Azzindani/Open_Reaction_Data huggingface dataset:
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][C:17]([CH3:20])=[C:16]([C:21]3[C:32](=[O:33])[N:31]([CH3:34])[C:24]4[N:25]=[C:26](SC)[N:27]=[CH:28][C:23]=4[CH:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:35][NH2:36]>C1COCC1>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([C:21]3[C:32](=[O:33])[N:31]([CH3:34])[C:24]4[N:25]=[C:26]([NH:36][CH3:35])[N:27]=[CH:28][C:23]=4[CH:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN
Reactant: CSc1ncc2cc(-c3cc(NC(=O)Nc4cc(C(C)(C)C)on4)ccc3C)c(=O)n(C)c2n1
Solvent: C1CCOC1
Product: CNc1ncc2cc(-c3cc(NC(=O)Nc4cc(C(C)(C)C)on4)ccc3C)c(=O)n(C)c2n1
Yield: 32 %

Procedure:
Using general method B, the carbamate of 5-t-butylisoxazol-3-amine (108 mg, 0.480 mmol) and Example A44 (150 mg, 0.480 mmol) were combined to give the intermediate sulfide, 1-(5-tert-butylisoxazol-3-yl)-3-(4-methyl-3-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (35 mg, 15% yield). Using a procedure analogous to Example A1, 1-(5-tert-butylisoxazol-3-yl)-3-(4-methyl-3-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (158 mg, 0.330 mmol) and 2.0N solution of methylamine in THF (1.7 mL) were combined and purified by chromatography (Biotage Si-25 column, 60-100% ethyl acetate/Hex) to afford 1-(5-tert-butylisoxazol-3-yl)-3-(4-methyl-3-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (49 mg, 32% yield). 1H NMR (300 MHz, DMSO-d6): δ 1.26 (s, 9H), 2.06 (s, 3H), 2.90 (s, 3H), 3.53-3.60 (m, 3H), 6.46 (s, 1H), 7.14-7.16 (m, 1H), 7.26-7.28 (m, 1H), 7.32 (s, 1H), 7.67 (s, 1H), 7.65-7.80 (br m, 1H), 8.60-8.65 (m, 1H), 8.72 (s, 1H), 9.47 (s, 1H); MS (ESI) m/z: 462.0 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C@@H:13]2[CH2:17][CH2:16][N:15]([CH3:18])[C:14]2=[O:19])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[N:20]1([C:24]([C:26]2[CH:31]=[N:30][C:29](Cl)=[CH:28][N:27]=2)=[O:25])[CH2:23][CH2:22][CH2:21]1.C(=O)([O-])[O-]>CC(N(C)C)=O>[N:20]1([C:24]([C:26]2[N:27]=[CH:28][C:29]([O:1][C:2]3[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C@@H:13]4[CH2:17][CH2:16][N:15]([CH3:18])[C:14]4=[O:19])[CH:11]=3)[C:5]([O:7][CH3:8])=[O:6])=[N:30][CH:31]=2)=[O:25])[CH2:23][CH2:22][CH2:21]1
Reactant: O=C(c1cnc(Cl)cn1)N1CCC1
Reactant: COC(=O)c1cc(O)cc(O[C@@H]2CCN(C)C2=O)c1
Agent: O=C([O-])[O-]
Solvent: CC(=O)N(C)C
Product: COC(=O)c1cc(Oc2cnc(C(=O)N3CCC3)cn2)cc(O[C@@H]2CCN(C)C2=O)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 68.5 %

