Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])[C:18](C4C=CC=C(B5OC(C)(C)C(C)(C)O5)C=4)=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:4][CH:3]=1.Br[C:43]1[CH:52]=[N:51][C:50]2[O:49][CH2:48][N:47]([CH2:53][C:54]3[CH:59]=[CH:58][C:57]([F:60])=[CH:56][CH:55]=3)[C:46](=[O:61])[C:45]=2[CH:44]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.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]>[F:60][C:57]1[CH:58]=[CH:59][C:54]([CH2:53][N:47]2[C:46](=[O:61])[C:45]3[CH:44]=[C:43]([C:18]4[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][C:10]5[O:9][C:8]([C:5]6[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=6)=[C:12]([C:13]([NH:15][CH3:16])=[O:14])[C:11]=5[CH:17]=4)[CH:52]=[N:51][C:50]=3[O:49][CH2:48]2)=[CH:55][CH:56]=1
Reactant: O=C1c2cc(Br)cnc2OCN1Cc1ccc(F)cc1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3cccc(B4OC(C)(C)C(C)(C)O4)c3)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3cnc4c(c3)C(=O)N(Cc3ccc(F)cc3)CO4)cc12
Temperature: 100 °C
Reaction time: 8 h
Yield: 70.3 %

Procedure:
To a degassed solution of 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzofuran-3-carboxamide (98 mg, 0.19 mmol) and 6-bromo-3-(4-fluorobenzyl)-2H-pyrido[3,2-e][1,3]oxazin-4(3H)-one (60 mg, 0.18 mmol) in DMF (2 mL) were added Pd(dppf)Cl2 (16 mg, 0.02 mmol) and K3PO4 (270 mg, 0.54 mmol) under N2. After being stirred at 100° C. overnight, the reaction mixture was cooled to RT and filtered. The filtrate was washed with brine and dried over Na2SO4. After being concentrated, the residue was purified by prep-TLC (PE:EtOAc=1:1) to give the product of 5-(3-(4-fluorobenzyl)-4-oxo-3,4-dihydro-2H-pyrido[3,2-e][1,3]oxazin-6-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (80 mg, yield: 70%). 1H-NMR (CDCl3, 400 MHz) δ 8.48 (d, J=2.4 Hz, 1H), 8.44 (d, J=2.4 Hz, 1H), 7.94 (dd, J=5.2, 8.8 Hz, 2H), 7.86 (s, 1H), 7.65 (s, 1H), 7.35 (dd, J=5.2, 8.4 Hz, 2H), 7.22 (t, J=8.8 Hz, 2H), 7.07 (t, J=8.8 Hz, 2H), 5.86 (d, J=4.4 Hz, 1H), 5.31 (s, 2H), 4.75 (s, 2H), 3.21 (s, 3H), 3.00 (d, J=5.2 Hz, 3H), 2.86 (s, 3H). MS (M+H)+: 633.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([I:18])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:7]2[OH:17].[C:19]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([I:18])[CH:5]=[C:6]2[C:11]=1[N:10]([CH3:19])[CH:9]=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]2=[O:17]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1cnc2c(F)cc(I)cc2c1O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)c1cn(C)c2c(F)cc(I)cc2c1=O
Temperature: 95 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
Ethyl 8-fluoro4-hydroxy-6-iodo-3-quinolinecarboxylate (18.1 g) prepared as an intermediate in Preparation No. 1 is dissolved in DMF (430 mL), and K2CO3 (36.1 g, 261 mmol) and methyl iodide (3.25 mL, 52.3 mmol) are added. The reaction mixture is heated to 95° C. for 6 h, then allowed to stir at room temperature overnight. The mixture is split into two parts. The first part is poured into H2O and extracted with five 100-mL portions of CH2Cl2. The combined organic layers are washed with five 200-mL H2O, dried over MgSO4, filtered, and concentrated in vacuo. The work-up is then repeated on the second portion of the reaction mixture to give a total of 15.8 g of the title compound.
Reaction SMILES: [Cl:1]Cl.C(O)(=O)C.[CH3:7][O:8][C:9]1[CH:32]=[CH:31][C:12]([O:13][C:14]2[CH:15]=[CH:16][C:17]3[O:22][CH:21]([C:23]([F:26])([F:25])[F:24])[C:20]([C:27]([OH:29])=[O:28])=[CH:19][C:18]=3[CH:30]=2)=[CH:11][CH:10]=1>>[Cl:1][C:32]1[CH:31]=[C:12]([CH:11]=[CH:10][C:9]=1[O:8][CH3:7])[O:13][C:14]1[CH:15]=[CH:16][C:17]2[O:22][CH:21]([C:23]([F:26])([F:25])[F:24])[C:20]([C:27]([OH:29])=[O:28])=[CH:19][C:18]=2[CH:30]=1
Reactant: ClCl
Reactant: COc1ccc(Oc2ccc3c(c2)C=C(C(=O)O)C(C(F)(F)F)O3)cc1
Solvent: CC(=O)O
Product: COc1ccc(Oc2ccc3c(c2)C=C(C(=O)O)C(C(F)(F)F)O3)cc1Cl
Yield: 53 %

