Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:9]1[CH:13]=[CH:12][N:11]=[C:10]1[CH:14]=O.O>C1(C)C=CC=CC=1>[CH2:1]([NH:8][CH2:14][C:10]1[S:9][CH:13]=[CH:12][N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1nccs1
Reactant: NCc1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc(CNCc2nccs2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.9 %

Procedure:
A stirred solution of N-benzylamine (0.56 mL, 5.1 mmol) and 2-thiazolecarboxaldehyde (0.55 g, 4.9 mmol) in toluene was heated to reflux for 2 hours with azeotropic removal of water. The solution was cooled to room temperature and concentrated to an oil. This oil was dissolved in 15 mL of ethanol and treated with excess NaBH4 and the mixture stirred overnight. Acetone was added and the mixture stirred 30 minutes and concentrated to a soild mass. This mass was partitioned between 2N aqueous NaOH and 2 portions of ethyl ether. The combined ethereal extracts were washed with water, brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by flash column chromatography on silica gel to provide 0.59 g (57%) of the title compound.
Reaction SMILES: [CH2:1]([N:4]([CH2:18][CH2:19][CH3:20])[CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[C:15](Cl)=[O:16])[O:7][CH2:6]1)[CH2:2][CH3:3].[CH2:21](N(CCC)C1CC2C(=CC=CC=2C(OC)=O)OC1)CC.[Li]C>O1CCCC1.[Cu]I>[CH2:1]([N:4]([CH2:18][CH2:19][CH3:20])[CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[C:15](=[O:16])[CH3:21])[O:7][CH2:6]1)[CH2:2][CH3:3]
Reactant: CCCN(CCC)C1COc2cccc(C(=O)OC)c2C1
Reactant: CCCN(CCC)C1COc2cccc(C(=O)Cl)c2C1
Agent: [Cu]I
Agent: [Li]C
Solvent: C1CCOC1
Product: CCCN(CCC)C1COc2cccc(C(C)=O)c2C1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
3-Dipropylamino-5-chloroformylchroman*HCl (4.42 g, 13.4 mmol), prepared from 3-dipropylamino-5-methyloxycarbonylchroman (Example 2) analogous to the procedure used in Example 3, in dry tetrahydrofuran (20 ml), was added to a pre-formed solution of lithium dimethylcuprate; prepared from MeLi and CuI, in 200 mL tetrahydrofuran at -78° C. The solution was stirred for 15 minutes at -78° C. and was then allowed to reach room temperature during 10 minutes. Then, 30 mL H20 was slowly added. The organic phase was decanted, dried with Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography (silica gel) by elution with ethyl acetate/hexane 1:8. The title compound was crystallized as salt from ethyl acetate. Mp 106°-108° C. (oxalate).
Reaction SMILES: N(C[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10])=[N+]=[N-].F[C:12](F)(F)S(O[Si](C)(C)C)(=O)=[O:14].[C:23](#N)[CH3:24]>>[C:23]([O:10][CH2:9][CH3:8])(=[O:14])[CH3:24].[CH3:9][CH2:8][CH2:7][CH:6]([CH3:5])[CH3:12]
Reactant: [N-]=[N+]=NCCCCCCO
Reactant: CC#N
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Product: CCCC(C)C
Product: CCOC(C)=O
Yield: 55 %

