Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]([F:29])=[C:14]([C@:16]3([CH3:28])[C:22]([F:24])([F:23])[C:21]([CH3:26])([CH3:25])[O:20][CH2:19][C:18](=O)[NH:17]3)[CH:15]=2)[CH:5]=[CH:6][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:39])=CC=1>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]([F:29])=[C:14]([C@:16]3([CH3:28])[C:22]([F:24])([F:23])[C:21]([CH3:26])([CH3:25])[O:20][CH2:19][C:18](=[S:39])[NH:17]3)[CH:15]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)OCC(=O)N[C@](C)(c2cc(C#Cc3cccc(Cl)c3)ccc2F)C1(F)F
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: CC1(C)OCC(=S)N[C@](C)(c2cc(C#Cc3cccc(Cl)c3)ccc2F)C1(F)F
Yield: 53.4 %

Procedure:
The reaction of (R)-5-[5-(3-chloro-phenylethynyl)-2-fluoro-phenyl]-6,6-difluoro-5,7,7-trimethyl-[1,4]oxazepan-3-one (233 mg, 552 μmol) with Lawesson's reagent (230 mg, 552 μmol) in 1,4-dioxane (15 ml) yielded the (R)-5-[5-(3-chloro-phenylethynyl)-2-fluoro-phenyl]-6,6-difluoro-5,7,7-trimethyl-[1,4]oxazepan-3-thione (129 mg, 53% yield) as a light yellow foam. MS (ISP): m/z=438.1 [M+H]+ and 440.2 [M+2+H]+.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([C:9]2[CH:10]=[CH:11][C:12](=[O:16])[N:13]([CH3:15])[CH:14]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].I[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1>>[OH:3][C:1]([C:4]1[S:8][C:7]([C:9]2[CH:10]=[CH:11][C:12](=[O:16])[N:13]([CH3:15])[CH:14]=2)=[CH:6][CH:5]=1)([C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)[CH3:2]
Reactant: Ic1ccncc1
Reactant: CC(=O)c1ccc(-c2ccc(=O)n(C)c2)s1
Product: Cn1cc(-c2ccc(C(C)(O)c3ccncc3)s2)ccc1=O
Yield: 21.3 %

Procedure:
Using 5-(5-acetylthiophen-2-yl)-1-methylpyridin-2(1H)-one (0.07 g, 0.3 mmol), 4-iodopyridine (0.12 g, 0.6 mmol), and the procedure described for example 7 and step 4, crude compound was obtained and further purified by preparative TLC (5% methanol in dichloromethane) to give 5-(5-(1-hydroxy-1-(pyridin-4-yl)ethyl)thiophen-2-yl)-1-methylpyridin-2(1H)-one as off-white solid (0.02 g, 21% yield) in 99.8% HPLC purity. 1H NMR (400 MHz, DMSO-d6): δ 8.48 (d, 2H), 7.97 (d, 1H), 7.65 (dd, 1H), 7.45-7.44 (t, 2H), 7.07 (d, 1H), 6.94 (d, 1H), 6.41-6.38 (m, 2H), 3.42 (s, 3H), 1.85 (s, 3H); LC-MS m/z calculated for [M+H]+ 313.09, found 313.1.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[O:5][C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[S:14](Cl)(=[O:16])=[O:15])=[N:3]1.[NH3:18]>O1CCCC1>[CH3:1][N:2]1[C:6](=[O:7])[O:5][C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[S:14]([NH2:18])(=[O:16])=[O:15])=[N:3]1
Reactant: Cn1nc(-c2ccccc2S(=O)(=O)Cl)oc1=O
Reactant: N
Solvent: C1CCOC1
Product: Cn1nc(-c2ccccc2S(N)(=O)=O)oc1=O
Reaction time: 1.5 h

Procedure:
To a suspension of 3.3 g of the product of Example 3 in 50 ml of tetrahydrofuran was added dropwise 3 ml of condensed ammonia while keeping the reaction temperature at -5° C. with external cooling. After stirring at 0° for 1.5 hours, the solvent was evaporated in vacuo and water was added to the residue to yield a precipitate. After filtration the isolated residue was washed with water, then dissolved in tetrahydrofuran and dried over MgSO4. After evaporation of the solvent in vacuo, 2.9 g of the subject compound was obtained as a crude solid; m.p. 168°-173° C.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:35][CH3:36])=[C:28]([O:31][CH2:32][CH2:33]Cl)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:37][CH2:38][CH2:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:35][CH3:36])=[C:28]([O:31][CH2:32][CH2:33][N:43]5[CH2:44][CH2:45][N:40]([CH2:39][CH2:38][OH:37])[CH2:41][CH2:42]5)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OCCN1CCNCC1
Reactant: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCCl
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCN1CCN(CCO)CC1
Yield: 13.5 %