Procedure:
A mixture of methyl 3-hydroxy-5-[(3R)-1-methyl-2-oxo-pyrrolidin-3-yl]oxy-benzoate (Intermediate 12) (265 mg, 1 mmol), azetidin-1-yl-(5-chloropyrazin-2-yl)methanone (Intermediate 32) (298 mg, 1.5 mmol) and polymer supported-carbonate (860 mg, 2.5 mmol) in DMA (5 mL) was stirred at 100° C. for 2 hours. The mixture was filtered and the DMA was removed under reduced pressure. The residue was purified by flash chromatography on silica eluting with 20-100% ethyl acetate in isohexane then 10% methanol in DCM to afford the product (292 mg, 68%). 1H NMR δ (300 MHz, CDCl3) 2.13-2.27 (m, 1H), 2.31-2.44 (m, 2H), 2.53-2.66 (m, 1H), 2.94 (s, 3H), 3.35-3.58 (m, 2H), 3.90 (s, 3H), 4.26 (t, 2H), 4.68 (t, 2H), 4.93 (t, 1H), 7.14 (s, 1H), 7.46 (s, 1H), 7.60 (s, 1H), 8.31 (s, 1H), 8.84 (s, 1H); m/z 427 (M+H)+
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:26])[NH:5][C:6]1[N:11]=[CH:10][C:9](B(O)O)=[C:8]([C:15]2[S:16][CH:17]=[C:18]([C:20]3[CH:21]=[N:22][N:23]([CH3:25])[CH:24]=3)[N:19]=2)[CH:7]=1)[CH3:2].Br[C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][N:37]=1)[N:34]([CH2:38][C:39]1[N:40]=[CH:41][N:42]([CH3:44])[CH:43]=1)[CH:33]=[C:32]([C:45]([O:47][CH2:48][CH3:49])=[O:46])[C:31]2=[O:50].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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>[CH2:1]([NH:3][C:4](=[O:26])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:28]2[CH:29]=[C:30]3[C:35](=[CH:36][N:37]=2)[N:34]([CH2:38][C:39]2[N:40]=[CH:41][N:42]([CH3:44])[CH:43]=2)[CH:33]=[C:32]([C:45]([O:47][CH2:48][CH3:49])=[O:46])[C:31]3=[O:50])=[C:8]([C:15]2[S:16][CH:17]=[C:18]([C:20]3[CH:21]=[N:22][N:23]([CH3:25])[CH:24]=3)[N:19]=2)[CH:7]=1)[CH3:2]
Reactant: CCNC(=O)Nc1cc(-c2nc(-c3cnn(C)c3)cs2)c(B(O)O)cn1
Reactant: CCOC(=O)c1cn(Cc2cn(C)cn2)c2cnc(Br)cc2c1=O
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CCNC(=O)Nc1cc(-c2nc(-c3cnn(C)c3)cs2)c(-c2cc3c(=O)c(C(=O)OCC)cn(Cc4cn(C)cn4)c3cn2)cn1
Temperature: 90 °C
Yield: 26.1 %

Procedure:
In a microwave vessel, 6-(3-ethylureido)-4-(4-(1-methyl-1H-pyrazol-4-yl)thiazol-2-yl)pyridin-3-ylboronic acid (Intermediate 98, 0.2 g, 0.54 mmol), ethyl 6-bromo-1-((1-methyl-1H-imidazol-4-yl)methyl)-4-oxo-1,4-dihydro-1,7-naphthyridine-3-carboxylate (Intermediate 102, 0.21 g, 0.54 mmol) and cesium carbonate (0.229 g, 0.70 mmol) were combined and suspended in a mixture of dioxane and water (5:1; 2.5 mL/0.5 mL). The suspension was degassed and purged with nitrogen. Pd(PPh3)4 (0.05 g, 0.04 mmol) was added and the mixture was degassed and purged a second time. The reaction mixture was heated in the microwave at 90° C. for 90 minutes. The reaction was partitioned between water and ethyl acetate, the layers were separated, and the organic phase was washed with saturated NaHCO3, water and brine, then dried over magnesium sulfate, and concentrated. The resulting solids were filtered, washed with acetonitrile followed by chloroform. Isolation gave 90 mg of the title compound as an off-white solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[CH:16]=[CH:15][C:14]2[NH:13][C:12]3[CH2:17][CH2:18][CH2:19][NH:20][C:21](=O)[C:11]=3[C:10]=2[CH:9]=1.O1CCOC[CH2:24]1>>[CH3:24][N:20]1[CH2:19][CH2:18][CH2:17][C:12]2[NH:13][C:14]3[CH:15]=[CH:16][C:8]([CH3:7])=[CH:9][C:10]=3[C:11]=2[CH2:21]1
Reactant: C1COCCO1
Reactant: Cc1ccc2[nH]c3c(c2c1)C(=O)NCCC3
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: Cc1ccc2[nH]c3c(c2c1)CN(C)CCC3

