Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([O:5][CH:6]1[CH2:9][N:8]([C:10]2[N:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:11]=2[C:12]([O:14][CH3:15])=[O:13])[CH2:7]1)(=O)=O.O[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[N:26]=1>>[F:21][C:20]([F:23])([F:22])[C:17]1[CH:18]=[N:19][C:10]([N:8]2[CH2:9][CH:6]([O:5][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[N:26]=3)[CH2:7]2)=[C:11]([CH:16]=1)[C:12]([O:14][CH3:15])=[O:13]
Reactant: Oc1cccc(C(F)(F)F)n1
Reactant: COC(=O)c1cc(C(F)(F)F)cnc1N1CC(OS(C)(=O)=O)C1
Product: COC(=O)c1cc(C(F)(F)F)cnc1N1CC(Oc2cccc(C(F)(F)F)n2)C1

Procedure:
The title compound (D89) (25 mg) was prepared according to the experimental procedure described in Description 88 starting from methyl 2-(3-((methylsulfonyl)oxy)azetidin-1-yl)-5-(trifluoromethyl)nicotinate (D68) (120 mg, 0.34 mmol) and 2-Hydroxy-6-(trifluoromethyl)pyridine (55.12 mg, 0.34 mmol, commercially available from Fluorochem#032990).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[CH:6][C:7]=1[OH:8].[CH:10](OCC)(OCC)OCC>C1(C)C=CC=CC=1>[CH3:9][C:5]1[CH:4]=[CH:3][C:2]2[N:1]=[CH:10][O:8][C:7]=2[CH:6]=1
Reactant: Cc1ccc(N)c(O)c1
Reactant: CCOC(OCC)OCC
Solvent: Cc1ccccc1
Product: Cc1ccc2ncoc2c1
Yield: 69 %

Procedure:
A 50 ml flask was charged with 6-amino-m-cresol (2 g, 16.24 mmole), 20 ml toluene and 5.4 ml triethyl orthoformate. The reaction mixture was refluxed for 2 hours. The mixture was concentrated down to about 2.3 g crude. Purification by silicagel column chromatography using 20% EtOAc/hexane provided 1.45 g brown oil (69% yield) that solidified in the freezer.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9](O)[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1)#[N:2].S(Cl)([Cl:22])=O>ClCCl>[Cl:22][CH:9]([C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1
Reactant: O=S(Cl)Cl
Reactant: N#Cc1ccc(C(O)CCc2ccc(F)cc2)cc1
Solvent: ClCCl
Product: N#Cc1ccc(C(Cl)CCc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-(4-cyanophenyl)-3-(4-fluorophenyl)-1-propanol (3.43 g, 13 mmol) is dissolved in dichloromethane (20 ml). Thionylchloride (1.2 ml, 16 mmol) is added dropwise to the cooled solution and the mixture is stirred in room temperature for 2 hours. The mixture is washed with water, dried and the solvent is evaporated. The residue is used for the next step without further purification.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:16]2=[N:17][S:18](=[O:22])(=[O:21])[CH2:19][CH2:20][N:15]2[CH:14]=[CH:13][CH:12]=1>C1COCC1.CO.[Pt](=O)=O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]1[C:16]2=[N:17][S:18](=[O:21])(=[O:22])[CH2:19][CH2:20][N:15]2[CH2:14][CH2:13][CH2:12]1
Reactant: O=S1(=O)CCN2C=CC=C(c3ccc4ccccc4c3)C2=N1
Agent: O=[Pt]=O
Solvent: CO
Solvent: C1CCOC1
Product: O=S1(=O)CCN2CCCC(c3ccc4ccccc4c3)C2=N1
Temperature: 25 °C
Reaction time: 7 h
Yield: 68.9 %

