:4](=[NH:8])[O:5]CC.[O:22]1CCC[CH2:23]1>C1(C)C=CC=CC=1>[O:15]([C:11]1[CH:10]=[C:9]([CH:3]2[O:2][C:23](=[O:22])[NH:5][C:4]2=[O:8])[CH:14]=[CH:13][CH:12]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=N)C(O)c1cccc(Oc2ccccc2)c1
Reactant: C1CCOC1
Agent: Cl
Solvent: Cc1ccccc1
Product: O=C1NC(=O)C(c2cccc(Oc3ccccc3)c2)O1

Procedure:
By the procedure of Example 3, ethyl 1-hydroxy-1-(3-phenoxyphenyl)methanecarboximidate hydrochloride (13 g.) in 500 ml. of tetrahydrofuran was converted to toluene recrystallized 5-(3-phenoxyphenyl)oxazolidine-2,4-dione (7.5 g., 66%; m.p. 104°-106° C.; m/e 269).
Reaction SMILES: [C:1]1(=[O:8])[CH:6]=[CH:5][C:4](=[O:7])[CH:3]=[CH:2]1.[CH3:9][C:10]([C:12]([CH3:14])=[CH2:13])=[CH2:11].O>C1(C)C=CC=CC=1.C(O)(=O)C>[CH3:9][C:10]1[CH2:11][C:6]2[C:1](=[O:8])[CH:2]=[CH:3][C:4](=[O:7])[C:5]=2[CH2:13][C:12]=1[CH3:14]
Reactant: C=C(C)C(=C)C
Reactant: O=C1C=CC(=O)C=C1
Solvent: O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CC1=C(C)CC2=C(C1)C(=O)C=CC2=O
Yield: 88 %

Procedure:
In toluene (60 ml) and acetic acid (10 ml), were dissolved 14.0 g (0.13 mol) of 1,4-benzoquinone, to which 20.0 g (0.24 mol) of 2,3-dimethyl-1,3-butadiene were added at -10° C. under stirring. Thereafter, the resultant mixture was gradually heated and stirred further for 3 hours at 40° C. The liquid reaction mixture was washed with water, and an organic layer was dried and concentrated under reduced pressure. Concentrated hydrochloric acid (1 ml) and ethanol (60 ml) were added to the residue, and the mixture was stirred for 1 hour at 40° C. After the liquid reaction mixture was concentrated under reduced pressure, the residue was dissolved in a liquid mixture of acetonitrile (100 ml) and water (30 ml). To the solution, were added 20.0 g (0.036 mol) of ceric ammonium nitrate at room temperature to stir the resultant mixture for 1 hour. The liquid reaction mixture was poured into water (200 ml) to make extraction with toluene (50 ml×2). The resulting organic layer was washed with water, dried and concentrated under reduced pressure to obtain 21.5 g of a crude product of the title compound (yield: 88%).
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:14]2=[C:17]3[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]3[C:8](=[O:22])[C:9]1[C:10]3[CH:21]=[CH:20][CH:19]=[CH:18][C:11]=3[O:12][C:13]=12.[Br:23][CH2:24][CH2:25][CH2:26]Br>>[Br:23][CH2:24][CH2:25][CH2:26][O:1][C:2]1[CH:16]=[CH:15][C:14]2=[C:17]3[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]3[C:8](=[O:22])[C:9]1[C:10]3[CH:21]=[CH:20][CH:19]=[CH:18][C:11]=3[O:12][C:13]=12
Reactant: O=C1c2c(oc3ccccc23)-c2ccc(O)c3cccc1c23
Reactant: BrCCCBr
Product: O=C1c2c(oc3ccccc23)-c2ccc(OCCCBr)c3cccc1c23

