Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1[S:8]([CH3:10])=O.C(S)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1CCN2C(=NCCC2)CC1>O1CCOCC1>[CH2:10]([S:8][C:7]1[C:2]([Br:1])=[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)[N:4]=[C:5]([NH2:11])[N:6]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Br
Reactant: SCc1ccccc1
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1nc(SCc2ccccc2)c(Br)c(-c2ccco2)n1

Procedure:
From 5-bromo-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl-amine, benzylmercaptan and DBU in dioxane. EI-MS m/e (%): 363 (M{81Br}+, 48), 361 (M{79Br}+, 46), 282 ([M—Br]+, 68), 249 (35), 91 (100).
Reaction SMILES: [C:1]([C:4]1[CH:30]=[CH:29][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]3[O:20][C:19]([C:21]([O:23]C)=[O:22])=[CH:18][C:17]=3[C:25]=2[CH2:26][CH:27]=[CH2:28])=[C:6]([CH2:31][CH2:32][CH3:33])[C:5]=1[OH:34])(=[O:3])[CH3:2].[OH-].[Na+]>O1CCOCC1>[C:1]([C:4]1[CH:30]=[CH:29][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]3[O:20][C:19]([C:21]([OH:23])=[O:22])=[CH:18][C:17]=3[C:25]=2[CH2:26][CH:27]=[CH2:28])=[C:6]([CH2:31][CH2:32][CH3:33])[C:5]=1[OH:34])(=[O:3])[CH3:2]
Reactant: C=CCc1c(OCCCOc2ccc(C(C)=O)c(O)c2CCC)ccc2oc(C(=O)OC)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C=CCc1c(OCCCOc2ccc(C(C)=O)c(O)c2CCC)ccc2oc(C(=O)O)cc12
Yield: 50.5 %

Procedure:
The ester of step (b) (1.43 g) was stirred in dioxan (30 ml) containing N sodium hydroxide (6.75 ml) for one hour. The green solution was acidified and extracted with ethyl acetate. Evaporation gave a residue which was chromatographed over silica with a mixture of dichloromethane, ether and formic acid (90:7:3) to give the title acid (0.7 g), mp 157°-158°.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH2:16])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1.[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([C:33](O)=[O:34])=[CH:25]1>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH:16][C:33]([C:26]3[C:27]4[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=4)[NH:24][CH:25]=3)=[O:34])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1
Reactant: O=C(O)c1c[nH]c2ccccc12
Reactant: NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(N)sc1-c1cccc(F)c1
Product: Nc1nc(C(=O)N2[C@H](CNC(=O)c3c[nH]c4ccccc34)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [2-amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl)-methanone with 1H-indole-3-carboxylic acid. LC-MS (basic): tR=0.78 min; [M+H]+=476.3.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:30])=[C:4]([F:29])[C:5]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=2[Cl:28])=[C:6]([CH:19]=1)[C:7]([NH:9][O:10][CH2:11][C@@H:12]1[CH2:16][O:15]C(C)(C)[O:13]1)=[O:8].Cl>O1CCCC1>[Cl:1][C:2]1[C:3]([F:30])=[C:4]([F:29])[C:5]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=2[Cl:28])=[C:6]([CH:19]=1)[C:7]([NH:9][O:10][CH2:11][C@@H:12]([OH:13])[CH2:16][OH:15])=[O:8]
Reactant: CC1(C)OC[C@@H](CONC(=O)c2cc(Cl)c(F)c(F)c2Nc2ccc(I)cc2Cl)O1
Agent: Cl
Solvent: C1CCOC1
Product: O=C(NOC[C@@H](O)CO)c1cc(Cl)c(F)c(F)c1Nc1ccc(I)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.8 %