Procedure:
To a stirred solution of chlorine in acetic acid (3.5 mL of 0.24 M solution, 0.84 mmol) was added 6-(4-methoxyphenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid (0.31 g, 0.85 mmol) (Example 7). After 1 hour additional chlorine in acetic acid (1.5 mL of 0.24 M solution, 0.36 mmol) was added. After three additional hours additional chlorine in acetic acid (0.25 ml of 0.25 M solution, 0.06 mmol) was added. After 2.5 hours the reaction was quenched with aqueous 10% sodium bisulfite solution and the resulting mixture extracted with ethyl acetate. Then organic phase was washed with water, brine, dried over MgSO4, filtered, and concentrated in vacuo yielding a brown oil. The oil was dissolved in a minimum of hexanes which induced crystallization. Vacuum filtration of the mixture provided the title compound as yellow crystals (0.18 g, 53%): mp 205-207° C. 1H NMR (acetone-d6 /300 MHz) 7.89 (s, 1H), 6.97-7.18 (m, 6H), 5.83 (q, 1H, J=7.0 Hz), 3.90 (s, 3H). FABLRMS m/z 400 (M+). FABHRMS m/z 399.0249 (M-H, Calc'd 399.0247). Anal. Calc'd for C18H12ClF3O5 : C, 53.95; H, 3.02; Cl, 8.85. Found: C, 53.78; H, 3.08; Cl, 8.98.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1([CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH2:17][CH2:16][CH2:15]1)[CH:6]=[C:5]2[CH2:27][N:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]1.[CH:41]1([NH:44][C:45](=[O:63])[C:46]2[CH:51]=[C:50](B3OC(C)(C)C(C)(C)O3)[C:49]([CH3:61])=[C:48]([F:62])[CH:47]=2)[CH2:43][CH2:42]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Si:20]([O:19][CH2:18][C:14]1([CH2:13][N:7]2[CH:6]=[C:5]([CH2:27][N:28]3[CH2:29][CH2:30][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:32][CH2:33]3)[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([C:50]4[CH:51]=[C:46]([C:45](=[O:63])[NH:44][CH:41]5[CH2:42][CH2:43]5)[CH:47]=[C:48]([F:62])[C:49]=4[CH3:61])[CH:3]=3)[C:8]2=[O:12])[CH2:17][CH2:16][CH2:15]1)([C:23]([CH3:24])([CH3:26])[CH3:25])([CH3:22])[CH3:21]
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cn(CC3(CO[Si](C)(C)C(C)(C)C)CCC3)c(=O)c3ccc(Br)cc23)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3(CO[Si](C)(C)C(C)(C)C)CCC3)cc(CN3CCN(C(=O)OC(C)(C)C)CC3)c2c1
Temperature: 75 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
A solution of tert-butyl 4-[(6-bromo-2-{[1-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclobutyl]methyl}-1-oxo-1,2-dihydroisoquinolin-4-yl)methyl]piperazine-1-carboxylate (Example 27c, 0.153 g) in DMF (4 mL) was treated with N-cyclopropyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.077 g), Pd-118 (4.71 mg) and potassium carbonate (0.067 g) under nitrogen. The resulting mixture was stirred at 75° C. for 8 h. The reaction was partitioned between ethyl acetate and water. The aqueous was extracted with ethyl acetate (2×100 mL) before washing the organics with water (3×100 mL) and brine (3×100 mL). The organic was dried (MgSO4), filtered, and evaporated under reduced pressure to afford the crude product. The crude product was purified (SiO2 chromatography, elution with 30% ethyl acetate/isohexane) to afford the subtitle compound (0.099 g) as an oil.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:9]=2[C:10]([OH:12])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[CH3:26]O>>[C:1]1([S:7][C:8]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:13][C:9]=2[C:10]([O:12][CH3:26])=[O:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1Sc1ccccc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(C(F)(F)F)ccc1Sc1ccccc1

