Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C@@H:8]1[C:12]2[NH:13][C:14](B3OC(C)(C)C(C)(C)O3)=[CH:15][C:11]=2[C:10](=[O:25])[NH:9]1.Br[C:27]1[CH:28]=[CH:29][CH:30]=[C:31]2[C:36]=1[N:35]=[C:34]([NH:37][C:38]([CH3:41])([CH3:40])[CH3:39])[N:33]([C:42]1[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=1)[C:32]2=[O:48]>>[C:38]([NH:37][C:34]1[N:33]([C:42]2[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=2)[C:32](=[O:48])[C:31]2[C:36](=[C:27]([C:14]3[NH:13][C:12]4[C@@H:8]([CH3:7])[NH:9][C:10](=[O:25])[C:11]=4[CH:15]=3)[CH:28]=[CH:29][CH:30]=2)[N:35]=1)([CH3:41])([CH3:39])[CH3:40]
Reactant: C[C@H]1NC(=O)c2cc(B3OC(C)(C)C(C)(C)O3)[nH]c21
Reactant: CC(C)(C)Nc1nc2c(Br)cccc2c(=O)n1-c1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C[C@H]1NC(=O)c2cc(-c3cccc4c(=O)n(-c5cccnc5)c(NC(C)(C)C)nc34)[nH]c21
Temperature: 80 °C
Yield: 73.1 %

Procedure:
Argon was bubbled into a slurry of potassium carbonate (Mallinkrodt; 0.074 g, 0.536 mmol), dichlorobis(p-dimethylaminophenylditbutylphosphine)palladium(ii) (Aldrich; 4.74 mg, 6.70 μmol), (R)-6-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (705; 0.070 g, 0.268 mmol), 8-bromo-2-(tert-butylamino)-3-(pyridin-3-yl)quinazolin-4(3H)-one (404a; 0.050 g, 0.134 mmol) for 1 min. The reaction was sealed and heated to 80° C. for 30 min. The reaction was adsorbed onto 0.7 g silica gel and dried in vacuo. The material was treated with purified by silica gel chromatography (12 g column) using 0-100% (90/10 DCM/MeOH) in DCM. The product-containing fractions were concentrated to afford (R)-2-(tert-butylamino)-8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(pyridin-3-yl)quinazolin-4(3H)-one (0.042 g, 0.098 mmol, 73% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.91 (1H, s), 8.74 (1H, dd, J=4.9, 1.6 Hz), 8.64 (1H, d, J=2.2 Hz), 7.91-7.99 (2H, m), 7.89 (1H, dd, J=7.8, 1.6 Hz), 7.59-7.69 (2H, m), 7.24 (1H, t, J=7.6 Hz), 6.77 (1H, d, J=1.6 Hz), 4.61 (1H, s), 4.49-4.58 (1H, m), 1.31-1.41 (12H, m). m/z (ESI, +ve ion) 429.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[CH2:16][CH:15]([OH:18])[CH2:14][CH2:13][C:12]=3[N:11]([C:19]([NH:21][C@@H:22]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:23]([NH:25][CH3:26])=[O:24])=[O:20])[N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].FC1C=C(C2C3CC4(OCCO4)CCC=3N(C(N[C@@H](C(C)(C)C)C(NC)=O)=O)N=2)C=CC=1F.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[CH2:16][C:15](=[O:18])[CH2:14][CH2:13][C:12]=3[N:11]([C:19]([NH:21][C@@H:22]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:23]([NH:25][CH3:26])=[O:24])=[O:20])[N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CNC(=O)[C@@H](NC(=O)n1nc(-c2ccc(F)c(F)c2)c2c1CCC(O)C2)C(C)(C)C
Agent: CNC(=O)[C@@H](NC(=O)n1nc(-c2ccc(F)c(F)c2)c2c1CCC1(C2)OCCO1)C(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: CNC(=O)[C@@H](NC(=O)n1nc(-c2ccc(F)c(F)c2)c2c1CCC(=O)C2)C(C)(C)C
Yield: 91 %