Procedure:
Compound 25] and 6-azidohexanol (0.017-0.44 g, 0.12-3.1 mmol) are dissolved in dry acetonitrile and, at 0° C., 4 Å molecular sieves (0.06-1.5 g) and trimethylsilyl trifluoromethanesulfonate (0.001-1.4 g, 0.005-5.1 mmol) are added. After the reaction is complete, the mixture is filtered and washed with saturated sodium bicarbonate solution. Concentration results in the crude product which is purified by chromatography on silica gel with an ethyl acetate/isohexane gradient (0.021-0.51 g, 0.01-0.27 mmol, about 55% yield). It is subsequently taken up in methanol/hydrazine hydrate (1:1) (1-30 ml) and heated at 80° C. until reaction is complete. After evaporation of the solvent, the crude product is taken up in dichloromethane/methanol (1:1) and stirred at 0° C. with acetic anhydride (0.03-4.1 mmol) until the reaction is complete. Evaporation is followed by reduction of the azide with hydrogen in the presence of catalytic amounts of palladium on carbon (10%) (0.001-0.15 g) in methanol (1-45 ml). The crude product compound [26] obtained after evaporation is purified by gel chromatography on Biogel P2 (0.0064-0.17 g, 0.007-0.18 mmol, about 65% yield). FAB-MS: M+H+ =920. 1H-NMR [300 MHz, D2O]: 4.92 (Fuc-H-1), 4.36 (GlcNAc-H-1), 4.28 (Gal-H-1), 4.1-3.35 (m), 3.29 (CH2 --NH3+OAc-), 2.19 (NANA-H-3eq.), 1.93 (NANA-NCOCH3), 1.81 (GlcNCOCH3), 1.77 (NANA-H-3ax.), 1.58-1.18 (O--(CH2)5 --CH2 --NH3+OAc-), 0.99 (Fuc-CH3) ppm.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6]([N:8]2[CH2:13][CH2:12][N:11]3[N:14]=[C:15]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[C:22]([Cl:27])[CH:21]=4)[C:16]([C:17]([NH2:19])=[O:18])=[C:10]3[CH2:9]2)=[O:7])[CH2:2]1.CCN(C(C)C)C(C)C.FC(F)(F)S(O[CH2:43][C:44]([F:47])([F:46])[F:45])(=O)=O>C1COCC1>[Cl:27][C:22]1[CH:21]=[C:20]([C:15]2[C:16]([C:17]([NH2:19])=[O:18])=[C:10]3[CH2:9][N:8]([C:6]([NH:5][CH:3]4[CH2:2][N:1]([CH2:43][C:44]([F:47])([F:46])[F:45])[CH2:4]4)=[O:7])[CH2:13][CH2:12][N:11]3[N:14]=2)[CH:25]=[CH:24][C:23]=1[F:26]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: NC(=O)c1c(-c2ccc(F)c(Cl)c2)nn2c1CN(C(=O)NC1CNC1)CC2
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1c(-c2ccc(F)c(Cl)c2)nn2c1CN(C(=O)NC1CN(CC(F)(F)F)C1)CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 12.4 %

Procedure:
To a stirred solution of Intermediate 339B (100 mg, 0.255 mmol) in THF (10 mL) was added DIPEA (0.222 mL, 1.273 mmol) followed by 2,2,2-trifluoroethyl trifluoromethanesulfonate (118 mg, 0.509 mmol) and stirred at RT for 16 h. The reaction mixture was quenched with a 10% aqueous solution of NaHCO3 and extracted with EtOAc (2×20 mL) The combined organic layer was dried over Na2SO4, filtered and the filtrate evaporated. The crude compound was purified by preparative HPLC to afford Compound 339 as an off-white solid (15 mg, 12%). HPLC retention times 10.73 min. and 11.90 min (Methods C and D). MS(ES): m/z=475 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ ppm 7.84 (dd, J=7.37, 2.08 Hz, 1H), 7.62-7.72 (m, 1H), 7.41-7.50 (m, 1H), 7.36 (br. s., 1H), 7.27 (d, J=6.80 Hz, 1H), 7.18 (br. s., 1H), 4.73 (s, 2H) 4.19-4.31 (m, 1H), 4.06-4.17 (m, 2H), 3.84 (d, J=5.67 Hz, 2H), 3.57-3.69 (m, 2H), 3.09-3.23 (m, 4H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3](OS(C(F)(F)F)(=O)=O)=[CH:2]1.C(N(CC)CC)C.[CH3:25][C:26]1([CH3:33])[C:30]([CH3:32])([CH3:31])[O:29][BH:28][O:27]1.C(Cl)Cl>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:25][C:26]1([CH3:33])[C:30]([CH3:32])([CH3:31])[O:29][B:28]([C:3]2[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[O:1][CH:2]=2)[O:27]1
Reactant: CC1(C)OBOC1(C)C
Reactant: O=S(=O)(Oc1coc2ccccc12)C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1(C)OB(c2coc3ccccc23)OC1(C)C
Temperature: 150 °C