Procedure:
To a solution of 9-naphthalen-2-yl-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (150 mg) in THF/methanol (30 mL/30 mL) was added platinum(IV) oxide (50 mg). The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 7 hr, and insoluble material was filtered off through celite. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by recrystallization (methanol-THF/diisopropyl ether) to give the title compound (104.7 mg).
Reaction SMILES: [S:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:4]=2[CH:3]=[CH:2]1.C(N(CC)CC)C.[CH3:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][C:26]([NH:28][C:29]1[N:34]=[CH:33][C:32]([C:35](Cl)=[O:36])=[CH:31][CH:30]=1)=[O:27]>ClCCl>[S:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][N:5]([C:35]([C:32]3[CH:31]=[CH:30][C:29]([NH:28][C:26](=[O:27])[CH2:25][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[CH3:18])=[N:34][CH:33]=3)=[O:36])[C:4]=2[CH:3]=[CH:2]1
Reactant: Cc1ccccc1CC(=O)Nc1ccc(C(=O)Cl)cn1
Reactant: c1cc2c(s1)CCCCN2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1CC(=O)Nc1ccc(C(=O)N2CCCCc3sccc32)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a cooled (0° C.) mixture of 0.306 g of 5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine and 1.11 μl of triethylamine in 5 ml of dichloromethane is added 1.2 g of 6-[(2-methylphenylacetyl)amino]pyridine-3-carbonyl chloride. The mixture is stirred at room temperature for 16 hours and diluted with 50 ml of dichloromethane. The mixture is washed with H2O, 1N NaHCO3, H2O, brine and dried (Na2SO4). The solution is concentrated to dryness under vacuum and the residue chromatographed on silica gel to give the product as a solid.
Reaction SMILES: [CH3:1][O:2][C@@H:3]([C@@H:33]([N:38]([CH3:46])[C:39](=[O:45])[C@H:40]([CH:42]([CH3:44])[CH3:43])[NH2:41])[C@@H:34]([CH3:37])[CH2:35][CH3:36])[CH2:4][C:5]([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[C@H:12]([O:31][CH3:32])[C@@H:13]([CH3:30])[C:14](=[O:29])[NH:15][C@H:16]([C:24]1[S:25][CH:26]=[CH:27][N:28]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:6].CN([P+](Br)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH2:74][C:75]1([C:81](O)=[O:82])[CH2:80][CH2:79][CH2:78][CH2:77][CH2:76]1>ClCCl>[NH2:74][C:75]1([C:81]([NH:41][C@@H:40]([CH:42]([CH3:44])[CH3:43])[C:39]([N:38]([C@@H:33]([C@@H:34]([CH3:37])[CH2:35][CH3:36])[C@H:3]([O:2][CH3:1])[CH2:4][C:5]([N:7]2[CH2:11][CH2:10][CH2:9][C@H:8]2[C@H:12]([O:31][CH3:32])[C@@H:13]([CH3:30])[C:14](=[O:29])[NH:15][C@H:16]([C:24]2[S:25][CH:26]=[CH:27][N:28]=2)[CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:6])[CH3:46])=[O:45])=[O:82])[CH2:80][CH2:79][CH2:78][CH2:77][CH2:76]1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)c1nccs1)OC)N(C)C(=O)[C@@H](N)C(C)C
Reactant: NC1(C(=O)O)CCCCC1
Agent: CN(C)[P+](Br)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)c1nccs1)OC)N(C)C(=O)[C@@H](NC(=O)C1(N)CCCCC1)C(C)C
Reaction time: 2 h
Yield: 35.5 %

Procedure:
To a solution of #50 (120 mg, 0.18 mmol, 1 eq.), Brop (84 mg, 0.21 mmol, 1.2 eq.) and diisopropylethylamine (0.1 mL, 0.54 mmol, 3 eq.) in dichloromethane (15 mL, 0.009 M) at 0° C. was added 1-aminocyclohexanecarboxylic acid (31 mg, 0.21 mmol, 1.2 eq.). After 2 hours, the mixture was quenched with water and extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (Gradient: 0% to 5% methanol in dichloromethane) to give #52 (50 mg, 35%). Rf 0.6 (10% methanol in dichloromethane). LC-MS (Protocol K): m/z 783.79 [M+H+]; 1H NMR (400 MHz, DMSO-d6), presumed to be a mixture of rotamers, characteristic signals: δ [8.64 (br d, J=8 Hz) and 8.87 (br d, J=9 Hz), total 1H], 8.18-8.28 (m, 1H), [7.77 (d, J=3.5 Hz) and 7.80 (d, J=3.3 Hz), total 1H], [7.63 (d, J=3.3 Hz) and 7.66 (d, J=3.3 Hz), total 1H], 7.12-7.31 (m, 5H), 5.35-5.43 and 5.49-5.57 (2 m, total 1H), [4.51 (dd, J=9, 8 Hz), and 4.61 (dd, J=9, 7 Hz), total 1H], 3.16, 3.19, 3.21 and 3.25 (4 s, total 6H), 2.93 and 3.02 (2 br s, total 3H), [1.05 (d, J=6.8 Hz) and 1.10 (d, J=6.8 Hz), total 3H].
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:31].Cl>[Zn].[Cl-].[NH4+].O.C(O)C>[ClH:31].[ClH:31].[NH2:16][C:13]1[CH:12]=[CH:11][C:10]([NH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:15][CH:14]=1
Reactant: COCCCCCCNc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: COCCCCCCNc1ccc(N)cc1