Procedure:
Preparation of 3-(3,4-difluorophenyl)-N—((S)-3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl)-5-hydroxy-4,5,6,7-tetrahydro-1H-indazole-1-carboxamide (67) A mixture of compound 63 (0.91 g) and p-toluenesulfonic acid (1.3 g) was heated in acetone and water at 50° C. until starting material was consumed. After evaporation of acetone, the residue was extracted between EtOAc and saturated sodium bicarbonate. The organic phase was dried over sodium sulfate and evaporated to dryness. The crude product was purified by column chromatography with 70% to 80% EtOAc/Hex to give (S)-3-(3,4-difluorophenyl)-N-(3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl)-5-oxo-4,5,6,7-tetrahydro-1H-indazole-1-carboxamide (0.75 g, 91% yield), which was reduced with sodium borohydride (1.0 equiv.) in MeOH to give compound 67 as a mixture of two diastereomers after purification with a preparative LC-MS. LCMS (+ESI) m/z=421.2 [M+H]+.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][NH:7][C:8]([C:10]1[N:11]=[C:12]([CH:15]([OH:47])[CH2:16][CH:17]([N:21]([CH2:39][O:40][C:41](=[O:46])[CH2:42][CH:43]([CH3:45])[CH3:44])[C:22](=[O:38])[CH:23]([NH:28][C:29]([CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][N:32]2[CH3:37])=[O:30])[CH:24]([CH3:27])[CH2:25][CH3:26])[CH:18]([CH3:20])[CH3:19])[S:13][CH:14]=1)=[O:9])([OH:3])=[O:2].[C:48](OC(=O)C)(=[O:50])[CH3:49].O1CCOCC1.O>N1C=CC=CC=1>[C:48]([O:47][CH:15]([C:12]1[S:13][CH:14]=[C:10]([C:8](=[O:9])[NH:7][CH2:6][CH2:5][CH2:4][C:1]([OH:3])=[O:2])[N:11]=1)[CH2:16][CH:17]([N:21]([CH2:39][O:40][C:41](=[O:46])[CH2:42][CH:43]([CH3:45])[CH3:44])[C:22](=[O:38])[CH:23]([NH:28][C:29]([CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][N:32]1[CH3:37])=[O:30])[CH:24]([CH3:27])[CH2:25][CH3:26])[CH:18]([CH3:20])[CH3:19])(=[O:50])[CH3:49]
Reactant: CC(=O)OC(C)=O
Reactant: CCC(C)C(NC(=O)C1CCCCN1C)C(=O)N(COC(=O)CC(C)C)C(CC(O)c1nc(C(=O)NCCCC(=O)O)cs1)C(C)C
Solvent: O
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CCC(C)C(NC(=O)C1CCCCN1C)C(=O)N(COC(=O)CC(C)C)C(CC(OC(C)=O)c1nc(C(=O)NCCCC(=O)O)cs1)C(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 81.6 %

