Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH:20]=1)[C:8]([N:10]=[S@@:11]([CH3:19])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])#[CH:2].I[C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1>>[CH3:19][S@:11](=[N:10][C:8]([C:7]1[CH:20]=[C:3]([C:1]#[C:2][C:22]2[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=2)[CH:4]=[N:5][CH:6]=1)=[O:9])(=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: C#Cc1cncc(C(=O)N=[S@@](C)(=O)c2ccccc2)c1
Reactant: O=C(O)c1ccc(I)cc1
Product: C[S@@](=O)(=NC(=O)c1cncc(C#Cc2ccc(C(=O)O)cc2)c1)c1ccccc1
Yield: 49 %

Procedure:
In a manner similar to that describe in Example 434, a mixture of (S)-5-ethynyl-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide and 4-iodobenzoic acid were reacted to give the title compound as a light yellow solid (30 mg, 49%).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:19][N:18]([C:20]3[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=3)[C:23]#[N:24])[C:17](=[O:28])[CH2:16]2)=[CH:11][C:10]=1[O:29][CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)C1C=CC=CC=1>CCO.CCOC(C)=O.[Pd]>[CH:30]1([O:29][C:10]2[CH:11]=[C:12]([CH:15]3[CH2:19][N:18]([C:20]4[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=4)[C:23]#[N:24])[C:17](=[O:28])[CH2:16]3)[CH:13]=[CH:14][C:9]=2[OH:8])[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: N#Cc1cccc(N2CC(c3ccc(OCc4ccccc4)c(OC4CCCC4)c3)CC2=O)c1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: N#Cc1cccc(N2CC(c3ccc(O)c(OC4CCCC4)c3)CC2=O)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 25.4 %

Procedure:
To benzonitrile 21 (1.7 g 3.8 mmol) in EtOH/EtOAc was added 200 mg of Pd—C and flushed with H2 three times. The mixture was stirred under H2 at r.t. for 72 h. The mixture was filtered through celite and the filtrate was concentrated. Extraction of the filtrate with EtOAc and washing with 2N HCl, sat. NaHCO3, sat. NaCl, followed by purification with silica gel gave 350 mg of the desired product. Yield: 26%.
Reaction SMILES: [N:1]12[CH2:7][C:4]([C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[OH:9])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.CC#N.[Br:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(OCC)(=O)C>[Br-:25].[OH:9][C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]12[CH2:7][N+:1]([CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([CH2:6][CH2:5]1)[CH2:2][CH2:3]2
Reactant: BrCCc1ccccc1
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)C2
Solvent: CCOC(C)=O
Solvent: CC#N
Product: OC(c1ccccc1)(c1ccccc1)C12CC[N+](CCc3ccccc3)(CC1)C2
Product: [Br-]
Temperature: 60 °C
Reaction time: 16 h
Yield: 71.9 %

Procedure:
To a solution of 1-azabicyclo[2.2.1]hept-4-yl(diphenyl)methanol (30.5 mg, 0.109 mmol) in 2 CH3CN/3 CHCl3 (2.5 mL) was added (2-bromoethyl)benzene (0.03 mL, 0.22 mmol). The solution was stirred at 60° C. for 16 h. The reaction was cooled down to room temperature. Trituration with ethyl acetate caused a solid to crash out of solution. This solid was filtered off, and washed with ethyl acetate to give the title compound (36.4 mg, 72%). EI-MS m/z 384 (M+) Rt (1.87 min).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([N+]([O-])=O)[CH:6]=1.[CH2:25]([P:27]([O:30]C)[O:28][CH3:29])[CH3:26]>C(#N)C>[CH2:25]([P:27]([C:7]1[CH:6]=[C:5]([O:4][C:3]2[CH:17]=[CH:18][C:19]([C:21]([F:24])([F:23])[F:22])=[CH:20][C:2]=2[Cl:1])[CH:10]=[CH:9][C:8]=1[N+:11]([O-:13])=[O:12])(=[O:30])[O:28][CH3:29])[CH3:26]
Reactant: CCP(OC)OC
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1[N+](=O)[O-]
Solvent: CC#N
Product: CCP(=O)(OC)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
Following the procedure of Example 1, 1.5 g (4.14 mmol) of 4-(2-chloro-4-trifluoromethylphenoxy)-1,2-dinitrobenzene, 0.81 g (6.6 mmol) of dimethyl ethylphosphonite and 3 ml of acetonitrile are reacted together to give methyl P-ethyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinate.
Reaction SMILES: [NH2:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C@@H:4]([OH:11])[CH2:3]1.[H-].[Na+].F[C:15]1[CH:16]=[CH:17][C:18]2[N:19]([C:21]([C@@H:24]3[CH2:28][CH2:27][CH2:26][N:25]3[CH3:29])=[N:22][N:23]=2)[CH:20]=1>CN(C=O)C.O>[CH3:29][N:25]1[CH2:26][CH2:27][CH2:28][C@H:24]1[C:21]1[N:19]2[CH:20]=[C:15]([O:11][C@@H:4]3[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[C@@H:2]([NH2:1])[CH2:3]3)[CH:16]=[CH:17][C:18]2=[N:23][N:22]=1
Reactant: CN1CCC[C@H]1c1nnc2ccc(F)cn12
Reactant: N[C@H]1C[C@H](O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCC[C@H]1c1nnc2ccc(O[C@H]3C[C@H](N)c4ccccc43)cn12
Temperature: 60 °C
Reaction time: 0.33 h