Procedure:
A 3 L single necked round bottomed flask equipped with a magnetic stirrer was charged with a solution of 5-chloro-2-(2-chloro-4-iodo-phenylamino)-N-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-3,4-difluoro-benzamide (69.9 g, 122 mmol) in tetrahydrofuran (1.5 L). Aqueous 1N hydrochloric acid (500 mL) solution was added and the reaction mixture was stirred at ambient temperature for 18 hrs. The reaction mixture was concentrated and extracted with ethyl acetate (3×800 mL). The organic extracts were washed with saturated aqueous sodium bicarbonate (500 ml) and brine (500 ml), and dried (MgSO4). The crude pale yellow solid was recrystallized from ethyl acetate/hexane and dried at 70° C. in vacuum oven to afford 5-Chloro-2-(2-chloro-4-iodo-phenylamino)-N-((S)-2,3-dihydroxy-propoxy)-3,4-difluoro-benzamide (35 g, 54%) as pale yellow crystals: m.p. 153-154° C.; [α]=+3.36° (c=1.04, methanol); 1H NMR (d6-DMSO) δ 12.02 (s, 1H), 8.85 (s, 1H), 7.74 (s, 1H), 7.64 (d, 1H), 7.45 (d, 1H), 6.66 (t, 1H), 4.82 (s, 1H), 4.58 (s, 1H), 3.88 (m, 2H), 3.74 (m, 3H); 19F NMR (d6-DMSO) δ −133.21 (s, 1F), −137.18 (s, 1F); MS (m/z): 534 (68), 532 (100), 483 (28), 481 (41), 440 (51). Anal. calcd/found for C16H13Cl2F2IN2O4: C, 36.05/36.36; H, 2.46/2.38; N, 5.25/5.30; F, 7.13/7.15; Cl, 13.30/13.76; I, 23.80/23.83.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH3:10])[N+:3]=1[O-].P(Cl)(Cl)Cl>C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=1
Reactant: COc1cc(C)[n+]([O-])c(Br)c1
Solvent: ClP(Cl)Cl
Solvent: CCOC(C)=O
Product: COc1cc(C)nc(Br)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
2-Bromo-6-methyl-4-methoxy-pyridine 1-oxide (3.3 g, 15 mmol) was dissolved in ethyl acetate (anhydrous, 100 ml), phosphorus trichloride (6.6 ml) was added dropwise and the mixture was stirred at room temperature for three hours. The precipitate was collected by filtration, washed with ethyl acetate and dried to yield 2.4 g of beige crystals (12 mmol, 79%) MS(APCI) m/z=203.9 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1([OH:20])[CH:8]=[C:7]([O:9]C)[N:6]=[C:5]([C:11]2[S:12][CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[N:15]=2)[NH:4]1.B(Cl)(Cl)Cl.O.C(Cl)Cl>ClCCCl>[OH:9][C:7]1[N:6]=[C:5]([C:11]2[S:12][CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[N:15]=2)[NH:4][C:3]([O:2][CH3:1])([OH:20])[CH:8]=1
Reactant: COC1=CC(O)(OC)NC(c2nc(C(F)(F)F)cs2)=N1
Agent: ClB(Cl)Cl
Solvent: ClCCCl
Solvent: ClCCl
Solvent: O
Product: COC1(O)C=C(O)N=C(c2nc(C(F)(F)F)cs2)N1
Temperature: 60 °C
Reaction time: 16 h
Yield: 38 %