Procedure:
To a solution of trifluoromethanesulfonic acid benzofuran-3-yl ester (half of the amount from step A) in THF is added triethylamine (732 mg, 7.23 mmol), 4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (3.2 mL of a 1.0M in THF, 3.2 mmol) and Pd(dppf)Cl2.CH2Cl2 (76 mg, 0.096 mmol). The mixture is heated at 150° C. under microwave conditions for 3 min. The mixture is filtered and the filtrate evaporated under reduced pressure. The residual oil is purified by flash chromatography using hexane/EtOAc (9:1) as eluent to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[CH:5][C:4]=1[CH2:15][CH2:16][CH2:17]I.[C-:19]#[N:20].[Na+].O>CS(C)=O>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[CH:5][C:4]=1[CH2:15][CH2:16][CH2:17][C:19]#[N:20]
Reactant: COc1cc(CCCI)c(OC)c2ccccc12
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(CCCC#N)c(OC)c2ccccc12
Yield: 92.3 %

Procedure:
A solution of 5.08 g of 3-(1,4-dimethoxy-2-naphthyl)propyl iodide (prepared as described in Preparation 30), and 0.70 g of sodium cyanide in 60 ml of dry dimethyl sulfoxide was stirred at 60° C. (external temperature) for 80 minutes. At the end of this time, the reaction mixture was cooled and poured into water, after which it was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 4:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 3.36 g of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:20][CH2:21][CH2:22][CH2:23][NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[C:4]2[C:9]([CH3:10])=[C:8]([CH3:11])[N:7]=[C:6](OC3C=CC=CC=3)[C:5]=2[N:19]=1.C([O-])(=O)C.[NH4+:33].Cl>C(Cl)(Cl)Cl.CO.C(OCC)C>[NH2:33][C:6]1[C:5]2[N:19]=[C:2]([CH3:1])[N:3]([CH2:20][CH2:21][CH2:22][CH2:23][NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[C:4]=2[C:9]([CH3:10])=[C:8]([CH3:11])[N:7]=1
Reactant: [NH4+]
Reactant: Cc1nc(Oc2ccccc2)c2nc(C)n(CCCCNS(C)(=O)=O)c2c1C
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CO
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: Cc1nc(N)c2nc(C)n(CCCCNS(C)(=O)=O)c2c1C
Temperature: 150 °C
Yield: 59.1 %

