Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C(C2C=CC=CC=2)=[N:8][C:9]2[CH:10]=[CH:11][C:12]3[C:18]4([CH:27]=[CH2:28])[CH2:19][CH2:20][C:21]5([CH2:26][CH:17]4[CH2:16][CH2:15][O:14][C:13]=3[CH:29]=2)[O:25][CH2:24][CH2:23][O:22]5)C=CC=CC=1>[Pd].CCO>[CH2:27]([C:18]12[CH2:19][CH2:20][C:21]3([O:25][CH2:24][CH2:23][O:22]3)[CH2:26][CH:17]1[CH2:16][CH2:15][O:14][C:13]1[CH:29]=[C:9]([NH2:8])[CH:10]=[CH:11][C:12]2=1)[CH3:28]
Reactant: C=CC12CCC3(CC1CCOc1cc(N=C(c4ccccc4)c4ccccc4)ccc12)OCCO3
Agent: [Pd]
Solvent: CCO
Product: CCC12CCC3(CC1CCOc1cc(N)ccc12)OCCO3
Temperature: 25 °C
Reaction time: 22 h
Yield: 97.5 %

Procedure:
A 500 mL round-bottom flask equipped with a 3-way stopcock was charged with rac-(7 aS,11aS)—N-(diphenylmethylene)-11a-vinyl-7,7a,8,10,11,11a-hexahydro-6H-spiro[dibenzo[b,d]oxepine-9,2′-[1,3]dioxolan]-3-amine (85, R2=Vinyl) (17.7 g, 38.0 mmol) and 10% palladium on carbon (2.02 g, 1.90 mmol) in EtOH (190 mL). The vessel was evacuated and backfilled with hydrogen from a balloon and the resulting suspension was allowed to stir at rt for about 22 h. The mixture was filtered through a pad of Celite® using rinses of EtOAc (3×25 mL). The combined filtrates were concentrated under reduced pressure and the resulting crude material was purified on silica gel (330 g, eluted with 0 to 50% EtOAc in heptane). Collection and concentration of the appropriate fractions gave rac-(7aR,11aS)-11a-ethyl-7,7a,8,10,11,11a-hexahydro-6H-spiro[dibenzo[b,d]oxepine-9,2′-[1,3]dioxolan]-3-amine (86, R2=Ethyl) (11.24 g, 97%). LC/MS, method 3, 2.14 min, MS m/z 304 (M+H)+. 1H NMR (400 MHz, CDCL3) δ 7.00 (d, J=8.4 Hz, 1H), 6.56-6.45 (m, 2H), 5.34 (bs, 1H), 4.21-4.11 (m, 1H), 3.98-3.85 (m, 4H), 3.72-3.60 (m, 1H), 2.69-2.56 (m, 1H), 2.34-2.24 (m, 1H), 2.19-2.03 (m, 2H), 1.93-1.80 (m, 1H), 1.79-1.65 (m, 2H), 1.64-1.36 (m, 4H), 1.35-1.25 (m, 1H), 0.61 (t, J=7.4 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8]C1C=C2C(C(C=O)=CN2)=CC=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29](Cl)[CH:30]=2)[N:25]([CH2:33][C:34]([OH:36])=[O:35])[CH:24]=1)(=[O:22])[NH2:21]>>[CH2:1]([O:8][C:28]1[CH:27]=[C:26]2[C:31]([C:23]([C:20](=[O:22])[NH2:21])=[CH:24][N:25]2[CH2:33][C:34]([OH:36])=[O:35])=[CH:30][CH:29]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1cn(CC(=O)O)c2ccc(Cl)cc12
Reactant: O=Cc1c[nH]c2cc(OCc3ccccc3)ccc12
Product: NC(=O)c1cn(CC(=O)O)c2cc(OCc3ccccc3)ccc12

