Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([N:16]3[CH2:19][CH:18]([C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[CH2:17]3)=[O:15])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[CH:26]1([CH:31]=O)[CH2:30][CH2:29][CH2:28][CH2:27]1.C(O)(=O)C.C([BH3-])#N>CO>[CH:26]1([CH2:31][N:1]2[CH2:6][CH2:5][CH:4]([C:7]3[CH:8]=[CH:9][C:10]([NH:13][C:14]([N:16]4[CH2:19][CH:18]([C:20]5[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=5)[CH2:17]4)=[O:15])=[CH:11][CH:12]=3)[CH2:3][CH2:2]2)[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: O=CC1CCCC1
Reactant: O=C(Nc1ccc(C2CCNCC2)cc1)N1CC(c2cccnc2)C1
Agent: [BH3-]C#N
Solvent: CO
Solvent: CC(=O)O
Product: O=C(Nc1ccc(C2CCN(CC3CCCC3)CC2)cc1)N1CC(c2cccnc2)C1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
In a 20 mL vial was added N-(4-(piperidin-4-yl)phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide, bistrifluoroacetic acid (67 mg, 0.12 mmol) dissolved in methanol, (2.0 mL) followed by the addition of cyclopentanecarbaldehyde (13 mg, 0.13 mmol) dissolved in methanol (0.45 mL), followed by the addition of acetic acid neat (68 μL, 1.2 mmol). The reaction mixture was shaken for 1 hour at 70° C. After that, MP-cyanoborohydride (272 mg, 2-3 mmol/g) resin was added and the resulting mixture was shaken at 70° C. overnight. The reaction mixture was filtered and concentrated to dryness. The residues were dissolved in 1:1 DMSO/methanol and purified by reverse phase chromoatography. 1H NMR (500 MHz, pyridine/d5-D2O Temp=90° C.) δ ppm 8.55 (dd, J=4.73, 1.68 Hz, 1 H) 8.40-8.48 (m, 1 H) 7.75 (d, J=8.54 Hz, 2 H) 7.56-7.61 (m, 1 H) 7.21 (d, J=8.54 Hz, 2 H) 7.16-7.19 (m, 1 H) 4.46 (t, J=8.24 Hz, 2 H) 4.10 (dd, J=8.09, 5.95 Hz, 2 H) 3.64-3.74 (m, 1 H) 3.28 (d, 2 H) 2.39-2.66 (m, 5 H) 2.02-2.26 (m, 3 H) 1.75-1.88 (m, 4 H) 1.40-1.59 (m, 4 H) 1.20-1.31 (m, 2 H); (ESI) m/z 419 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[C:10](O)(=O)[CH2:11][OH:12]>>[Br:1][C:2]1[CH:3]=[C:4]2[N:9]=[C:10]([CH2:11][OH:12])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(O)CO
Reactant: Nc1cc(Br)cnc1N
Product: OCc1nc2cc(Br)cnc2[nH]1

Procedure:
A procedure similar to that described in Preparation 43 was repeated, except that 7.00 g of 5-bromo-2,3-diaminopyridine (prepared as described in Preparation 57) and 8.50 g of glycolic acid were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a 10:1 by volume mixture of ethyl acetate and methanol as the eluent, to give 7.05 g of the title compound, melting at 230-233° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[Cl:13][C:14]1[C:15]([F:27])=[CH:16][C:17]([N+:24]([O-:26])=[O:25])=[C:18]([S:20](Cl)(=[O:22])=[O:21])[CH:19]=1.N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:13][C:14]1[C:15]([F:27])=[CH:16][C:17]([N+:24]([O-:26])=[O:25])=[C:18]([S:20]([NH:12][C:9]2[CH:10]=[CH:11][C:2]([Cl:1])=[C:3]3[C:8]=2[N:7]=[CH:6][CH:5]=[CH:4]3)(=[O:22])=[O:21])[CH:19]=1
Reactant: O=[N+]([O-])c1cc(F)c(Cl)cc1S(=O)(=O)Cl
Reactant: Nc1ccc(Cl)c2cccnc12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cc(F)c(Cl)cc1S(=O)(=O)Nc1ccc(Cl)c2cccnc12
Yield: 12 %