Procedure:
N-[4-(2,6,7-trimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl)butyl]methanesulfonamide (4.20 g, 10.4 mmol) and ammonium acetate (42 g) were combined and then heated in a sealed tube at 150° C. for 36 hrs. The reaction mixture was allowed to cool and then it was dissolved in chloroform. The solution was extracted with 10% aqueous sodium hydroxide solution. The aqueous layer was separated and then extracted multiple times with chloroform. The organic layers were combined, dried over magnesium sulfate and then concentrated under reduced pressure to provide a yellow oil. The oil was dissolved in methanol and combined with 1M hydrochloric acid in diethyl ether (10.4 mL). The resulting white precipitate was isolated by filtration and dried. The solid was dissolved in water and the solution was adjusted to pH 10 with solid sodium carbonate. The resulting white precipitate was isolated by filtration, washed with diethyl ether and then dried in a vacuum oven at 80° C. to provide 2.00 g of N-[4-(4-amino-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-1-yl)butyl]methanesulfonamide, m.p. 228-230° C. Analysis: Calculated for C14H23N5O2S: % C, 51.67; % H, 7.12; % N, 21.52; Found: % C, 51.48; % H, 6.95; % N, 21.51.
Reaction SMILES: [N:1]1([C:7]2[N:12]3[N:13]=[C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH:15]=[C:11]3[N:10]=[C:9]([NH:22][NH2:23])[CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:24][C:25]1([CH3:34])[CH2:29][C:28]2[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=2[O:26]1.[C:35](O)(=O)C.O>C(O)C>[CH3:24][C:25]1([CH3:34])[CH2:29][C:28]2[CH:30]=[CH:31][CH:32]=[C:33]([CH:35]=[N:23][NH:22][C:9]3[CH:8]=[C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[N:12]4[N:13]=[C:14]([C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)[CH:15]=[C:11]4[N:10]=3)[C:27]=2[O:26]1
Reactant: CC(=O)O
Reactant: NNc1cc(N2CCOCC2)n2nc(-c3ccccc3)cc2n1
Reactant: CC1(C)Cc2ccccc2O1
Solvent: O
Solvent: CCO
Product: CC1(C)Cc2cccc(C=NNc3cc(N4CCOCC4)n4nc(-c5ccccc5)cc4n3)c2O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
To a solution of 7-morpholin-4-yl-2-phenyl-pyrazolo[1,5-a]pyrimidin-5-yl-hydrazine (20 mg, 0.065 mM) in absolute ethanol (2.0 mL), there were added 2,2-dimethyl-2,3-dihydro-benzofuran (17 mg, 0.097 mM) and acetic acid (2.0 μL) and the mixture was stirred at room temperature for 3 hours. Water was added to the mixture, the mixture was then extracted with ethyl acetate and then the resulting organic phase was washed with a saturated aqueous common salt solution. After the drying of the organic phase over anhydrous magnesium sulfate, the organic phase was concentrated under reduced pressure. The resulting residue was purified by the NH-silica gel column chromatography (ethyl acetate:hexane=1:2) to thus give the title compound (18 mg, yield: 60%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:13]([NH:14][C:15](=[O:31])[CH2:16][C:17](=O)[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[CH:19]=2)=[CH:12][C:11]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[F:38])=[C:10]([N:39]([CH3:41])[CH3:40])[CH:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:40][N:39]([CH3:41])[C:10]1[C:11]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[F:38])=[CH:12][C:13]2[NH:14][C:15](=[O:31])[CH2:16][C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)[CH:19]=3)=[N:7][C:8]=2[CH:9]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccncc3)c2)cc1-c1ccccc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)c1cc2c(cc1-c1ccccc1F)NC(=O)CC(c1cccc(-c3ccncc3)c1)=N2

Procedure:
The title compound was prepared from {2-dimethylamino-2′-fluoro-5-(3-oxo-3-(3-pyridin-4-yl-phenyl)-propionylamino]-biphenyl-4-yl}-carbamic acid tert-butyl ester (Example M35) (302 mg, 0.531 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (208 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([O:11][CH2:12][CH2:13][N:7]3[CH:6]3[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18][CH:5]23)[CH:10]=1.[CH3:26][O:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1.C>>[CH3:26][O:27][C:28]1[CH:33]=[C:32]([C:2]2[CH:3]=[C:4]3[C:8]4=[C:9]([O:11][CH2:12][CH2:13][N:7]4[CH:6]4[CH2:14][CH2:15][NH:16][CH2:17][CH2:18][CH:5]34)[CH:10]=2)[CH:31]=[CH:30][CH:29]=1.[CH3:26][O:27][C:28]1[CH:33]=[C:32]([C:2]2[CH:3]=[C:4]3[C:8]4=[C:9]([O:11][CH2:12][CH2:13][N:7]4[CH:6]4[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:17][CH2:18][CH:5]34)[CH:10]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: CC(C)(C)OC(=O)N1CCC2c3cc(Br)cc4c3N(CCO4)C2CC1
Agent: C
Product: COc1cccc(-c2cc3c4c(c2)C2CCN(C(=O)OC(C)(C)C)CCC2N4CCO3)c1
Product: COc1cccc(-c2cc3c4c(c2)C2CCNCCC2N4CCO3)c1
Yield: 139.7 %