Procedure:
Alternatively, the title compound is prepared by reaction of 3-hydroxy-7-oxo-7H-benzo[b]phenaleno[2,1-d]furan with 1,3-dibromopropane as previously described.
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][C:56]([C:59]([F:62])([F:61])[F:60])=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[N:71]1([C:77]2[CH:84]=[CH:83][C:80]([CH:81]=O)=[CH:79][CH:78]=2)[CH2:76][CH2:75][O:74][CH2:73][CH2:72]1>C(O)C.CN(C=O)C>[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][C:56]([C:59]([F:62])([F:61])[F:60])=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]2[N:43]=[C:81]([C:80]3[CH:79]=[CH:78][C:77]([N:71]4[CH2:76][CH2:75][O:74][CH2:73][CH2:72]4)=[CH:84][CH:83]=3)[NH:42][C:39]2=[N:40][CH:41]=1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3ccc(C(F)(F)F)nc3)CC2)c1[N+](=O)[O-]
Reactant: O=Cc1ccc(N2CCOCC2)cc1
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(CN2CCN(c3c(Br)cnc4[nH]c(-c5ccc(N6CCOCC6)cc5)nc34)CC2)cn1
Reaction time: 6 h
Yield: 23.2 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-bromo-3-nitro-4-(4-((6-(trifluoromethyl)pyridin-3-yl)methyl)piperazin-1-yl)pyridin-2-amine (20 mg, 0.043 mmol), DMF (0.15 mL), ethanol (0.85 mL), 1M Na2S2O4 (3 eq, 0.13 mmol, 0.13 mL) and 4-morpholin-4-yl-benzaldehyde (1.1 eq, 0.048 mmol, 9 mg). After 6 h, concentration in vacuo and purification by preparative tlc (CH2Cl2-MeOH, 95:5) gave the product (6 mg, 23%) as a pale yellow solid; δH (500 MHz, DMSO-d6) 2.65 (t, J=4.4 Hz, 4H, piperazine N(CH2)2), 3.24 (t, J=4.9 Hz, 4H, morpholine N(CH2)2), 3.66 (t, J=4.5 Hz, 4H, piperazine N(CH2)2), 3.73 (s, 2H, CH2), 3.76 (t, J=4.9 Hz, 4H, morpholine O(CH2)2), 7.06 (d, J=9.0 Hz, 2H, phenyl H-3 & H-5), 7.90 (d, br, J=8.0 Hz, 1H, pyridine H-5), 8.04 (d, J=9.0 Hz, 2H, phenyl H-2 & H-6), 8.08 (dd, J=8.1, 1.0 Hz, 1H, pyridine H-4), 8.18 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.77 (s, br, 1H, pyridine H-2), 13.23 (s, br, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: Br[C:2]1[C:3]([CH3:8])=[N:4][NH:5][C:6]=1[CH3:7].[O:9]=[S:10]1(=[O:37])[CH2:15][CH2:14][CH:13]([C:16]2[C:24]3[C:19](=[C:20]([C:34]([NH2:36])=[O:35])[CH:21]=[C:22](B4OC(C)(C)C(C)(C)O4)[CH:23]=3)[NH:18][CH:17]=2)[CH2:12][CH2:11]1.C([O-])([O-])=O.[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1.O>[CH3:8][C:3]1[C:2]([C:22]2[CH:23]=[C:24]3[C:19](=[C:20]([C:34]([NH2:36])=[O:35])[CH:21]=2)[NH:18][CH:17]=[C:16]3[CH:13]2[CH2:12][CH2:11][S:10](=[O:9])(=[O:37])[CH2:15][CH2:14]2)=[C:6]([CH3:7])[NH:5][N:4]=1
Reactant: CC1(C)OB(c2cc(C(N)=O)c3[nH]cc(C4CCS(=O)(=O)CC4)c3c2)OC1(C)C
Reactant: Cc1n[nH]c(C)c1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1n[nH]c(C)c1-c1cc(C(N)=O)c2[nH]cc(C3CCS(=O)(=O)CC3)c2c1
Temperature: 120 °C
Yield: 10.8 %

Procedure:
4-Bromo-3,5-dimethyl-1H-pyrazole (35 mg, 0.2 mmol), 3-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxamide (30 mg, 0.072 mmol) and K2CO3 (50 mg, 0.36 mmol) was taken up in a 3:1 mixture of 1,4-dioxane/water (2 mL) in a microwave vial. The mixture was degassed by bubbling argon through it for 5 min. PdCl2(dppf) (8 mg, 0.011 mmol) was added, and the reaction was heated in a microwave for 10 min at 120° C. The reaction mixture was concentrated, diluted in DMSO, and purified on a Gilson HPLC(NH4OH buffer), giving 3 mg (11%) of the title compound.
Reaction SMILES: [CH3:1][CH:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([Cl:12])[CH:10]=[CH:11][C:4]=2[S:3]1.[Si:13]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]=O)[CH:23]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>N1CCCCC1.C1C=CC=CC=1.C(OCC)(=O)C>[Si:13]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24](/[CH:28]=[CH:1]/[CH:2]2[N:7]=[CH:6][C:5]3[CH:8]=[C:9]([Cl:12])[CH:10]=[CH:11][C:4]=3[S:3]2)[CH:23]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:14])[CH3:15]
Reactant: CC1N=Cc2cc(Cl)ccc2S1
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(C=O)c1
Solvent: CCOC(C)=O
Solvent: C1CCNCC1
Solvent: c1ccccc1
Product: CC(C)(C)[Si](C)(C)OCc1cccc(/C=C/C2N=Cc3cc(Cl)ccc3S2)c1
Reaction time: 30 h