Procedure:
A 0.10 M solution of 13b (15.0 mg, 0.0220 mmol) in pyridine (0.220 mL) was cooled to 0° C., and acetic anhydride (10.4 μL, 0.110 mmol) was added. The reaction mixture was allowed to warm to rt over 2 h and was stirred at rt for 24 h. The reaction mixture was then cooled to 0° C., and a 1:1 mixture of dioxane/water (0.630 mL) was added. The mixture was allowed to warm to rt and was stirred for 12 h at rt. The solvent was removed under reduced pressure. Column chromatography (100:0 to 90:10 CH2Cl2:MeOH) afforded 13.0 mg (81%) of 3 as an amorphous solid. [α]D23=+24.3 (c=0.7, MeOH). IR: 1371, 1420, 1497, 1544, 1667, 1741, 2342, 2360, 2840, 2872, 2929, 2961, 3293, 3368 cm−1. 1H NMR (500 MHz, MeOD): δ 0.79 (d, 3H, J=6.7 Hz), 0.85 (d, 3H, J=6.9 Hz), 0.87-0.92 (m, 6H), 0.96 (d, 3H, J=6.6 Hz), 1.05 (d, 3H, J=6.3 Hz), 1.15-1.23 (m, 1H), 1.35-1.42 (m, 1H), 1.57-1.65 (m, 3H), 1.69-1.72 (m, 1H), 1.77-1.81 (m, 1H), 1.84-1.93 (m, 4H), 1.95-2.01 (m, 2H), 2.08-2.18 (m, 2H), 2.13 (s, 3H), 2.28-2.39 (m, 4H), 2.33 (s, 3H), 2.48-2.53 (m, 1H), 2.94 (app d, 1H, J=10.1 Hz), 3.08 (app d, 1H, J=11.3 Hz), 3.40-3.43 (m, 2H), 4.41 (br s, 1H), 4.60 (d, 1H, J=9.5 Hz), 5.40 (d, 1H, J=12.4 Hz), 5.87 (d, 1H, J=10.8 Hz), 6.13 (d, 1H, J=10.8 Hz), 8.18 (s, 1H). 13C NMR (125 MHz, MeOD) δ 10.7, 16.4, 20.3, 20.70, 20.76, 22.73, 22.74, 23.7, 25.54, 22.56, 26.7, 26.9, 31.1, 32.2, 34.7, 35.9, 37.4, 40.2, 44.18, 44.25, 55.2, 56.5, 69.7, 70.7, 125.6, 150.8, 163.2, 170.7, 171.9, 173.3, 173.8, 176.4, 180.5. HRMS (FAB) calcd for C35H58N5O9S (M+H): 724.3955. Found: 724.3937.
Reaction SMILES: C(NC(C1SC(NC(N(CC(OC)OC)CC2C=CC(F)=CC=2)=O)=NC=1C)=O)C1C=CC=CC=1.CO[CH:37]([O:68]C)[CH2:38][N:39]([CH2:59][CH2:60][C:61]1[CH:66]=[CH:65][C:64]([F:67])=[CH:63][CH:62]=1)[C:40](=[O:58])[NH:41][C:42]1[S:43][C:44]([C:48]([NH:50][CH2:51][C:52]2[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=2)=[O:49])=[C:45]([CH3:47])[N:46]=1>>[F:67][C:64]1[CH:63]=[CH:62][C:61]([CH2:60][CH2:59][N:39]2[CH2:38][CH:37]([OH:68])[N:41]([C:42]3[S:43][C:44]([C:48]([NH:50][CH2:51][C:52]4[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=4)=[O:49])=[C:45]([CH3:47])[N:46]=3)[C:40]2=[O:58])=[CH:66][CH:65]=1
Reactant: COC(CN(CCc1ccc(F)cc1)C(=O)Nc1nc(C)c(C(=O)NCc2cccnc2)s1)OC
Agent: COC(CN(Cc1ccc(F)cc1)C(=O)Nc1nc(C)c(C(=O)NCc2ccccc2)s1)OC
Product: Cc1nc(N2C(=O)N(CCc3ccc(F)cc3)CC2O)sc1C(=O)NCc1cccnc1
Yield: 21 %

Procedure:
Following the procedure as described in Example 16, making variations as required to replace N-benzyl-2-(3-(2,2-dimethoxyethyl)-3-(4-fluorobenzyl)ureido)-4-methylthiazole-5-carboxamide with 2-(3-(2,2-dimethoxyethyl)-3-(4-fluorophenethyl)ureido)-4-methyl-N-(pyridin-3-ylmethyl)thiazole-5-carboxamide, the title compound was obtained as a colorless solid in 21% yield: mp 182-184° C. (ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 8.61-8.48 (m, 2H), 7.67 (d, J=7.2 Hz, 1H), 7.28 (br s, 1H), 7.18-7.03 (m, 2H), 6.97 (d, J=8.6 Hz, 2H), 6.12-5.93 (m, 2H), 4.72 (br s, 1H), 4.57 (d, J=5.7 Hz, 2H) 3.65-3.45 (m, 3H), 3.34-3.29 (m, 1H), 2.85 (t, J=7.2 Hz, 2H), 2.57 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 162.3, 160.1, 157.1, 153.4, 153.3, 149.2, 149.0, 135.6, 133.6, 130.1, 130.0, 117.2, 115.7, 115.4, 77.2, 50.2, 44.8, 41.4, 33.1, 17.2; MS (ES+) m/z 456.3 (M+1).
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][C:5]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:6]([C:8](OCC)=[O:9])[N:7]=1.[NH3:19]>>[C:8]([C:6]1[N:7]=[C:3]([NH:2][CH3:1])[S:4][C:5]=1[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)(=[O:9])[NH2:19]
Reactant: CCOC(=O)c1nc(NC)sc1-c1ccncc1
Reactant: N
Product: CNc1nc(C(N)=O)c(-c2ccncc2)s1
Reaction time: 120 h

