Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[O:11][C:12]3[C:13](=[C:15]([C:27]#[N:28])[C:16]([CH3:26])=[C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18]=3F)[N:14]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:36][N:37]([CH3:43])[C@H:38]1[CH2:42][CH2:41][NH:40][CH2:39]1>CS(C)=O>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[O:11][C:12]3[C:13](=[C:15]([C:27]#[N:28])[C:16]([CH3:26])=[C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18]=3[N:40]3[CH2:41][CH2:42][C@H:38]([N:37]([CH3:43])[CH3:36])[CH2:39]3)[N:14]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(c2nc3c(C#N)c(C)c(-c4ccccc4)c(F)c3o2)CC1
Reactant: CN(C)[C@H]1CCNC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(c2nc3c(C#N)c(C)c(-c4ccccc4)c(N4CC[C@H](N(C)C)C4)c3o2)CC1
Temperature: 90 °C
Reaction time: 4 h
Yield: 25.4 %

Procedure:
2-(1-Acetylpiperidin-4-yl)-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-104) (0.23 g, 0.61 mmol) was dissolved in dimethyl sulfoxide (7 ml), triethylamine (0.18 ml, 1.30 mmol) and (3S)-3-(dimethylamino)pyrrolidine (85.0 μl, 0.67 mmol) were added, followed by stirring an external temperature of about 90° C. for 4 hours. After dilution with ethyl acetate, this was washed with water, dried over anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure and the resulting residue was purified by silica gel column chromatography (silica gel 10 g, dichloromethane:methanol=30:1) to obtain a colorless oil (73 mg, 25%). This was dissolved in dioxane and freeze-dried into solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)C>[C:16]1([CH:12]2[NH:13][CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[C:23]([F:34])([F:33])[F:22])=[CH:3][CH:4]=3)=[O:9])[CH2:11]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(c1ccc(Br)cc1)N1CCNC(c2ccccc2)C1
Reactant: OB(O)c1ccccc1C(F)(F)F
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=C(c1ccc(-c2ccccc2C(F)(F)F)cc1)N1CCNC(c2ccccc2)C1
Temperature: 120 °C

Procedure:
This compound could be made in the following manner: 100 mg of (4-bromo-phenyl)-(3-phenyl-piperazin-1-yl)-methanone would be combined with 1 equiv. of 2-trifluoromethylphenyl boronic acid, 10 mol % of tetrakis(triphenylphosphine) palladium(0), 2M aqueous sodium carbonate solution, toluene and ethanol. The reaction mixture would be heated in a sealed tube at 120° C. overnight. The reaction mixture would be filtered through Celite and concentrated in vacuo. The residue would be diluted with water and extracted with ethyl acetate. The combined organic phases would be washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material would be purified by flash chromatography to afford (3-phenyl-piperazin-1-yl)-(2′-trifluoromethyl-biphenyl-4-yl)-methanone.
Reaction SMILES: CN(C)/[CH:3]=[C:4](/[C:10](=[O:19])[C:11]1[CH:16]=[C:15]([I:17])[CH:14]=[CH:13][C:12]=1F)\[C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl.[CH3:22][O:23][CH2:24][CH:25]([NH2:29])[CH:26]([CH3:28])[CH3:27].C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[I:17][C:15]1[CH:16]=[C:11]2[C:12](=[CH:13][CH:14]=1)[N:29]([CH:25]([CH:26]([CH3:28])[CH3:27])[CH2:24][O:23][CH3:22])[CH:3]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:10]2=[O:19]
Reactant: CCOC(=O)/C(=C\N(C)C)C(=O)c1cc(I)ccc1F
Reactant: COCC(N)C(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(C(COC)C(C)C)c2ccc(I)cc2c1=O
Temperature: 60 °C
Reaction time: 48 h
Yield: 59.1 %