Procedure:
The N-(6-methoxyhexyl)-N-(4-nitrophenyl)amine (16) obtained above was reduced with a boiling zinc/ammonium chloride/water/ethanol mixture. The corresponding amine was isolated in dihydrochloride form.
Reaction SMILES: CS(OCC1O[N:10]=[C:9]([C@@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17](=[O:32])[C:18]([F:31])([F:30])[C:19]2([OH:29])[CH2:24][C:23]([CH3:26])([CH3:25])[CH2:22][C:21]([CH3:28])([CH3:27])[CH2:20]2)C=1)(=O)=O.CS(OCC1[O:40][C:41]([C@@H:44]2CC[CH2:46][N:45]2[C:49](=O)C(F)(F)C2(O)CC(C)(C)CC(C)(C)C2)=[N:42]N=1)(=O)=O>>[CH3:46][N:45]([CH2:44][C:41]1[O:40][C:9]([C@@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17](=[O:32])[C:18]([F:31])([F:30])[C:19]2([OH:29])[CH2:20][C:21]([CH3:28])([CH3:27])[CH2:22][C:23]([CH3:26])([CH3:25])[CH2:24]2)=[N:10][N:42]=1)[CH3:49]
Reactant: CC1(C)CC(C)(C)CC(O)(C(F)(F)C(=O)N2CCC[C@H]2c2nnc(COS(C)(=O)=O)o2)C1
Reactant: CC1(C)CC(C)(C)CC(O)(C(F)(F)C(=O)N2CCC[C@H]2c2cc(COS(C)(=O)=O)on2)C1
Product: CN(C)Cc1nnc([C@@H]2CCCN2C(=O)C(F)(F)C2(O)CC(C)(C)CC(C)(C)C2)o1

Procedure:
The procedure of Example 6 was repeated, except that the compound obtained in Example 3-(5) was replaced by the compound obtained in Example 9-(6); this gave the titled compound.
Reaction SMILES: COC([N:5]1[C:13]2[C:8](=[C:9]([NH:14][C:15]([NH:17][CH:18]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([F:28])[CH:26]=4)[O:21][CH2:20][CH2:19]3)=[O:16])[CH:10]=[CH:11][CH:12]=2)[CH:7]=[N:6]1)=O.COC(N1C2C(=C(NC(NC3C4C(=CC(C(C)(C)C)=CC=4)OCC3)=O)C=CC=2)C=N1)=O>>[F:28][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[O:21][CH2:20][CH2:19][CH:18]2[NH:17][C:15]([NH:14][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:8]=1[CH:7]=[N:6][NH:5]2)=[O:16]
Reactant: COC(=O)n1ncc2c(NC(=O)NC3CCOc4ccc(F)cc43)cccc21
Agent: COC(=O)n1ncc2c(NC(=O)NC3CCOc4cc(C(C)(C)C)ccc43)cccc21
Product: O=C(Nc1cccc2[nH]ncc12)NC1CCOc2ccc(F)cc21