Procedure:
A solution of ethyl 2-methylamino-5-(4-pyridyl)-4-thiazolecarboxylate (2.36 g) in 26% methanolic ammonia (100 ml) was allowed to stand at ambient temperature for 5 days. The reaction mixture was evaporated in vacuo and the residue was washed with tetrahydrofuran to give 4-carbamoyl-2-methylamino-5-(4-pyridyl)thiazole (1.0 g). mp 212°-213° C. (from tetrahydrofuran-methanol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:17]#[N:18])=[C:6]([NH:8][C:9](=O)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=1.[OH-:19].[Na+].OO.Cl>O>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5]([C:17](=[O:19])[NH:18][C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N:8]2)=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(Cl)cc1NC(=O)c1ccccc1
Reactant: [OH-]
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: O
Product: O=c1[nH]c(-c2ccccc2)nc2cc(Cl)ccc12
Temperature: 80 °C
Reaction time: 24 h

Procedure:
To a suspension of N-(5-chloro-2-cyanophenyl)benzamide (150 mg, 0.58 mmol) in H2O (5 mL) was added in sequence NaOH (100 mg, 2.5 mmol) and H2O2 (30% in H2O, 0.25 mL, 2.2 mmol). The reaction was heated to 80° C. for 24 h then cooled to rt and stirred at rt for 1 d. Aq HCl (2 M, 6 mL) was added forming a thick precipitate that was collected by a filtration. The filter cake was washed with H2O several times affording the title compound as a creamy-white solid; MS (ES+): m/z 257.1 (100) [MH+]; HPLC: tR=3.34 min (OpenLynx, polar—5 min).
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6](Cl)[C:7]=1[CH2:8][C:9]([C:11]1[C:16]2[C:17]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:18][O:19][C:15]=2[C:14]([O:26][CH3:27])=[CH:13][CH:12]=1)=[O:10]>CN(C=O)C.CO.[C].[Pd]>[CH2:24]([O:23][C:21]([CH2:20][C:17]1[C:16]2[C:11]([C:9](=[O:10])[CH2:8][C:7]3[CH:2]=[CH:3][N:4]=[CH:5][CH:6]=3)=[CH:12][CH:13]=[C:14]([O:26][CH3:27])[C:15]=2[O:19][CH:18]=1)=[O:22])[CH3:25]
Reactant: CCOC(=O)Cc1coc2c(OC)ccc(C(=O)Cc3c(Cl)cncc3Cl)c12
Agent: [Pd]
Solvent: CO
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1coc2c(OC)ccc(C(=O)Cc3ccncc3)c12
Reaction time: 6 h
Yield: 59.7 %

Procedure:
Compound 119 (0.04 g) obtained in Example 119 was dissolved in DMF-methanol (1:1) (1.0 ml), and 10% palladium carbon (0.016 g) was added thereto, followed by hydrogenation at normal temperature and normal pressure for 6 hours. The catalyst was removed and the filtrate was concentrated. Water and a saturated aqueous solution of sodium bicarbonate were added to the residue, and a precipitate was collected by filtration and dried to give Compound 120 (0.02 g, 9%) as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[S:3])[NH2:2].Br[CH2:16][C:17]([C:19]1[CH:23]=[C:22]([CH3:24])[O:21][C:20]=1[CH3:25])=O>>[CH3:25][C:20]1[O:21][C:22]([CH3:24])=[CH:23][C:19]=1[C:17]1[N:2]=[C:1]([C:4]2[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=2)[C:7]([O:9][CH2:10][CH3:11])=[O:8])[S:3][CH:16]=1
Reactant: Cc1cc(C(=O)CBr)c(C)o1
Reactant: CCOC(=O)c1cccc(C(N)=S)c1
Product: CCOC(=O)c1cccc(-c2nc(-c3cc(C)oc3C)cs2)c1
Yield: 16 %