Procedure:
Tert-butyl 5-(3-methoxyphenyl)-1,2,6b,7,8,10,11,11a-octahydro-9H-azepino[4,5-b][1,4]oxazino[2,3,4-hi]indole-9-carboxylate (502 mg, 70%) was prepared via coupling of tert-butyl 5-bromo-1,2,6b,7,8,10,11,11a-octahydro-9H-azepino[4,5-b][1,4]oxazino[2,3,4-hi]indole-9-carboxylate (671 mg, 1.64 mmol) with 3-methoxyphenyl boronic acid (374 mg, 2.46 mmol) as illustrated by the general procedure described in Example 534 Step C. CIMS (Methane) m/z=437 [MH]+. The corresponding hydrochloride salt of the title compound was formed from tert-butyl 5-(3-methoxyphenyl)-1,2,6b,7,8,10,11,11a-octahydro-9H-azepino[4,5-b][1,4]oxazino[2,3,4-hi]indole-9-carboxylate (500 mg) using the procedure described in Example 534 Step D. Then, this salt was free-based using 6 N NaOH, to give the title compound (395 mg, 99%). 1H NMR (CDCl3, 500 MHz) δ1.80-2.30 (m, 4H), 2.75-2.98 (m, 3H), 3.00-3.12 (m, 1H), 3.13-3.29 (m, 2H), 3.43-3.53 (m, 1H), 3.63-3.78 (m, 1H), 3.85 (s, 3H), 4.11 (brs, 1H), 4.41 (brs, 2H), 6.82 (dd, 1H, J=0.8, 8.3 Hz), 6.88 (s, 1H), 6.90 (s, 1H), 7.02 (s, 1H), 7.10 (d, 1H, J=8.3 Hz), 7.30 (t, 1H, J=8.3 Hz) ppm. CIMS (Methane) m/z=337 [MH]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:29][C:30]2[C:35]([C:36]3[CH:41]=[CH:40][N:39]=[N:38][CH:37]=3)=[CH:34][C:33]([C:42]3[CH:47]=[CH:46][CH:45]=[C:44]([C:48]([F:51])([F:50])[F:49])[CH:43]=3)=[C:32]([Cl:52])[CH:31]=2)=[CH:4][C:5]([F:28])=[C:6]([S:8]([N:11](CC2C=CC(OC)=CC=2OC)[C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:10])=[O:9])[CH:7]=1.FC(F)(F)C(O)=O.CO>ClCCl>[Cl:1][C:2]1[C:3]([O:29][C:30]2[C:35]([C:36]3[CH:41]=[CH:40][N:39]=[N:38][CH:37]=3)=[CH:34][C:33]([C:42]3[CH:47]=[CH:46][CH:45]=[C:44]([C:48]([F:51])([F:49])[F:50])[CH:43]=3)=[C:32]([Cl:52])[CH:31]=2)=[CH:4][C:5]([F:28])=[C:6]([S:8]([NH:11][C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Oc3cc(Cl)c(-c4cccc(C(F)(F)F)c4)cc3-c3ccnnc3)cc2F)c(OC)c1
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1nncs1)c1cc(Cl)c(Oc2cc(Cl)c(-c3cccc(C(F)(F)F)c3)cc2-c2ccnnc2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 24.2 %