Procedure:
100 g of 2-(phenylthio)-5-trifluoromethyl-benzoic acid, 750 ml of absolute methanol and 100 ml of sulphuric acid are heated under reflux for 24 hours. The solution is concentrated under reduced pressure and treated with water and benzene. After equilibration, the organic phase is washed successively with saturated aqueous sodium chloride solution, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution. The benzene phase is subsequently dried over sodium sulphate, filtered and evaporated. There is obtained methyl 2-(phenylthio)-5-trifluoromethyl-benzoate as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:10]2[C:5](=[CH:6][C:7]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:8][CH:9]=2)[NH:4][CH2:3]1.Cl[C:19]1[C:28]2[C:23](=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:25]=[CH:26][CH:27]=2)[N:22]=[C:21]([CH3:33])[C:20]=1[CH3:34].C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][C:2]1([CH3:17])[C:10]2[C:5](=[CH:6][C:7]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:8][CH:9]=2)[N:4]([C:19]2[C:28]3[C:23](=[C:24]([C:29]([F:32])([F:30])[F:31])[CH:25]=[CH:26][CH:27]=3)[N:22]=[C:21]([CH3:33])[C:20]=2[CH3:34])[CH2:3]1
Reactant: CC1(C)CNc2cc(N3CCOCC3)ccc21
Reactant: Cc1nc2c(C(F)(F)F)cccc2c(Cl)c1C
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1nc2c(C(F)(F)F)cccc2c(N2CC(C)(C)c3ccc(N4CCOCC4)cc32)c1C

Procedure:
Prepared according to procedure T using 4-(3,3-dimethylindolin-6-yl)morpholine (0.116 g, 0.5 mmol), 4-chloro-2,3-dimethyl-8-(trifluoromethyl)quinoline (0.19 g, 0.73 mmol), cesium carbonate (0.326 g, 1 mmol), Pd2(dba)3 (0.046 g, 0.05 mmol) and (±) BINAP (0.124 g, 0.2 mmol) were added together in 1,4-dioxane (2 mL). Crude residue was purified via HPLC to give 4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-indol-1-yl)-2,3-dimethyl-8-(trifluoromethyl)quinoline. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.06 (2H, dd, J=11.3, 8.2 Hz), 7.61 (1H, t, J=7.8 Hz), 7.05 (1H, d, J=8.2 Hz), 6.24 (1H, dd, J=8.2, 2.0 Hz), 5.48 (1H, s), 3.70 (1H, d, J=9.0 Hz), 3.51-3.62 (5H, m), 2.79-2.87 (4H, m), 2.71 (3H, s), 2.23 (3H, s), 1.44 (3H, s), 1.39 (3H, s). Mass Spectrum (ESI) m/e=456 (M+1).
Reaction SMILES: O[C@H](CCCCCCCCCC(C)C)CC(OC)=O.[CH3:20][CH:21]([CH3:40])[CH2:22][CH:23]=[CH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33](=[O:39])[CH2:34][C:35]([O:37][CH3:38])=[O:36]>>[OH:39][C@H:33]([CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH:21]([CH3:40])[CH3:20])[CH2:34][C:35]([O:37][CH3:38])=[O:36]
Reactant: COC(=O)CC(=O)CCCCCCCCC=CCC(C)C
Agent: COC(=O)C[C@H](O)CCCCCCCCCC(C)C
Product: COC(=O)C[C@H](O)CCCCCCCCCCCC(C)C
Yield: 91.6 %