Procedure:
To a solution of compound 288 (460 mg, 1 eq.) in DCE (10 mL) was added BCl3 (3.16 mL, 2 eq.). The mixture was stirred at 60° C. for 16 hrs. Water and DCM were then added. Organics were separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was triturated in a DCM/pentane mixture to yield compound 289 as a beige solid in 38% yield. MS (ESI, EI+): m/z=278 (MH+).
Reaction SMILES: [C:1]([O:4][C:5]1[C:22]2[C@@H:21]3[C@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C@@H:16]([OH:23])[CH2:15][CH2:14]4)[CH2:11][CH2:10][C:9]=2[CH:8]=[C:7]([O:24][CH3:25])[CH:6]=1)(=[O:3])[CH3:2].O.[C:27](OC(=O)C)(=[O:29])[CH3:28]>N1C=CC=CC=1>[C:1]([O:4][C:5]1[C:22]2[C@@H:21]3[C@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C@@H:16]([O:23][C:27](=[O:29])[CH3:28])[CH2:15][CH2:14]4)[CH2:11][CH2:10][C:9]=2[CH:8]=[C:7]([O:24][CH3:25])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc2c(c(OC(C)=O)c1)[C@H]1CC[C@]3(C)[C@@H](O)CC[C@H]3[C@@H]1CC2
Solvent: c1ccncc1
Solvent: O
Product: COc1cc2c(c(OC(C)=O)c1)[C@H]1CC[C@]3(C)[C@@H](OC(C)=O)CC[C@H]3[C@@H]1CC2

Procedure:
A solution of 1-acetoxy-3-methoxyestra-1,3,5(10)-triene-17β-ol (0.95 g, 2.8 mM) in 20 ml of acetic anhydride and 5 ml of pyridine is heated on a steam bath for 1 hr. The resulting yellow solution is cooled and poured into 300 ml of cold H2O. The suspension is filtered, and the resulting white solid is recrystallized from methanol-H2O to give 1,17β-diacetoxy-3-methoxyestra-1,3,5(10)-triene as a white solid, yield 0.75 g (70%); m.p. 120°-121°.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[CH2:12]Br.Cl.[CH2:15]([NH2:17])[CH3:16].CCN(CC)CC>CN(C=O)C>[CH2:15]([N:17]1[CH2:12][C:4]2[C:3](=[CH:8][CH:7]=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=2)[CH2:2]1)[CH3:16]
Reactant: O=[N+]([O-])c1ccc(CBr)c(CBr)c1
Reactant: CCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN1Cc2ccc([N+](=O)[O-])cc2C1
Temperature: 20 °C
Reaction time: 1.5 h
Yield: 55.7 %

Procedure:
A mixture of dibromide 118 (9.27 g, 30.0 mmol), ethylamine hydrochloride (2.45 g, 30.0 mmol) and Et3N (21 mL, 150 mmol) in DMF (100 mL) was stirred at 20° C. for 90 min. The mixture was partitioned between EtOAc and aqueous Na2CO3 solution. The organic fraction was washed with water, dried and the solvent evaporated to give isoindole 245 (3.21 g, 56%) as a dark oil: 1H NMR δ 8.11 (dd, J=8.1, 2.1 Hz, 1H, H-6), 8.05 (d, J=2.1 Hz, 1H, H-4), 7.34 (d, J=8.1 Hz, 1H, H-7), 3.99 (s, 4H, H-1, H-3), 2.82 (q, J=7.2 Hz, 2H, CH2), 1.22 (t, J=7.2 Hz, 3H, CH3); HRMS (FAB+) calcd for C10H13N2O2 (MH+) m/z 193.0977, found 193.0983.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][C@@H:17]2[CH3:22])[C:5]2[CH2:10][N:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][C:6]=2[N:7]=1.[F:23][C:24]1[CH:25]=[C:26]([CH:28]=[C:29]([F:40])[C:30]=1B1OC(C)(C)C(C)(C)O1)[NH2:27]>>[CH2:8]([NH:9][C:11](=[O:12])[NH:27][C:26]1[CH:28]=[C:29]([F:40])[C:30]([C:2]2[N:3]=[C:4]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][C@@H:17]3[CH3:22])[C:5]3[CH2:10][N:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][C:6]=3[N:7]=2)=[C:24]([F:23])[CH:25]=1)[CH3:6]
Reactant: CC1(C)OB(c2c(F)cc(N)cc2F)OC1(C)C
Reactant: CCOC(=O)N1Cc2nc(Cl)nc(N3CCOC[C@@H]3C)c2C1
Product: CCNC(=O)Nc1cc(F)c(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CN(C(=O)OCC)C3)c(F)c1
Temperature: 130 °C
Yield: 14 %