Procedure:
5-Chloro-4-(2-chloro-5-(pyridazin-4-yl)-3′-(trifluoromethyl)biphenyl-4-yloxy)-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide (Preparation 53, 231 mg, 0.29 mmol) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (1 mL) added. The resulting solution was stirred at room temperature for 18 hours. Methanol (2 mL) was added and the reaction was stirred for 10 minutes. The resulting mixture was evaporated and azeotroped with methanol (2×10 mL). The residue was partitioned between ethyl acetate (50 mL) and water (20 mL). The ethyl acetate was separated and dried over MgSO4 and evaporated. The residue was chromatographed on silica eluting with dichloromethane:methanol:acetic acid 100:0:0 to 95:5:0.5 in 1% stages of methanol. The column product was stirred in dichloromethane (10 mL) for 20 minutes, the solid filtered off, and stirred in dichloromethane (5 mL) at reflux for 10 minutes. The solid was filtered to give the title compound (45 mg, 25%) as a white solid.
Reaction SMILES: [O:1]=[S:2]1(=[O:20])[C:6]2[CH:7]=[C:8]([NH:11][C:12](=[O:19])OCC(Cl)(Cl)Cl)[CH:9]=[CH:10][C:5]=2[CH:4]=[CH:3]1.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26]1[N:30]=[C:29]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[S:28][N:27]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[O:20]=[S:2]1(=[O:1])[C:6]2[CH:7]=[C:8]([NH:11][C:12]([N:34]3[CH2:33][CH2:32][N:31]([C:29]4[S:28][N:27]=[C:26]([C:22]5[S:21][CH:25]=[CH:24][CH:23]=5)[N:30]=4)[CH2:36][CH2:35]3)=[O:19])[CH:9]=[CH:10][C:5]=2[CH:4]=[CH:3]1
Reactant: O=C(Nc1ccc2c(c1)S(=O)(=O)C=C2)OCC(Cl)(Cl)Cl
Reactant: c1csc(-c2nsc(N3CCNCC3)n2)c1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=C(Nc1ccc2c(c1)S(=O)(=O)C=C2)N1CCN(c2nc(-c3cccs3)ns2)CC1

Procedure:
A mixed solution of 2,2,2-trichloroethyl (1,1-dioxido-1-benzothien-6-yl)carbamate (257 mg, 0.720 mmol), 1-[3-(2-thienyl)-1,2,4-thiadiazol-5-yl]piperazine (200 mg, 0.792 mmol) and diisopropylethylamine (0.129 ml, 0.720 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 70° C. for 3 hours. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Chloroform was added to the residue, and 69.6 mg (21.0%) of the desired product as a solid was separated by filtration.
Reaction SMILES: CC1[CH2:7][CH2:6][CH2:5][N:4]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]1=[O:15].I[CH2:17][CH3:18].[CH:19]([N-]C(C)C)(C)[CH3:20].[Li+].CN(P(N(C)C)(N(C)C)=O)C>C1COCC1>[CH2:19]([C:17]1([CH3:18])[CH2:7][CH2:6][CH2:5][N:4]([CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:3]1=[O:15])[CH3:20]
Reactant: CCI
Reactant: CC1CCCN(Cc2ccccc2)C1=O
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CCC1(C)CCCN(Cc2ccccc2)C1=O