Procedure:
(1S,3S)-3-Amino-indan-1-ol (110 mg, 0.74 mmol) was added to a suspension of NaH (60% in mineral oil, 87 mg, 2.17 mmol) in anhydrous DMF (5 mL) at RT and stirred for 20 min. Intermediate 5b (160 mg, 0.72 mmol) was then added in one portion and the mixture heated at 60° C. for 3 h. After cooling the mixture was diluted with water (20 mL) and extracted with EtOAc (3×50 mL). The combined organics were washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by FCC, using 0-10% MeOH in DCM, to give the title compound as give a foam (132 mg, 52%). LCMS (Method 1): Rt 0.34 min, m/z 350 [MH+]. 1H NMR (300 MHz, CDCl3): 1.95-2.16 (6H, m), 2.24 (3H, s), 2.26-2.45 (2H, m), 2.77 (1H, ddd, J 14.1, 7.0, 2.0), 3.23-3.30 (1H, m), 4.02-4.09 (1H, m), 4.71 (1H, t, J 6.8), 5.68 (1H, dd, J 6.2, 1.9), 7.04 (1H, dd, J 9.9, 2.2), 7.29-7.50 (4H, m), 7.64 (1H, dd, J 9.9, 0.9), 8.35 (1H, d, J 2.2).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.[H-].[Na+].[Br:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[C:14](F)[CH:13]=1.O>C1COCC1>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[C:16]([NH:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH:17]=1
Reactant: Nc1ccnc(Cl)n1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1ccc(Br)cc1Nc1ccnc(Cl)n1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
To a solution of 2-chloropyrimidin-4-amine (8.83 g, 68.18 mmol) in THF (250 mL) at 0° C. was added sodium hydride (60% dispersion in oil, 4.36 g, 181.82 mmol) portionwise. The reaction mixture was stirred at 0° C. to RT for 10 minutes before addition of 4-bromo-2-fluoro-1-nitrobenzene (10 g, 45.45 mmol). The reaction mixture was stirred at 65° C. for 1 hr, then after cooling to RT, water was added resulting in formation of a yellow precipitate. The solid was collected by suction filtration and was washed with water. The filtrate was extracted with DCM. The organics were washed with water, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (Isolute column, 1% MeOH in DCM) then combined with the solid collected by suction filtration to give the title compound: 1HNMR (250 MHz, DMSO) δ 6.91 (1H, d, J=5.79 Hz), 7.61 (1H, dd, J=8.76, 2.21 Hz), 7.91-8.05 (2H, m), 8.29 (1H, d, J=5.79 Hz), 10.40 (1H, s); LC-MS: m/z=+328.9, 330.8 (M+H)+.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7](=[O:33])[C@H:8]([NH:22][C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[CH2:9][C:10]1[C:11]([CH2:20]O)=[C:12]2[C:16](=[C:17]([Cl:19])[CH:18]=1)[NH:15][N:14]=[CH:13]2>ClCCl>[CH3:5][O:6][C:7](=[O:33])[C@H:8]([NH:22][C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[CH2:9][C:10]1[C:11]([CH2:20][Cl:3])=[C:12]2[C:16](=[C:17]([Cl:19])[CH:18]=1)[NH:15][N:14]=[CH:13]2
Reactant: COC(=O)[C@@H](Cc1cc(Cl)c2[nH]ncc2c1CO)NC(=O)OCc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COC(=O)[C@@H](Cc1cc(Cl)c2[nH]ncc2c1CCl)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 86 %