Procedure:
Lithium aluminum hydride (3 g, 78.95 mmol) was placed in 1,4-dioxane (100 mL) under inert atmosphere and 9-methyl-2,3,4,5-tetrahydroazepino[4,3-b]indol-1(6H)-one (3 g, 14.018 mmol) was added, and the mixture heated to reflux for 15 h. The reaction was monitored by TLC. The reaction was quenched with saturated aqueous sodium sulfate at 0° C., and the reaction mixture filtered. The filtrate was dried over anhydrous sodium sulfate and evaporated to dryness to afford solid, which was washed with water followed by EtOAc, and dried to afford 1.25 g of the title compound.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[F:10][C:11]([C:14]1[CH:15]=[C:16]([CH:32]=[CH:33][CH:34]=1)[O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:25]([NH2:31])=[N:26][CH:27]=[C:28]([CH3:30])[CH:29]=2)=[CH:20][CH:19]=1)([F:13])[CH3:12]>C1COCC1>[F:10][C:11]([C:14]1[CH:15]=[C:16]([CH:32]=[CH:33][CH:34]=1)[O:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[C:25]3=[N:31][S:6](=[O:8])(=[O:7])[CH2:5][CH2:4][N:26]3[CH:27]=[C:28]([CH3:30])[CH:29]=2)=[CH:22][CH:23]=1)([F:13])[CH3:12]
Reactant: O=S(=O)(Cl)CCCl
Reactant: Cc1cnc(N)c(-c2ccc(Oc3cccc(C(C)(F)F)c3)cc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1=CN2CCS(=O)(=O)N=C2C(c2ccc(Oc3cccc(C(C)(F)F)c3)cc2)=C1
Reaction time: 0.17 h

Procedure:
To a suspension of NaH (60%, 96 mg) in THF (dry) (10 mL) was added 2-chloroethanesulfonyl chloride (0.101 mL) at 0° C. and the mixture was stirred for 10 min at the same temperature. A solution of 3-(4-(3-(1,1-difluoroethyl)phenoxy)phenyl)-5-methylpyridin-2-amine (164 mg) in THF (dry) (10 mL) was added at 0° C. and the mixture was stirred at room temperature under nitrogen overnight. The mixture was quenched with water at 0° C. Water, EtOAc and THF were added and the mixture was extracted. Silica-gel was added to the organic phase and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (silica gel, eluted with MeOH in EtOAc) and concentrated in vacuo to give 9-{4-[3-(1,1-difluoroethyl)phenoxy]phenyl}-7-methyl-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide as a white solid. Platinum(IV) oxide (30 mg) was added to a solution of the prepared 9-{4-[3-(1,1-difluoroethyl)phenoxy]phenyl}-7-methyl-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide in THF (dry) (15 mL) and MeOH (15 mL). The mixture was stirred at room temperature under hydrogen for 3 hr. Activated carbon was added and the insoluble solid was removed by filtration through silica gel/Celite pad (eluted with EtOAc, to remove catalytic poison). Platinum(IV) oxide (30 mg) was added and the mixture was stirred at room temperature under hydrogen overnight. Activated carbon was added and the insoluble solid was removed by filtration through silica gel/Celite pad (eluted with EtOAc) and the filtrate was concentrated in vacuo. The residue was crystallized from THF/IPE to give the title compound (47.6 mg) as colorless crystals.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10](=[O:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[O:22][CH2:23][C:24]([CH3:27])([CH3:26])[N:25]=1>>[CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]2[O:22][CH2:23][C:24]([CH3:27])([CH3:26])[N:25]=2)([OH:13])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCN(Cc2ccccc2)C1
Reactant: CC1(C)COC(c2ccccc2Br)=N1
Product: CC1(C)COC(c2ccccc2C2(O)CCN(Cc3ccccc3)C2)=N1