Procedure:
In a similar fashion using route 14 general procedure 27, using 5-chloro-quinolin-8-ylamine (Intermediate 27) (750 mg, 4.2 mmol), 5-chloro-4-fluoro-2-nitro-benzenesulfonyl chloride (Intermediate 218) (1.5 g, 5.4 mmol), DMAP (cat), pyridine (8 ml) and DCM (15 ml) gave the title compound (210 mg, 12%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:13][C:12](=C)[CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[OH:16]>ClCCl>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:13][C:12](=[O:16])[CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CO
Reactant: C=C1CC(CNC(=O)OC(C)(C)C)C1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC1CC(=O)C1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
In a round bottom flask were placed 9 g of the product from Step A of Example 9, 100 mL of methanol, and 400 mL of dichloromethane. The solution was cooled to -78° C., and ozone was bubbled through the reaction mixture until the solution was blue. The system was flushed with nitrogen for 2.5 h, and then treated with 34 mL of dimethylsulide. After 1 h at -78° C., 0° C. for 1 h, and room temperature for 1 h, the solution was stored in a refrigerator at 5° C. overnight before being concentrated. The crude material was purified by column chromatography to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:13][CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:26](I)[CH3:27]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:14][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19]2)[CH2:26][CH3:27])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: CCI
Reactant: COC(=O)c1cc(Cl)cc(NCC2CCCC2)c1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCN(CC1CCCC1)c1cc(Cl)cc(C(=O)OC)c1C
Temperature: 80 °C
Yield: 91.2 %

Procedure:
To a stirred solution of methyl 5-chloro-3-((cyclopentylmethyl)amino)-2-methylbenzoate (1.0 g, 3.54 mmol) in DMF (10 mL), cesium carbonate (2.31 g, 7.09 mmol) and ethyl iodide (5.53 g, 35.4 mmol) were added. The resulting reaction mass was heated at 80° C. for 12 h. The mixture was cooled to room temperature and filtered. The residue was washed with ethyl acetate and the filtrate was concentrated to a residue which was purified by column chromatography to afford the title compound (1.0 g, 91%).
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[CH:10][C:5]2=[N:6][C:7](=[S:9])[N:8]=[C:4]2[CH:3]=1.C[Si](C)(C)N[Si](C)(C)C.Br[C:23]1([O:36][C@H:35]([CH2:37][O:38][C:39](=[O:41])[CH3:40])[C@@H:30]([O:31][C:32](=[O:34])[CH3:33])[C@H:25]1[O:26][C:27](=[O:29])[CH3:28])O.[I-].[Na+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:11]([Cl:12])=[CH:10][C:5]2[N:6]([C@@H:23]3[O:36][C@H:35]([CH2:37][O:38][C:39](=[O:41])[CH3:40])[C@@H:30]([O:31][C:32](=[O:34])[CH3:33])[C@H:25]3[O:26][C:27](=[O:29])[CH3:28])[C:7](=[S:9])[NH:8][C:4]=2[CH:3]=1
Reactant: CC(=O)OC[C@H]1OC(O)(Br)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: S=C1N=c2cc(Cl)c(Cl)cc2=N1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [I-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(=O)OC[C@H]1O[C@@H](n2c(=S)[nH]c3cc(Cl)c(Cl)cc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of dry 5,6-dichlorobenzimidazole-2-thione (3, 2.19 g 10 mmole), hexamethyldisilazane (4 ml) and (NH4)2SO4 (0.1 g) was heated at reflux temperature with stirring for 15 hr under anhydrous conditions. The clear brown reaction mixture was fractionated to remove unreacted HMDS under reduced pressure (water aspirator) to afford the disilylated compound. The silylated compound was mixed with 1-bromo-2,3,5-tri-O-acetyl-D-ribofuranose (from 3.5 g (11 mmole) of tetraacetylsugar) and sodium iodide (0.05 g). The mixture was then fused at 110° C. (oil bath temperature) with stirring for 45 minutes under reduced pressure. The reaction mixture which had been cooled to room temperature was dissolved in CHCl3. The CHCl3 solution was washed with a cold saturated aqueous sodium bicarbonate solution (100 ml×4) and then cold water (100 ml×4). The CHCl3 phase was dried over Na2SO4 and evaporated on a water bath (40° C.) to dryness to yield a syrup [5,6-dichloro-1-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl) benzimidazole-2-thione]. The syrup was dissolved in methanolic ammonia (methanol saturated with ammonia at 0° C., 100 ml) and allowed to stand at room temperature for 24 hours. After the methanolic ammonia had been removed at room temperature, a syrup remained which was triturated with cold water (30 ml). The solid material (2.548 g) which separated was collected by filtration and was applied to a flash column chromatography on silica gel with CH2Cl2 -MeOH (15:1) as eluant. Fractions were collected (25 ml each), and fractions containing the desired compound were combined and evaporated to obtain 53 which was crystallized from aq. EtOH. Overall yield 2.0 g, 57.0%, mp 241° C.
Reaction SMILES: [Br:1][C:2]1[C:22]([CH3:23])=[CH:21][C:5]([O:6][C:7](=[O:20])[C:8]#[C:9][C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=2)[C:13]([O:15][CH3:16])=[O:14])=[CH:4][C:3]=1[CH3:24]>ClCCl.FC(F)(F)C(O)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Br:1][C:2]1[C:22]([CH3:23])=[C:21]2[C:5](=[CH:4][C:3]=1[CH3:24])[O:6][C:7](=[O:20])[CH:8]=[C:9]2[C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=1)[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1cccc(C#CC(=O)Oc2cc(C)c(Br)c(C)c2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cccc(-c2cc(=O)oc3cc(C)c(Br)c(C)c23)c1
Reaction time: 3 h
Yield: 71.3 %