Procedure:
Thionyl chloride (2 mL) was added to a solution of 2-(R)-benzyloxycarbonylamino-3-(7-chloro-4-hydroxymethyl-1H-indazol-5-yl)-propionic acid methyl ester (245 mg, 0.59 mmol) in dichloromethane (3 mL). Mixture was stirred at room temperature for 1.5 hours. Mixture was concentrated. Residue was dissolved in dichloromethane (15 mL) then washed with saturated aqueous sodium bicarbonate (2×10 mL). Organic was dried (magnesium sulfate), filtered and concentrated. Title compound was obtained as an orange solid in 86% yield. Material was carried forward without further purification. 1H NMR (300 MHz, CDCl3): δ=8.19 (s, 1H), 7.32 (m, 5H), 7.16 (s, 1H), 5.49 (d, J=7.3, 2H), 5.07 (d, J=4.4, 2H), 4.85 (s, 2H), 4.68 (d, J=7.0, 1H), 3.72 (s, 3H), 3.27 (m, 2H). MS m/e (M+H)+=436.1.
Reaction SMILES: CS(O[CH2:6][C@@H:7]1[C@@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:15]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@H:10]2[NH:11][C:12](=[O:14])[O:13][C@H:9]2[CH2:8]1)(=O)=O.[F-:33].C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C>[CH2:26]([O:25][C@@H:15]1[C@H:10]2[NH:11][C:12](=[O:14])[O:13][C@H:9]2[CH2:8][C@H:7]([CH2:6][F:33])[C@H:16]1[O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: [F-]
Reactant: CS(=O)(=O)OC[C@H]1C[C@@H]2OC(=O)N[C@@H]2[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Product: O=C1N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H](CF)C[C@@H]2O1
Yield: 43.2 %

Procedure:
To a solution of ((3aS,4R,5R,6R,7aS)-4,5-bis(benzyloxy)-2-oxooctahydrobenzo[d]oxazol-6-yl)methyl methanesulfonate (2.24 g, 4.86 mmol) in dry acetonitrile (12 mL) at room temperature was added a solution of tetrabutylammonium fluoride (4.933 g, 24.3 mmol) in dry acetonitrile (16 mL). The mixture was heated at reflux under N2 for 4 h. Solvent was evaporated under reduced pressure. The residue was dissolved in EtOAc (150 mL), washed with water (2×) and brine, and dried with MgSO4. The solvent was evaporated to give the crude product. This was purified by SiO2 column, eluted with 30-50% EtOAc in hexanes to give (3aS,4R,5R,6S,7aS)-4,5-bis(benzyloxy)-6-(fluoromethyl)hexahydrobenzo[d]oxazol-2(3H)-one (810 mg, 43%). MS m/z 408.1 (M+23, 100%); 1H NMR (400 MHz, CDCl3) δ 7.31-7.42 (m, 10H), 4.99 (s, 1H), 4.93 (d, J=11.7 Hz, 1H), 4.84 (d, J=11.0 Hz, 1H), 4.79 (dd, J=9.2 Hz, 3.2 Hz, 0.5H), 4.65-4.71 (m, 1.5H), 4.65 (d, J=11.1 Hz, 1H), 4.59 (d, J=11.7 Hz, 1H), 4.37 (ddd, J=47.4 Hz, 9.2 Hz, 2.3 Hz, 1H), 3.58 (t, J=6.8 Hz, 1H), 3.51 (t, J=7.8 Hz, 1H), 3.44 (t, J=8.9 Hz, 1H), 2.22 (dt, J=14.9 Hz, 2.9 Hz, 1H), 1.94-2.10 (m, 1H), 1.85-1.93 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](O)([CH2:11][CH3:12])[CH2:9][CH3:10])=[CH:4][CH:3]=1.[C:14]1([CH3:21])[C:19]([OH:20])=[CH:18][CH:17]=[CH:16][CH:15]=1.OS(O)(=O)=O>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:17]=[CH:18][C:19]([OH:20])=[C:14]([CH3:21])[CH:15]=2)([CH2:11][CH3:12])[CH2:9][CH3:10])=[CH:4][CH:3]=1
Reactant: CCC(O)(CC)c1ccc(Br)cc1
Reactant: Cc1ccccc1O
Agent: O=S(=O)(O)O
Solvent: O
Product: CCC(CC)(c1ccc(Br)cc1)c1ccc(O)c(C)c1
Temperature: 0 °C
Yield: 63 %