Procedure:
The reaction of 3-methyl-1-phenylmethyl-2-piperidinone (Meyers A I, Kunnen K B, Still W C (1987) "Conformational effects on the regiochemical metalation of C5-C13 N-benzyl lactams" J. Am. Chem. Soc., 109, 4405-4407.) (3.25 g, 16 mmol) with iodoethane (3.92 g, 25.1 mmol) in the presence of lithium diisopropylamide (prepared by treating diisopropylamine (2.42 g, 24 mmol) with butyllithium in hexanes (2.5M, 9.2 mL, 22.9 mmol)) in THF (45 mL) and HMPA (2.4 mL, 13.8 mmol) as described above in the preparation of Example 10, gave 5.90 g of pale yellow colored oil. Column chromatography over silica gel (hexanes-EtOAc, 9:1) afforded the product lactam (2.52 g, 68%) as a colorless viscous liquid. Analytical sample was prepared by bulb-to-bulb distillation (pot temp. 110°-115° C. (1 mmHg)).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C@@:9]12[C:15]([CH3:17])([CH3:16])[C@@H:12]([CH2:13][CH2:14]1)[CH:11]([C:18](Cl)=[O:19])[C:10]2=[O:21].[C:22]([O:26][C:27]([NH:29][NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[F:37])=[O:28])([CH3:25])([CH3:24])[CH3:23].O>ClCCl>[C:22]([O:26][C:27]([NH:29][N:30]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[F:37])[C:18]([CH:11]1[C:10](=[O:21])[C@:9]2([CH3:8])[C:15]([CH3:17])([CH3:16])[C@H:12]1[CH2:13][CH2:14]2)=[O:19])=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)NNc1ccccc1F
Reactant: CC1(C)[C@H]2CC[C@]1(C)C(=O)C2C(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NN(C(=O)C1C(=O)[C@@]2(C)CC[C@@H]1C2(C)C)c1ccccc1F
Temperature: 25 °C
Reaction time: 0.05 h

Procedure:
Triethylamine (3 mL, 21.5 mmol) was added dropwise to a cooled (0° C.) solution of (1S,4S)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl chloride (Intermediate 25; 1.50 g, 7.0 mmol) in dichloromethane (18 mL), yielding a thick suspension. This was stirred for 3 min and then N′-(2-fluoro-phenyl)-hydrazinecarboxylic acid tert-butyl ester (Intermediate 29; 1.20 g, 5.3 mmol) was added in one portion. The reaction mixture was allowed to warm to room temperature and stir for 2.5 h. The mixture was added to water (50 mL) and extracted with dichloromethane (3×40 mL). The combined organic layers were washed with brine (30 mL), dried (magnesium sulfate), filtered, evaporated, and dried under high vacuum at room temperature for 30 min to give N′-(2-fluoro-phenyl)-N′-((1S,4S)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl)-hydrazinecarboxylic acid tert-butyl ester (2.67 g, 124% of the expected amount) as an orange foam. This was used directly in the next step without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2([C:19]([NH2:21])=[O:20])[CH2:18][CH2:17]2)[C:5]([Cl:22])=[CH:4][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[NH2:29][C:30]1[CH:31]=[N:32][N:33]([CH:35]2[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:36]2)[CH:34]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1>[C:19]([C:16]1([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][CH2:8][C:6]2[C:5]([Cl:22])=[CH:4][N:3]=[C:2]([NH:29][C:30]3[CH:31]=[N:32][N:33]([CH:35]4[CH2:36][CH2:37][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:39][CH2:40]4)[CH:34]=3)[N:7]=2)[CH2:18][CH2:17]1)(=[O:20])[NH2:21]
Reactant: NC(=O)C1(c2ccccc2CCc2nc(Cl)ncc2Cl)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(N)cn2)CC1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(n2cc(Nc3ncc(Cl)c(CCc4ccccc4C4(C(N)=O)CC4)n3)cn2)CC1

Procedure:
A suspension of 1-(2-(2-(2,5-dichloropyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxamide A14 (0.100 g, 0.297 mmol), Cs2CO3 (0.291 g, 0.892 mmol) and tert-butyl 4-(4-amino-1H-pyrazol-1-yl)piperidine-1-carboxylate (0.158 g, 0.595 mmol) in 1,4-dioxane (2 mL) was sonicated for 10 minutes. Xantphos (6.9 mg, 12 μmol) and Pd(II) acetate (1.3 mg, 5.9 μmol) were added and the mixture was irradiated in the microwave at 120° C. for 20 minutes. The mixture was adsorbed onto silica gel and purified by column chromatography (Biotage Isolera, 40 g SiO2 cartridge, 0-100% EtOAc in cyclohexane then 0-10% MeOH in EtOAc) to give the title compound A20 as a brown solid (21 mg, 12%). LCMS-C: rt 5.54 min; m/z 565.9 [M+H]+.