Procedure:
To a stirring solution of methyl 3-(3-(4-bromo-3,5-dimethylphenoxy)-3-oxoprop-1-yn-1-yl)benzoate (9-3) (95 mg, 0.25 mmol) in dichloromethane (1 mL) and trifluoroacetic acid (2 mL) was added palladium acetate (5 mg, 0.02 mmol) under ice-cooling. After stirred for 3 h under ice-cooling, the mixture was diluted with 1,2-dichloromethane and evaporated to dryness. Chromatography of the residue on a silica gel (chloroform:hexanes=1:1-1:0) gave title compound 9-4 (69 mg, 73% yield) as a light brown gum.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([F:31])([C:14]2[S:15][CH:16]=[C:17]([CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)[N:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:32]>CO.O1CCOCC1>[ClH:32].[F:31][C:11]1([C:14]2[S:15][CH:16]=[C:17]([CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)[N:18]=2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(F)(c2nc(COc3ccc(S(C)(=O)=O)cc3)cs2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(OCc2csc(C3(F)CCNCC3)n2)cc1
Reaction time: 8 h

Procedure:
To a solution of 4-fluoro-4-[4-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (Example 87, 4.24 g, 9.01 mmol) in methanol (50 mL) was added 4 N HCl in dioxane (15 mL). The resulting solution was stirred overnight. The mixture was then evaporated to dryness in vacuo to afford the desired product as a white solid.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li].[CH3:11][O:12][C:13]1[CH:28]=[CH:27][C:16]([CH2:17][O:18][C:19]2[CH:20]=[C:21]([C:25]#[CH:26])[CH:22]=[CH:23][CH:24]=2)=[CH:15][CH:14]=1.CON(C)[C:32](=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>O1CCCC1>[C:33]1([C:32](=[O:39])[C:26]#[C:25][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([O:18][CH2:17][C:16]3[CH:15]=[CH:14][C:13]([O:12][CH3:11])=[CH:28][CH:27]=3)[CH:20]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CON(C)C(=O)c1ccccc1
Reactant: C#Cc1cccc(OCc2ccc(OC)cc2)c1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Product: COc1ccc(COc2cccc(C#CC(=O)c3ccccc3)c2)cc1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
Place lithium hexamethyldisilazane (2 mL of a 1M solution in tetrahydrofuran, 2 mmol) and tetrahydrofuran (8 mL) under an argon atmosphere and cool to 0° C. Add a solution of 3-(4-methoxybenzyloxy)phenylacetylene (0.48 g, 2 mmol) in tetrahydrofuran and stir the brown solution for 45 minutes at 0° C. Add N-methoxy-N-methylbenzamide (0.4 g, 2.4 mmol), remove the cooling bath and stir at room temperature for 1 hour. Partition the mixture between ethyl ether and water, separate the organic phase and dry (MgSO4). Filter and evaporate the solvent in vacuo to yield an oil. Filter through silica gel and elute with 10% ethyl acetate/hexane to yield a crude solid. Recrystallize (hexane, ethyl ether) to yield 0.26 g (1st crop) and 0.15 g (2nd crop) of the title compound; mp 79°-80° C.