Procedure:
The urea intermediate from Example 65A (200 mg, 0.38 mmol) and 1-(2-hydroxyethyl)piperazine (0.139 mL, 1.14 mmol) in the manner described in Example 57B to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(2-(4-(2-hydroxyethyl)piperazin-1-yl)ethoxy)-7-methoxyquinazolin-4-ylthio)phenyl)urea as a colorless solid (32 mg, 14%). 1H NMR (300 MHz, DMSO-d6) δ 9.58 (brs, 1H), 9.00 (brs, 1H), 8.69 (s, 1H), 7.84 (s, 1H), 7.26-7.49 (m, 5H), 6.49 (s, 1H), 4.26-4.37 (m, 3H), 3.99 (s, 3H), 3.40-3.50 (m, 2H), 2.75-2.79 (m, 2H), 2.30-2.50 (m, 9H), 1.27 (s, 9H); LC-MS (ESI) m/z 622 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:14])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([CH3:14])[CH2:9][CH2:10][C:11]([O:13][CH3:15])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(CCC(=O)O)C(=O)OC(C)(C)C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)CCN(C)C(=O)OC(C)(C)C
Yield: 99.2 %

Procedure:
To a solution of 3-(tert-butoxycarbonyl(methyl)amino)propanoic acid (7.0 g, 0.032 mol) and K2CO3 (13.3 g, 0.096 mol) in DMF (100 mL) was added MeI (9.0 g, 0.064 mol) at rt. The resultant solution was stirred at rt for 3 hrs. The reaction mixture was quenched with ice water and extracted with ethyl acetate (2×). The combined organic layer was dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (gradient elution 0%-10% EtOAc/petroleum ether) to afford methyl 3-(tert-butoxycarbonyl(methyl)amino)propanoate (6.9 g, 92%) as a white solid. ESI-MS (EI+, m/z): 118 [M−100+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]([NH2:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C1C=CN=CC=1)C>[CH3:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]([NH:13][S:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:22])=[O:21])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1cc(N)c2ncccc2c1C
Agent: CN(C)c1ccncc1
Product: Cc1cc(NS(=O)(=O)c2ccccc2)c2ncccc2c1C
Yield: 8.4 %

Procedure:
In a similar fashion using route 14 general procedure 27, 5,6-dimethylquinolin-8-amine (Intermediate 55) (60 mg, 0.38 mmol), benzenesulfonyl chloride (72 mg, 0.41 mmol) and DMAP (cat.) gave the title compound (10 mg, 10%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:6]([CH3:16])[N:5]=[C:4]([O:17][CH2:18][C:19]([N:21]([CH3:28])[CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[O:20])[N:3]=1.Br[CH2:30][C:31]1[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=1>>[C:35]([C:34]1[CH:37]=[CH:38][C:31]([CH2:30][N:25]2[CH2:24][CH2:23][CH:22]([N:21]([CH3:28])[C:19](=[O:20])[CH2:18][O:17][C:4]3[N:3]=[C:2]([CH3:1])[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[C:6]([CH3:16])[N:5]=3)[CH2:27][CH2:26]2)=[CH:32][CH:33]=1)#[N:36]
Reactant: Cc1nc(OCC(=O)N(C)C2CCNCC2)nc(C)c1NC(=O)OC(C)(C)C
Reactant: N#Cc1ccc(CBr)cc1
Product: Cc1nc(OCC(=O)N(C)C2CCN(Cc3ccc(C#N)cc3)CC2)nc(C)c1NC(=O)OC(C)(C)C

Procedure:
The title compound was synthesized from Compound 31 and 4-(bromomethyl)benzonitrile in the same manner as in Example 32.
Reaction SMILES: [CH3:1][C:2]1[C:6](B(O)O)=[C:5]([CH3:10])[O:4][N:3]=1.Br[C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[C:15]12[O:25][CH2:24][CH2:23][O:22]1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.CC(P(C(C)(C)C)C1[CH-]C=CC=1)(C)C.CC(P(C(C)(C)C)C1[CH-]C=CC=1)(C)C.[Cl-].[Cl-].[Fe+2].[Pd+2]>[CH3:1][C:2]1[C:6]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16](=[O:21])[C:15]23[O:25][CH2:24][CH2:23][O:22]2)=[C:5]([CH3:10])[O:4][N:3]=1
Reactant: Cc1noc(C)c1B(O)O
Reactant: O=C1Nc2ccc(Br)cc2C12OCCO2
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(C)(C)P(c1ccc[cH-]1)C(C)(C)C
Solvent: C1COCCO1
Solvent: O
Product: Cc1noc(C)c1-c1ccc2c(c1)C1(OCCO1)C(=O)N2
Temperature: 110 °C
Yield: 60.2 %

Procedure:
A mixture of 3,5-dimethylisoxazol-4-ylboronic acid (159 g, 1.13 mol), dichloro[1,1′-bis(di-tert-butylphosphino)ferrocene]palladium(II) (23.6 g, 29 mmol), 5′-bromospiro[[1,3]dioxolane-2,3′-indolin]-2′-one (236 g, 0.87 mol) and Na2CO3 (184 g, 1.7 mol) in dioxane/H2O (1200 mL/300 mL) was heated to 110° C. for 12 h. The mixture was filtered through a pad of celite and concentrated in vacuo. The crude product was dissolved in CH2Cl2 (2 L), then hexane 2 L was added and the mixture was filtered again, the organic phase was concentrated in vacuo to give target product (150 g, 60%). 1H NMR (400 MHz, DMSO-d6): δH 10.56 (s, 1H), 7.31-7.33 (m, 2H), 6.93 (d, J=8.0 Hz, 1H), 4.27-4.35 (m, 4H), 2.35 (s, 3H), 2.18 (s, 3H). MS (ESI) m/e [M+1]+ 287.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]([S:8][CH:9]2[N:12]([C:13](=[C:27](OS(C)(=O)=O)[CH3:28])[C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C:11](=[O:34])[CH:10]2[NH:35][C:36](=[O:45])[CH2:37][O:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:7])[CH2:3][CH2:2]1.[NH:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1>C1C=CC=CC=1>[CH:1]1([CH2:4][O:5][C:6]([S:8][CH:9]2[N:12]([C:13](=[C:27]([N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)[CH3:28])[C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C:11](=[O:34])[CH:10]2[NH:35][C:36](=[O:45])[CH2:37][O:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)=[O:7])[CH2:3][CH2:2]1
Reactant: CC(OS(C)(=O)=O)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SC(=O)OCC1CC1
Reactant: C1COCCN1
Solvent: c1ccccc1
Product: CC(=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SC(=O)OCC1CC1)N1CCOCC1
Reaction time: 8 h

Procedure:
To a solution of p-nitrobenzyl α-[4-cyclopropylmethoxycarbonylthio-3-phenoxyacetamido-2-oxoazetidin-1-yl]-α-(1-methanesulfonyloxyethylidene)acetate (1.12 g) in benzene (11 ml) is added morpholine (0.26 ml) under ice cooling, and the mixture is kept at 10° C. overnight. The reaction mixture is washed with water, dried, and evaporated under reduced pressure. Purification of the obtained residue (1 g) by chromatography over silica gel (10 g) using a mixture of benzene and ethyl acetate (1:2) gives p-nitrobenzyl α-[4-cyclopropylmethoxycarbonylthio-3-phenoxyacetamido-2-oxoazetidin-1-yl]-α-(1-morpholinoethylidene)acetate (602 mg). Foam.
Reaction SMILES: [CH2:1]([N:8]([CH2:15][C:16]([O:18]C)=[O:17])[CH2:9][C:10]1([CH2:13]I)[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C=O)C.[H-].[Na+]>>[CH2:1]([N:8]1[CH:15]([C:16]([OH:18])=[O:17])[CH2:13][C:10]2([CH2:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CN(Cc1ccccc1)CC1(CI)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)C1CC2(CC2)CN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of methyl (benzyl{[1-(iodomethyl)cyclopropyl]methyl}amino)acetate (0.10 g, 0.00027 mol) in DMF (2.0 mL, 0.026 mol) at RT was added sodium hydride (16 mg, 0.00040 mol). The reaction mixture was stirred at RT for 1 h to achieve the desired cyclization and hydrolysis of the methyl ester. The reaction was quenched by the addition of water and acidified with 1 N HCl to pH 3-4 and washed with EtOAc. The aqueous layer was concentrated in vacuo to afford the desired product as a yellow solid, which was used in the next step without purification. LC/MS: m/e 232.2 (M+1H)+.
Reaction SMILES: [F:1][C:2]([F:46])([F:45])[O:3][C:4]1[CH:44]=[CH:43][C:7]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][N:16]([C:18]3[S:19][C:20]4[C:25](Cl)=[N:24][C:23]([CH:27]5[CH2:29][CH2:28]5)=[N:22][C:21]=4[N:30]=3)[CH2:15][CH2:14][N:13]2[S:31]([C:34]2[CH:39]=[CH:38][C:37]([CH:40]3[CH2:42][CH2:41]3)=[CH:36][CH:35]=2)(=[O:33])=[O:32])=[O:11])=[CH:6][CH:5]=1.C([O-])=O.[NH4+]>C(O)C.C(OCC)(=O)C.[C].[Pd]>[F:46][C:2]([F:1])([F:45])[O:3][C:4]1[CH:44]=[CH:43][C:7]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][N:16]([C:18]3[S:19][C:20]4[CH:25]=[N:24][C:23]([CH:27]5[CH2:29][CH2:28]5)=[N:22][C:21]=4[N:30]=3)[CH2:15][CH2:14][N:13]2[S:31]([C:34]2[CH:35]=[CH:36][C:37]([CH:40]3[CH2:42][CH2:41]3)=[CH:38][CH:39]=2)(=[O:33])=[O:32])=[O:11])=[CH:6][CH:5]=1
Reactant: O=C(NCc1ccc(OC(F)(F)F)cc1)[C@H]1CN(c2nc3nc(C4CC4)nc(Cl)c3s2)CCN1S(=O)(=O)c1ccc(C2CC2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(NCc1ccc(OC(F)(F)F)cc1)[C@H]1CN(c2nc3nc(C4CC4)ncc3s2)CCN1S(=O)(=O)c1ccc(C2CC2)cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 46.8 %

Procedure:
To a mixture of the compound (54 mg) obtained in Step 1 and ammonium formate (49 mg) in ethanol (2.0 ml) was added 10% palladium carbon (50 mg) at 80° C. After stirring at 80° C. for 30 min, ammonium formate (49 mg) and 10% palladium carbon (50 mg) were added. After stirring at 80° C. for 30 min, the reaction mixture was allowed to return to room temperature, and the reaction mixture was diluted with ethyl acetate. The mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by thin layer silica gel chromatography (ethyl acetate) to give the title compound (24 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:21][N:22]2[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]2)=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:7]=[CH:6]2.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]>ClCCl>[F:38][C:37]([F:40])([F:39])[C:35]([OH:41])=[O:36].[F:38][C:37]([F:40])([F:39])[C:35]([OH:41])=[O:36].[CH3:1][O:2][C:3]1[C:4]([CH2:21][N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:12]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)(=[O:13])=[O:14])[CH:7]=[CH:6]2
Reactant: COc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1CN1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1CN1CCNCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl 4-{[5-methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}piperazine-1-carboxylate (0.050 g, 0.102 mmol, Intermediate 76) was dissolved in dichloromethane (4 mL) and TFA (1 mL) was added. The mixture was stirred and rt for 2 h and evaporated. The crude product was purified by reversed phase preparative HPLC using ACE Prep UV C8 150×30 mm, flow 38 mL/min, gradient time 8.5 min using the eluent system: water/0.1% TFA and CH3CN (20-40% MeCN), fractions collected based on UV-signal (254 nm). The purest fractions were pooled and the acetonitrile was evaporated. Yield: 29 mg (46%). Brown liquid, off white solid after 1 h. Isolated as the TFA salt. MS (ESI+) for C20H23N3O3S m/z 386.4 (M+H)+.
Reaction SMILES: O.O.Cl[Sn]Cl.[N+:6]([C:9]1[CH:10]=[C:11]2[C:17]([C:18]([F:21])([F:20])[F:19])=[N:16][NH:15][C:12]2=[N:13][CH:14]=1)([O-])=O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[F:21][C:18]([F:19])([F:20])[C:17]1[C:11]2[C:12](=[N:13][CH:14]=[C:9]([NH2:6])[CH:10]=2)[NH:15][N:16]=1
Reactant: O=[N+]([O-])c1cnc2[nH]nc(C(F)(F)F)c2c1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1cnc2[nH]nc(C(F)(F)F)c2c1
Yield: 102.6 %

Procedure:
SnCl2.2H2O (1.3 g, 5.7 mmol) was added to 5-nitro-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine (0.19 g, 0.82 mmol) in ethyl acetate (20 mL). The resulting solution was heated to reflux for 3 hours. The cooled yellow solution was treated with dilute aqueous sodium bicarbonate. The resulting slurry was filtered through celite, and the filter cake was washed with ethyl acetate. The layers were separated, and the organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated to yield 3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine-5-amine (0.17 g, 99%) as a film.
Reaction SMILES: [CH2:1](C1C=CC=CC=1O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[OH:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2([C:52]3[CH:57]=[CH:56][C:55]([OH:58])=[CH:54][CH:53]=3)[C:37]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:31]([C:45]3[CH:50]=[CH:49][C:48]([OH:51])=[CH:47][CH:46]=3)([C:38]3[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=3)[C:30]3[C:25]2=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:20][CH:19]=1>>[CH2:1]([C:22]1[CH:23]=[C:18]([OH:17])[CH:19]=[CH:20][C:21]=1[C:24]1([C:52]2[CH:53]=[CH:54][C:55]([OH:58])=[CH:56][C:57]=2[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:30]=2[C:31]([C:38]2[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][C:39]=2[CH2:22][CH2:23][CH2:18][CH2:19][CH2:20][CH2:21][CH2:24][CH2:25][CH3:26])([C:45]2[CH:50]=[CH:49][C:48]([OH:51])=[CH:47][C:46]=2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:37][CH2:36][CH3:35])[C:32]2[C:37]1=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCCc1ccccc1O
Reactant: Oc1ccc(C2(c3ccc(O)cc3)c3ccccc3C(c3ccc(O)cc3)(c3ccc(O)cc3)c3ccccc32)cc1
Product: CCCCCCCCCc1cc(O)ccc1C1(c2ccc(O)cc2CCCCCCCCC)c2ccccc2C(c2ccc(O)cc2CCCCCCCCC)(c2ccc(O)cc2CCCCCCCCC)c2ccccc21

Procedure:
The reaction product from Example 13 and 2-nonylphenol should be substituted for the phenol of Example 15 in this Example and the procedures of Example 12 should be followed in this Example to obtain the product herein.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:28]4[CH:33]=[CH:32][C:31](B5OC(C)(C)C(C)(C)O5)=[CH:30][CH:29]=4)[CH:24]=3)[CH:19]=2)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:43]([O:47][C:48]([N:50]1[CH:55]([C:56]2[NH:60][C:59]3[CH:61]=[C:62](Br)[CH:63]=[CH:64][C:58]=3[N:57]=2)[CH:54]2[CH2:66][CH:51]1[CH2:52][CH2:53]2)=[O:49])([CH3:46])([CH3:45])[CH3:44].C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.C(OCC)(=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].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>[C:43]([O:47][C:48]([N:50]1[CH:55]([C:56]2[NH:60][C:59]3[CH:61]=[C:62]([C:31]4[CH:30]=[CH:29][C:28]([C:23]5[CH:22]=[CH:21][C:20]6[C:25](=[CH:26][CH:27]=[C:18]([C:15]7[NH:14][C:13]([CH:9]8[CH2:10][CH2:11][CH2:12][N:8]8[C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])=[N:17][CH:16]=7)[CH:19]=6)[CH:24]=5)=[CH:33][CH:32]=4)[CH:63]=[CH:64][C:58]=3[N:57]=2)[CH:54]2[CH2:66][CH:51]1[CH2:52][CH2:53]2)=[O:49])([CH3:46])([CH3:44])[CH3:45]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(B5OC(C)(C)C(C)(C)O5)cc4)ccc3c2)[nH]1
Reactant: CC(C)(C)OC(=O)N1C2CCC(C2)C1c1nc2ccc(Br)cc2[nH]1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5ccc6nc(C7C8CCC(C8)N7C(=O)OC(C)(C)C)[nH]c6c5)cc4)ccc3c2)[nH]1
Temperature: 90 °C
Yield: 59.4 %