Procedure:
Method as described for example 47 using (S)-ethyl 2-chloro-4-(3-methylmorpholino)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (intermediate 11) and 3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline as starting materials. Reaction mixture heated in by microwave at 130° C. for 1 h. The mixture was filtered through a celite 545 pre-packed cartridge (2.5 g), washed with MeOH and the solvent removed in vacuo. The residue was purified by prep. HPLC at high pH, yielding the title compound (55 mg, 0.13 mmol, 14%).
Reaction SMILES: [CH2:1]([S:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])[C:2]#[CH:3].[OH:10][CH2:11][C:12]1([CH2:16][CH2:17][CH3:18])[CH2:15]O[CH2:13]1>>[CH2:16]([C:12]12[CH2:11][O:10][C:7]([CH2:6][CH2:5][S:4][CH2:1][C:2]#[CH:3])([O:9][CH2:15]1)[O:8][CH2:13]2)[CH2:17][CH3:18]
Reactant: C#CCSCCC(=O)O
Reactant: CCCC1(CO)COC1
Product: C#CCSCCC12OCC(CCC)(CO1)CO2

Procedure:
4-n-Propyl-1-[2-(prop-2-ynylthio)ethyl]-2,6,7-trioxabicyclo[2.2.2]octane was prepared from 3-(prop-2-ynylthio)propionic acid and 3-hydroxymethyl-3-n-propyloxetane using methodology described in Example I.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[N:10](CC=C)[C:9]=2[C:8](=[O:18])[NH:7][C:6]1=[O:19])[CH2:2][CH2:3][CH3:4].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].N1CCOCC1.Cl>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.CCOC(C)=O>[CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[NH:10][C:9]=2[C:8](=[O:18])[N:7]([CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:6]1=[O:19])[CH2:2][CH2:3][CH3:4]
Reactant: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CCCC
Reactant: CCOC(=O)CCCBr
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCCCn1c(=O)n(CCCC(=O)OCC)c(=O)c2[nH]c(Cl)nc21
Temperature: 55 °C
Reaction time: 4 h
Yield: 67 %

Procedure:
To 3-butyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (6.0 g, 21.24 mmol) in dry DMF (100 ml) was added Cs2CO3 (7.62 g, 23.36 mmol) followed by ethyl 4-bromobutyrate (4.556 g, 23.36 mmol). The mixture was heated at 55° C. for 18 h and allowed to cool then degassed by repeatedly evacuating and readmitting nitrogen. Morpholine (14.9 g, 171 mmol) was added followed by tetrakis(triphenylphosphine)palladium(0) (4.0 g, 3.46 mmol) and the mixture was stirred for 4 h. EtOAc (300 ml) and 2M HCl (150 ml) and water (100 ml) were added and the organic phase separated, washed with brine (3×100 ml) and filtered. The filtrate was dried (Na2SO4) and evaporated. The crude product (10 g) was purified by aminopropyl SPE (3×20 g), loading in THF/MeOH (1:1), washing with THF/MeOH (1:1) and neat MeOH and eluting the product with DCM/MeOH (1:1) containing 5% added AcOH to afford the title compound (5.08 g).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:10]2[O:11][CH2:12][CH:13]([C:14]3[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=3)[C:9]=2[C:8]=1[CH3:29])(=O)=O.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CCCC)CCCC)CCC.C(O)=O>C1(C)C=CC=CC=1.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>[CH:20]([C:17]1[CH:18]=[CH:19][C:14]([CH:13]2[CH2:12][O:11][C:10]3[C:23]4[C:28]([CH:7]=[C:8]([CH3:29])[C:9]2=3)=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:15][CH:16]=1)([CH3:22])[CH3:21]
Reactant: Cc1c2c(c3ccccc3c1OS(=O)(=O)C(F)(F)F)OCC2c1ccc(C(C)C)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCCCN(CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc2ccccc2c2c1C(c1ccc(C(C)C)cc1)CO2
Temperature: 90 °C
Reaction time: 16 h
Yield: 18 %