Procedure:
In a manner similar to the synthesis of compound 114, compound 113 (100 mg, 0.338 mmol) was reduced by a two step procedure to afford 115 as a colorless oil (93 mg, 92%, two steps). Rf=0.50 (hexane/ethyl acetate, 4/1, v/v); [α]25D=−6.0° (c=1.0, CHCl3); 1H NMR (300 MHz, CDCl3): δ 3.95 (m, 1H, H-3), 3.66 (s, 3H, OCH3), 2.47 (dd, 1H, J2a,2b=16.2 Hz, J2a,3=3.3 Hz, H-2a), 2.36 (dd, 1H, J2a,2b=16.2 Hz, J2b,3=9.0 Hz, H-2b), 1.53-1.32 (m, 3H, H-4, H-15), 1.21-1.03 [m, 20H, H-(5-14)], 0.81 (d, 6H, J15,16=6.3 Hz, H-16); 13C NMR (75 MHz, CDCl3): δ 173.47 (C═O), 67.97 (C-3), 51.67 (CH3O), 41.08 (C-2), 39.02 (C-12), 36.51 (C-4), 22.62 (C-14). HR MS (m/z) calculated for C18H36O3 [M+Na]+, 323.2557. found, 323.1925.
Reaction SMILES: [CH3:1][C:2]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:6])[C:3]([OH:5])=[O:4].[Si:14]([O:21][C@H:22]1[CH2:31][C@H:30](O)[C@H:29]2[C:24]([CH:25]=[CH:26][C@H:27]([CH3:50])[C@@H:28]2[CH2:33][CH2:34][C@H:35]2[O:40][C:39](=[O:41])[CH2:38][C@H:37]([O:42][Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44])[CH2:36]2)=[CH:23]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>>[Si:14]([O:21][C@H:22]1[CH2:31][C@H:30]([O:4][C:3](=[O:5])[C:2]([CH3:1])([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH3:6])[C@H:29]2[C:24]([CH:25]=[CH:26][C@H:27]([CH3:50])[C@@H:28]2[CH2:33][CH2:34][C@H:35]2[O:40][C:39](=[O:41])[CH2:38][C@H:37]([O:42][Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:44])[CH3:45])[CH2:36]2)=[CH:23]1)([C:17]([CH3:18])([CH3:19])[CH3:20])([CH3:16])[CH3:15]
Reactant: CC(C)(Oc1ccccc1)C(=O)O
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Product: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](OC(=O)C(C)(C)Oc3ccccc3)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Yield: 87.3 %