Procedure:
Reaction of 1-benzyl-3-pyrrolidone and 2-(2-bromophenyl)-4,4-dimethyl-2-oxazoline by the method described in Example 1c provides 1-benzyl-3-[2-(4,4-dimethyl-2-oxazolin-2-yl)phenyl]-3-hydroxypyrrolidine as an oil.
Reaction SMILES: [CH3:1][C:2]([CH3:36])([CH2:5][C@@:6]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:11][C:10](=[O:12])[N:9]([C@H:13]([C:15]2[CH:20]=[CH:19][C:18](B3OC(C)(C)C(C)(C)O3)=[CH:17][CH:16]=2)[CH3:14])[CH2:8][CH2:7]1)[C:3]#[N:4].Cl[C:38]1[CH:39]=[CH:40][C:41](=[O:44])[NH:42][N:43]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][C:2]([CH3:36])([CH2:5][C@@:6]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[O:11][C:10](=[O:12])[N:9]([C@H:13]([C:15]2[CH:16]=[CH:17][C:18]([C:38]3[CH:39]=[CH:40][C:41](=[O:44])[NH:42][N:43]=3)=[CH:19][CH:20]=2)[CH3:14])[CH2:8][CH2:7]1)[C:3]#[N:4]
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)C#N)(c2ccccc2)OC1=O
Reactant: O=c1ccc(Cl)n[nH]1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@@H](c1ccc(-c2ccc(=O)[nH]n2)cc1)N1CC[C@](CC(C)(C)C#N)(c2ccccc2)OC1=O
Yield: 13.4 %

Procedure:
A mixture of 2,2-dimethyl-3-((R)-2-oxo-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)propanenitrile (150 mg, 0.31 mmol), 6-chloropyridazin-3-(2H)-one (62 mg, 0.47 mmol), Pd(Ph3P)2Cl2 (15 mg), and aq. Cs2CO3 solution (2 mL, 2M) in 1,4-dioxane (10 mL) was stirred at reflux for 2 h. When the reaction was finished, the mixture was diluted with water, and extracted with EtOAc. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated to give the crude product, which was purified by preparative TLC to give 2,2-dimethyl-3-((R)-2-oxo-3-((S)-1-(4-(6-oxo-1,6-dihydropyridazin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-6-yl)propanenitrile (18.9 mg, 15%). LC-MS Method 2 tR=1.053 min, m/z=457.3; 1H NMR (CDCl3): δ1.16 (s, 3H), 1.25 (s, 3H), 1.38 (d, 3H), 2.21 (s, 2H), 2.24 (m, 1H), 2.40 (m, 2H), 2.86 (m, 1H), 5.61 (m, 1H), 6.86 (m, 2H), 6.95 (m, 1H), 7.29 (m, 5H), 7.32 (m, 2H), 7.56 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[O:20]1[CH:25]=[CH:24][CH2:23][CH2:22][CH2:21]1.B(F)(F)F.CCOCC.C(OCC)(=O)C>CCOCC.B(F)(F)F.CCOCC>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[N:11]=[CH:10][N:9]([CH:21]3[CH2:22][CH2:23][CH2:24][CH2:25][O:20]3)[C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:14][CH:15]=1
Reactant: C1=COCCC1
Reactant: Fc1ccc(-c2nc[nH]c2-c2ccc(F)cc2)cc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: Fc1ccc(-c2ncn(C3CCCCO3)c2-c2ccc(F)cc2)cc1
Reaction time: 8 h
Yield: 85.1 %