Reaction SMILES: [C:1]([N:8]1[CH2:12][C@H:11]([F:13])[CH2:10][C@H:9]1[C:14]([OH:16])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[F-].[Na+].[F:19]C1(F)N(C)CCN1C>ClCCl>[C:1]([N:8]1[CH2:12][C@H:11]([F:13])[CH2:10][C@H:9]1[C:14]([F:19])=[O:16])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1C(=O)O
Reactant: CN1CCN(C)C1(F)F
Agent: [F-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1C(=O)F
Reaction time: 0.08 h
Yield: 90.1 %

Procedure:
(2S,4R)—N-Boc-4-fluoropyrrolidine-2-carboxylic acid (1.17 g, 5.0 mmol) and NaF (0.63 g, 15 mmol) were taken in a Teflon® reactor and suspended in 10 ml of anhydrous dichloromethane. It was cooled with ice. A solution of 2,2-difluoro-1,3-dimethylimidazolidine (0.817 g, 6.0 mmol) in 2 ml of dichloromethane was slowly added. After 5 minutes stirring, the ice bath was removed and stirring was continued at room temperature for 20 minutes. All the volatiles were removed at reduced pressure and the obtained viscous liquid was mixed with 50 ml of pentane and washed with water (50 ml×2). The organic layer was dried over anhydrous magnesium sulfate and filtered. Removal of solvent at reduced pressure gave 1.06 g of (2S,4R)—N-Boc-4-fluoropyrrolidine-2-carbonyl fluoride (Ie) as a colorless oil. Yield; 90%. 19F NMR (282 MHz, CDCl3) (as a 4:6 mixture of rotamers) δ (ppm) 28.66 (s, 0.4 F, COF), 28.10 (s, 0.6 F, COF), −177.16 (m, 0.4 F, CF), −177.83 (m, 0.6 F, CF): 1H NMR (300 MHz, CDCl3) (as a mixture of rotamers) δ 1.42 (s, 0.6×9H, t-Bu), 1.44 (s, 0.4×9H, t-Bu), 2.0-2.8 (m, 2H), 3.45-4.0 (m, 2H), 4.51 (m, 1H), 5.22 (dm, 1H, J=51.6 Hz): 13C NMR (75 MHz, CDCl3) (as a mixture of two rotamers) δ 90.70 (d, J=179.9 Hz, CF), 91.61 (d, J=179.9 Hz, CF), 153.07 (s, CON), 154.17 (s, CON), 161.90 (d, J=368.4 Hz, COF), 162.11 (d, J=368.4 Hz, COF): IR (Neat, KBr) 1848 (COF) cm−1: High Resolution Mass/ESI-APCI method (solvent; methanol); (M-F+OCH3+Na)+ 270.1114 [calcd 270.1112 for (C11H18FNO4+Na)].
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[CH2:3][N:4]=[C:5]([NH2:26])[NH:6][C:7]1[S:8][C:9]([CH3:25])=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17](=[N:20][S:21]([CH3:24])(=[O:23])=[O:22])SC)[N:11]=1.[CH3:29][NH2:30]>>[F:28][C:2]([F:1])([F:27])[CH2:3][N:4]=[C:5]([NH2:26])[NH:6][C:7]1[S:8][C:9]([CH3:25])=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([NH:30][CH3:29])=[N:20][S:21]([CH3:24])(=[O:22])=[O:23])[N:11]=1
Reactant: CSC(=NS(C)(=O)=O)NCCCCc1nc(NC(N)=NCC(F)(F)F)sc1C
Reactant: CN
Product: CNC(=NS(C)(=O)=O)NCCCCc1nc(NC(N)=NCC(F)(F)F)sc1C
Reaction time: 8 h