Procedure:
The title compound was prepared using the procedure as described in Example 1E, substituting the product of Example 10C for the product of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ 13.00 (broad s, 1H), 8.60 (s, 1H), 8.02 (s, 1H), 7.67 (d, J=7.5 Hz, 1H), 7.21 (m, 1H), 7.08-7.00 (m, 3H), 6.92-6.80 (m, 2H), 4.92 (m, 1H), 4.35-4.11 (m, 2H), 2.20-1.93 (m, 2H). MS (DCI) m/e 327 (M+H)+. Calcd. For C17H15N4O2F.0.1H2O: C, 62.23; H, 4.67; N, 17.07. Found: C, 62.31; H, 4.46; N, 16.74.
Reaction SMILES: [NH2:1][C@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:13]=[N:14][N:15]([CH2:17][CH2:18][O:19][CH3:20])[CH:16]=3)[CH:10]=2)[N:5]([C:21](=[O:23])[CH3:22])[C@@H:4]([CH3:24])[CH2:3]1.Br[C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][N:27]=1.CN(C1C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=CC=CC=1)C.CC(C)([O-])C.[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:20][O:19][CH2:18][CH2:17][N:15]1[CH:16]=[C:12]([C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[N:5]([C:21](=[O:23])[CH3:22])[C@@H:4]([CH3:24])[CH2:3][C@H:2]3[NH:1][C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][N:27]=2)[CH:13]=[N:14]1
Reactant: Cc1ccc(Br)nc1
Reactant: COCCn1cc(-c2ccc3c(c2)[C@H](N)C[C@H](C)N3C(C)=O)cn1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: COCCn1cc(-c2ccc3c(c2)[C@H](Nc2ccc(C)cn2)C[C@H](C)N3C(C)=O)cn1
Temperature: 120 °C
Yield: 38 %

Procedure:
1-((2S,4R)-4-Amino-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone (for a preparation see Intermediate 7) (100 mg, 0.304 mmol), 2-bromo-5-methylpyridine (105 mg, 0.609 mmol), Davephos (23.97 mg, 0.061 mmol), Pd2(dba)3 (27.9 mg, 0.030 mmol) and sodium tert-butoxide (58.5 mg, 0.609 mmol) were combined in 1,4-dioxane (3 ml) and the mixture degassed over a period of 20 min. The mixture was heated at 120° C. for 25 min (microwave). The reaction mixture was partitioned between water (100 ml) and DCM (3×100 ml). The organics were combined, dried (hydrophobic frit) and evaporated under vacuum. The residual brown oil was dissolved in DMSO (2×1 ml) and purified by MDAP (HpH ×2). The solvent was evaporated under vacuum to give 1-((2S,4R)-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-2-methyl-4-((5-methylpyridin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone (49 mg, 0.117 mmol, 38% yield) as a yellow glass. LCMS (formate), Rt 0.61 min, MH+ 420.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[O:6][CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH:12]=O.[CH:14]([CH:16]=[CH2:17])=[O:15].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.ClCCl>[O:9]1[C:4]2=[C:3]3[C:2](=[CH:11][CH:10]=[C:5]2[O:6][CH2:7][CH2:8]1)[O:1][CH2:17][C:16]([CH:14]=[O:15])=[CH:12]3
Reactant: O=Cc1c(O)ccc2c1OCCO2
Reactant: C=CC=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=CC1=Cc2c(ccc3c2OCCO3)OC1

Procedure:
3 g (16.6 mmol) of the compound obtained in Step B and 1.4 g (25 mmol) of acrolein are added to a suspension of 3.48 g (25 mmol) of potassium carbonate in 40 ml of 1,4-dioxane; the medium is then heated at reflux under argon for 3 hours. After cooling and filtering off the salts, the solvent is evaporated in vacuo. The residue obtained is taken up in dichloromethane and then washed with water. The organic phase is dried over magnesium sulphate and then concentrated in vacuo. Chromatography on a silica column (eluant:ethyl acetate/petroleum ether 10/90) allows the title compound to be obtained in the form of a yellow solid.
Reaction SMILES: [F:1][C@@H:2]1[C:21]2[C@:16]([CH3:23])([CH:17]=[CH:18][C:19](=[O:22])[CH:20]=2)[C@:15]2([F:24])[C@H:4]([C@H:5]3[C@:12]([CH3:26])([CH2:13][C@@H:14]2[OH:25])[C@@H:8]([C:9](=[O:11])[CH3:10])[C@H:7]([CH3:27])[CH2:6]3)[CH2:3]1.[Cl-].[NH4+].C[OH:31]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:1][C@@H:2]1[C:21]2[C@:16]([CH3:23])([CH:17]=[CH:18][C:19](=[O:22])[CH:20]=2)[C@:15]2([F:24])[C@H:4]([C@H:5]3[C@:12]([CH3:26])([CH2:13][C@@H:14]2[OH:25])[C@@H:8]([C:9](=[O:11])[CH:10]=[O:31])[C@H:7]([CH3:27])[CH2:6]3)[CH2:3]1
Reactant: CC(=O)[C@H]1[C@H](C)C[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]21C
Reactant: CO
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: [Cl-]
Product: C[C@@H]1C[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]2(C)[C@H]1C(=O)C=O