Procedure:
A procedure similar to that described in Example 10, above, was followed, but using 654 mg of 2-methyl-2-phenoxypropionic acid and 1.0 g of (4R,6R)-6-{(1S,2S,6S,8S,8aR)-2-[1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above], to give 1.13 g of the title compound as a colorless foam.
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([NH:24][CH2:25][CH2:26][NH:27][CH2:28][CH2:29][OH:30])[CH:10]=[CH:11][C:12]=3[NH:17][CH2:18][CH2:19][NH:20][CH2:21][CH2:22][OH:23])[C:7](=[O:31])[C:6]=2[C:5]([OH:32])=[CH:4][CH:3]=1.[CH3:33][N:34]([CH3:43])[C:35]1[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=1>C1(C)C=CC=CC=1>[CH3:33][N:34]([CH3:43])[C:35]1[CH:42]=[CH:41][C:38]([CH:39]2[N:27]([CH2:26][CH2:25][NH:24][C:9]3[C:8]4[C:7](=[O:31])[C:6]5[C:15](=[C:2]([OH:1])[CH:3]=[CH:4][C:5]=5[OH:32])[C:14](=[O:16])[C:13]=4[C:12]([NH:17][CH2:18][CH2:19][N:20]4[CH2:21][CH2:22][O:23][CH:39]4[C:38]4[CH:41]=[CH:42][C:35]([N:34]([CH3:43])[CH3:33])=[CH:36][CH:37]=4)=[CH:11][CH:10]=3)[CH2:28][CH2:29][O:30]2)=[CH:37][CH:36]=1
Reactant: O=C1c2c(O)ccc(O)c2C(=O)c2c(NCCNCCO)ccc(NCCNCCO)c21
Reactant: CN(C)c1ccc(C=O)cc1
Solvent: Cc1ccccc1
Product: CN(C)c1ccc(C2OCCN2CCNc2ccc(NCCN3CCOC3c3ccc(N(C)C)cc3)c3c2C(=O)c2c(O)ccc(O)c2C3=O)cc1

Procedure:
A suspension of 3.11 g. of 1,4-dihydroxy-5,8-bis[[2-(2-hydroxyethylamino)ethyl]amino]anthraquinone [prepared as described in Example 1(A)] in 60 ml. of toluene containing 3.13 g. of p-dimethylaminobenzaldehyde is stirred and heated at reflux for 5 hours by the procedure of Example 1(B). The hot reaction solution is filtered and is allowed to stand for several days. The crystallized product is collected by filtration and washed with toluene to yield 4.34 g. of the product of the Example as dark-blue crystals, m.p. 150°-154° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[C:11]([F:14])[CH:12]=[CH:13][C:7]=2[C:6]=1[CH:15]1[CH2:20][CH2:19][N:18](C(=O)C)[CH2:17][CH2:16]1)=[O:4].[ClH:24]>CO>[ClH:24].[CH3:1][O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[C:11]([F:14])[CH:12]=[CH:13][C:7]=2[C:6]=1[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)=[O:4]
Reactant: COC(=O)c1sc2cc(F)ccc2c1C1CCN(C(C)=O)CC1
Agent: Cl
Solvent: CO
Product: COC(=O)c1sc2cc(F)ccc2c1C1CCNCC1
Temperature: 25 °C
Yield: 74 %

Procedure:
A solution of 24.4 g (66.8 mmol) of 3-(1-acetyl-piperidin-4-yl)-6-fluoro-benzo[b]thiophene-2-carboxylic acid methyl ester in 400 mL of MeOH and 50 mL of concentrated HCl was heated a reflux for 2 days. When the solution was allowed to cool to room temperature the white precipitate was filtered, washed with methanol and dried to give 17.9 g (74%) of product as a white powder. MS (electrospray): exact mass calculated for C15H16FNO2S, 293.09; m/z found, 294.1 [M+H]+. 1H NMR (DMSO-d6, 400 MHz): 9.38 (br s, 1H), 9.02 (br s, 1H), 8.60 (dd, J=9.19, 5.09 Hz, 1H), 7.98 (dd, J=9.00, 2.54 Hz, 1H), 7.36 (dt, J=9.00, 2.54 Hz, 1H), 4.37 (br t, J=12.72 Hz, 1H), 3.87 (s, 3H), 3.40 (br d, J=11.93 Hz, 2H), 3.02 (q, J=11.35 Hz, 2H), 2.61 (dq, J=13.30, 3.72 Hz, 2H), 1.77 (br d, J=12.91 Hz, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:17][S:18]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)(=[O:20])=[O:19].C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O.O1CCOCC1>[CH:14]1([C:12]2[NH:11][N:10]=[C:9]([NH:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:24]4[CH:25]=[CH:26][C:21]([S:18]([CH3:17])(=[O:20])=[O:19])=[CH:22][CH:23]=4)[N:7]=3)[CH:13]=2)[CH2:16][CH2:15]1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Clc1nccc(Nc2cc(C3CC3)[nH]n2)n1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2nccc(Nc3cc(C4CC4)[nH]n3)n2)cc1
Temperature: 100 °C
Yield: 5.4 %