Procedure:
A mixture of 124 g (0.484 mole) of 4,5-bis(4-fluorophenyl)imidazole, 84 g (1.0 mole) dihydropyran, 20 g boron trifluoride etherate and 1 l ethyl acetate was heated at reflux over a weekend. Analysis by TLC (ethyl acetate) showed the presence of some unchanged starting material, so 20 g (~0.24 mole) of dihydropyran and 5 g boron trifluoride etherate was added and heating was continued overnight. The mixture was then diluted with 1 l ether and washed with 10% sodium bicarbonate solution (3×1 l). The organic layer was dried and concentrated on a rotary evaporator. The residual solid was recrystallized from methylcyclohexane (removing some insoluble starting material by filtration) to give 140.2 g (85%) of 4,5-bis(4-fluorophenyl)-1-(2-tetrahydropyranyl)imidazole as a white solid, mp 149°-152°. F-NMR indicated purity ~95%. A smaller run was chromatographed to give pure material mp 158°-9°. IR: 3.25μ (=CH); 3.38, 3.49μ (sat. CH); 6.22, 6.28, 6.41, 6.60, 6.69μ (C=C and/or C=N); 8.20μ (CF); 9μ region (C--O--C). H-NMR: m(1.4-2.1 δ, 6H); m (3.4 δ,1H); m (4.0 δ, 1H); m (4.7 δ, 1H); m (6.6-7.5 δ, 8H); s (7.8 δ, 1H). F-NMR: two multiplets (112.4 δ and 116.5 δ, each decouples to a singlet).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]2[CH2:13][CH2:12][C:11](=[O:14])[N:10]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]4[N:32](C(C)(C)C)[N:31]=[N:30][N:29]=4)=[CH:18][CH:17]=3)[C:5]=2[N:6]=[C:7]([CH3:9])[N:8]=1.CS(O)(=O)=O>C1(C)C=CC=CC=1>[OH:1][CH2:2][C:3]1[C:4]2[CH2:13][CH2:12][C:11](=[O:14])[N:10]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]4[NH:32][N:31]=[N:30][N:29]=4)=[CH:20][CH:21]=3)[C:5]=2[N:6]=[C:7]([CH3:9])[N:8]=1
Reactant: Cc1nc(CO)c2c(n1)N(Cc1ccc(-c3ccccc3-c3nnnn3C(C)(C)C)cc1)C(=O)CC2
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Product: Cc1nc(CO)c2c(n1)N(Cc1ccc(-c3ccccc3-c3nnn[nH]3)cc1)C(=O)CC2
Yield: 19.3 %

Procedure:
A mixture of 4-hydroxymethyl-2-methyl-8-[2'-(1-tert-butyl-1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-5,8-dihydro-6H-pyrido[2,3-d]pyrimidin-7-one (550 mg, 1.14 mmol), methanesulfonic acid (1.10 g, 11.40 mmol), and toluene (10 mL) was heated under reflux for 4 days. The mixture was concentrated, 1N KOH (11.4 mL) was added, and the mixture was extracted with CHCl3 (discarded). The aqueous phase was acidified to pH4-5 with 1N HCl and extracted with CHCl3. The extracts were dried and concentrated to give 94 mg of a yellow foam. Trituration with acetone and recrystallization from EtOH gave 46 mg (9%) of product as a white solid, mp 246°-247° C.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH2:7][NH:8][CH2:9][CH2:10][CH2:11][C:5]=2[CH:4]=[CH:3]1.[C:12]([C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N.[OH-].[Na+]>ClCCl>[C:12]([C:20]1[CH:21]=[CH:22][C:23]([C:24]([N:8]2[CH2:9][CH2:10][CH2:11][C:5]3[CH:4]=[CH:3][O:2][C:6]=3[CH2:7]2)=[O:25])=[CH:27][CH:28]=1)(=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: c1cc2c(o1)CNCCC2
Reactant: O=C(O)c1ccc(C(=O)c2ccccc2)cc1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccccc1)c1ccc(C(=O)N2CCCc3ccoc3C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.128 g of the above crude 5,6,7,8-tetrahydro-4H-furo[2,3-c]azepine hydrochloride, 0.21 g (0.94 mmol) of 4-benzoylbenzoic acid and 0.43 ml (3.1 mmol) of triethylamine in 30 ml of dichloromethane, 0.14 ml (0.94 mmol) of diethyl cyanophosphonate was added dropwise under ice-cooling, followed by overnight stirring at room temperature. The reaction mixture was poured into aqueous sodium hydroxide and extracted with dichloromethane 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=3/1 to 1/1) to yield the desired product.
Reaction SMILES: Br[C:2]1[O:3][C:4]2[C:24]([O:25][C:26](=[O:28])[CH3:27])=[C:23]([O:29][CH3:30])[CH:22]=[CH:21][C:5]=2[C:6]=1[C:7](=[O:20])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=1.[C-:31]#[N:32].[Na+]>CS(C)=O>[C:31]([C:2]1[O:3][C:4]2[C:24]([O:25][C:26](=[O:28])[CH3:27])=[C:23]([O:29][CH3:30])[CH:22]=[CH:21][C:5]=2[C:6]=1[C:7](=[O:20])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=1)#[N:32]
Reactant: [C-]#N
Reactant: COc1cc(C(=O)c2c(Br)oc3c(OC(C)=O)c(OC)ccc23)cc(OC)c1OC
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cc(C(=O)c2c(C#N)oc3c(OC(C)=O)c(OC)ccc23)cc(OC)c1OC
Reaction time: 3.5 h
Yield: 61.1 %