Procedure:
3.0 g. of 6α,9α-difluoro-11β-hydroxy-16α-methyl-1,4-pregnadiene-3,20-dione is dissolved in 300 ml. of methanol. After adding 1.0 g. of copper (II) acetate, air is sucked through the solution for 30 minutes and the solution is then combined with saturated ammonium chloride solution. The mixture is extracted with dichloromethane, the organic phase is washed with water and dried over sodium sulfate. After evaporating the solvent under vacuum, 3.3 g. of 6α,9α-difluoro-11β-hydroxy-3,20-dioxo-16α-methyl-1,4-pregnadien-21-al is obtained in the form of a foam.
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[N:9][N:10]=[C:6]2[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)=[C:4]([C:21]2[CH:26]=[CH:25][N:24]=[C:23]([Cl:27])[CH:22]=2)[N:3]=1.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH:39]=[C:38](OS(C(F)(F)F)(=O)=O)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29].[Cl-].[Li+].C[Sn](C)C.C[Sn](C)C.[F-].[K+]>O1CCOCC1.C1(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)C=CC=CC=1>[C:28]([O:32][C:33]([N:35]1[CH2:36][CH:37]=[C:38]([C:2]2[N:7]3[CH:8]=[N:9][N:10]=[C:6]3[C:5]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=3)=[C:4]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([Cl:27])[CH:22]=3)[N:3]=2)[CH2:39][CH2:40]1)=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: FC(F)(F)c1cccc(-c2c(-c3ccnc(Cl)c3)nc(Cl)n3cnnc23)c1
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Sn](C)C
Agent: [Cl-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC=C(c2nc(-c3ccnc(Cl)c3)c(-c3cccc(C(F)(F)F)c3)c3nncn23)CC1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
5-Chloro-7-(2-chloro-4-pyridyl)-8-(3-(trifluoromethyl)phenyl)-1,2,4-triazolo[4,3-c]pyrimidine (2.0 g, 5.0 mmol), 1-(t-butoxycarbonyl)-4-(trifluoromethyl sulfonyloxy)-1,2,3,6-tetrahydropyridine (2.0 g, 6.0 mmol), lithium chloride (6.64 g, 15.0 mmol), hexamethylditin (2.0 g, 6.0 mmol) and tetrakistriphenylphosphinopalladium (0.3 g, 0.25 mmol) were combined in dioxane (25 ml) and the resulting solution was heated to 90° C. for 18 hours. The mixture was added to aq. KF and was stirred for 2 hours and then partitioned with methylene chloride. The organic layer was dried over sodium sulfate, filtered and concentrated to a syrup. Purification by column chromatography on silica gel (30% ethyl acetate in hexane) gave the product as a syrup; MS m/z (M+H)+ 557.2; C27H24F3ClN6O2 require 556.2.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:11])=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.[CH3:12][S:13](Cl)(=[O:15])=[O:14]>N1C=CC=CC=1>[C:9]([CH2:8][C:4]1[C:3]([CH3:11])=[C:2]([NH:1][S:13]([CH3:12])(=[O:15])=[O:14])[CH:7]=[CH:6][CH:5]=1)#[N:10]
Reactant: Cc1c(N)cccc1CC#N
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: Cc1c(CC#N)cccc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.5 %