Procedure:
To a stirred suspension of 3-(4-bromophenyl)-pentan-3-ol (2.45 g, 10 mmol) and o-cresol 1.05 mL, 10.2 mmol) in H2O (1.0 mL) chilled to 0° C. was added conc H2SO4 (4.0 g) dropwise. After 1.5 h the reaction mixture was diluted with H2O (50 mL) and extracted with Et2O (2×50 mL). The combined extracts were washed with water, satd NaHCO3, and brine, then dried (anhyd Na2SO4) and concentrated under reduced pressure. The resulting crude product was chromatographed (silica, EtOAC/Hex, 0:100 to 10:90) to afford the title compound (2.1 g, 64% non-optimized) as a colorless liquid: 1H-NMR (CDCl3) δ 7.36 (2H, d, J=8.6), 7.05 (2H, d, J=8.6), 6.83-6.88 (2H, m), 6.67 (1H, d, J=8.1), 4.52 (1H, br s), 2.20 (3H, s), 2.04 (4H, q, J=7.3), 0.61 (6H, t, J=7.3).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[C:4]([CH:19]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([O:22]CC)=[O:21])[C:3]=1[CH3:30].[CH3:31][N:32]([CH2:34][C:35]#[CH:36])[CH3:33].C1COCC1.CCO>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.[Cu]I.O>[C:26]([O:25][CH:19]([C:4]1[C:3]([CH3:30])=[C:2]([C:36]#[C:35][CH2:34][N:32]([CH3:33])[CH3:31])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[C:20]([OH:22])=[O:21])([CH3:29])([CH3:27])[CH3:28]
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)c(Br)c2ccccc2c1-c1ccc(Cl)cc1
Reactant: C#CCN(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(C(OC(C)(C)C)C(=O)O)c(-c2ccc(Cl)cc2)c2ccccc2c1C#CCN(C)C
Temperature: 100 °C
Yield: 17.9 %