Procedure:
To a solution of 3-(4-isopropylphenyl)-4-methyl-2,3-dihydronaphtho[1,2-b]furan-5-yl trifluoromethanesulfonate obtained in Reference Example 253 (2.23 g, 4.96 mmol), dichlorobis(triphenylphosphine)palladium (210 mg, 0.30 mmol), 1,3-bis(diphenylphosphino)propane (310 mg, 0.750 mmol) and tributylamine (5 mL, 21 mmol) in toluene (15 mL) was added formic acid (0.5 mL) at room temperature, and the mixture was stirred under argon atmosphere at 90° C. for 16 hours. Water was added to the reaction solution, which was extracted with ethyl acetate, the organic layer was washed with water and a saturated brine and then was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:20) to obtain 270 mg (yield 18%) of the title compound. Oily matter.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][C:2]=1[CH3:8].ClC1C=C(C=CC=1)C(OO)=[O:14].S([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:8][C:2]1[CH:3]=[C:4]([CH3:7])[CH:5]=[CH:6][N+:1]=1[O-:14]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccnc(C)c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc[n+]([O-])c(C)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 66.9 %

Procedure:
To a solution of 2,4-lutidine (2.0 g, 18.7 mmol) in methylene chloride (100 mL) was added 3-chloroperoxybenzoic acid (5.07 g, 29.4 mmol), which was stirred for 20 minutes at room temperature. A small amount of saturated aqueous sodium hydrogen sulfite solution was added to the reaction solution, and the organic layer was separated after vigorous stirring. This organic layer was washed with 5 N aqueous sodium hydroxide solution (5.9 mL), and dried over anhydrous magnesium sulfate. The solvent was evaporated under a reduced pressure to obtain the title compound (1.54 g, 66.9%). The title compound was used in the following reaction without being purified.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH2:14][CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][C:4]=2[O:16][CH2:17][C:18]([O:20]CC)=O.CC(C)([O-])C.[K+].[Cl-].[NH4+]>O1CCCC1>[NH:1]1[C:2]2=[C:15]3[C:10](=[N:9][C:8]4=[CH:7][CH:6]=[CH:5][C:4](=[C:3]24)[O:16][CH2:17][C:18]1=[O:20])[CH2:11][CH2:12][CH2:13][CH2:14]3
Reactant: CCOC(=O)COc1cccc2nc3c(c(N)c12)CCCC3
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C1COc2cccc3nc4c(c(c23)N1)CCCC4
Reaction time: 1 h
Yield: 82.7 %

Procedure:
Ethyl [(9-amino-1,2,3,4-tetrahydroacridin-8-yl)oxy]acetate (14.50 g) was dissolved in dry tetrahydrofuran (350 ml) and potassium t-butoxide (6.0 g) was added. After stirring for 1 hr, 100 ml saturated ammonium chloride solution (100 ml) was added, and stirring was continued for 30 min. The reaction mixture was evaporated under reduced pressure. The solid was collected and washed with water to give 10.15 g (82.65%) of product, mp 201°-202° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][NH2:16])=[CH:10][C:9]([I:17])=[C:8]2[C:4]=1[CH2:5][NH:6][C:7]2=[O:18].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[Cl:2][C:3]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][NH:16][S:27]([CH3:26])(=[O:29])=[O:28])=[CH:10][C:9]([I:17])=[C:8]2[C:4]=1[CH2:5][NH:6][C:7]2=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: NCCCOc1cc(I)c2c(c1Cl)CNC2=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)NCCCOc1cc(I)c2c(c1Cl)CNC2=O
Temperature: 25 °C
Reaction time: 13 h
Yield: 47 %