Procedure:
To the 2-[2-(2,2,2-trifluoroethyl)guanidino]-4-[4-(3-methylsulphonyl-2-methylisothioureido)butyl]-5-methylthiazole was added a 30% w/v ethanolic solution of methylamine (5 ml.) and the mixture allowed to stand overnight at ambient temperature. It was then evaporated to dryness and 2-[2-(2,2,2-trifluoroethyl)guanidino]-4-[4-(2-methylsulphonyl-3-methylguanidino)butyl]-5-methylthiazole (0.17 g.) was isolated as the maleate salt from acetone, m.p. 165°-166°.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.[CH3:19][O:20][C:21]1[C:22]([NH2:36])=[N:23][CH:24]=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:26]=1.C([O-])([O-])=O.[K+].[K+]>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>[CH3:19][O:20][C:21]1[C:22]([NH2:36])=[N:23][CH:24]=[C:25]([C:2]2[S:6][C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:4][C:3]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[CH:26]=1
Reactant: Brc1sc(-c2ccccc2)nc1-c1ccncc1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cnc1N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1cc(-c2sc(-c3ccccc3)nc2-c2ccncc2)cnc1N
Temperature: 25 °C

Procedure:
A mixture of 5-bromo-2-phenyl-4-(pyridin-4-yl)thiazole (20 mg, 0.062 mmol), 3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (39 mg, 0.157 mmol), and aqueous 2.0 M K2CO3 solution (0.5 ml, 1 mmol) in dioxane (0.5 mL) was sparged with Ar. Pd(PPh3)4 (181 mg, 0.157 mmol) was added, the reaction was sealed and irradiated at 120° C. for 15 min. While allowing to cool to rt, the reaction partitioned and the resulting layers were separated. The aqueous phase was extracted with EtOAc (3×) and the combined organic phases were washed with brine, dried (Na2SO4), and concentrated. The resulting residue was purified by reverse phase HPLC to give, after freeze drying, 3-methoxy-5-(2-phenyl-4-(pyridin-4-yl)thiazol-5-yl)pyridin-2-amine as the TFA salt: LCMS (m/z): 361.0 (MH+), tR=0.58 min.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([N:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[CH2:6][C:7]#[N:8])C.N#N>CO>[N:9]1([CH:5]2[CH2:6][CH2:7][NH:8][C:4]2=[O:3])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CCOC(=O)C(CC#N)N1CCCCC1
Agent: N#N
Solvent: CO
Product: O=C1NCCC1N1CCCCC1
Temperature: 50 °C
Reaction time: 16 h
Yield: 58.9 %