Procedure:
A mixture of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (200 mg, 0.85 mmol, 1.0 equiv.), 4-(methylsulfonyl)phenylboronic acid (187 mg, 0.93 mmol, 1.1 equiv.), Pcy3 (57 mg, 0.204 mmol, 0.24 equiv.), Pd2 (dpa)3 (78 mg, 0.085 mmol, 0.1 equiv.), K3PO4 (722 mg, 3.4 mmol, 4 equiv.), dioxane (5 ml) and water (1 ml) was added to the filtrate. The reaction mixture was heated to 100° C. for 15 h under nitrogen atmosphere. The residue was purified by silica gel chromatography (CH2Cl2/methanol 500:1 to 100:1) to afford title compound N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(4-(methylsulfonyl)phenyl) pyrimidin-4-amine (Compound 15) (16.2 mg, 5.4%) as white solid. LC-MS (m/z)=356.0 [M+H]+; 1H NMR (300 MHz, DMSO-d6): δ 0.73 (m, 2H), 0.94 (m, 2H), 1.91 (m, 1H), 3.26 (s, 3H), 8.06 (d, J=8.7 Hz, 2H), 8.40 (d, J=6 Hz, 2H), 8.53 (d, J=8.4 Hz, 2H), 9.99 (s, 1H), 12.10 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1O.CC1C=CC(S([O:20][CH2:21][CH2:22][CH2:23][NH:24][C:25]2[C:26](=[O:42])[N:27]([C:38]([CH3:41])([CH3:40])[CH3:39])[S:28](=[O:37])(=[O:36])[C:29]=2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)(=O)=O)=CC=1>>[C:38]([N:27]1[C:26](=[O:42])[C:25]([NH:24][CH2:23][CH2:22][CH2:21][O:20][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])=[C:29]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[S:28]1(=[O:37])=[O:36])([CH3:40])([CH3:39])[CH3:41]
Reactant: Cc1ccc(S(=O)(=O)OCCCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)cc1
Reactant: COc1ccccc1O
Product: COc1ccccc1OCCCNC1=C(c2ccccc2)S(=O)(=O)N(C(C)(C)C)C1=O
Yield: 72 %

Procedure:
The title compound was prepared as described for Example 12 from 2-methoxyphenol and 3-[(2-tert-butyl-1,1-dioxido-3-oxo-5-phenyl-2,3-dihydroisothiazol-4-yl)amino]propyl 4-methylbenzenesulfonate with a reaction time of 15 mins. Purified by silica gel column chromatography (Horizons Biotage) using 15% EtOAc in petroleum ether 40-60° C. as eluent to give the title compound (0.077 mg, 72%). 1H NMR (500 MHz CDCl3): δ 7.54-7.50 (m, 2H), 7.43-7.40 (m, 3H), 6.97-6.94 (m, 1H), 6.92-6.88 (m, 2H), 6.81 (dd, 1H), 5.88 (t, 1H), 3.94 (t, 2H), 3.89 (s, 3H, 3.14-3.09 (m, 2H), 1.88-1.84 (m, 2H), 1.75 (s, 9H); 13C NMR (125 MHz CDCl3): δ 159.8, 149.9, 148.1, 135.6, 131.8, 129.7, 128.8, 125.5, 121.9, 120.9, 113.8, 111.9, 106.9, 67.5, 61.6, 55.9, 42.6, 29.1, 27.9; Mass Spectrum M+H+ 445.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([C:26]#[N:27])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([S:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])CCC.[NH2:28][CH2:29][C:30]([OH:32])=[O:31]>>[C:26]([C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([S:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:12]=2)[C:17]([OH:18])=[C:8]([C:6]([NH:28][CH2:29][C:30]([OH:32])=[O:31])=[O:7])[N:9]=1)#[N:27]
Reactant: NCC(=O)O
Reactant: CCCCOC(=O)c1nc(C#N)c2cc(Sc3ccccc3)ccc2c1O
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2ccc(Sc3ccccc3)cc12