Procedure:
4-Chloro-5-(3-aminopropoxy)-7-iodoisoindolinone hydrochloride (100 mg, 0.248 mmol) was suspended in dichloromethane (3.0 mL), and the suspension was added with triethylamine (0.104 mL, 0.744 mmol) and methanesulfonyl chloride (0.029 mL, 0.372 mmol), followed by stirring at room temperature for 13 hours. The solvent was evaporated under reduced pressure, and the residue was purified by slurry using water and acetonitrile to obtain 4-chloro-5-[3-(methanesulfonylamino)propoxy]-7-iodoisoindolinone (51.8 mg, yield 47%).
Reaction SMILES: FC1C=CC(S(CCC)(=O)=O)=CC=1C#C[Si](C)(C)C.[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:35]#[CH:36])([CH3:23])([CH3:22])[CH3:21].[CH3:38][O:39][CH:40]1[C:44]2[CH:45]=[CH:46][C:47](Br)=[CH:48][C:43]=2[S:42](=[O:51])(=[O:50])[C:41]1([CH3:53])[CH3:52]>>[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:35]#[C:36][C:47]1[CH:46]=[CH:45][C:44]2[CH:40]([O:39][CH3:38])[C:41]([CH3:53])([CH3:52])[S:42](=[O:50])(=[O:51])[C:43]=2[CH:48]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: COC1c2ccc(Br)cc2S(=O)(=O)C1(C)C
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Agent: CCCS(=O)(=O)c1ccc(F)c(C#C[Si](C)(C)C)c1
Product: COC1c2ccc(C#Cc3cc(Cl)ccc3OCC(=O)OC(C)(C)C)cc2S(=O)(=O)C1(C)C

Procedure:
Following the general method as outlined in Intermediate 107, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 6-bromo-2,2-dimethyl-1,1-dioxido-2,3-dihydro-1-benzothien-3-yl methyl ether (Intermediate 248), the title compound was obtained after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [F:1][CH:2]([F:33])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[C:12]1[C:13]2[N:14]([N:18]=[C:19]([NH:21][C:22]3[CH:32]=[CH:31][C:25]4[CH2:26][CH2:27][NH:28][CH2:29][CH2:30][C:24]=4[CH:23]=3)[N:20]=2)[CH:15]=[CH:16][CH:17]=1.Cl[CH2:35][C:36]([N:38]([CH3:40])[CH3:39])=[O:37]>>[F:33][CH:2]([F:1])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[C:12]1[C:13]2[N:14]([N:18]=[C:19]([NH:21][C:22]3[CH:32]=[CH:31][C:25]4[CH2:26][CH2:27][N:28]([CH2:35][C:36]([N:38]([CH3:40])[CH3:39])=[O:37])[CH2:29][CH2:30][C:24]=4[CH:23]=3)[N:20]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: Fc1ccc(OCC(F)F)c(-c2cccn3nc(Nc4ccc5c(c4)CCNCC5)nc23)c1
Reactant: CN(C)C(=O)CCl
Product: CN(C)C(=O)CN1CCc2ccc(Nc3nc4c(-c5cc(F)ccc5OCC(F)F)cccn4n3)cc2CC1