Procedure:
A mixture of 2-bromo-7-acetoxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxybenzofuran (25 mg, 0.05 mmol) and sodium cyanide (15 mg, 0.38 mmol) in dry DMSO (1 mL) under nitrogen at room temperature was stirred for 3.5 hours (monitored by tlc), quenched with saturated ammonium chloride solution and diluted with ethylacetate (20 mL). The organic layer was separated, dried over magnesium sulfate and the solvent distilled to afford the crude material which was purified over silica gel column (eluent—Hexane:diethyl-ether 1:1 to 0:100) to afford the desired product as pale cream solid (13 mg, 65%); 1H NMR (300 MHz, CDCl3) δ: 7.29 (d, 1H, J=8.71 Hz), 7.19 (s, 2H, benzoyl Hs), 6.06 (d, 1H, J=8.77 Hz), 5.82 (b, 1H, OH), 3.99 (s, 3H, OMe), 3.96 (s, 3H, OMe), 3.88 (s, 6H, 2×OMe).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:28]([NH:30]C(=O)OC(C)(C)C)([CH3:29])[C:27](=[O:38])[NH:26][C:4]=2[N:5]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][CH2:18][C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])[N:9]=2)[N:7]=1.FC(F)(F)C(O)=O>C(Cl)Cl.CCOC(C)=O>[NH2:1][C:2]1[C:3]2[C:28]([NH2:30])([CH3:29])[C:27](=[O:38])[NH:26][C:4]=2[N:5]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][CH2:18][C:19]([F:25])([F:24])[C:20]([F:21])([F:23])[F:22])[N:9]=2)[N:7]=1
Reactant: CC(C)(C)OC(=O)NC1(C)C(=O)Nc2nc(-c3nn(CCC(F)(F)C(F)(F)F)c4ncccc34)nc(N)c21
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC1(N)C(=O)Nc2nc(-c3nn(CCC(F)(F)C(F)(F)F)c4ncccc34)nc(N)c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The intermediate from Step A (111 mg, 0.205 mmol) was dissolved in DCM (2.0 mL) and trifluoroacetic acid (0.39 mL, 5.12 mmol). The solution was stirred overnight at room temperature. The reaction was then diluted with EtOAc and washed with 1N NaOH aq. (twice) and brine. The solution was then dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography using a MeOH/EtOAc gradient to give the indicated product. m/z=443.1 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30](=[O:33])[CH2:31]Br)[CH2:26][CH2:25]2)=[C:20](/[CH:34]=[CH:35]\[CH3:36])[CH:19]=1)([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:37]1[C:46]2[C:41](=[N:42][CH:43]=[C:44]([C:47]3([CH3:54])[NH:51][C:50](=[O:52])[NH:49][C:48]3=[O:53])[CH:45]=2)[O:40][CH2:39][CH2:38]1>>[CH2:1]([O:8][C:9]([C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30](=[O:33])[CH2:31][N:49]3[C:48](=[O:53])[C:47]([C:44]4[CH:45]=[C:46]5[O:37][CH2:38][CH2:39][O:40][C:41]5=[N:42][CH:43]=4)([CH3:54])[NH:51][C:50]3=[O:52])[CH2:26][CH2:25]2)=[C:20]([CH:34]=[CH:35][CH3:36])[CH:19]=1)([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(c2cnc3c(c2)OCCO3)NC(=O)NC1=O
Reactant: C/C=C\c1cc(C(OCc2ccccc2)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(C(=O)CBr)CC1
Product: CC=Cc1cc(C(OCc2ccccc2)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(C(=O)CN2C(=O)NC(C)(c3cnc4c(c3)OCCO4)C2=O)CC1