Procedure:
A solution of ethyl 2-(4-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate (40 mg, 81.7 μmol), N,N-dimethylpropargylamine (26 μL, 0.245 mmol), PdCl2(PPh3)2 (5.7 mg, 16.3 μmol), CuI (3.1 mg, 16.3 μmol) and THF (1.00 mL) was heated to 70° C. for 18 h in a sealed vessel. Conversion was incomplete, so the vessel was charged with more PdCl2(PPh3)2 (5.7 mg, 16.3 μmol) and CuI (3.1 mg, 16.3 μmol) and heated to 100° C. for an additional 26 h. The reaction was cooled to 23° C. THF (1.0 mL), EtOH (absolute, 500 μL), and H2O (500 μL) were added followed by LiOH monohydrate (100 mg, 2.37 mmol). The reaction was heated to 100° C. for 4 h. After cooling to 23° C., the crude reaction was filtered through a 0.45 micron filter, and directly purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H2O+0.1% TFA). The product-containing fractions were combined and lyophilized, giving the title compound (mono trifluoroacetic acid salt) (6.8 mg, 15%). 1H NMR (400 MHz, DMSO-d6) δ 12.92 (s, broad, 1H), 10.26 (s, broad, 1H), 8.30 (d, J=8.6 Hz, 1H), 7.71-7.62 (m, 3H), 7.47-7.43 (m, 2H), 7.34 (d, J=8.2 Hz, 1H), 7.22 (d, J=8.6 Hz, 1H), 5.03 (s, 1H), 4.56 (s, 2H), 2.96 (s, 6H), 2.72 (s, 3H), 0.90 (s, 9H). 19F NMR (377 MHz, DMSO-d6) δ−74.1 (s) LCMS-ESI+ (m/z): [M+H]+ calcd for C28H31ClNO3: 464.2; Found: 464.0.
Reaction SMILES: [CH3:1][C:2]([CH3:58])([CH2:10][C:11]([O:13][C@H:14]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@@H:16]([CH2:17][CH2:18][C@:19]3([CH3:55])[C@@H:28]2[CH2:27][CH2:26][C@H:25]2[C@@:20]3([CH3:54])[CH2:21][CH2:22][C@@:23]3(/[CH:40]=[CH:41]/[C:42]([NH:44][C@H:45]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=4[Cl:53])[CH3:46])=[O:43])[CH2:35][C:34](=[O:36])[C:33]([CH:37]([CH3:39])[CH3:38])=[C:24]32)[C:15]1([CH3:57])[CH3:56])=[O:12])[C:3]([O:5]C(C)(C)C)=[O:4].FC(F)(F)C(O)=O>ClCCl>[Cl:53][C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=1[C@@H:45]([NH:44][C:42](=[O:43])/[CH:41]=[CH:40]/[C@:23]12[CH2:35][C:34](=[O:36])[C:33]([CH:37]([CH3:39])[CH3:38])=[C:24]1[C@@H:25]1[C@@:20]([CH3:54])([CH2:21][CH2:22]2)[C@@:19]2([CH3:55])[C@@H:28]([C@:29]3([CH3:32])[C@@H:16]([CH2:17][CH2:18]2)[C:15]([CH3:56])([CH3:57])[C@@H:14]([O:13][C:11](=[O:12])[CH2:10][C:2]([CH3:1])([CH3:58])[C:3]([OH:5])=[O:4])[CH2:31][CH2:30]3)[CH2:27][CH2:26]1)[CH3:46]
Reactant: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)OC(C)(C)C)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)N[C@@H](C)c2ccccc2Cl)CC1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)N[C@@H](C)c2ccccc2Cl)CC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.3 %

Procedure:
To a solution of 1-tert-butyl 4-((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((E)-3-(((S)-1-(2-chlorophenyl)ethyl)amino)-3-oxoprop-1-en-1-yl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) 2,2-dimethylsuccinate (150 mg, 0.183 mmol), trifluoroacetic acid (1 mL, 12.98 mmol) in dichloromethane (4 mL) stirred at rt. The reaction mixture was stirred at rt for 2 h. The reaction mixture was evaporated and then purified by preparative-HPLC (Mobile Phase A: Water (0.05% TFA), B: ACN; Gradient 89-89% B in 0-7.5 min, stop at 12 min; Flow Rate (ml/min) 30.00; Retention Time (min) 7.0) to give the title compound (70 mg, 0.092 mmol, 50.1%) as a white solid. 1H NMR (400 MHz, METHANOL-d4) δ=7.43-7.32 (m, 2H), 7.32-7.18 (m, 2H), 6.81 (d, J=15.8 Hz, 1H), 6.01 (d, J=15.8 Hz, 1H), 5.41 (q, J=6.9 Hz, 1H), 4.48 (dd, J=5.1, 11.2 Hz, 1H), 3.30-3.24 (m, 1H), 2.94-2.81 (m, 1H), 2.72-2.49 (m, 2H), 2.30-0.75 (m, 50H); LC/MS: m/z calculated 761.4. Found 762.3 (M+1)+.
Reaction SMILES: F[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)=O.O.[NH2:22][NH2:23].CCOC(C)=O.Cl>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[C:3]3[C:2](=[C:7]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:5][CH:4]=3)[NH:23][N:22]=2)=[CH:15][CH:16]=1
Reactant: O=C(c1ccc(F)cc1)c1cccc(C(F)(F)F)c1F
Reactant: NN
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CCOC(C)=O
Product: Fc1ccc(-c2n[nH]c3c(C(F)(F)F)cccc23)cc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
(2-Fluoro-3-trifluoromethyl-phenyl)-(4-fluoro-phenyl)-methanone (6.58 g, 23 mmol) was dissolved in 20 ml of pyridine. Hydrazine hydrate (7.36 mL, 230 mmol) and 4-(dimethylamino)-pyridine (2.8 g, 23 mmol) were added. The reaction mixture was stirred overnight at 110° C. After cooling to room temperature, EtOAc and 2N HCl were added. The organic phase was washed three times with brine, dried over NaSO4 and concentrated under vacuum. Purification of the crude product by plug filtration (silica gel, CH2Cl2) provided 5.18 g product as a white solid.
Reaction SMILES: [CH:1]([Li])([CH3:3])[CH3:2].[CH:5]([O:8][B:9](OC(C)C)[O:10][CH:11]([CH3:13])[CH3:12])([CH3:7])[CH3:6]>>[CH:1]([B:9]([O:10][CH:11]([CH3:13])[CH3:12])[O:8][CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: [Li]C(C)C
Product: CC(C)OB(OC(C)C)C(C)C
Temperature: 80 °C