Procedure:
A mixture of 1.08 g of 2-methyl-6-chloro-1,3-benzthiazine 1.51 g of 3-formylbenzyl alcohol t-butyldimethylsilyl ether and 5 drops of piperidine in 60 ml of benzene was heated to reflux in a Dean-Stark trap for 1 hour. An additional 5 drops of piperidine were added and the refluxing continued from 30 hours. The mixture was diluted with 400 ml of ethyl acetate and washed with water (1×40 ml) and brine (1×40 ml). The organic layer was dried over magnesium sulfate and concentrated to 2 g of crude product which was chromatographed on silica gel using 5% ethyl acetate in hexane (v:v), 188 mg, m.p. 58°-60° C.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]([CH3:12])[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C([Mg]Cl)(C)C.Br[C:19]1[CH:47]=[CH:46][C:22]([C:23]([N:25]([C:39]2[C:44]([Cl:45])=[CH:43][CH:42]=[CH:41][N:40]=2)[C@@H:26]2[CH2:31][CH2:30][CH2:29][N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27]2)=[O:24])=[CH:21][CH:20]=1>C1COCC1.CC1OCCC1.[Cl-].[Zn+2].[Cl-].[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[Cl:45][C:44]1[C:39]([N:25]([C:23](=[O:24])[C:22]2[CH:21]=[CH:20][C:19]([C:2]3[CH:3]=[N:4][N:5]([CH3:12])[C:6]=3[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:47][CH:46]=2)[CH:26]2[CH2:31][CH2:30][CH2:29][N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27]2)=[N:40][CH:41]=[CH:42][CH:43]=1
Reactant: CCOC(=O)c1c(I)cnn1C
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N(C(=O)c2ccc(Br)cc2)c2ncccc2Cl)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: CC1CCCO1
Solvent: C1CCOC1
Product: CCOC(=O)c1c(-c2ccc(C(=O)N(c3ncccc3Cl)C3CCCN(C(=O)OC(C)(C)C)C3)cc2)cnn1C
Temperature: -52 °C
Reaction time: 2 h

Procedure:
Preparation 13 ethyl 4-iodo-1-methyl-1H-pyrazole-5-carboxylate (108.5 g, 387.4 mmol) was dissolved in 1 L of THF and the resulting solution was cooled to −52° C. Isopropylmagnesium chloride (2 mol/L solution in THF, 200 mL, 400 mmol) was added over 27 minutes keeping the internal temperature <−39° C., followed by addition of zinc chloride (1.9 mol/L in 2-MeTHF, 120 mL, 230 mmol) over 15 minutes keeping the internal temperature <−39° C. The reaction was then warmed to 40° C. followed by addition of Preparation 10 tert-butyl (3R)-3-[(4-bromobenzoyl)(3-chloropyridin-2-yl)amino]piperidine-1-carboxylate (158.27 g, 319.9 mmol) and 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (4.60 g, 6.92 mmol). The reaction was warmed further to 55° C. and held for 2 h. After cooling to room temperature, the crude reaction mixture was filtered through Celite® and the filtrate was concentrated to give a foam. This material was re-dissolved in 1 L of 2-MeTHF and washed with 400 mL of water followed by filtration of the biphasic mixture and phase separation. 2-MeTHF was removed in vacuo and replaced with EtOH, then the solution was concentrated to a final volume of 1.5 L, resulting in precipitation of solids which were collected via filtration. After drying, the title compound was isolated as a tan solid (141.5 g, 78% yield).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[NH2:7][C:8]1[N:13]=[C:12](Cl)[CH:11]=[CH:10][N:9]=1.[F:15][C:16]1[CH:25]=[C:24]([F:26])[CH:23]=[C:22]2[C:17]=1[C:18]([NH:34][C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[N:39][C:40]=1[N:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1)=[C:19]([CH3:33])[C:20]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)=[N:21]2.O1CCOCC1>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.O>[NH2:7][C:8]1[N:13]=[C:12]([C:37]2[CH:36]=[C:35]([NH:34][C:18]3[C:17]4[C:22](=[CH:23][C:24]([F:26])=[CH:25][C:16]=4[F:15])[N:21]=[C:20]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=4)[C:19]=3[CH3:33])[C:40]([N:41]3[CH2:42][CH2:43][O:44][CH2:45][CH2:46]3)=[N:39][CH:38]=2)[CH:11]=[CH:10][N:9]=1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Nc1cc(B(O)O)cnc1N1CCOCC1
Reactant: Nc1nccc(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Nc1cc(-c2ccnc(N)n2)cnc1N1CCOCC1
Temperature: 120 °C