Procedure:
was prepared from 6-benzyloxy-1H-indole-3-carbaldehyde [92855-64-6] using similar protocols as described in Scheme A11 for the preparation of (3-carbamoyl-5-chloro-indol-1-yl)-acetic acid. White solid. MS (LC/MS): 325 [M+H]+, 649 [2M+H]+; tR (HPLC conditions b): 4.06 min.
Reaction SMILES: [O:1]([C:8]1[C:9]([OH:18])=[N:10][CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:20][C:21](=[O:40])[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]2[CH:36]=[C:35]([CH3:37])[CH:34]=[C:33](Br)[CH:32]=2)=[CH:26][C:25]=1[CH3:39]>>[CH3:39][C:25]1[CH:26]=[C:27]([O:30][C:31]2[CH:32]=[C:33]([O:18][C:9]3[C:8]([O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:13][C:12]([C:14]([F:17])([F:15])[F:16])=[CH:11][N:10]=3)[CH:34]=[C:35]([CH3:37])[CH:36]=2)[CH:28]=[CH:29][C:24]=1[CH2:23][CH2:22][C:21]([OH:40])=[O:20]
Reactant: COC(=O)CCc1ccc(Oc2cc(C)cc(Br)c2)cc1C
Reactant: Oc1ncc(C(F)(F)F)cc1Oc1ccccc1
Product: Cc1cc(Oc2ccc(CCC(=O)O)c(C)c2)cc(Oc2ncc(C(F)(F)F)cc2Oc2ccccc2)c1

Procedure:
The title compound is prepared according to Example 8 by using 3-phenoxy-5-trifluoromethyl-pyridin-2-ol and 3-[4-(3-bromo-5-methyl-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester to afford 32 mg (6%). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calcd for C29H24O5NF3 523, found 524 (M+1, 100%).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]3[N:20]=[CH:19][N:18]=[C:17]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=4[NH:31][C:32]([C@H:34]4[CH2:39][CH2:38][CH2:37][CH2:36][N:35]4[CH2:40][CH:41]([CH3:43])[CH3:42])=[O:33])[CH:16]=3)[C:8]=2[N:9]=1)(=[O:3])[CH3:2].C(NC1SC2C=CC=C(OC3N=CN=C(C4C=CC(C(F)(F)F)=CC=4NC([C@@H]4CCCCN4CC(C)C)=O)C=3)C=2N=1)(=O)C>>[C:1]([NH:4][C:5]1[S:6][C:7]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]3[N:20]=[CH:19][N:18]=[C:17]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:29])([F:30])[F:28])=[CH:23][C:22]=4[NH:31][C:32]([CH:34]4[CH2:39][CH2:38][CH2:37][CH2:36][N:35]4[CH2:40][CH:41]([CH3:43])[CH3:42])=[O:33])[CH:16]=3)[C:8]=2[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4NC(=O)[C@H]4CCCCN4CC(C)C)ncn3)cccc2s1
Agent: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4NC(=O)[C@@H]4CCCCN4CC(C)C)ncn3)cccc2s1
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4NC(=O)C4CCCCN4CC(C)C)ncn3)cccc2s1

Procedure:
(2R)-N-(2-(6-(2-Acetamidobenzo[d]thiazol-4-yloxy)pyrimidin-4-yl)-5-(trifluoromethyl)phenyl)-1-isobutylpiperidine-2-carboxamide and (2S)-N-(2-(6-(2-Acetamidobenzo[d]thiazol-4-yloxy)pyrimidin-4-yl)-5-(trifluoromethyl)phenyl)-1-isobutylpiperidine-2-carboxamide. Chiral separation [Chiralcel OD-H (250×21 mm, 5μ), A: hexane (0.2% diethylamine), B: ethanol (0.2% diethylamine), isocratic: 60:40 A:B, 20 mL/min] of N-(2-(6-(2-acetamidobenzo[d]-thiazole-4-yloxy)pyrimidin-4-yl)-5-(trifluoromethyl)phenyl)-1-isobutylpiperidine-2-carboxamide (Example 51) afforded the title compounds as amorphous solids. MS (ESI, pos. ion) m/z: 613 (M+1).
Reaction SMILES: C[CH:2]([CH:6]1[C:10]2=[C:11]([C:20](=[O:28])[C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[C:12]3[C:13](Br)=[CH:14][C:15]([F:18])=[CH:16][C:17]=3[N:9]2[CH2:8][CH2:7]1)[C:3]([O-:5])=[O:4].C([Sn](CCCC)(CCCC)[C:34]1[S:35][CH:36]=[CH:37][CH:38]=1)CCC>>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([C:20]([C:11]2[C:12]3[C:13]([C:34]4[S:35][CH:36]=[CH:37][CH:38]=4)=[CH:14][C:15]([F:18])=[CH:16][C:17]=3[N:9]3[CH2:8][CH2:7][CH:6]([CH2:2][C:3]([OH:5])=[O:4])[C:10]=23)=[O:28])=[CH:26][CH:25]=1
Reactant: CC(C(=O)[O-])C1CCn2c1c(C(=O)c1ccc(Cl)cc1)c1c(Br)cc(F)cc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Product: O=C(O)CC1CCn2c1c(C(=O)c1ccc(Cl)cc1)c1c(-c3cccs3)cc(F)cc12