Procedure:
The title compound was synthesized from 1-Cyano-4-hydroxy-7-phenylsulfanyl-isoquinoline-3-carboxylic acid butyl ester and glycine in analogy to example 1b; MS-(−)-ion: M−1=378.0.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)=[O:18])[CH2:13][CH2:12]1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](Cl)=[O:33].O.Cl>N1C=CC=CC=1.C(OCC)(=O)C>[ClH:25].[Cl:26][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][C:22]=1[Cl:25])[C:17]([N:14]1[CH2:15][CH2:16][N:11]([CH2:10][CH2:9][NH:8][C:32](=[O:33])[C:31]2[CH:35]=[CH:36][CH:37]=[C:29]([O:28][CH3:27])[CH:30]=2)[CH2:12][CH2:13]1)=[O:18]
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: NCCN1CCN(C(=O)c2ccc(Cl)c(Cl)c2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccncc1
Product: COc1cccc(C(=O)NCCN2CCN(C(=O)c3ccc(Cl)c(Cl)c3)CC2)c1
Reaction time: 16 h

Procedure:
The product from step (iii) above (0.15 g) was dissolved in pyridine (2 ml) and 3-methoxybenzoyl chloride (0.064 g) added. After 16 hours at room temperature, water and ethyl acetate were added, the organic phase separated, dried and concentrated to an oil. Purification by chromatography (dichloromethane:methanol, 95:5) gave an oil which was treated with 1.0M ethereal hydrogen chloride solution to give the titled product as a solid (0.043 g).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]([NH:13][C:14]([CH3:25])([CH3:24])[CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])=[O:12])=[CH:9][NH:10][C:5]2=[N:4][CH:3]=1.[C:26]([O:32][CH2:33]Cl)(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[C:26]([O:32][CH2:33][N:10]1[C:5]2[C:6](=[N:7][C:2]([Br:1])=[CH:3][N:4]=2)[C:8]([C:11](=[O:12])[NH:13][C:14]([CH3:25])([CH3:24])[CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:18])[CH3:19])=[CH:9]1)(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)NC(=O)c1c[nH]c2ncc(Br)nc12
Reactant: CC(C)(C)C(=O)OCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)NC(=O)c1cn(COC(=O)C(C)(C)C)c2ncc(Br)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 44 %

Procedure:
To a stirred mixture of 2-bromo-N-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide in DMF (5 mL) was added chloromethyl pivalate (288 mg, 1.92 mmol) followed by K2CO3 (353 mg, 2.56 mmol). The mixture was stirred at room temperature for 16 hours, then poured into water and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine and dried over Na2SO4. After filtration and concentration, the residue was purified by column chromatography on silica gel eluting with petroleum ether/EtOAc (5:1, v/v) to give (2-bromo-7-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-ylcarbamoyl)-5H-pyrrolo[3,2-b]pyrazin-5-yl)methyl pivalate (305 mg, 44% over two steps) as a yellow solid. MS: (M+H)+=541; 1H NMR (300 MHz, CDCl3): δ 8.41 (s, 1H), 8.33 (s, 1H), 7.84 (s, 1H), 6.20 (s, 2H), 3.71 (s, 2H), 1.49 (s, 6H), 1.15 (s, 9H), 0.90 (s, 9H), 0.09 (s, 6H).