Procedure:
2-(7-{8-[2-(2,2-Difluoro-ethoxy)-5-fluoro-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino}-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-N,N-dimethyl-acetamide was prepared from {8-[2-(2,2-difluoro-ethoxy)-5-fluoro-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl}-(2,3,4,5-tetrahydro-1H-3-benzazepin-7yl)-amine (0.097 g, 0.210 mmol) and 2-chloro-N,N-dimethyl-acetamide (0.033 mL, 0.321 mmol) in a manner analogous to Example 313 to give product (0.045 g, 39%). MP=218° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.53 (s, 1H), 8.78 (d, 1H), 7.62 (m, 2H), 7.40 (m, 2H), 7.29 (m, 2H), 7.00 (m, 2H), 6.23 (br m, 1H), 4.35 (m, 2H), 3.22 (s, 2H), 3.05 (s, 3H), 2.80 (br m, 7H), 2.60 (m, 4H). MS=539 (MH)+.
Reaction SMILES: [C:1]([NH:4][CH:5]([CH3:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10](OS(C(F)(F)F)(=O)=O)=[CH:9][CH:8]=1)(=[O:3])[CH3:2].[C:22]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH3:33])=[CH:26][CH:25]=1)#[CH:23]>CN(C=O)C.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>[CH3:21][CH:5]([NH:4][C:1](=[O:3])[CH3:2])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:23]#[C:22][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH3:33])=[CH:26][CH:25]=2)=[CH:9][CH:8]=1
Reactant: CC(=O)NC(C)Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1
Reactant: C#Cc1ccc(OCCC)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CCCOc1ccc(C#Cc2ccc(CC(C)NC(C)=O)cc2)cc1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
To 0.33 g (1.00 mmol) trifluoromethanesulfonic acid 4-(2-acetylamino-propyl)-phenyl ester (I53.2) and 0.18 g (1.10 mmol) 1-ethynyl-4-propoxybenzene in 3 mL DMF and 0.60 mL (4.50 mmol) TEA are added 0.04 g (0.06 mmol) bis-(triphenylphosphin)-palladiumdichlorid. The mixture is stirred in a sealed tube at 80° C. for 24 h. The reaction mixture is partitioned between EtOAc and water, the organic layer is dried with Na2SO4 and the solvent is removed in vacuo. The residue is purified by column chromatographie (silica gel, DCM/EtOAc 1/1). The resulting product is triturated with diethylether and dried at 80° C. in vacuo.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:40])[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:21]([NH:22]C(=O)C(C)(C)C)=[N:20][CH:19]=[C:18]([C@@H:29]3[CH2:34][CH2:33][CH2:32][C@@H:31]([S:35]([CH3:38])(=[O:37])=[O:36])[CH2:30]3)[N:17]=2)=[CH:12][C:11]=1[F:39])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[NH2:22][C:21]1[C:16]([C:13]2[CH:14]=[CH:15][C:10]([C:9]([NH:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:40])=[C:11]([F:39])[CH:12]=2)=[N:17][C:18]([C@@H:29]2[CH2:34][CH2:33][CH2:32][C@@H:31]([S:35]([CH3:38])(=[O:36])=[O:37])[CH2:30]2)=[CH:19][N:20]=1
Reactant: CC(C)(C)C(=O)Nc1ncc([C@@H]2CCC[C@@H](S(C)(=O)=O)C2)nc1-c1ccc(C(=O)NCc2ccccc2)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CS(=O)(=O)[C@@H]1CCC[C@@H](c2cnc(N)c(-c3ccc(C(=O)NCc4ccccc4)c(F)c3)n2)C1
Temperature: 80 °C
Yield: 25.4 %

Procedure:
To (+/−)-N-benzyl-2-fluoro-4-(6-((1R,3R)-3-(methylsulfonyl)cyclohexyl)-3-pivalamidopyrazin-2-yl)benzamide (25 mg, 0.044 mmol) in MeOH (221 μL) was added potassium carbonate (61.0 mg, 0.441 mmol). The resulting mixture was heated at 80° C. for 4 h. The reaction mixture was filtered and concentrated. Purified with auto-prep to provide 5.4 mg of (+/−)-4-(3-amino-6-((1R,3R)-3-(methylsulfonyl)cyclohexyl)pyrazin-2-yl)-N-benzyl-2-fluorobenzamide in 20.11% yield. LCMS (m/z): 483.1 (MH+), 0.78 min. 1H NMR (400 MHz, MeOD-d4) δ ppm 8.00-7.81 (m, 2H) 7.76-7.56 (m, 2H) 7.43-7.16 (m, 5H) 4.65-4.55 (m, 2H) 3.61-3.51 (m, 1H), 3.46-3.36 (m, 2H) 2.87-2.97 (m, 3H) 2.61-2.48 (m, 1H) 2.19-1.95 (m, 3H) 1.92-1.78 (m, 3H).