Procedure:
Starting from (+/−)-methyl[8-bromo-9-(4-chlorobenzoyl)-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate and tributyl(thien-2-yl)stannane, the title compound was synthesized following the procedures described in Example 42 and Step 10 of Example 7.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11](Br)[C:10]=1[CH2:16][CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][C:19]1=[O:24].CNCCNC.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.[Cu]I>[CH2:1]([S:8][C:9]1[C:10]([CH2:16][CH3:17])=[C:11]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][C:19]2=[O:24])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1COCCN1
Reactant: CCc1c(Br)cccc1SCc1ccccc1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCc1c(SCc2ccccc2)cccc1N1CCOCC1=O
Temperature: 110 °C

Procedure:
Intermediate 4 (1.075 g, 3.5 mmol), morpholin-3-one (389 mg, 3.85 mmol), CuI (67 mg, 0.35 mmol), N,N′-dimethylethylene diamine (75 μl, 0.7 mmol) and K2CO3 (1.064 g, 7.7 mmol) were suspended in toluene (30 ml) under argon and heated to 110° C. for 20 h. After cooling to RT the reaction mixture was quenched by addition of 100 ml sat. aq. NH4Cl, 150 ml concentrated NH3 in water and 100 ml water and extracted three times with ethyl acetate. The organic layers were combined and washed with water and sat. aq. NaCl-solution, dried with MgSO4, filtered and evaporated to dryness. The resulting oil crystallizes upon standing and was triturated with n-heptane-MTBE (19:1).
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C@@H:7]2[CH2:11][CH2:10][CH2:9][N:8]2[CH2:12][C@@H:13]([OH:33])[CH2:14][O:15][C@@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:19]=2/[CH:26]=[CH:27]/[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH3:17])=[CH:4][C:3]=1[F:36].C1C(=C(C#N)C#N)C=CC(=C(C#N)C#N)C=1.[BH4-].[Na+]>O.O.O.O.O.O.[Ni](Cl)Cl.O.C(O)C.O1CCCC1>[Cl:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C@@H:7]2[CH2:11][CH2:10][CH2:9][N:8]2[CH2:12][C@@H:13]([OH:33])[CH2:14][O:15][C@@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:19]=2[CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH3:17])=[CH:4][C:3]=1[F:36]
Reactant: CCOC(=O)/C=C/c1c(OC)cccc1[C@@H](C)OC[C@H](O)CN1CCC[C@H]1Cc1ccc(Cl)c(F)c1
Agent: Cl[Ni]Cl
Agent: N#CC(C#N)=c1ccc(=C(C#N)C#N)cc1
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CCOC(=O)CCc1c(OC)cccc1[C@@H](C)OC[C@H](O)CN1CCC[C@H]1Cc1ccc(Cl)c(F)c1
Reaction time: 0.08 h
Yield: 49 %

Procedure:
A solution of ethyl (2E)-3-{2-[(1R)-1-({(2R)-3-[(2S)-2-(4-chloro-3-fluorobenzyl)pyrrolidin-1-yl]-2-hydroxypropyl}oxy)ethyl]-6-methoxy phenyl}prop-2-enoate (516 mg, 992.3 μmol), which had been obtained in Example 168 (168a), in mixture of tetrahydrofuran (10 mL) and ethanol (2 mL) was added with nickel (II) chloride hexahydrate (117.9 mg, 496.1 μmol) and 7,7,8,8-tetracyanoquinodimethane (101.3 mg, 496.1 μmol), and stirred for 5 minutes under ice cooling. After stirring, a solution of sodium borohydride (150 mg, 3.97 mmol) in mixture of tetrahydrofuran (5 mL) and ethanol (1 mL) was added dropwise slowly thereto under ice cooling. Upon the completion of the dropwise addition, the mixture was stirred for 1 hour at room temperature, added with water (20 mL), and filtered. The solvent was distilled off under reduced pressure. The residue was extracted with ethyl acetate (40 mL×2). After that, the organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (n-hexane/ethyl acetate=1/2) to give the title compound as a colorless oily substance (253 mg, yield 49%).
Reaction SMILES: [C:1]1([N:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]3[N:20]=[N:21][NH:22][CH:23]=3)=[C:9]([O:24]CC3C=CC=CC=3)[C:8]2=[O:32])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(N2C=CC(CCCC3N=NNC=3)=C(O)C2=O)C=CC=CC=1>C1COCC1>[C:1]1([N:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]3[N:20]=[N:21][NH:22][CH:23]=3)=[C:9]([OH:24])[C:8]2=[O:32])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=c1c(OCc2ccccc2)c(CCCCCCc2c[nH]nn2)ccn1-c1ccccc1
Agent: O=c1c(O)c(CCCc2c[nH]nn2)ccn1-c1ccccc1
Solvent: C1CCOC1
Product: O=c1c(O)c(CCCCCCc2c[nH]nn2)ccn1-c1ccccc1
Yield: 68.4 %

Procedure:
Reaction of 158e (0.15 g, 0.35 mmol) in anhydrous THF as described for synthesis of 159b gave 159e (0.081 g, 69%) of pure product. 1H NMR (400 MHz, CDCl3) δ 7.81 (m, 3H), 7.42 (m, 2H), 7.32 (m, 1H), 6.77 (m, 2H), 6.12 (t, J=7.1 Hz, 1H), 4.38 (t, J=7.1 Hz, 2H), 3.95 (m, 2H), 1.95 (m, 2H), 1.76 (d, J=7.0 Hz, 2H), 1.39 (m, 4H). 13C NMR (100 MHz, CDCl3) δ 158.20, 147.25, 146.40, 130.30, 128.60, 127.85, 126.65, 125.40, 119.65, 113.90, 106.80, 50.20, 49.60, 30.05, 28.95, 26.00, 25.90. HRMS (FAB) calcd for C19H23N4O2 [M+H]+ 339.1821. found 339.1814.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[C:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:18]=1)[N:9]=[C:8]2[NH:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35](C(OC(C)(C)C)=O)[N:34]=[CH:33]2.[NH:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1>CS(C)=O>[C:23]1([C:19]2[CH:18]=[C:17]([C:10]3[N:9]=[C:8]([NH:29][C:30]4[CH:31]=[C:32]5[C:36](=[CH:37][CH:38]=4)[NH:35][N:34]=[CH:33]5)[C:7]4[C:12](=[CH:13][C:14]([O:15][CH3:16])=[C:5]([O:4][CH2:3][CH2:2][N:46]5[CH2:51][CH2:50][O:49][CH2:48][CH2:47]5)[CH:6]=4)[N:11]=3)[CH:22]=[CH:21][CH:20]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C1COCCN1
Reactant: COc1cc2nc(-c3cccc(-c4ccccc4)c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2cc1OCCCl
Solvent: CS(C)=O
Product: COc1cc2nc(-c3cccc(-c4ccccc4)c3)nc(Nc3ccc4[nH]ncc4c3)c2cc1OCCN1CCOCC1
Temperature: 85 °C
Reaction time: 48 h
Yield: 50 %

Procedure:
To a mixture of tert-butyl 5-(6-(2-chloroethoxy)-2-[(3-phenyl)phenyl)-7-methoxyquinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.25 g, 0.40 mmole) in DMSO (2 mL) was added morpholine (1.32 g, 1.33 mL, 15.2 mmole) and the reaction was stirred at 85° C. for 48 h. The mixture was poured onto ice-water and the crude product was filtered. The product was then dissolved in a mixture of CH2Cl2 and CH3OH and the solution was concentrated in vacuo. The residue was purified via preparative TLC (SiO2, 10% CH2Cl2/CH3OH) to give 2-[(3-phenyl)phenyl)-N-(1H-indazol-5-yl)-7-methoxy-6-(2-morpholinoethoxy)quinazolin-4-amine (0.131 g, 0.20 mmole, 50%). MS 572.2 (M+). HPLC retention time 5.27 mins.
Reaction SMILES: CO[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10]Br.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH2:21][CH2:22][CH2:23][NH2:24])[CH:18]=[CH:19][CH:20]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH2:21][CH2:22][CH2:23][N:24]2[CH2:10][C:5]3[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:3]2=[O:12])[CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)c1ccccc1CBr
Reactant: COc1cccc(CCCN)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1cccc(CCCN2Cc3ccccc3C2=O)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 62.6 %

Procedure:
A mixture of 2-bromomethyl-benzoic acid methyl ester (0.115 g, 0.5 mmol), 3-(3-methoxy-phenyl)-propylamine (0.110 g, 0.6 mmol), and K2CO3 (0.207 g, 1.5 mmol) in toluene (3 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-[3-(3-methoxy-phenyl)-propyl]-2,3-dihydro-isoindol-1-one (0.088 g, 62%). 1H NMR (300 MHz, CDCl3): δ (ppm) 2.0 (m, 2H), 2.66 (t, 2H), 3.64 (t, 2H), 3.82 (s, 3H), 4.36 (s, 2H), 6.78 (m, 2H), 7.16-7.58 (m, 5H), 7.84 (d, 1H). GC-MS: m/z 281 (M)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C:17]2[CH:22]=[C:21](Br)[CH:20]=[CH:19][C:18]=2[CH3:24])O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[OH:30][C@H:31]1[C@H:38]2[C@H:34]([O:35][C:36]([CH3:40])([CH3:39])[O:37]2)[O:33][C@H:32]1[C:41](N1CCOCC1)=[O:42].C([Mg]Cl)(C)(C)C>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:17]2[CH:22]=[C:21]([C:41]([C@@H:32]3[O:33][C@H:34]4[O:35][C:36]([CH3:40])([CH3:39])[O:37][C@H:38]4[C@@H:31]3[OH:30])=[O:42])[CH:20]=[CH:19][C:18]=2[CH3:24])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)O[C@@H]2O[C@@H](C(=O)N3CCOCC3)[C@@H](O)[C@@H]2O1
Reactant: Cc1ccc(Br)cc1C(O)c1ccc(OCc2ccccc2)cc1
Agent: CC(C)(C)[Mg]Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)[C@@H]2O[C@H]3OC(C)(C)O[C@H]3[C@@H]2O)cc1Cc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.5 %

Procedure:
To a solution of 2-(4-(benzyloxy)benzyl)-4-bromo-1-methylbenzene (34, 2.71 g, 7.4 mmol) in THF (37 mL) under nitrogen at −78° C. was slowly added n-butyllithium (3.3 mL of 2.5 M solution in hexanes, 8.1 mmol), and the reaction was stirred for 30 min. Meanwhile, to a solution of ((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)(morpholino)methanone (2.02 g, 7.4 mmol) in THF (37 mL) under nitrogen at 0° C. was added tert-butylmagnesium chloride (8.1 mL of 1 M solution in THF, 8.1 mmol). The reaction was stirred for 20 min, then added slowly by cannula to the aryl lithium solution at −78° C. The reaction was allowed to gradually warm to room temperature over 3 hours, then quenched with saturated aqueous NH4Cl, diluted with EtOAc, washed with H2O and brine (with back extraction), dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by silica gel flash chromatography (gradient 0-50% EtOAc/hexanes) to give 2.44 g (70% yield) of the product 35 as a white foam. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.86 (dd, J=7.8, 1.8 Hz, 1 H), 7.75-7.80 (m, 1 H), 7.27-7.49 (m, 6 H), 7.04 (d, J=8.6 Hz, 2 H), 6.86-6.96 (m, 2 H), 6.09 (d, J=3.5 Hz, 1 H), 5.32 (d, J=2.8 Hz, 1 H), 5.04 (s, 2 H), 4.60 (d, J=3.5 Hz, 1H), 4.53-4.58 (m, 1 H), 3.98 (s, 2 H), 3.03 (d, J=4.3 Hz, 1 H), 2.31 (s, 3 H), 1.56 (s, 3 H), 1.36 (s, 3 H); MS (ES+) [M+H]+=475.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:8])=[CH:4][CH:5]=[CH:6][CH:7]=1.C[Al](C)C.C[O:14][C:15](=O)[C:16]1[CH:21]=[CH:20][C:19]([S:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[C:18]([NH:31][C:32]2[C:33]3[CH:41]=[CH:40][C:39]([CH3:42])=[N:38][C:34]=3[N:35]=[CH:36][N:37]=2)[CH:17]=1.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1>[CH3:30][O:29][C:26]1[CH:25]=[CH:24][C:23]([S:22][C:19]2[CH:20]=[CH:21][C:16]([C:15]([NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[CH3:8])=[O:14])=[CH:17][C:18]=2[NH:31][C:32]2[C:33]3[CH:41]=[CH:40][C:39]([CH3:42])=[N:38][C:34]=3[N:35]=[CH:36][N:37]=2)=[CH:28][CH:27]=1
Reactant: Cc1ccccc1N
Reactant: COC(=O)c1ccc(Sc2ccc(OC)cc2)c(Nc2ncnc3nc(C)ccc23)c1
Agent: C[Al](C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1ccc(Sc2ccc(C(=O)Nc3ccccc3C)cc2Nc2ncnc3nc(C)ccc23)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.5 %

Procedure:
To a solution of o-toluidine (0.208 mL, 1.94 mmol) in toluene (10 mL) was added AlMe3 (0.97 mL, 1.94 mmol) and the reaction mixture stirred for 30 minutes at room temperature. Then, the product from Example 148A (140 mg, 0.324 mmol) was added in one portion and the reaction mixture refluxed for 3 hours. The reaction mixture was cooled to room temperature and poured into a rapidly stirring solution of Rochelle's salt. After stirring the solution overnight at room temperature, the reaction was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over MgSO4, and concentrated under vacuum to a residue that was purified by silica gel chromatography using methanol in dichloromethane as eluent to provide the title compound (106 mg, 65%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 2.21 (s, 3H), 2.69 (s, 3H), 3.78 (s, 3H), 7.00 (d, J=8.82 Hz, 2H), 7.11-7.35 (m, 5H), 7.40 (d, J=8.82 Hz, 2H), 7.57 (d, J=8.46 Hz, 1H), 7.84 (d, J=6.99 Hz, 1H), 8.00 (s, 1H), 8.59 (s, 1H), 8.81 (d, J=8.09 Hz, 1H), 9.87 (s, 1H), 10.20 (s, 1H); MS (APCI) m/z 508 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:10]2[C:9]3[CH2:11][NH:12][CH2:13][CH2:14][C:8]=3[NH:7][C:6]=2[N:5]=[CH:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.CCOC(C)=O.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[C:10]3[C:9]4[CH2:11][NH:12][CH2:13][CH2:14][C:8]=4[NH:7][C:6]=3[N:5]=[CH:4][CH:3]=2)=[CH:18][CH:17]=1
Reactant: Clc1ccnc2[nH]c3c(c12)CNCC3
Reactant: OB(O)c1ccc(F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Fc1ccc(-c2ccnc3[nH]c4c(c23)CNCC4)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 28.8 %

Procedure:
4-Chloro-6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrole (100 mg, 0.48 mmol), 4-fluorophenylboronic acid (135 mg, 0.96 mmol), Pd(OAc)2 (5 mg, 0.02 mmol), S-Phos (20 mg, 0.05 mmol), and K2CO3 (266 mg, 1.93 mmol) were dissolved in dioxane/H2O (2.2 mL, 10/1, v/v), and stirred overnight at 100° C. The reaction mixture diluted with EtOAc/H2O, and filtered through an Extrelut column. The column was washed with EtOAc, and the filtrate was concentrated. The crude material was triturated with EtOAc, filtered, washed with EtOAc, and dried under vacuum to provide 6 (37 mg, 29% yield) as a tan solid. LC-MS (M+H=269, obsd.=269).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([C:16]2([CH3:21])[O:20][CH2:19][CH2:18][O:17]2)[C:5]([O:6][CH:7]([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:4]([CH:22]=C)[C:3]=1[F:24].[O:25]=[O+][O-]>C(Cl)Cl>[Cl:1][C:2]1[CH:15]=[C:14]([C:16]2([CH3:21])[O:20][CH2:19][CH2:18][O:17]2)[C:5]([O:6][CH:7]([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:4]([CH:22]=[O:25])[C:3]=1[F:24]
Reactant: C=Cc1c(F)c(Cl)cc(C2(C)OCCO2)c1OC(C)C(=O)OCC
Reactant: O=[O+][O-]
Solvent: ClCCl
Product: CCOC(=O)C(C)Oc1c(C2(C)OCCO2)cc(Cl)c(F)c1C=O
Temperature: 25 °C
Yield: 98 %

Procedure:
A solution of ethyl 2-[4-chloro-3-fluoro-6-(2-methyl-1,3-dioxolan-2-yl)-2-vinylphenoxy]propanoate (400 mg, 1.11 mmol) in methylene chloride (40 mL) at −78° C. was treated with ozone until a purple color persisted. The reaction mixture was purged with oxygen, treated with dimethyl sulfide (1 mL) and warmed to room temperature. The reaction mixture was concentrated to give the crude product (392 mg, 98%) as a mixture of enantiomers that was used without further purification. LCMS calculated for C16H19ClFO6 (M+H)+: m/z=361.1; found: 361.1.
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[CH3:20][O:21][NH2:22].CCN(C(C)C)C(C)C>>[CH3:20][O:21][NH:22][C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Reactant: CON
Solvent: CCN(C(C)C)C(C)C
Product: CONC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, methoxyamine and DIEA to give 2-methoxyamino-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 286 (MH+).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[N:8]=[CH:7][C:6]([C@@H:9]2[CH2:11][C@H:10]2[C:12]([OH:14])=O)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.Cl.[CH:50]1([N:54]2[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]2)[CH2:53][CH2:52][CH2:51]1>CN(C=O)C.CCOC(C)=O.CCCCCC>[CH:50]1([N:54]2[CH2:59][CH2:58][N:57]([C:12]([C@@H:10]3[CH2:11][C@H:9]3[C:6]3[CH:7]=[N:8][C:3]([C:2]([F:1])([F:16])[F:15])=[CH:4][CH:5]=3)=[O:14])[CH2:56][CH2:55]2)[CH2:53][CH2:52][CH2:51]1
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccc(C(F)(F)F)nc1
Reactant: C1CC(N2CCNCC2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: O=C([C@@H]1C[C@H]1c1ccc(C(F)(F)F)nc1)N1CCN(C2CCC2)CC1
Reaction time: 0.03 h
Yield: 35.2 %

Procedure:
To a stirring solution of 26C (16 mg, 0.070 mmol) in DMF (0.5 mL) at ambient temperature was added DIPEA (0.050 mL, 0.28 mmol) and TBTU (23 mg, 0.070 mmol). After stirring for 2 min, 4A (16 mg, 0.08 mmol) was added in one portion. After stirring for 19 h, the reaction was concentrated under reduced pressure. The residue was diluted with EtOAc (15 mL) then washed successively with dilute aq. K2CO3 (5 mL), H2O (2 mL), and brine (3 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was subjected to flash chromatography (basic alumina-8 g; gradient elution: 5% EtOAc/Hexane for 1 min then 5-100% EtOAc/Hexane over 13 min at 18 mL/min) to afford 8.7 mg 26D (36% yield). m/z (ES+) M+1=285.2; HPLC tR=0.75 min. 1H NMR (500 MHz, CDCl3) δ 8.53 (dd, J=2.1, 0.6 Hz, 1H), 7.59 (d, J=8.2 Hz, 1H), 7.55 (dd, J=8.2, 2.1 Hz, 1H), 3.69-3.59 (m, 4H), 2.74 (quintet, J=7.9 Hz, 1H), 2.60 (ddd, J=9.0, 6.3, 4.0 Hz, 1H), 2.36-2.29 (m, 4H), 2.05 (m, 3H), 1.93-1.82 (m, 2H), 1.79-1.66 (m, 3H), 1.35 (ddd, J=8.7, 6.3, 4.6 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:3]=1[CH3:18].Br[C:20]1[CH:25]=[N:24][C:23]([CH:26]2[CH2:28][CH2:27]2)=[CH:22][N:21]=1>>[Cl:1][C:2]1[C:3]([CH3:18])=[CH:4][C:5]([C:20]2[CH:25]=[N:24][C:23]([CH:26]3[CH2:28][CH2:27]3)=[CH:22][N:21]=2)=[CH:6][C:7]=1[CH3:8]
Reactant: Brc1cnc(C2CC2)cn1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C)c1Cl
Product: Cc1cc(-c2cnc(C3CC3)cn2)cc(C)c1Cl

Procedure:
The title compound is prepared from 2-chloro-1,3-dimethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzene and 2-bromo-5-cyclopropyl-pyrazine following a procedure analogous to that described in Step 1 of Intermediate 56. LC (method 11): tR=1.28 min; Mass spectrum (ESI+): m/z=259/261 (Cl) [M+H]+.