Procedure:
(Z)-1-(4-{4-[2-(benzyloxy)-1,1,1,3,3,3-hexafluoropropan-2-yl]-2-(prop-1-en-1-yl)phenyl}piperazin-1-yl)-2-bromoethanone and 5-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)-5-methylimidazolidine-2,4-dione were used for a similar reaction and treatment as Example 14-1, and the title compound was obtained as a yellow oil.
Reaction SMILES: C([N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]1[S:13][C:12]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][C:21](=[O:23])[CH3:22])[CH:15]=2)=[N:11][C:10]=1[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)C=C.C1([SiH3])C=CC=CC=1>ClCCl.C(O)(=O)C.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>[CH2:24]([C:10]1[N:11]=[C:12]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][C:21](=[O:23])[CH3:22])[CH:15]=2)[S:13][C:9]=1[C:5]1[NH:6][CH:7]=[CH:8][N:4]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: C=CCn1ccnc1-c1sc(-c2ccnc(NC(C)=O)c2)nc1Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [SiH3]c1ccccc1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(=O)Nc1cc(-c2nc(Cc3ccccc3)c(-c3ncc[nH]3)s2)ccn1
Temperature: 40 °C
Reaction time: 3 h
Yield: 52.7 %

Procedure:
To a solution of N-{4-[5-(1-allyl-1H-imidazol-2-yl)-4-benzyl-1,3-thiazol-2-yl]pyridin-2-yl}acetamide (0.210 g, 0.0505 mmol) in dichloromethane (0.38 mL) and acetic acid (0.13 mL) was added tetrakis(triphenylphosphine)palladium(0) (0.00292 g, 0.00253 mmol) followed by phenylsilane (0.0318 mL, 0.258 mmol). The solution was stirred at 40° C. for 3 hours. The solution was cooled to room temperature then concentrated in vacuo and diluted with ethyl acetate and saturated sodium bicarbonate solution. The layers were separated and the aqueous phase was extracted three more times with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography was performed to yield the title compound (0.0100 g, 53%). LCMS: (FA) ES+, 376. 1H NMR (400 MHz, d4-methanol) δ: 8.67-8.63 (m, 1H), 8.38-8.35 (m, 1H), 7.63-7.59 (m, 1H), 7.25-7.07 (m, 7H), 4.42 (s, 2H), 2.20 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]#[C:12][C:13]([OH:15])=[O:14])[CH:8]=[CH:9][CH:10]=1)=[O:4].[Br:16][C:17]1[C:22]([CH3:23])=[CH:21][C:20](O)=[CH:19][C:18]=1[CH3:25].C1CCC(N=C=NC2CCCCC2)CC1>CN(C)C1C=CN=CC=1.ClCCl>[Br:16][C:17]1[C:22]([CH3:23])=[CH:21][C:20]([O:14][C:13](=[O:15])[C:12]#[C:11][C:7]2[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=2)[C:3]([O:2][CH3:1])=[O:4])=[CH:19][C:18]=1[CH3:25]
Reactant: COC(=O)c1cccc(C#CC(=O)O)c1
Reactant: Cc1cc(O)cc(C)c1Br
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cccc(C#CC(=O)Oc2cc(C)c(Br)c(C)c2)c1
Yield: 49.1 %

Procedure:
To a stirring solution of 3-(3-methoxycarbonylphenyl)propiolic acid (9-2) (102 mg, 0.50 mmol), 4-bromo-3,5-dimethylphenol (103 mg, 0.51 mmol) and 4-(dimethylamino)pyridine (12 mg, 0.10 mmol) in dichloromethane (2 mL) was added a solution of DCC (114 mg, 0.55 mmol) in dichloromethane (1 mL) under ice-cooling. The mixture was stirred under ice-cooling for 30 min then stirred at room temperature for 18 h. The mixture was diluted with dichloromethane filtered through a pad of Celite. The filtrate was evaporated to dryness, which was chromatographed on a silica gel (dichloromethane:hexanes=2:3) to give title compound 9-3 (95 mg, 49% yield) as a white solid.