Procedure:
(3-Amino-2-methyl-phenyl)-acetonitrile (11.1 g) was dissolved in 80 ml of pyridine. The solution was cooled in an ice bath and 11.3 g of methanesulfonyl chloride was added. The reaction mixture was removed from the ice bath and stirred at room temperature for 30 minutes; 10 ml of water was added, and the mixture was stirred for 30 minutes, poured into ethyl acetate (EtOAc), washed with cold hydrochloric acid, washed with water, dried, and evaporated to give 16.1 g of N-(3-cyanomethyl-2-methyl-phenyl)-methanesulfonamide as a light yellow solid. ##STR120##
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][CH:11]([CH2:13][NH:14][C@H:15]3[CH2:20][CH2:19][C@H:18]([C:21]4[CH:30]=[CH:29][C:24]5[NH:25][C:26](=[O:28])[O:27][C:23]=5[CH:22]=4)[CH2:17][CH2:16]3)[O:10][N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].[BH-](OC(C)=O)(OC(C)=O)O[C:35](C)=O.[Na+]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:12][CH:11]([CH2:13][N:14]([CH3:35])[C@H:15]3[CH2:16][CH2:17][C@H:18]([C:21]4[CH:30]=[CH:29][C:24]5[NH:25][C:26](=[O:28])[O:27][C:23]=5[CH:22]=4)[CH2:19][CH2:20]3)[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=c1[nH]c2ccc([C@H]3CC[C@H](NCC4CC(c5ccc(F)cc5)=NO4)CC3)cc2o1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(CC1CC(c2ccc(F)cc2)=NO1)[C@H]1CC[C@H](c2ccc3[nH]c(=O)oc3c2)CC1
Reaction time: 3 h

Procedure:
A mixture of trans-6-(4-{[3-(4-fluoro-phenyl)-4,5-dihydro-isoxazol-5-ylmethyl]-amino}-cyclohexyl)-3H-benzoxazol-2-one (51) (190 mg, 0.464 mmol) from Step 7, p-formaldehyde (70 mg, 2.32 mmol), and 2N NaOH (1 mL) in MeOH (15 mL) was stirred for 3 hours, NaBH(OAc)3 (138 mg, 0.650 mmol) was added, and the reaction mixture was stirred overnight. Solid NaOH was added until the solution turned clear. The reaction mixture was concentrated under reduced pressure. Purification by flash chromatography (silica gel, 95:5:1 CH2Cl2:MeOH:NH4OH) gave trans-6-(4-{[3-(4-fluoro-phenyl)-4,5-dihydro-isoxazol-5-ylmethyl]-methyl-amino}-cyclohexyl)-3H-benzoxazol-2-one (52) (60 mg, 31%), as a white foam: mp 109-114° C.; IR (KBr): 3430, 2927, 1772 cm−1; 1H NMR (500 MHz, DMSO-d6) δ 7.74 (dd, J=6, 3 Hz, 2H), 7.27 (m, 2H), 7.13 (s, 1H), 6.97 (m, 2H), 4.55 (m, 1H), 3.33 (m, 2H), 3.18 (m, 2H), 2.56 (m, 1H), 2.44 (m, 1H), 2.28 (s, 3H), 1.87 (m, 4H), 1.38 (m, 2H), 1.26 (m, 2H); API-MS (m/z): 424 [M+H]+; HRMS-API (m/z): [M+H]+ calcd for C24H26FN3O3, 424.2036; found, 424.2036; HPLC: method A, 5.39 minutes (98.1%); method B, 10.86 minutes (>99%).
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(Cl)Cl>O>[NH2:9][C:3]1[NH:4][C:5](=[O:8])[N:6]=[CH:7][C:2]=1[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: Nc1nc(=O)[nH]cc1Br
Reactant: C1CCNCC1
Solvent: O
Solvent: ClCCl
Product: Nc1[nH]c(=O)ncc1N1CCCCC1
Yield: 89 %