Procedure:
In the same manner as in Example 28, ethyl 3-thiocarbamoylbenzoate was reacted with 3-bromoacetyl-2,5-dimethylfuran to obtain ethyl 3-[4-(2,5-dimethyl-3-furyl)-2-thiazolyl]benzoate. The product was recrystallized from ethanol. Yield: 16%, Pale yellow prisms. Melting point: 100 to 101° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:27])[C:3]([NH:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH:13]=[CH:12]2)=O.P(Cl)(Cl)(Cl)=O>C(#N)C>[CH:2]([C:3]1[C:10]2=[C:11]3[C:15](=[CH:16][CH:17]=[C:9]2[O:8][CH2:7][CH2:6][N:5]=1)[N:14]([S:18]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)(=[O:20])=[O:19])[CH:13]=[CH:12]3)([CH3:1])[CH3:27]
Reactant: CC(C)C(=O)NCCOc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: CC(C)C1=NCCOc2ccc3c(ccn3S(=O)(=O)c3ccccc3)c21
Yield: 98.7 %

Procedure:
To 2-methyl-N-(2-{[1-(phenylsulfonyl)-1H-indol-5-yl]oxy}ethyl)propanamide (Intermediate 37, 0.13 g, 0.33 mmol) in acetonitrile (200 mL) was phosphoryl chloride (2.5 mL) added and the reaction mixture was heated at reflux for 20 hours. The reaction mixture was evaporated to give the title compound (120 mg). MS m/z 369 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][NH:8][CH:9]=1)=[O:4].[CH2:10]=[O:11].C(N(CC)CC)C>CC(C)=O>[OH:11][CH2:10][N:7]1[CH:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:9]=[N:8]1
Reactant: C=O
Reactant: COC(=O)c1cn[nH]c1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cnn(CO)c1
Temperature: 130 °C
Reaction time: 1 h
Yield: 79.6 %

Procedure:
The mixture of 1.40 g of 4-methoxycarbonyl-1H-pyrazole, 0.37 g of paraformaldehyde and 0.11 g of triethylamine was stirred at 130° C. for 1 hour. 0.74 g of paraformaldehyde and 2 ml of triethylamine were added to the mixture and stirred at 130° C. for 2 hours. After the reaction mixture was cooled to room temperature, acetone was added. After the mixture was filtered, the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.38 g of 1-(hydroxymethyl)-4-methoxycarbonyl-1H-pyrazole.
Reaction SMILES: [CH3:1][C:2]([O:4][CH2:5][N:6]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:8]2([CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[C:7]1=[O:20])=[O:3].[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][C:2]([O:4][CH2:5][N:6]1[C:19]2[C:14](=[CH:15][C:16]([CH2:26][C:25]3[CH:28]=[CH:29][C:22]([Cl:21])=[CH:23][CH:24]=3)=[CH:17][CH:18]=2)[C:8]2([CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)[C:7]1=[O:20])=[O:3]
Reactant: CC(=O)OCN1C(=O)C2(CCNCC2)c2ccccc21
Reactant: O=Cc1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(=O)OCN1C(=O)C2(CCNCC2)c2cc(Cc3ccc(Cl)cc3)ccc21

Procedure:
1-(Methylcarbonyloxy-methyl)-spiro[indoline-3,4′-piperidin]-2-one (0.026 g, 0.095 mmol) and 4-chloro-benzaldehyde (0.02 g, 0.14 mmol) were dissolved in dry 1,2-dichloroethane (1.5 mL). To the reaction mixture was then added glacial acetic acid (0.006 g, 0.095 mmol) under nitrogen atmosphere and the reaction mixture was stirred at room temperature for 30 minutes. To the reaction mixture was then added, at room temperature, sodium triacetoxyborohydride (0.034 g, 0.16 mmol) under nitrogen atmosphere and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was then partitioned with aqueous NaHCO3 and dichloromethane. The organic layer was washed with brine, dried with Na2SO4, filtered and the solvent evaporated in vacuo to yield a crude oil. The crude oil was purified via flash chromatography (2.5% methanol/dichloromethane) to yield the title compound as a solid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].CC1C=CC=CC=1C1C=CC(C(O)=O)=CC=1C(F)(F)F.[CH3:36][C:37]1[C:38](B(O)O)=[CH:39][S:40][CH:41]=1.C(=O)([O-])[O-].[K+].[K+]>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.O>[CH3:36][C:37]1[C:38]([C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=2[C:12]([F:15])([F:14])[F:13])=[CH:39][S:40][CH:41]=1
Reactant: COC(=O)c1ccc(Br)c(C(F)(F)F)c1
Reactant: Cc1cscc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1ccccc1-c1ccc(C(=O)O)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(-c2cscc2C)c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 99.6 %