Procedure:
To a solution of ethyl 3-(dimethylamino)-2-(2-fluoro-5-iodobenzoyl)acrylate (Intermediate 24, 1 g, 2.56 mmol) dissolved in THF (10 mL) was added 1-methoxy-3-methylbutan-2-amine hydrochloride (366 mg, 2.38 mmol) followed by potassium carbonate. The reaction mixture was stirred at 60° C. for 2 d. The reaction mixture was concentrated under reduced pressure and the residue was resuspended in DMF (10 mL). Potassium carbonate was added (978 mg, 7.08 mmol), and the reaction mixture was stirred at 70° C. for 2 h. The reaction mixture was cooled down to room temperature and quenched with 1 N HCl. The reaction mixture was partitioned between water (20 mL) and ethyl acetate (20 mL). The aqueous layer was extracted with ethyl acetate, and the organics were dried and concentrated to provide ethyl 6-iodo-1-(1-methoxy-3-methylbutan-2-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (623 mg, 60%).
Reaction SMILES: [C:1]1(=[O:10])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][NH:2]1.[OH-:11].[Na+:12]>>[NH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:1]([O-:10])=[O:11].[Na+:12]
Reactant: [OH-]
Reactant: O=C1CCCCCCCN1
Agent: [Na+]
Product: NCCCCCCCC(=O)[O-]
Temperature: 110 °C

Procedure:
A 5 L three-neck round bottom flask was fitted with a heating mantle, an overhead mechanical stirrer, a reflux condenser, and a thermometer. A suspension of 2-azacyclononanone (83 g, 0.59 moles, 1.0 equiv.) in 5 M aqueous sodium hydroxide (650 mL, 3.23 moles, 5.5 equiv.) was charged into the round bottom flask. The mixture was heated to reflux (internal temperature about 110° C.) for 4 hours to yield a clear yellow solution. The heating mantle and reflux condenser were removed. After the solution cooled to room temperature, it was diluted with water (650 mL) and cooled further in an ice bath.
Reaction SMILES: C(OC([NH:8][C@@H:9]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:10]1[CH:11]=[C:12]([CH:25]=[CH:26][CH:27]=1)[O:13][CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1)=O)(C)(C)C.[ClH:34].O1CCOCC1>CO>[ClH:34].[NH2:8][C@@H:9]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:10]1[CH:11]=[C:12]([CH:25]=[CH:26][CH:27]=1)[O:13][CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(COc2cccc([C@@H](NC(=O)OC(C)(C)C)c3ccccc3)c2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)c1ccc(COc2cccc([C@@H](N)c3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
To a solution of (S)-methyl 4-((3-(((tert-butoxycarbonyl)amino)(phenyl)methyl)-phenoxy)methyl)benzoate (3.21 g, 7.20 mmol) in methanol (36 mL) was added hydrogen chloride in dioxane (4 M, 9.0 mL, 36 mmol). The reaction mixture was stirred at RT for 16 hours. The solvent was removed at reduced pressure to afford the title compound (2.65 g, >95%).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:4]([CH3:6])([CH3:5])[CH:3]1[C:7](Cl)=[O:8].[NH2:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][C:2]1([CH3:10])[C:4]([CH3:6])([CH3:5])[CH:3]1[C:7]([NH:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1)=[O:8]
Reactant: N#Cc1ccc(N)cc1
Reactant: CC1(C)C(C(=O)Cl)C1(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)C(C(=O)Nc2ccc(C#N)cc2)C1(C)C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 33.7 %

Procedure:
Add a solution of 2,2,3,3-tetramethyl-cyclopropane-carbonyl chloride (5 g, 31.1 mmol) in anhydrous DCM to a mixture of 4-aminobenzonitrile (3.34 g, 28.3 mmol) and triethylamine (4.3 mL, 31 mmol) in anhydrous DCM (20 mL) at 0° C. After stirring at 0° C. for 20 min, warm the mixture to room temperature and stir overnight. Partition the reaction mixture between DCM (500 mL) and water (250 mL) and extract the aqueous phase with DCM (250 mL). Wash combined organic extracts with water (3×250 mL), dry over Na2SO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (1:0 over 36 min; 1:0 to 3:1 gradient over 36 min; 3:1 to 1:1 gradient over 71 min; 50 mL/min) to obtain the desired intermediate as a solid (2.31 g, 34%). MS (ES+) m/z: 243.2 (M+H)+.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][CH2:6][C:7](Cl)=[O:8].[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][C:11]1=[O:19]>C(=S)=S>[Cl:5][CH2:6][C:7]([C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[NH:10][C:11](=[O:19])[CH2:12]2)=[O:8]
Reactant: O=C1Cc2ccccc2N1
Reactant: O=C(Cl)CCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: O=C1Cc2cc(C(=O)CCl)ccc2N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.2 %

Procedure:
The following reagents were combined in the order listed under nitrogen at room temperature: aluminum chloride (17 g, 0.130 moles), carbon disulfide (40 mL), chloroacetyl chloride (3.01 g, 0.027 moles), and oxindole (2.73 g, 0.021 moles). The reaction mixture was warmed to reflux and stirring continued at this temperature for 3 h. The reaction was cooled to room temperature and the liquid was carefully decanted off. Ice water was added dropwise to the remaining residue under nitrogen (slowly and carefully). Addition of water was ceased when a total of 50 mL had been added and the reaction was stirred for 1 h at room temperature. The tan solid was collected by filtration, washed 3 times with water and dried in vacuo at 72° C. to give a light tan solid (3.4 g, 79% yield). 1H NMR (DMSO-d6) δ3.62 (s, 2H); 5.15 (s, 2H); 6.96 (d, 1H); 7.84 (s, 1H); 7.91 (d, 2H); 10.84 (bs, 1H). APCI-MS m/z 208 (M−H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH2:29][CH3:30])[N:3]=1.[NH2:31][C:32]1[CH:33]=[CH:34][C:35]([C@@H:43]2[CH2:48][CH2:47][C@H:46]([C:49]([O:51][CH2:52][CH3:53])=[O:50])[CH2:45][CH2:44]2)=[C:36]2[C:40]=1[C:39](=[O:41])[N:38]([CH3:42])[CH2:37]2>>[CH2:20]([O:19][P:18]([CH2:17][C:16]1[CH:26]=[CH:27][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:31][C:32]3[CH:33]=[CH:34][C:35]([C@@H:43]4[CH2:44][CH2:45][C@H:46]([C:49]([O:51][CH2:52][CH3:53])=[O:50])[CH2:47][CH2:48]4)=[C:36]4[C:40]=3[C:39](=[O:41])[N:38]([CH3:42])[CH2:37]4)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[C:14]([O:28][CH2:29][CH3:30])[CH:15]=1)([O:22][CH2:23][CH3:24])=[O:25])[CH3:21]
Reactant: CCOc1cc(CP(=O)(OCC)OCC)ccc1Nc1ncc(C(F)(F)F)c(Cl)n1
Reactant: CCOC(=O)[C@H]1CC[C@@H](c2ccc(N)c3c2CN(C)C3=O)CC1
Product: CCOc1cc(CP(=O)(OCC)OCC)ccc1Nc1ncc(C(F)(F)F)c(Nc2ccc([C@H]3CC[C@@H](C(=O)OCC)CC3)c3c2C(=O)N(C)C3)n1

Procedure:
The title compound was prepared according to the procedure for Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-ethoxybenzyl)phosphonate (Compound 244A 123.2 mg, 0.26 mmol) and ethyl cis-4-(7-amino-2-methyl-1-oxo-2,3-dihydro-1H-isoindol-4-yl)cyclohexanecarboxylate (100.0 mg, 0.32 mmol). The reaction mixture was concentrated in vacuo and purified by on an ISCO CombiFlash®Rf System eluting with: 0→5% MeOH in DCM] to afford 143.3 mg (73%) of the desired product. 1H NMR (400 MHz, MeOD) δ ppm 8.44 (d, J=10.36 Hz, 1H), 8.35 (s, 1H), 7.89 (d, J=8.34 Hz, 1H), 7.24 (d, J=8.59 Hz, 1H), 7.06 (t, J=2.15 Hz, 1H), 6.92 (dt, J=8.21, 2.21 Hz, 1H), 4.52 (s, 2H), 4.26 (q, J=7.16 Hz, 2H), 4.05-4.19 (m, 6H), 3.29 (s, 2H), 3.19 (s, 3H), 2.79 (br. s., 1H), 2.63-2.73 (m, 1H), 2.30 (d, J=7.33 Hz, 2H), 1.76 (d, J=6.06 Hz, 6H), 1.42 (t, J=6.95 Hz, 3H), 1.27-1.38 (m, 9H). MS (ES+): m/z 749.30/750.31 (100/25) [MH+] HPLC: tR=1.82 min (Micromass TOF: polar—3 min).
Reaction SMILES: Cl[C:2]1[NH:7][C:6](=[O:8])[N:5]([CH:9]([CH3:11])[CH3:10])[C:4](=[O:12])[CH:3]=1.[F:13][C:14]([F:24])([F:23])[C@@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[NH2:16].CN1C(=O)CCC1>O.CC#N>[CH:9]([N:5]1[C:4](=[O:12])[CH:3]=[C:2]([NH:16][C@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14]([F:13])([F:23])[F:24])[NH:7][C:6]1=[O:8])([CH3:11])[CH3:10]
Reactant: N[C@H](c1ccccc1)C(F)(F)F
Reactant: CC(C)n1c(=O)cc(Cl)[nH]c1=O
Solvent: CC#N
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)n1c(=O)cc(N[C@H](c2ccccc2)C(F)(F)F)[nH]c1=O
Temperature: 180 °C
Yield: 34 %

Procedure:
To a 0.2-0.5 mL microwave vial was added 1.3 (85 mg, 0.45 mmol) and (R)-2,2,2-trifluoro-1-phenylethan-1-amine (200 uL, excess). The reaction mixture sealed and heated at 180° C. in a microwave reactor for 40 minutes. The reaction mixture was cooled to ambient temperature and then NMP (1 mL) was added to completely dissolve the solid. Next, a 2:1 H2O/CH3CN mixture (6 mL) was added which resulted in precipitation. The solid was isolated by filtration, washed with H2O and dried to give 50 mg (34%) of the title compound as a white solid. LC/MS: m/z (ES+) 328 (M+H)+. 1H-NMR (400 MHz, DMSO-d6): δ ppm 9.79 (br s, 1H), 7.50-7.40 (m, 5H), 5.66-5.56 (m, 2H), 4.92-4.87 (m, 2H), 1.28-1.25 (m, 6H).
Reaction SMILES: C([C:3]1(CC)[CH:8]([C:9]([CH:11]([C:15]([O-:17])=[O:16])C([O-])=O)=[O:10])[C:7]([F:18])=[C:6]([O:19][CH:20]([F:22])[F:21])[C:5]([F:23])=[C:4]1[F:24])C.O.[C:28]1(C)C=CC(S(O)(=O)=O)=C[CH:29]=1.O.C(=O)(O)[O-].[Na+]>O1CCOCC1>[F:22][CH:20]([F:21])[O:19][C:6]1[C:7]([F:18])=[C:8]([CH:3]=[C:4]([F:24])[C:5]=1[F:23])[C:9]([CH2:11][C:15]([O:17][CH2:28][CH3:29])=[O:16])=[O:10]
Reactant: CCC1(CC)C(F)=C(F)C(OC(F)F)=C(F)C1C(=O)C(C(=O)[O-])C(=O)[O-]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)CC(=O)c1cc(F)c(F)c(OC(F)F)c1F

Procedure:
The whole of the diethyl-3-difluoromethoxy-2,4,5trifluorobenzoylmalonate [(XIV), R1 =--OCHF2, R3' =H, R17 =C2H5, X=X'=F] [prepared as described in step (a) above] was dissolved in 200 ml of dioxane, and then 4.52 g (0.0238 moles) of p-toluenesulfonic acid monohydrate were added to the resulting solution. The mixture was then heated under reflux for 6 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure. 100 ml of water and 2.52 g (0.03 moles) of sodium bicarbonate were added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure to give 5.66 g of ethyl 3-difluoromethoxy-2,4,5-trifluorobenzoylacetate as a reddish brown liquid.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([C:15]34[CH2:22][CH2:21][C:18]([CH2:23][C:24]([O:26][CH3:27])=[O:25])([CH2:19][CH2:20]3)[CH2:17][O:16]4)=[CH:11][CH:10]=2)O1.Br[C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37]([C:39]2[O:43][C:42]([CH2:44][CH3:45])=[N:41][C:40]=2[CH3:46])=[O:38])=[CH:32][CH:31]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(COC)OC>O.C(O)C>[CH2:44]([C:42]1[O:43][C:39]([C:37]([NH:36][C:33]2[CH:34]=[CH:35][C:30]([C:9]3[CH:10]=[CH:11][C:12]([C:15]45[CH2:22][CH2:21][C:18]([CH2:23][C:24]([O:26][CH3:27])=[O:25])([CH2:19][CH2:20]4)[CH2:17][O:16]5)=[CH:13][CH:14]=3)=[CH:31][CH:32]=2)=[O:38])=[C:40]([CH3:46])[N:41]=1)[CH3:45]
Reactant: CCc1nc(C)c(C(=O)Nc2ccc(Br)cc2)o1
Reactant: COC(=O)CC12CCC(c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)(CC1)OC2
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: COCCOC
Solvent: O
Product: CCc1nc(C)c(C(=O)Nc2ccc(-c3ccc(C45CCC(CC(=O)OC)(CC4)CO5)cc3)cc2)o1
Temperature: 80 °C
Yield: 142.1 %

Procedure:
A vial was charged with methyl 2-(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)acetate (14 mg, 0.036 mmol), N-(4-bromophenyl)-2-ethyl-4-methyloxazole-5-carboxamide (22.4 mg, 0.072 mmol), PdCl2(dppf)-CH2Cl2adduct (4.44 mg, 5.44 μmol), potassium phosphate (15.4 mg, 0.072 mmol), dimethoxyethane (0.6 ml), ethanol (0.2 ml), and water (0.1 ml) at room temperature. The vial was sealed, flushed with nitrogen for three times and heated at 80° C. for 16 hours. The mixture was purified by flash chromatography (heptanes/acetone 1/1, washed with acetone/ethanol 1/1) to afford methyl 2-(1-(4′-(2-ethyl-4-methyloxazole-5-carboxamido)-[1,1′-biphenyl]-4-yl)-2-oxabicyclo[2.2.2]octan-4-yl)acetate (25 mg, 40% purity, 56% yield) as white solid. LC/MS, ESI-MS(+1) m/z 489.1, RT 1.53 (Condition E).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:5][C:6]=1[C:7](=[O:9])[CH3:8].[H-].[Na+].C(O)(=O)C.[CH3:23][O:24][C:25](=O)[O:26]C>>[Cl:1][C:2]1[S:3][C:4]([CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:5][C:6]=1[C:7](=[O:9])[CH2:8][C:25]([O:24][CH3:23])=[O:26]
Reactant: COC(=O)OC
Reactant: CC(=O)c1cc(CN2CCOCC2)sc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)CC(=O)c1cc(CN2CCOCC2)sc1Cl
Temperature: 95 °C
Yield: 41 %

Procedure:
To a solution of 1-(2-chloro-5-(4-morpholinylmethyl)-3-thienyl)ethanone (Preparation 63, 9.53 g) in dimethylcarbonate (200 mL) is added NaH (1.53 g; 60%, dispersion in mineral oil) portionwise at ambient temperature. The reaction mixture is heated to 95° C. for 3 h. The reaction vessel is cooled to ambient temperature and the mixture is poured into ice cold water (500 mL) containing acetic acid (15 mL). The aqueous layer is extracted with Et2O (3×100 mL). The organic layer is separated, dried over MgSO4, filtered, and concentrated in vacuo. The crude brown liquid is purified by silica gel column chromatography (4/1, hexanes/EtOAc) to afford 4.77 g (41%) of the title compound as a tan solid. Physical characteristics: m.p. 67-68° C.; 1H NMR (300 MHz, CDCl3) δ7.21, 3.99, 3.78, 3.71, 3.60, 2.50; IR (diffuse reflectance) 2822, 1738, 1663, 1461, 1399, 1350, 1336, 1316, 1286, 1265, 1156, 1113, 1009, 1004, 864 cm−1; MS (ESI+) m/z 318; Anal. Found: C, 48.89; H, 5.13; N. 4.45.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][N:8]=1.[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[S:28](Cl)(=[O:30])=[O:29]>>[CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][N:8]=1)[S:28]([C:22]1[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=1[F:20])(=[O:30])=[O:29]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Reactant: COc1ccc(CNc2ccc(F)cn2)c(OC)c1
Product: COc1ccc(CN(c2ccc(F)cn2)S(=O)(=O)c2ccc(F)cc2F)c(OC)c1

Procedure:
The title compound was prepared according to the method described for Preparation 11 using N-(2,4-dimethoxybenzyl)-5-fluoropyridin-2-amine (Preparation 20) and 2,4-difluorobenzene-1-sulfonyl chloride.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[C:16]([CH2:18]S([O-])(=O)=O)[CH:15]=[CH:14][CH:13]=2)=[N:3]1.C(N(CC)CC)C.[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.C(OCC)(=O)C>CN(C=O)C.O>[N:30]1([CH2:18][C:16]2[N:17]=[C:12]([C:4]3[S:5][C:6]4[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=4[C:2](=[O:1])[N:3]=3)[CH:13]=[CH:14][CH:15]=2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: O=c1nc(-c2cccc(CS(=O)(=O)[O-])n2)sc2ccccc12
Reactant: C1CCNCC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=c1nc(-c2cccc(CN3CCCCC3)n2)sc2ccccc12
Temperature: 70 °C
Reaction time: 18 h
Yield: 55.1 %

Procedure:
6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-2-pyridylmethanesulfonate (0.30 g, 0.86 mmol), triethylamine (0.20 ml, 1.42 mmol) and piperidine (0.081 g, 0.95 mmol) were dissolved in DMF (30 ml), and the mixture was stirred at 70° C. for 18 hrs. The reaction mixture was combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was recrystallized from n-hexane-ethyl acetate to give the titled compound (0.16 g, 54%) as pale yellow crystals.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:40])([F:39])[C:5]1[CH:6]=[C:7]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[CH2:8][NH:9][CH:10]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][CH:20]([CH3:22])[CH3:21])=[O:18])[C:12]2[C:23]([CH3:31])=[C:24]([C:27]([F:30])([F:29])[F:28])[CH:25]=[CH:26][C:11]1=2.[CH3:41][N:42](C)C=O.N#CBr>CS(C)=O.C(OCC)(=O)C.O>[F:40][C:4]([F:3])([F:39])[C:5]1[CH:6]=[C:7]([CH:32]=[C:33]([C:35]([F:36])([F:38])[F:37])[CH:34]=1)[CH2:8][N:9]([C:41]#[N:42])[CH:10]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][CH:20]([CH3:21])[CH3:22])=[O:18])[C:12]2[C:23]([CH3:31])=[C:24]([C:27]([F:28])([F:29])[F:30])[CH:25]=[CH:26][C:11]1=2
Reactant: Cc1c(C(F)(F)F)ccc2c1N(C(=O)OC(C)C)CCCC2NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CN(C)C=O
Agent: N#CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1c(C(F)(F)F)ccc2c1N(C(=O)OC(C)C)CCCC2N(C#N)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 1 h
Yield: 40 %

Procedure:
To a suspension of sodium hydride 60% in mineral oil (32 mg, 0.81 mmol) in dry dimethyl sulfoxide (3 mL), add isopropyl 5-(3,5-bistrifluoromethyl-benzylamino)-9-methyl-8-trifluormethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (300 mg, 0.54 mmol) and dry dimethylformamide (2 mL). Add cyanogen bromide (176 mg, 1.62 mmol) and stir the reaction mixture at room temperature overnight. Add sodium hydride 60% in mineral oil (32 mg, 0.81 mmol) and cyanogen bromide (176 mg, 1.62 mmol) and stir at room temperature for one hour. Add additional sodium hydride 60% in mineral oil (32 mg, 0.81 mmol) and cyanogen bromide (176 mg, 1.62 mmol) and stir one hour. Add water and ethyl acetate. Separate the layers and dry the organic phase over anhydrous magnesium sulfate, filter and remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to afford the titled compound (124 mg, 40%). MS (ES+): 582 (M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[N:23][CH:24]=1>>[CH3:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([NH:18][C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[N:3]=2)=[CH:24][N:23]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Reactant: COc1ccc(N)cn1
Product: COc1ccc(Nc2cc(C(F)(F)F)nc(-c3cccnc3)n2)cn1

Procedure:
The title compound was prepared from 4-chloro-2-(3-pyridinyl)-6-trifluoromethylpyrimidine (50 mg, 0.192 mmol) and 5-amino-2-methoxypyridine (35 mg, 0.288 mmol) similar to Example 180 and was isolated as a solid (30 mg, 45%). 1H NMR (CDCl3): 9.65 (brs, 1H), 8.72–8.69 (m, 2H), 8.26 (d, J=2.7 Hz, 1H), 7.71 (d, J=6.9 Hz, 1H), 7.44–7.40 (m, 2H), 6.86 (d, J=9.0 Hz, 1H), 6.74 (s, 1H), 3.98 (s, 3H).
Reaction SMILES: NC1C=CC(C)=C(C(C2C=CC(NC3C=CC(C(F)(F)F)=CC=3)=CC=2Cl)=O)C=1.[Cl:29][C:30]1[CH:35]=[C:34]([NH:36][C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:38]=2[CH3:44])[CH:33]=[CH:32][C:31]=1[C:45]([C:47]1[CH:52]=[C:51]([N+:53]([O-])=O)[CH:50]=[CH:49][C:48]=1[CH3:56])=[O:46]>>[NH2:53][C:51]1[CH:50]=[CH:49][C:48]([CH3:56])=[C:47]([C:45]([C:31]2[CH:32]=[CH:33][C:34]([NH:36][C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:38]=3[CH3:44])=[CH:35][C:30]=2[Cl:29])=[O:46])[CH:52]=1
Reactant: Cc1cc(F)ccc1Nc1ccc(C(=O)c2cc([N+](=O)[O-])ccc2C)c(Cl)c1
Agent: Cc1ccc(N)cc1C(=O)c1ccc(Nc2ccc(C(F)(F)F)cc2)cc1Cl
Product: Cc1cc(F)ccc1Nc1ccc(C(=O)c2cc(N)ccc2C)c(Cl)c1

Procedure:
The reaction was carried out similarly as described in the preparation of compound 415, using compound 437 (0.41 mmol). The crude product was used without any further purification.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([F:23])([C:14](=[O:22])[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>ClCCl>[F:23][C:11]1([C:14](=[O:22])[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(F)(C(=O)c2ccc(F)cc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1ccc(F)cc1)C1(F)CCNCC1

Procedure:
4-Fluoro-4-(4-fluoro-benzoyl)-piperidine-1-carboxylic acid tert-butyl ester (0.122 g, 0.375 mmol) was solved in dichloromethane (2 mL) and trifluoroacetic acid (0.258 mL, 3.37 mmol) was added at 0° C. Aqueous NaHCO3 was slowly added until pH 9 and the mixture extracted with 3 times with dichloromethane and ethyl acetate. The solvent was evaporated to yield g (0. mmol, 100%) of a white solid that was used without purification on the next steps. MS (m/e): 226.1 (M+H+).