Procedure:
Method 8 was followed using 1 eq. of 5-bromocytosine and 15 eq. of piperidine (as solvent). The reaction was cooled and added to CH2Cl2 and H2O. The solid was filtered, rinsed with H2O, and dried yielding 6-amino-5-(piperidin-1-yl)pyrimidin-2(1H)-one as a solid (89%). LCMS (m/z): 195.0 (MH+); LC Rt=1.28 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:23]([O:24][CH3:25])=[CH:22][C:6]2[N:7]([CH2:10][C:11]3[CH:21]=[CH:20][C:14]4[N:15]=[C:16]([S:18][CH3:19])[O:17][C:13]=4[CH:12]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1.ClC1C=CC=C(C(OO)=[O:34])C=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:23]([O:24][CH3:25])=[CH:22][C:6]2[N:7]([CH2:10][C:11]3[CH:21]=[CH:20][C:14]4[N:15]=[C:16]([S:18]([CH3:19])=[O:34])[O:17][C:13]=4[CH:12]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1
Reactant: COc1cc2ncn(Cc3ccc4nc(SC)oc4c3)c2cc1OC
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc2ncn(Cc3ccc4nc(S(C)=O)oc4c3)c2cc1OC
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 44.9 %

Procedure:
To a stirred solution of 6-((5,6-dimethoxy-1H-benzo[c]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]oxazole (270 mg, 0.761 mmol) from Step 2 of Example 34 in DCM (5 mL) at 0° C. was added 70% meta-chloroperbenzoic acid (262 mg, 1.14 mmol), and the mixture was allowed to warm to rt and stirred for a further 4.5 h. To the mixture was added saturated aq NaHCO3 and the organic layer was separated. The aqueous layer was extracted with DCM and the combined organic layers were washed with saturated aq NaHCO3. The organic layer was separated, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified via silica gel flash chromatography eluting with 100% DCM to 10% MeOH in DCM to afford 6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]oxazole (127 mg, 45%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 8.24 (s, 1H), 7.85-7.92 (m, 2H), 7.48 (d, J=8.3 Hz, 1H), 7.21 (s, 1H), 7.20 (s, 1H), 5.62 (s, 2H), 3.76 (s, 6H), 3.18 (s, 3H). LCMS (ESI) m/z 372 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[C:13]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][CH3:23])=[O:21])[CH2:16][CH2:15]2)=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[C:6]([Cl:24])[CH:5]=1)(=O)[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:31].[Na+].O1CCCC1>CO.C(#N)C>[NH2:31][CH:1]([C:4]1[C:13]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][CH3:23])=[O:21])[CH2:16][CH2:15]2)=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[C:6]([Cl:24])[CH:5]=1)[CH3:2]
Reactant: COC(=O)N1CCN(c2c(C(C)=O)cc(Cl)c3cccnc23)CC1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC#N
Product: COC(=O)N1CCN(c2c(C(C)N)cc(Cl)c3cccnc23)CC1
Temperature: 65 °C

Procedure:
A mixture of methyl 4-(7-acetyl-5-chloroquinolin-8-yl)piperazine-1-carboxylate (0.018 g, 0.052 mmol) and ammonium acetate (0.0399 g, 0.518 mmol) in methanol (0.2 mL) and acetonitrile (0.2 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, to the resulting mixture was added 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.13 mL, 0.13 mmol). The reaction was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with sat. NaHCO3 solution, extracted with dichloromethane, dried over MgSO4 and concentrated to give the desired product. LCMS calculated for C17H22ClN4O2 (M+H)+: m/z=349.1; Found: 349.1.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:8][CH3:9])[C:4](OC)=[O:5].[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=1>>[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH:16][C:4](=[O:5])[CH:3]([O:8][CH3:9])[O:2][CH3:1])=[CH:13][CH:12]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: COC(=O)C(OC)OC
Product: COC(OC)C(=O)NCc1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
Into a vial was added methyl dimethoxyacetate (0.98 g, 7.3 mmol) and 4-chlorobenzylamine (1.0 g, 7.3 mmol), this mixture was stirred at 50° C. for 2 d. The product was recrystallized from Heptane to yield the desired product as an oil that solidified over time. MS (ES+): m/z=244.09/246.05 [MH+]. HPLC: tR=2.80 min (ZQ2, polar—5 min).