Procedure:
Methyl 4-bromo-3-(trifluoromethyl)benzoate (Intermediate 19, step 1) (3.50 g; 12.37 mmol; 1 eq.), 4-methyl-3-thiopheneboronic acid (1.93 g; 13.60 mmol; 1.10 eq.), potassium carbonate (8.54 g; 61.83 mmol; 5 eq.), tetrakis(triphenylphosphine)palladium(0) (1.43 g; 1.24 mmol; 0.10 eq.) were taken up in Toluene (17.50 mL) and water (17.50 mL) under N2 atmosphere. The reaction mixture was purged with vacuum, then degassed with N2 for 5 minutes and then refluxed for 24 hours. The reaction mixture was cooled to RT, filtered over a pad of celite and washed with toluene (200 mL). The filtrate was concentrated affording a brown oil that was taken in EtOAc (300 mL). The organic layer was washed with a saturated aqueous solution of NaHCO3 solution (100 mL), water (100 mL) and brine (100 mL), dried over MgSO4 and concentrated affording the title compound as a brown oil (3.7 g, 99%). HPLC (Method A) Rt 5.21 min (Purity: 68.1%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)[CH:2]=1.[ClH:23].O1CCOCC1>CO>[ClH:23].[ClH:23].[ClH:23].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CCCc2cccnc2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: c1cncc(CCCN2CCNCC2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 420 mg of tert-butyl 4-[3-(pyridin-3-yl)propyl]piperazine-1-carboxylate in 6 mL of methanol was added 2 mL of a 4 M hydrogen chloride-dioxane solution, followed by stirring at room temperature for 16 hours. The solvent was evaporated under reduced pressure to obtain 395 mg of 1-[3-(pyridin-3-yl)propyl]piperazine trihydrochloride.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][CH2:4][C:3]1([CH2:12][CH:13]([CH3:15])[CH3:14])[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(Cl)Cl.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>N1C=CC=CC=1>[CH2:12]([C:3]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:5][CH2:6][CH:2]1[O:1][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:13]([CH3:14])[CH3:15]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)C1(CC(C)C)CCCC1O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C1(CC(C)C)CCCC1OC(=O)c1ccccc1
Reaction time: 12 h

Procedure:
Ethyl 2-hydroxy-1-iso-butyl-cyclopentane carboxylate (5.00 g) was diluted using 60 ml of methylene chloride. At room temperature and with magnetic stirring, pyridine (2.85 ml) was slowly added, then benzoyl chloride (4.15 ml,) was dropwise added. Upon the completion of the addition, the reaction was continued for 12 hours. Then solvent was removed, and the residue was extracted using ethyl acetate and water. Organic layer was washed, in turn, using 10% hydrochloric acid aqueous solution to pH of about 2, using saline solution to neutrality, using 10% aqueous solution of sodium carbonate for three times, and then using saline solution to neutrality. The organic layer was dried, and removing solvent gave 7.70 g of brown liquid. MS: m/e 319(M+′+1), 318(M+′), 273, 244, 213, 196, 105(base), 77.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[C:16]([F:17])[C:11]3=[N:10][C:9]=2[C:18]2[CH:19]=[C:20]([CH:32]=[CH:33][CH:34]=2)[C:21]([NH:23][C:24]2[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=2[F:31])=[O:22])[CH:5]=[CH:4][N:3]=1.[N:35]1([CH:41]2[CH2:46][CH2:45][N:44]([C:47]3[CH:53]=[CH:52][C:50]([NH2:51])=[C:49]([O:54][CH3:55])[CH:48]=3)[CH2:43][CH2:42]2)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>FC(F)(F)CO.CO.C(Cl)Cl.CCCCCC>[N:35]1([CH:41]2[CH2:46][CH2:45][N:44]([C:47]3[CH:53]=[CH:52][C:50]([NH:51][C:2]4[N:7]=[C:6]([C:8]5[N:12]6[CH:13]=[CH:14][CH:15]=[C:16]([F:17])[C:11]6=[N:10][C:9]=5[C:18]5[CH:19]=[C:20]([CH:32]=[CH:33][CH:34]=5)[C:21]([NH:23][C:24]5[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=5[F:31])=[O:22])[CH:5]=[CH:4][N:3]=4)=[C:49]([O:54][CH3:55])[CH:48]=3)[CH2:43][CH2:42]2)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: COc1cc(N2CCC(N3CCCCC3)CC2)ccc1N
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3c(F)cccn3c2-c2ccnc(Cl)n2)c1
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CO
Solvent: OCC(F)(F)F
Solvent: O
Product: COc1cc(N2CCC(N3CCCCC3)CC2)ccc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3c(F)cccn23)n1
Temperature: 145 °C
Yield: 63.2 %

Procedure:
To 3-[3-(2-chloro-4-pyrimidinyl)-8-fluoroimidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluoro-phenyl)benzamide (Example 188, step A) (100 mg, 0.21 mmol) and 4-(1,4′-bipiperidin-1′-yl)-2-(methyloxy)aniline (Example 22, step C) (54 mg, 0.19 mmol) in 2,2,2-trifluoroethanol (2 mL) was added p-toluenesulfonic acid monohydrate (95 mg, 0.50 mmol). The mixture was stirred and heated on a microwave at 145° C. for 30 min, then cooled to rt. The mixture was neutralized with 0.5M sodium methoxide in MeOH. The mixture was concentrated under vacuum and the residue purified by silica gel chromatography to give a yellow solid. The solid was dissolved in minimal DCM, then hexane was added until a precipitate was formed. The slurry was cooled at −10° C. for 30 min, then poured through a Teflon filter, washing the solids with cold hexanes. The solids were dried under vacuum to give the title compound (90 mg, 0.12 mmol, 66%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 10.26 (s, 1H), 9.20 (br s, 1H), 8.52 (s, 1H), 8.34 (s, 1H), 8.24 (d, 1H, J=5.13 Hz), 8.07 (d, 1H, J=7.88 Hz), 7.83 (d, 1H, J=7.70 Hz), 7.62 (t, 1H, J=7.79 Hz), 7.34-7.45 (m, 3H), 7.21 (t, 2H, J=8.06 Hz), 6.93-6.99 (m, 1H), 6.66 (d, 1H, J=2.20 Hz), 6.45-6.50 (m, 2H), 3.79 (s, 3H), 3.70-3.77 (m, 2H), 2.59-2.68 (m, 2H), 2.42-2.48 (m, 4H), 2.28-2.37 (m, 1H), 1.76-1.83 (m, 2H), 1.35-1.60 (m, 8H). MS (ESI): 733 [M+H]+.
Reaction SMILES: [OH:1][CH:2]([CH2:34][CH2:35]CCCCCCCCCCCCC)[CH:3]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]CCCC)[C:4]([O:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9])=[O:5].ClC(Cl)(Cl)C(=N)O[CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1.FC(F)(F)S(O)(=O)=O>C(Cl)Cl>[CH2:53]([O:1][CH:2]([CH2:34][CH2:35][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:3][CH2:2][CH2:34][CH3:35])[CH:3]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:4]([O:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9])=[O:5])[C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1
Reactant: CCCCCCCCCCCCCCCCCCC(C(=O)OCC(=O)c1ccccc1)C(O)CCCCCCCCCCCCCCC
Reactant: N=C(OCc1ccccc1)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCC(OCc1ccccc1)C(CCCCCCCCCCCCCC)C(=O)OCC(=O)c1ccccc1
Temperature: 25 °C
Yield: 75.6 %

Procedure:
Then, phenacyl 3-hydroxy-2-n-octadecyl-octadecanoate (IV) (1.81 g, 2.94 millimole) was dissolved in dry methylene chloride (80 ml) under, argon atmosphere, and benzyl 2,2,2-trichloro-acetimidate (0.66 ml, 3.53 millimole) and trifluoromethane sulfonic acid (0.052 ml, 0.59 millimole) were successively added dropwise thereto with ice cooling. The reaction mixture was allowed to warm to room temperature, and to react for 17 hours, then methylene chloride was added to the reaction mixture, and the obtained solution was successively washed with saturated aqueous sodium bicarbonate solution and water, and then dried over anhydrous sodium sulfate. The solvent was distilled off from the solution. The residue was dissolved in a developing solvent (benzene:n-hexane=6:4), and fractionated through silicagel column (benzene:n-hexane=6:4), and the fast eluting fractions comprising impurities were discarded and then the later colorless fractions were pooled and the solvent was distilled off to give phenacyl 3-benzyloxy-2-n-tetradecyl-octadecanoate (V) (783.9 mg) in the form of colorless oil.