Procedure:
A solution of dichlorobis(triphenylphosphine)palladium(ii) (19.5 mg, 0.028 mmol), sodium carbonate (88 mg, 0.83 mmol), 2-amino-4-chloropyrimidine (35.9 mg, 0.28 mmol), 5-(5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-ylamino)-6-morpholinopyridin-3-ylboronic acid (0.28 mmol; described herein), 1,4-dioxane (6 mL), and water (1.5 mL) was heated in a microwave at 120° C. for 60 min. The reaction was then partitioned between EtOAc and water, and the organic layer dried (magnesium sulfate) and concentrated. Chromatography afforded N-(5-(2-amino-4-pyrimidinyl)-2-(4-morpholinyl)-3-pyridinyl)-5,7-difluoro-3-methyl-2-(2-pyridinyl)-4-quinolinamine as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ ppm 8.73-8.79 (1H, m), 8.58 (1H, d, J=2.3 Hz), 8.28 (1H, d, J=5.1 Hz), 7.85-7.96 (2H, m), 7.63-7.70 (1H, m), 7.48-7.59 (2H, m), 7.41 (1H, ddd, J=6.8, 4.7, 2.2 Hz), 6.98-7.10 (2H, m), 5.35 (2H, br. s.), 3.95 (4H, d, J=2.3 Hz), 3.10-3.70 (4H, m), 2.22 (3H, s). Mass Spectrum (ESI) m/e=527.2 (M+1).
Reaction SMILES: CC(C)([O-])C.[Na+].[N:7]1([C:13](=[O:15])[CH3:14])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.Br[C:17]1[CH:22]=[CH:21][C:20]([CH:23](OC)[O:24]C)=[C:19]([F:28])[CH:18]=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1>[C:13]([N:7]1[CH2:12][CH2:11][N:10]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[O:24])=[C:19]([F:28])[CH:18]=2)[CH2:9][CH2:8]1)(=[O:15])[CH3:14]
Reactant: CC(=O)N1CCNCC1
Reactant: COC(OC)c1ccc(Br)cc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: CC(=O)N1CCN(c2ccc(C=O)c(F)c2)CC1
Temperature: 100 °C
Reaction time: 16 h
Yield: 59.8 %

Procedure:
Palladium(II) acetate (111 mg, 0.49 mmol), 2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl (469 mg, 0.98 mmol) and sodium tert-butoxide (4.88 g, 49.2 mmol) were combined and the flask was purged with nitrogen. A solution of 1-piperazin-1-ylethanone (4.1 g, 32 mmol) and 4-bromo-1-(dimethoxymethyl)-2-fluoro-benzene (6.13 g, 24.6 mmol) in 1,4-dioxane (82 mL) was then added and the reaction was stirred at 100° C. for 16 hours. The reaction was then filtered through diatomaceous earth and concentrated. The resulting residue was dissolved in 50 mL of THF and 50 mL of 1 N aqueous HCl was added and the reaction was stirred at ambient temperature for 16 hours. The reaction was then neutralized with saturated aqueous Na2CO3 and extracted with dichloromethane (x3), dried with MgSO4, concentrated and purified by silica gel column chromatography (0-10% methanol in dichloromethane) to give 4-(4-acetylpiperazin-1-yl)-2-fluoro-benzaldehyde (3.68 g, 60% yield). LCMS (m/z) ES+ 251 [M+1]+.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([CH3:11])(=[O:10])=[O:9].[Br:12]N1C(=O)CCC1=O>OS(O)(=O)=O>[Br:12][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[C:3]([S:8]([CH3:11])(=[O:9])=[O:10])[CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CS(=O)(=O)c1ccccc1I
Agent: O=S(=O)(O)O
Product: CS(=O)(=O)c1cc(Br)ccc1I
Reaction time: 4 h
Yield: 86.2 %

Procedure:
A suspension of 1-iodo-2-(methylsulfonyl)benzene (Intermediate 201; 1.45 g; 5.14 mmol) in conc. H2SO4 (4 mL) was treated with N-bromosuccinimide (1.01 g; 5.65 mmol) and the resulting mixture was stirred for 4 h. The reaction mixture was carefully poured on crushed ice and extracted with EtOAc. The organic phase was washed twice with NaOH 0.1 N and brine, dried over MgSO4, filtered and concentrated to dryness affording the title compound as a white solid (1.6 g, 86%).
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18])([OH:10])[CH2:4][N:5]1[CH:9]=[N:8][CH:7]=[N:6]1.[CH2:19]([S:23](Cl)(=[O:25])=[O:24])[CH2:20][CH2:21][CH3:22]>>[CH2:19]([S:23]([NH:1][CH2:2][C:3]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18])([OH:10])[CH2:4][N:5]1[CH:9]=[N:8][CH:7]=[N:6]1)(=[O:25])=[O:24])[CH2:20][CH2:21][CH3:22]
Reactant: NCC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Reactant: CCCCS(=O)(=O)Cl
Product: CCCCS(=O)(=O)NCC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl

Procedure:
Following the procedure described in example 1 but using 3-amino-2-(2,4-dichlorophenyl)-1-(1H-1,2,4-triazol-1-yl)propan-2-ol and butanesulfonylchloride, the title compound was obtained in a similar yield as a solid foam: