Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: 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.[C:47]([O:51][C:52]([N:54]1[CH2:59][CH2:58][N:57]([C:60]2[C:65]([CH:66]3[CH2:68][CH2:67]3)=[C:64](Cl)[N:63]=[CH:62][N:61]=2)[CH2:56][CH2:55]1)=[O:53])([CH3:50])([CH3:49])[CH3:48].[C:70](=[NH:83])([C:77]1[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=1)[C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=1.C1(C)C=CC=CC=1>CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:47]([O:51][C:52]([N:54]1[CH2:59][CH2:58][N:57]([C:60]2[C:65]([CH:66]3[CH2:68][CH2:67]3)=[C:64]([N:83]=[C:70]([C:71]3[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=3)[C:77]3[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=3)[N:63]=[CH:62][N:61]=2)[CH2:56][CH2:55]1)=[O:53])([CH3:50])([CH3:49])[CH3:48]
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc(Cl)c2C2CC2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2ncnc(N=C(c3ccccc3)c3ccccc3)c2C2CC2)CC1
Temperature: 95 °C
Yield: 89.3 %

Procedure:
A round bottom flask was charged with Pd(OAc)2 (84 mg, 0.37 mmol) and rac-BINAP (234 mg, 0.37 mmol) and purged with N2. To the flask was added 4-(5-cyclopropyl-6-chloro-pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (1.27 g, 3.75 mmol), benzophenone imine (815 mg, 4.50 mmol), NaOBut (793 mg, 8.25 mmol) and toluene (24 mL). The mixture was heated to 95° C. for 1 hour. After cooling to room temperature, the reaction was diluted with EtOAc, filtered through Celite, and concentrated. The crude product was purified by column chromatography (hexanes:EtOAc, 2:1) to give 4-[6-(Benzhydrylidene-amino)-5-cyclopropyl-pyrimidin-4-yl]-piperazine-1-carboxylic acid tert-butyl ester (1.62 g, 89%) as a colorless oil. 1H NMR (CDCl3, 400 MHz) δ 8.38 (s, 1H), 7.41 (m, 10H), 3.40 (m, 4H), 3.32 (m, 4H), 1.46 (s, 9H), 0.93 (m, 1H), 0.86 (m, 2H), 0.59 (m, 2H). LCMS (APCI+) m/z 484 [M+H]+; Rt=3.94 min.
Reaction SMILES: [NH:1]([C:8]1[N:9]=[CH:10][C:11]2[CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14][C:12]=2[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CC(C)=O.CC(O)C>[C:2]1([NH:1][C:8]2[N:9]=[CH:10][C:11]3[CH2:17][NH:16][CH2:15][CH2:14][C:12]=3[N:13]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(Nc3ccccc3)ncc2C1
Agent: Cl
Solvent: CC(C)=O
Solvent: CC(C)O
Product: c1ccc(Nc2ncc3c(n2)CCNC3)cc1
Temperature: 25 °C
Reaction time: 27 h

Procedure:
A solution of t-butyl 2-anilino-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate, Intermediate 7 (2.51 g, 7.69 mmol) in acetone (20 mL) was treated with 5-6 N HCl solution in i-PrOH (6 mL) and the reaction mixture was stirred at room temperature for 27 hours. The solvent was removed in vacuo and the salt was dissolved in water. The aqueous layer was washed with EtOAc and basified with 1.0 N NaOH(aq). The alkaline mixture was extracted with CH2Cl2 (2×100 mL) and the combined CH2Cl2 extracts were dried (MgSO4), filtered, and concentrated to a yellow, crystalline solid (1.25 g, 72%).
Reaction SMILES: [C:1]([C:5]1[CH2:6][CH2:7][NH:8][CH2:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:11][N:12]=[C:13]=[S:14]>O1CCCC1>[CH3:11][NH:12][C:13]([N:8]1[CH2:7][CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:10][CH2:9]1)=[S:14]
Reactant: CN=C=S
Reactant: CC(C)(C)C1=CCNCC1
Solvent: C1CCOC1
Product: CNC(=S)N1CC=C(C(C)(C)C)CC1

Procedure:
In 60 ml. of ml.of anhydrous tetrahydrofuran, there is dissolved 12.0 grams of 4-t-butyl-1,2,3,6-tetrahydropyridine. Stirring is initiated and there is added 7.3 grams of methylisothiocyanate in 25 ml. of anhydrous tetrahydrofuran. After stirring the reaction mixture for 18 hours at room temperature, the tetrahydrofuran is evaporated in vacuo at 50°C/20 mmHg. The resulting oil is crystallized from methylene chloride/pentane 1:1 to give N-methyl-4-t-butyl-1,2,3,6-tetrahydro-1-pyridinethiocarboxamide; m.p. 76° to 78°C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[C:5]2[C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1.[CH3:29][N:30]([CH3:36])[CH:31]1[CH2:35][CH2:34][NH:33][CH2:32]1>C(OCC)(=O)C.CO>[CH3:29][N:30]([CH3:36])[CH:31]1[CH2:35][CH2:34][N:33]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([CH3:12])[C:6]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[C:5]3[C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[CH2:32]1
Reactant: CN(C)C1CCNC1
Reactant: Cc1nc2ccc(Br)cc2c(-c2ccc(S(C)(=O)=O)cc2)c1C(=O)C(F)(F)F
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1nc2ccc(N3CCC(N(C)C)C3)cc2c(-c2ccc(S(C)(=O)=O)cc2)c1C(=O)C(F)(F)F
Reaction time: 16 h
Yield: 47 %

Procedure:
The title compound was prepared from 1-[6-Bromo-4-(4-methanesulfonyl-phenyl)-2-methyl-quinolin-3-yl]-2,2,2-trifluoro-ethanone [example 23] and 3-(dimethylamino)pyrrolidine according to the procedure of example 25, except that the reaction time was of 16 h and that ethyl acetate/methanol (9:1) was used. Yield: 47%; MS: m/z=506 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:23]=[C:22]([CH:24]([OH:28])C(O)C)[C:21]([O:29][CH2:30]OC)=[C:20]([C:33]([O:35][CH2:36][O:37][CH3:38])=[O:34])[CH:19]=3)[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].I([O-])(=O)(=O)=O.[Na+].[OH2:45].[CH3:46]O>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:23]=[C:22]([CH:24]=[O:28])[C:21]([O:29][CH3:30])=[C:20]([C:33]([O:35][CH2:36][O:37][CH3:38])=[O:34])[C:19]=3[O:45][CH3:46])[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: O
Reactant: CCOc1ccc(-c2nc(-c3cc(C(=O)OCOC)c(OCOC)c(C(O)C(C)O)c3)cs2)cc1OCC
Reactant: CO
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Product: CCOc1ccc(-c2nc(-c3cc(C=O)c(OC)c(C(=O)OCOC)c3OC)cs2)cc1OCC
Temperature: 25 °C
Reaction time: 14 h

Procedure:
In a mixed solvent consisting of 100 ml of tetrahydrofuran and 40 ml of water was dissolved 3.7 g of 2-(3,4-diethoxyphenyl)-4-[3-methoxymethoxycarbonyl-4-methoxymethoxy-5-(1-propenyl)phenyl]thiazole. To the solution were added 100 mg of osmium tetroxide (OsO4) and 5.6 g of sodium periodate (NaIO4), and the mixture was stirred at room temperature for 14 hours. The reaction mixture was filtered. The filtrate was concentrated to a 1/3 volume. To the concentrate was added 100 ml of ethyl acetate, and phase separation was conducted. The organic layer was washed with 40 ml of a saturated aqueous sodium chloride solution, dried and subjected to distillation to remove the solvent. The residue was purified by silica gel column chromatography (elutant: dichloromethane) to obtain 600 mg of 2-(3,4-diethoxyphenyl)-4-(3-methoxymethoxycarbonyl-4-methoxymethoxy-5-formylphenyl)thiazole (compound A) and 1.28 g of 2-(3,4-diethoxyphenyl)-4-[3-methoxymethoxycarbonyl-4-methoxymethoxy-5-(1,2-dihydroxypropyl)phenyl]thiazole (compound B). The 2-(3,4-diethoxyphenyl)-4-[3-methoxymethoxycarbonyl-4-methoxymethoxy-5-(1,2-dihydroxypropyl)phenyl]thiazole (compound B) was dissolved in 40 ml of methanol. To the solution were added 5 g of sodium periodate (NaIO4) and 10 ml of water, and the mixture was stirred at room temperature for 14 hours. The solvent was removed from the reaction mixture by distillation. The residue was mixed with 80 ml of ethyl acetate and 40 ml of water, and phase separation was conducted. The organic layer was washed with 20 ml of a saturated aqueous sodium chloride solution, dried and subjected to distillation to remove the solvent. The residue was combined with 600 mg of the above-obtained 2-(3,4-diethoxyphenyl)-4-(3-methoxymethoxycarbonyl-4-methoxymethoxy-5-formylphenyl)thiazole (compound A). The mixture was recrystallized from ethanol to obtain 1.6 g of 2-(3,4-diethoxyphenyl)-4-(3-methoxymethoxycarbonyl-4-methoxy-methoxy-5-formylphenyl)thiazole as white acicular crystals.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=[N:8]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:30]1[C:31]([N:50]2[CH2:54][CH2:53][C@@H:52]([OH:55])[CH2:51]2)=[N:32][CH:33]=[C:34]([CH:49]=1)[C:35]([NH:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][C:45]([F:48])([F:47])[F:46])=[CH:40][CH:39]=1)=[O:36]>C1(C)C=CC=CC=1.CCOC(C)=O.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>[OH:55][C@@H:52]1[CH2:53][CH2:54][N:50]([C:31]2[C:30]([C:11]3[N:7]([CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)[N:8]=[CH:9][CH:10]=3)=[CH:49][C:34]([C:35]([NH:37][C:38]3[CH:39]=[CH:40][C:41]([O:44][C:45]([F:48])([F:47])[F:46])=[CH:42][CH:43]=3)=[O:36])=[CH:33][N:32]=2)[CH2:51]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2ccnn2C2CCCCO2)c1
Temperature: 110 °C
Reaction time: 2.5 h

Procedure:
1-(Tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester (59.9 g, 214.4 mmol), K3PO4 (105.7 g, 498.1 mmol) and Pd(PPh3)4 (9.6 g, 8.30 mmol) were added to a suspension of (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 2.2, 74 g, 165.8 mmol) in toluene (740 mL) and stirred at 110° C. for 2.5 h under argon. The mixture was then diluted with EtOAc (2 L), washed with water (2×1 L) and dried over Na2SO4. The solvent was evaporated off under reduced pressure and the crude residue was purified by flash chromatography (Silica gel, 2 kg, DCM/MeOH 95:5). The resulting material was dissolved in a mixture of MeOH (500 mL) and THF (800 mL) and was treated with Si-Thiol (Biotage, 15 g, 19.5 mmol) at RT for 17 h. The mixture was filtered and the solvent was evaporated off under reduced pressure to give a residue which was crystallized from MeOH to give the title compound as a white crystalline solid. HPLC (Condition 5) tR=5.99 min, UPLC-MS (Condition 6) m/z=518.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.42 (br. s, 3H) 1.63-1.98 (m, 4H) 2.20-2.37 (m, 1H) 2.71-2.94 (m, 1H) 3.21 (d, J=6.65 Hz, 3H) 3.32-3.51 (m, 1H) 3.69-3.92 (m, 1H) 4.08-4.24 (m, 1H) 4.75-4.88 (m, 1H) 4.89-5.17 (m, 1H) 6.29-6.49 (m, 1H) 7.32 (d, J=8.99 Hz, 2H) 7.59 (s, 1H) 7.78-8.10 (m, 3H) 8.80 (t, J=2.54 Hz, 1H) 10.05-10.28 (m, 1H).
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[C:9]([O:19][C@@H:20]([C@H:22]4[CH2:26][NH:25][C:24](=[O:27])[CH2:23]4)[CH3:21])=[N:10][C:11](C4C=CN=CC=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1.[CH3:28][O:29][C:30]1[C:35]([O:36][CH3:37])=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][N:31]=1>>[CH:1]1([N:4]2[C:8]3[C:9]([O:19][C@@H:20]([C@H:22]4[CH2:26][NH:25][C:24](=[O:27])[CH2:23]4)[CH3:21])=[N:10][C:11]([C:33]4[CH:32]=[N:31][C:30]([O:29][CH3:28])=[C:35]([O:36][CH3:37])[CH:34]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1
Reactant: C[C@@H](Oc1nc(-c2ccncc2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cnc1OC
Product: COc1cc(-c2cc3ncn(C4CC4)c3c(O[C@H](C)[C@H]3CNC(=O)C3)n2)cnc1OC
Yield: 60.3 %

Procedure:
Prepared by Suzuki coupling reaction procedure, as previously described for the synthesis of (R)-4-((R)-1-((3-cyclopropyl-6-(pyridin-4-yl)-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one:, using instead 2,3-dimethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (217.8 mg, 0.82 mmol) as a starting material, to afford 70.0 mg (60.3%) of (R)-4-((R)-1-((3-cyclopropyl-6-(5,6-dimethoxypyridin-3-yl)-3H-imidazo[4,5-c]pyridin-4yl)oxy)ethyl)pyrrolidin-2-one:. 1H NMR (300 MHz, DMSO-d6) δ 8.46 (d, J=2.4 Hz 1H), 8.287 (s, 1H), 7.90 (d, J=2.4 Hz 1H), 7.879 (s, 1H), 7.57 (s, 1H). 5.59-5.55 (m, 1H), 3.9 (d, J=2.4 Hz 6H), 3.71-3.66 (m, 1H), 3.38 (t, J=18 Hz, 1H), 3.25 (dd, J=12, 15 Hz, 1H), 2.89-2.82 (m, 1H), 2.36-2.3 (m, 2H), 1.43 (d, J=6.4 Hz, 3H), 1.119-1.09 (m, 4H). LCMS-ESI+ (m/z): [M+H]+ calcd for C22H25N5O4:423.19; found 424.08.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I:7][C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1.[I:15][C:16]1[CH:29]=[C:28]([I:30])[CH:27]=[C:26]([I:31])[C:17]=1[O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]Cl.O>CN(C=O)C>[I:7][C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=1)[O:14][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][O:18][C:17]1[C:26]([I:31])=[CH:27][C:28]([I:30])=[CH:29][C:16]=1[I:15]
Reactant: Oc1cccc(I)c1
Reactant: ClCCCCCCOc1c(I)cc(I)cc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Ic1cccc(OCCCCCCOc2c(I)cc(I)cc2I)c1
Temperature: 110 °C
Yield: 53.8 %

Procedure:
A mixture of potassium carbonate (3.0 g, 21.9 mmol, 1.1 eq), 3-iodophenol (4.4 g, 19.9 mmol) and 6-(2,4,6-triiodophenoxy)-1-chlorohexane (11.75.g, 19.9 mmol) in 50 ml of DMF was heated to 110° C. for 1.5 hours and then cooled. The mixture was poured into water and extracted with ethyl acetate. The organic layer was dried (magnesium sulfate) and evaporated to give a solid which was filtered through basic alumina (hexanes-ethyl acetate). The filtrate was concentrated under vacuum leaving the crude product as a solid. Recrystallization from cyclohexane afforded 8.29 g (54%) of the desired product after drying at room temperature under high vacuum, mp 65°-66° C.
Reaction SMILES: Cl[SiH](Cl)Cl.[C:5]1([PH:11](=O)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(N(CC)CC)C.[OH-].[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl>[C:12]1([PH:11][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=[PH](c1ccccc1)c1ccccc1
Agent: Cl[SiH](Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: c1ccc(Pc2ccccc2)cc1
Yield: 79 %

Procedure:
Trichlorosilane (0.1 ml, 1 mmol) was added, at room temperature, to a suspension of (1H, 1H, 2H, 2H-perfluorooctyl)diphenylphosphine oxide (55 mg, 0.1 mmol) and triethylamine (0.1 ml, 0.7 mmol) in toluene (5 ml). The mixture was then heated at 100 C. overnight and then allowed to cool. Aqueous sodium hydroxide (40 ml of a 1M solution) was added and the resulting mixture extracted with ether (4×25 ml). The organic fractions were combined, dried (MgSO4) and concentrated in vacuo to give the crude product. The product was purified by flash column chromatography on silica gel, eluting with hexane to give a white crystalline solid (42 mg, 0.079 mmol, 79%), mp (CH2Cl2) 44-45° C. (Found: M+,532.0600. C20H14F13P requires M+, 532.0625).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[C:5]([CH3:17])=[CH:4][N:3]=1.[NH2:18][C:19]1[C:24]([O:25][CH3:26])=[CH:23][C:22]([N:27]2[CH2:32][CH2:31][CH:30]([NH:33]C(=O)OC(C)(C)C)[CH2:29][CH2:28]2)=[C:21]([CH3:41])[CH:20]=1>>[NH2:33][CH:30]1[CH2:31][CH2:32][N:27]([C:22]2[C:21]([CH3:41])=[CH:20][C:19]([NH:18][C:2]3[N:7]=[C:6]([C:8]4[C:16]5[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=5)[NH:10][CH:9]=4)[C:5]([CH3:17])=[CH:4][N:3]=3)=[C:24]([O:25][CH3:26])[CH:23]=2)[CH2:28][CH2:29]1
Reactant: Cc1cnc(Cl)nc1-c1c[nH]c2ccccc12
Reactant: COc1cc(N2CCC(NC(=O)OC(C)(C)C)CC2)c(C)cc1N
Product: COc1cc(N2CCC(N)CC2)c(C)cc1Nc1ncc(C)c(-c2c[nH]c3ccccc23)n1

Procedure:
Starting materials: 3-(2-chloro-5-methylpyrimidin-4-yl)-1H-indole (INTERMEDIATE 1) tert-butyl 1-(4-amino-5-methoxy-2-methylphenyl)piperidin-4-ylcarbamate (INTERMEDIATE 29).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25](Cl)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:14])=[O:13])(C)(C)C.[NH2:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[C:35]([O:40][CH3:41])[CH:34]=1>>[NH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([OH:39])=[C:35]([O:40][CH3:41])[CH:34]=3)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:13])=[O:14]
Reactant: COc1cc(CN)ccc1O
Reactant: CC(C)(C)OC(=O)NCCCN(Cc1cccc(-c2ccnc(Cl)n2)c1)S(C)(=O)=O
Product: COc1cc(CNc2nccc(-c3cccc(CN(CCCN)S(C)(=O)=O)c3)n2)ccc1O