Procedure:
Purge a mixture of 3-cyano-2-piperidin-1-yl-propionic acid ethyl ester (2.36 g, 11.2 mmol) and PtO2 hydrate (0.400 g) in methanol (40 mL) with N2 and stir under 50 psi of H2 at 50° C. for 16 hours. Cool the reaction and filter through hyflo. Remove the solvent from the filtrate in vacuo to afford crude product and purify with a 0 to 10% methanol in CH2Cl2 gradient to afford 1.11 g (59%) of the titled product. Rf=0.18 (9/1 CH2Cl2/methanol). ES MS (m/z): 169 (M+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][CH:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1.[CH3:25][O:26][C:27]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[CH:29][C:28]=1[OH:42]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][CH:18]2[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]2)=[CH:3][C:2]([C:31]2[CH:30]=[CH:29][C:28]([OH:42])=[C:27]([O:26][CH3:25])[CH:32]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:15][CH2:16]1
Reactant: CN1CCC(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Product: COc1cc(-c2ccc3ncc(C(=O)C4CC4)c(NC4CCN(C)CC4)c3c2)ccc1O
Yield: 63.2 %

Procedure:
Following general procedure F, [6-bromo-4-(1-methylpiperidin-4-ylamino)quinolin-3-yl](cyclopropyl)methanone (47 mg, 0.121 mmol) was reacted with 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (45 mg, 0.182 mmol) to afford the desired product (33 mg, 63%) as a yellow solid: 1H NMR (300 MHz, CD3OD) δ 9.17 (s, 1H), 8.33 (d, J=1.8 Hz, 1H), 8.05 (dd, J=8.7, 1.9 Hz, 1H), 7.92 (d, J=8.7 Hz, 1H), 7.27 (d, J=2.1 Hz, 1H), 7.19 (dd, J=8.2, 2.1 Hz, 1H), 6.94 (d, J=8.2 Hz, 1H), 4.36 (s, 1H), 3.97 (s, 3H), 3.34 (s, 1H), 3.08 (s, 2H), 2.94-2.82 (m, 1H), 2.65 (s, 2H), 2.53 (s, 3H), 2.28 (d, J=13.9 Hz, 2H), 1.89 (d, J=10.3 Hz, 2H), 1.26-1.17 (m, 2H), 1.17-1.08 (m, 2H); ESI MS m/z 432 [C26H29N3O3+H]+; HPLC (AUC), tR=9.78 min.
Reaction SMILES: O[CH2:2][CH:3]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.O=S(Cl)[Cl:19].C(=O)(O)[O-].[Na+]>ClCCl>[Cl:19][CH2:2][CH:3]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1
Reactant: OCC(CN1CCOCC1)c1ccccc1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: ClCC(CN1CCOCC1)c1ccccc1
Yield: 76.6 %

Procedure:
To a solution of 1-hydroxy-3-morpholino-2-phenylpropane (650 mg, 2.94 mmol) prepared in the above (3) dissolved in dichloromethane (10 ml), SOCl2 (420 mg, 3.53 mmol) in dichloromethane (5 ml) was added while chilling with ice. After the resulting solution was stirred to cause reaction at room temperature for 23 hours, saturated aqueous sodium bicarbonate was added while chilling with ice. The prepared solution was extracted with dichloromethane, and the extract was washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate. Subsequently, the solvent was removed by distillation under reduced pressure to obtain a crude product. The product was purified by silica gel column chromatography using acetone/hexane=1/5 to obtain 540 mg of the titled compound as a colorless oil (yield: 76.6%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][C:13]1[CH:22]=[C:21]2[C:16]([C:17]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]#[C:33][CH2:34][O:35][CH3:36])=[C:28]4[O:37][CH2:38][O:39][C:27]=34)=[C:18]([C:23]#[N:24])[CH:19]=[N:20]2)=[CH:15][C:14]=1[O:40][CH3:41].[I-].[Na+].[ClH:44]>C(OCC)(=O)C.C(OCC)C>[ClH:6].[ClH:44].[C:23]([C:18]1[CH:19]=[N:20][C:21]2[C:16]([C:17]=1[NH:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]#[C:33][CH2:34][O:35][CH3:36])=[C:28]3[O:37][CH2:38][O:39][C:27]=13)=[CH:15][C:14]([O:40][CH3:41])=[C:13]([O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[CH:22]=2)#[N:24]
Reactant: COCC#Cc1ccc(Nc2c(C#N)cnc3cc(OCCOCCCl)c(OC)cc23)c2c1OCO2
Reactant: C1CCNC1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COCC#Cc1ccc(Nc2c(C#N)cnc3cc(OCCOCCN4CCCC4)c(OC)cc23)c2c1OCO2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Pyrrolidine (10 ml) was added to a mixture of 7-[2-(2-chloroethoxy)ethoxy]-3-cyano-6-methoxy-4-[4-(3-methoxyprop-1-ynyl)-2,3-methylenedioxyanilino]quinoline (0.225 g) and sodium iodide (0.133 g) and the reaction mixture was stirred at ambient temperature for 24 hours. The reaction mixture was evaporated and the residue was triturated under methylene chloride. The resultant solid was washed with water and dried. The material so obtained was dissolved in the minimum quantity of ethyl acetate and a solution of hydrogen chloride in diethyl ether (1M) was added. The resultant solid was isolated, washed with diethyl ether and dried. There was thus obtained the title compound as a solid (0.145 g); NMR Spectrum: (DMSOd6 and CD3CO2D at 100° C.) 1.84–1.89 (m, 4H), 3.29–3.39 (m, 9H), 3.88 (m, 2H), 3.94 (m, 2H), 3.96 (s, 3H), 4.3 (s, 2H), 4.36 (m, 2H), 6.04 (s, 2H), 6.84 (d, 1H), 6.94 (d, 1H), 7.46 (s, 1H), 7.87 (s, 1H), 8.56 (s, 1H); Mass Spectrum: M+H+ 545.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1.[Li]CCCC.[CH3:18][C:19]1([CH3:30])[C:23]([CH3:25])([CH3:24])[O:22][B:21](OC(C)C)[O:20]1>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]([B:21]3[O:22][C:23]([CH3:25])([CH3:24])[C:19]([CH3:30])([CH3:18])[O:20]3)=[CH:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(-c2ccco2)cc1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccc(-c3ccc(F)cc3)o2)OC1(C)C
Temperature: -78 °C

Procedure:
To a solution of 2-(4-fluorophenyl)furan (1.50 g, 9.25 mmol) in dry tetrahydrofuran (100 mL) was added a solution of n-BuLi (4.4 mL, 2.5M solution in hexane) dropwise with stirring at −78° C. under nitrogen. The resulting solution was warmed slowly to −40° C. over 45 min and stirred at this temperature for another 30 min. The mixture was cooled again below −78° C. followed by dropwise addition of 4,4,5,5-tetramethyl-2-(propan-2-yloxy)-1,3,2-dioxaborolane (3.42 g, 18.38 mmol). After warming to room temperature, the mixture was quenched with NH4Cl (aq) and extracted with ethyl acetate (3×80 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the residue (1.20 g crude), which was used to the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17](O)=[O:18])[CH:13]=[N:14]2)=[CH:9][CH:8]=1.C(Cl)(=O)C([Cl:26])=O>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]([Cl:26])=[O:18])[CH:13]=[N:14]2)=[CH:9][CH:8]=1
Reactant: O=C(O)c1cnc2cc(OCc3cccc(Cl)c3)ccc2c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cnc2cc(OCc3cccc(Cl)c3)ccc2c1

Procedure:
To a solution of 7-((3-chlorobenzyl)oxy)quinoline-3-carboxylic acid (Example 46, product from Step A, 50 mg, 0.16 mmol) in DCM (1.5 mL) was added oxalyl chloride (0.1 mL, 1.13 mmol), followed by 1 drop of DMF. After 30 minutes the reaction was concentrated under reduced pressure to afford a yellow foam, and further dried under high vacuum for 15 minutes to afford the title compound, which was used without further purification in the next step.