Procedure:
A mixture of 2-(5-{6-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (248 mg, 0.438 mmol, 1.1 eq.), 3-(6-Bromo-1H-benzoimidazol-2-yl)-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (1 eq., 156 mg, 0.399 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)(3%, 10 mg), tetrakis(triphenylphosphine)palladium (3%, 14 mg) and potassium carbonate (3.3 eq., 182 mg) in 4 mL DME and 2 mL water was heated to 90° C. under Argon for 1 hour. The reaction mixture was cooled and diluted in ethyl acetate and washed with saturated sodium bicarbonate solution. The organic layer dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 20 to 100% ethyl acetate/hexane) to give 3-[6-(4-{6-[2-(1-tert-Butoxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-naphthalen-2-yl}-phenyl)-1H-benzoimidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (178 mg, yield 59%). LCMS-ESI−: calc'd for C46H50N6O4: 750.93; Found: 751.3 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:20][CH2:19][C:18]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:11][C:10]=3[CH:9]2[C:21]2[CH:22]=[CH:23][C:24]3[O:28][CH2:27][CH2:26][C:25]=3[CH:29]=2)=[N:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1)CCC>O1CCOCC1.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>[N:36]1[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=1[C:2]1[CH:7]=[N:6][C:5]([N:8]2[CH2:20][CH2:19][C:18]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:11][C:10]=3[CH:9]2[C:21]2[CH:22]=[CH:23][C:24]3[O:28][CH2:27][CH2:26][C:25]=3[CH:29]=2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(N2CCc3c([nH]c4ccccc34)C2c2ccc3c(c2)CCO3)nc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: c1ccc(-c2ccc(N3CCc4c([nH]c5ccccc45)C3c3ccc4c(c3)CCO4)nc2)nc1

Procedure:
The product from step A above, (0.4 g, 0.896 mmol), 2-tributylstannanylpyridine (0.8 g, 2.17 mmol) and Pd(PPh3)4 (0.12 g, 0.104 mmol) were stirred in 1,4-dioxane (5 mL) at 88° C. for 24 h. The reaction mixture was filtered through a plug of Celite with CH2Cl2 and then concentrated to a small volume. Preparative TLC (3:7 ethyl acetate/hexane; then 5% CH3OH/CH2Cl2) yielded the product as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[CH:10][C:5]=2[S:4][C:3]=1[CH:15]=[CH:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([CH:25]=[CH:26][C:27]([O:29][CH3:30])=[O:28])=[C:21]([CH3:31])[CH:20]=1)=[O:18].C1COCC1>CO.[C].[Pd]>[CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([F:13])([F:14])[F:12])=[CH:10][C:5]=2[S:4][C:3]=1[CH2:15][CH2:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])=[C:21]([CH3:31])[CH:20]=1)=[O:18]
Reactant: COC(=O)C=Cc1ccc(C(=O)C=Cc2sc3cc(C(F)(F)F)ccc3c2C)cc1C
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)CCc1ccc(C(=O)CCc2sc3cc(C(F)(F)F)ccc3c2C)cc1C
Yield: 44.6 %

Procedure:
Methyl 3-[4-[3-[3-methyl-6-(trifluoromethyl)benzothiophen-2-yl]propenoyl]-2-methylphenyl]acrylate (85 mg, 0.19 mmol) was hydrogenated in MeOH (1 mL)/THF (1 mL) for 1 hour at room temperature using 10% palladium-carbon (17 mg) as a catalyst. After removal of the catalyst by filtration, the filtrate was concentrated to dryness. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1), to give the titled compound as a pale yellow crystal (38 mg, yield 44%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]=1[O:18][CH2:19][C:20]1[CH:21]=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1)[CH2:6][NH:7]C(=O)OC(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][NH2:7])[CH:15]=[CH:16][C:17]=1[O:18][CH2:19][C:20]1[CH:21]=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1
Reactant: COc1ccc(COc2ccc(CNC(=O)OC(C)(C)C)cc2OC)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(COc2ccc(CN)cc2OC)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.8 %

Procedure:
To a stirred solution of tert-butyl 3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzylcarbamate (31.92 g, 85.25 mmol) in dichloromethane (100 mL) was added trifluoroacetic acid (75 mL, 973.5 mmol). The resulting yellow solution was allowed to stir at room temperature. After 2 h, the reaction mixture was concentrated to dryness, and the residue was dissolved in water (250 mL). The acidic solution was extracted with diethyl ether (2×125 mL; organic phases discarded). The aqueous phase was then made basic with concentrated ammonium hydroxide. The basic aqueous phase was then extracted with dichloromethane (2×200 mL). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated to provide 21.46 g (92%) of (3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)methanamine as an off-white solid.