Procedure:
Intermediate 4 was coupled with 4-Aminomethyl-2-methoxy-phenol following procedure F and the resulting product deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 472. 1H NMR (Varian 300 MHz, CDCl3—CD3OD, shifts relative to the solvent peak at 7.24 ppm) δ 8.2 (m, 3H) 7.6 (m, 2H) 7.3 (m, 2H) 6.8 (m, 2H) 4.4 (s, 2H) 3.8 (s, 2H) 3.7 (m, 2H) 3.4 (s, 3H) 2.9 (s, 3H) 2.8 (m, 2H) 1.7 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].S([O-])(=O)(=O)C.[C:21]1([CH2:27][O:28][C:29]2[C:30]([O:39][CH2:40][CH2:41]O)=[CH:31][C:32]3[C:37]([CH:38]=2)=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C=O.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:41][CH2:40][O:39][C:30]2[C:29]([O:28][CH2:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)=[CH:7][CH:6]=1
Reactant: OCCOc1cc2ccccc2cc1OCc1ccccc1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCCOc2cc3ccccc3cc2OCc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (2.29 g) in dimethylformamide (30 mL) under argon was treated with 55% sodium hydride (0.552 g), stirred for 15 minutes and treated with the mesylate (4.3 g) prepared from 2-[3-(phenylmethoxy)-2-naphthalenyloxy]ethanol. The mixture was heated under argon at 60° C. overnight. The cooled mixture was treated with glacial acetic acid (2 drops) and the volatiles were removed under vacuum. The residue was mixed with water and extracted with dichloromethane. The organic layer was washed with water, dried (Na2SO4), filtered, and evaporated to give crude product. The material was purified by HPLC (dichloromethane-hexane; 3:1 plus 2% ethyl acetate) to provide, after crystallization from dichloromethane-methanol, 3.0 g of alpha-oxo-4-[[2-[3-(phenylmethoxy)-2-naphthalenyloxy]ethyl]oxy]benzeneacetic acid methyl ester as a colorless solid, mp 115°-117° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]3)[C:8]2=[O:11])=[CH:4][CH:3]=1.[F:18][C:19]([F:23])([F:22])[CH2:20][NH2:21].CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:16][CH2:15][CH:14]([NH:21][CH2:20][C:19]([F:23])([F:22])[F:18])[CH2:13][CH2:12]3)[C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: O=C1CCC2(CC1)Cc1ccc(Br)cc1C2=O
Reactant: NCC(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: O=C1c2cc(Br)ccc2CC12CCC(NCC(F)(F)F)CC2
Temperature: 25 °C
Yield: 16.8 %

Procedure:
In a 25 mL round bottom flask was placed 6′-bromospiro[cyclohexane-1,2′-indene]-1′,4(3′H)-dione (501 mg, 1.716 mmol) and it was dissolved in dichloroethane (5.7 mL). To this solution was added the trifluoro ethylamine (162 μL, 2.059 mmol), AcOH (124 μL, 2.059 mmol), and NaBH(OAc)3 (582 mg, 2.746 mmol) at last. The reaction was stirred at room temperature. When the reaction was completed it was quenched with saturated NaHCO3 (aq) (20 mL) and diluted with ethyl acetate (20 mL). The phases were separated and the aqueous phase was back-extracted with ethyl acetate twice (5 mL/each). The combined organic phases were dried over Na2SO4, filtered and concentrated under reduce pressure. The crude material was purified by flash chromatography (ISCO, 40 g SiO2 cartridge, ethyl acetate/hexanes as the eluents). At the end, two isomers were obtained and their corresponding fractions were combined separately and concentrated under reduce pressure yielding 6′-bromo-4-(2,2,2-trifluoroethylamino)spiro[cyclohexane-1,2′-inden]-1′(3′H)-one (axial, 97b) (420 mg, 1.120 mmol) and 6′-bromo-4-(2,2,2-trifluoroethylamino)spiro[cyclohexane-1,2′-inden]-1′(3′H)-one (equatorial, 98b) (108 mg, 0.288 mmol) (82% yield). Compound 97b: M+H=375.9, 1H NMR=(CDCl3, 400 MHz) δ 7.85 (d, J=1.6 Hz, 1H), 7.67 (dd, J=8.0, 1.6 Hz, 1H), 7.29 (d, J=8.0 Hz, 1H), 3.21 (q, J=9.2 Hz, 2H), 2.93 (s, 2H), 2.90 (m, 1H), 2.01-1.94 (m, 2H), 1.87-1.81 (m, 2H), 1.75-1.68 (m, 2H), 1.38-1.29 (m, 2H). Compound 98b: M+H=375.8, 1H NMR=(CDCl3, 400 MHz) δ 7.86 (d, J=1.6 Hz, 1H), 7.68 (dd, J=8.0, 1.6 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 3.24 (q, J=9.6 Hz, 2H), 2.95 (s, 2H), 2.68 (m, 1H), 2.03-1.97 (m, 2H), 1.81-1.74 (ddd, J=14.0, 14.0, 3.6 Hz, 2H), 1.46 (m, 2H), 1.31-1.21 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]([C:8](=[O:17])[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([CH3:16])[CH:10]=1)=[CH:5]OC.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:1][O:2][C:3](=[O:18])[C:4]([C:8](=[O:17])[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([CH3:16])[CH:10]=1)=[CH:5][NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC=C(C(=O)OC)C(=O)c1ccc(C)c(C)c1
Reactant: Nc1ccccc1
Product: COC(=O)C(=CNc1ccccc1)C(=O)c1ccc(C)c(C)c1
Temperature: 25 °C
Yield: 46.6 %