Procedure:
The title compound was prepared following the procedure of Example 1, from isopropyllithium (177 mL, 101 mmol) and triisopropoxyborane (19.0 g, 101 mmol). Solvent was removed at 0° C. and 15 mm Hg. The oil bath was heated to 80° C. Yield: 16.3 g (94.2 mmol, 93%), bp 138° C. (749 mm Hg); n20D 1.3853; proton NMR (CDCl3) δ4.40 (septet, J=18 Hz, 2H); 1.13 (d, J=18 Hz, 12H), 0.93 (bs, 7H); boron NMR (neat δ+30.5 ppm (s). Anal. Calcd. for C9H21BO2 : C, 62.80; H, 12.22; B, 6.29. Found: C, 62.59; H, 12.59; B, 5.93.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[CH2:8]([N:10]([CH2:13][CH3:14])[CH2:11]C)[CH3:9].CN(C=[O:19])C>>[CH2:8]([N:10]([CH2:13][CH3:14])[C:11]([N:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1)=[O:19])[CH3:9]
Reactant: O=C1CCNCC1
Reactant: CN(C)C=O
Reactant: CCN(CC)CC
Product: CCN(CC)C(=O)N1CCC(=O)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of piperidin-4-one in DMF was added triethylamine (1.5 eq.) N,N-diethylacetamide chloride (1.5 eq.). The resulting solution was stirred at room temperature for 5 hours or until completion observed by TLC. The solvent was evaporated and the residue was partitioned in H2O and EtOAc. The aqueous layer was extracted with EtOAc and the combined organic layers were dried over Na2SO4 and concentrated. The crude product was purified by a CombiFlash chromatography system using silica gel cartridge and CH2Cl2/MeOH gradient eluent to afford 4-oxo-piperidine-1-carboxylic acid diethylamide, which was subsequently reacted with 3-hydroxybenzaldehyde (2.5 eq.) in acetic acid (99.7%) and purged with HCl gas (0.5-1 h). After stirring at room temperature for 3 hours, the solvent was evaporated and the crude was purified by a Combiflash chromatography system with hexanes/EtOAc as eluent, followed by crystallization from MeOH, to afford Compound 12 as a yellow crystalline solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][C:6]1=[O:10].[CH2:11]([O:13][C:14]([C:16]1[C:17](=[O:39])[C:18]2[CH:23]=[N:22][C:21](S(C)(=O)=O)=[N:20][C:19]=2[N:28]([C:30]2[CH:31]=[C:32]3[C:36](=[CH:37][CH:38]=2)[CH2:35][CH2:34][CH2:33]3)[CH:29]=1)=[O:15])[CH3:12]>>[CH2:11]([O:13][C:14]([C:16]1[C:17](=[O:39])[C:18]2[CH:23]=[N:22][C:21]([NH:1][CH2:2][CH2:3][CH2:4][N:5]3[CH2:9][CH2:8][CH2:7][C:6]3=[O:10])=[N:20][C:19]=2[N:28]([C:30]2[CH:31]=[C:32]3[C:36](=[CH:37][CH:38]=2)[CH2:35][CH2:34][CH2:33]3)[CH:29]=1)=[O:15])[CH3:12]
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(S(C)(=O)=O)ncc2c1=O
Reactant: NCCCN1CCCC1=O
Product: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(NCCCN3CCCC3=O)ncc2c1=O

Procedure:
Using the procedure outlined in Example 1 Step F, the title compound was prepared from 1-(3-amino-propyl)-pyrrolidin-2-one and 8-indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 1(Step E) 25 mg, 0.052 mmol). 17 mg of 8-Indan-5-yl-5-oxo-2-[3-(2-oxo-pyrrolidin-1-yl)-propylamino]-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester was obtained as a white solid. 1H NMR (400 MHz, CDCl3) δ (ppm): 9.25 (s, 1H), 8.46 (s, 1H), 7.33 (d, J=7.7 Hz, 1H), 7.23 (s, 1H), 7.16 (d, J=7.7 Hz, 1H), 6.26 (br, 1H), 4.37 (q, J=7.3 Hz, 2H), 3.36 (m, 2H), 3.27 (m, 2H), 3.00 (m, 4H), 2.37 (t, J=7.9 Hz, 2H), 2.18 (m, 2H), 2.00 (m, 2H), 1.60 (m, 4H), 1.38 (t, J=7.3 Hz).
Reaction SMILES: [CH2:1]([S:3][CH2:4][CH2:5][C:6](Cl)=[O:7])[CH3:2].[NH2:9][CH2:10][C:11]([N:13]1[CH2:19][C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[O:16][C:15]2[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:14]1=2)=[O:12].C(N(CC)CC)C>C(Cl)Cl>[Cl:28][C:26]1[CH:25]=[CH:24][C:15]2[O:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[CH2:19][N:13]([C:11](=[O:12])[CH2:10][NH:9][C:6](=[O:7])[CH2:5][CH2:4][S:3][CH2:1][CH3:2])[C:14]=2[CH:27]=1
Reactant: CCSCCC(=O)Cl
Reactant: NCC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCSCCC(=O)NCC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reaction time: 3 h

Procedure:
A solution of 3-(ethylthio)propanoyl chloride (0.87 grams) in methylene chloride (10 mL) was added dropwise to a stirred solution of 10-(aminoacetyl)-8- chloro-10,11-dihydrodibenz-[b,f][1,4]oxazepine (1.50 grams) and triethylamine (0.84 mL) in methylene chloride (40 mL) in an ice bath at 5° C. under nitrogen. The ice bath was removed, and the reaction was stirred for 3 hours. The reaction was diluted with methylene chloride (50 mL) and washed with 50 mL each of 1N HCl, saturated aqueous sodium bicarbonate, and brine. The solution was then dried over MgSO4 and evaporated in vacuo. The yield of the title compound was 1.90 grams (90%). Mp: 148°-151° C.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:17]3[C:18]4[CH:33]=[CH:32][CH:31]=[CH:30][C:19]=4[S:20][C:21]=3[C:22]3[CH:27]=[CH:26][C:25]([O:28]C)=[CH:24][CH:23]=3)=[O:16])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.N1C=CC=CC=1.CCOC(C)=O>O>[N:1]1([CH2:6][CH2:7][CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]([C:17]3[C:18]4[CH:33]=[CH:32][CH:31]=[CH:30][C:19]=4[S:20][C:21]=3[C:22]3[CH:23]=[CH:24][C:25]([OH:28])=[CH:26][CH:27]=3)=[O:16])=[CH:13][CH:14]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(-c2sc3ccccc3c2C(=O)c2ccc(CCCN3CCCC3)cc2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: O=C(c1ccc(CCCN2CCCC2)cc1)c1c(-c2ccc(O)cc2)sc2ccccc12
Temperature: 160 °C
Reaction time: 16 h
Yield: 111.5 %

Procedure:
A 100 mL round bottom flask containing 300 mg (0.66 mmol) of 2-(4-methoxyphenyl)benzo[b]thiophen-3-yl 4-[3-(1-pyrrolidinyl)propyl]phenyl ketone (Part A) was filled with 20 g of pyridine hydrochloride. The flask was heated to 160° C. to melt the solid. After 16 h, the reaction was cooled to warm temperature, diluted with 50 mL of H2O, and transferred to separatory funnel containing 50 mL H2O and 50 mL of EtOAc. The two layers were separated and the aqueous layer was extracted with EtOAc (2×50 mL). The combined EtOAc layers were dried over Na2SO4 and concentrated in vacuo to give 325 mg of a yellow oil. Purification by radial chromatography (SiO2; gradient of 2-10% MeOH in CH2Cl2) afforded 200 mg (0.45 mmol; 69%) of the title compound as a viscous yellow oil.