Procedure:
Crude 2-(3,4-dimethyl-benzoyl)-3-methoxy-acrylic acid methyl ester 1a(13.7 g, 55.1 mmol) and of aniline (5.12 g, 55.1 mmol) were heated neat at 100° C. for 30 minutes, then cooled down to room temperature and recrystallized from dichloromethane/hexane to yield 7.94 g of 2-(3,4-Dimethyl-benzoyl)-3-phenylamino-acrylic acid methyl ester 2a as a yellow crystalline solid: LC-MSD, m/z for C19H19NO3 [M+H]+=310.4; HPLC retention time: 2.8 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:22]2[S:26][C:25]([C:27]3(O)[CH2:30][CH2:29][CH2:28]3)=[N:24][CH:23]=2)=[C:4]2[CH:10]=[C:9]([I:11])[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.C(N(S(F)(F)[F:38])CC)C>ClCCl.O1CCOCC1>[Cl:1][C:2]1[C:3]([C:22]2[S:26][C:25]([C:27]3([F:38])[CH2:30][CH2:29][CH2:28]3)=[N:24][CH:23]=2)=[C:4]2[CH:10]=[C:9]([I:11])[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2c(I)cc3c(-c4cnc(C5(O)CCC5)s4)c(Cl)cnc32)cc1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2c(I)cc3c(-c4cnc(C5(F)CCC5)s4)c(Cl)cnc32)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a cold (0° C.) solution of 1-(5-(5-chloro-2-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)thiazol-2-yl)cyclobutanol (Example 8A) (330 mg, 0.563 mmol) in dichloromethane (6 mL) and dioxane (6 mL) was added diethylaminosulfur trifluoride (0.149 mL, 1.127 mmol) in a single portion via syringe. The reaction was stirred at 0° C. for 2 hours and was then quenched by the addition of saturated sodium bicarbonate solution and ethyl acetate. The layers were separated, and the aqueous layer was extracted with additional ethyl acetate (2×). The combined organics were dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with a gradient of hexane to 25% ethyl acetate in hexane, to give the title compound. 1H NMR (300 MHz, DMSO-d6) 8.51 (s, 1H), 8.24 (d, J=2.8 Hz, 1H), 7.97 (d, J=8.4 Hz, 2H), 7.47 (d, J=8.0 Hz, 2H), 7.24 (s, 1H), 2.80-2.63 (m, 4H), 2.37 (s, 3H), 2.09-1.96 (m, 1H), 1.94-1.85 (m, 1H).