Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([PH:7](=[S:14])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18].[OH-].[K+].O>C(Cl)Cl>[C:19]1([C:17]([CH2:16][P:7](=[S:14])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:18])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: S=[PH](c1ccccc1)c1ccccc1
Reactant: O=C(CCl)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: O=C(CP(=S)(c1ccccc1)c1ccccc1)c1ccccc1
Reaction time: 0.75 h

Procedure:
A stirred mixture of diphenylphosphine sulfide (0.218 g, 0.001 mol) and chloroacetophenone (0.216 g, 0.0014 mol) in methylene chloride (4 ml) was cooled to 8–10° C. in an ice-water bath. Small pieces of solid potassium hydroxide (0.196 g, 0.0035 mol) were added while stirring under nitrogen atmosphere. After 45 minute, water (2 ml) was added and the organic layer was separated, washed with more water (2 ml) and dried over sodium sulfate. The solvent was removed under reduced pressure using a rotary evaporator and the oily residue was crystallized from ethyl acetate-hexane mixture to give 0.19 g (56.5%) of star shaped crystals. mp=83–84° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:23]([O:25][C:26](=[O:37])[C@@H:27](OS(C(F)(F)F)(=O)=O)[CH3:28])[CH3:24]>C1COCC1>[CH2:23]([O:25][C:26](=[O:37])[C@H:27]([N:7]1[C:6]2[CH:12]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[O:10][CH2:9][C:8]1=[O:11])[CH3:28])[CH3:24]
Reactant: CCOC(=O)[C@H](C)OS(=O)(=O)C(F)(F)F
Reactant: O=C1COc2ccc(Br)cc2N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](C)N1C(=O)COc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.9 %

Procedure:
To a mixture of 6-bromo-4H-benzo[1,4]oxazin-3-one (59 g, 259 mmol) in anhydrous THF (800 mL) was added KHMDS solution (1M in THF, 259 mL, 259 mmol) drop-wise at 0° C. and the reaction mixture was stirred for 30 min. (S)-2-trifluoromethanesulfonyloxy-propionic acid ethyl ester (Preparation #10, Step B, 117 g, 466 mmol) was added. The reaction mixture was warmed to ambient temperature and stirred for 2 h. The reaction mixture was quenched by the addition of water (1000 mL). The organic phase was separated and the aqueous solution was extracted with EtOAc (4×500 mL). The combined organic phase was washed with brine (1 L), dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 5-10% EtOAc in petroleum ether) to give (R)-2-(6-bromo-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester (82.4 g, 97%) as a brown liquid. 1H NMR (400 MHz, CDCl3) δ 7.12 (d, J=8.8 Hz, 1H), 6.97 (s, 1H), 6.92 (d, J=8.8 Hz, 1H), 5.23 (q, J=6.8 Hz, 2H), 4.67-4.58 (d, J=14.8 Hz, 2H), 4.26-4.20 (m, 2H), 1.60 (d, J=6.8 Hz, 3H), 1.23 (t, J=7.6 Hz, 3H). SFC (Table 1, Method 29) Rt=4.146 min.; [α]D20=31.45 (C=0.002 g/mL in methanol).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[S:11][C:10]([NH2:12])=[N:9][C:8]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.[CH:19]1([C:22](Cl)=[O:23])[CH2:21][CH2:20]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[S:11][C:10]([NH:12][C:22]([CH:19]3[CH2:21][CH2:20]3)=[O:23])=[N:9][C:8]=2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:3]=1
Reactant: O=C(Cl)C1CC1
Reactant: Cc1nc(-c2sc(N)nc2-c2ccccc2)no1
Product: Cc1nc(-c2sc(NC(=O)C3CC3)nc2-c2ccccc2)no1

Procedure:
Prepared from 5-(5-methyl-[1,2,4]oxadiazol-3-yl)-4-phenyl-thiazol-2-ylamine and cyclopropanecarbonyl chloride.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:21]=[CH:20][C:12]3[N:13]=[C:14]([NH:16][C:17](=[O:19])[CH3:18])[S:15][C:11]=3[CH:10]=2)O1.[CH3:23][O:24][C:25]1[N:30]=[C:29](Cl)[CH:28]=[C:27]([Cl:32])[N:26]=1.C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC.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.O.CCO>[Cl:32][C:27]1[N:26]=[C:25]([O:24][CH3:23])[N:30]=[C:29]([C:9]2[CH:21]=[CH:20][C:12]3[N:13]=[C:14]([NH:16][C:17](=[O:19])[CH3:18])[S:15][C:11]=3[CH:10]=2)[CH:28]=1
Reactant: CC(=O)Nc1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2s1
Reactant: COc1nc(Cl)cc(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: COc1nc(Cl)cc(-c2ccc3nc(NC(C)=O)sc3c2)n1
Yield: 13.6 %

Procedure:
Argon is bubbled through a mixture of N-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzothiazol-2-yl]-acetamide (1.12 g, 3.52 mmol), 2-methoxy-4,6-dichloropyrimidine (700 mg, 3.91 mmol), Na2CO3 (625 mg, 5.9 mmol), and bis(triphenylphosphine)palladium(II) chloride (280 mg, 0.4 mmol), in dimethoxyethane (8 mL), water (3.4 mL) and EtOH (2.2 mL) for 10 minutes. The mixture is irradiated by microwave at 160° C. for 10 minutes added water (20 mL) and extracted with EtOAc (40 mL). The organic extracts are combined and dried over magnesium sulfate, filtered and concentrated to afford N-[6-(6-chloro-2-methoxy-pyrimidin-4-yl)-benzothiazol-2-yl]-acetamide (160 mg) as a solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C=O)C>[CH2:11]([NH:18][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: NCc1ccccc1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1NCc1ccccc1
Temperature: 80 °C
Yield: 105.3 %

Procedure:
According to a modification of a procedure by Goker, H. et. al. (II Farmaco 1998, 53, 415-420) a mixture of 1-fluoro-2-nitro-benzene (1067) (1.1 mL, 10.4 mmol) and benzylamine (2.35 mL, 21.5 mmol) in DMF (5 mL) was heated overnight at 80° C. The reaction mixture was concentrated to give an orange solid which was filtered, washed with water and dried to afford benzyl-(2-nitro-phenyl)-amine (1068) (2.5 g, 100%). 1H NMR 6 (400 MHz, CDCl3) 8.44 (b, 1H, NH), 8.22-8.19 (dd, 1H), 7.41-7.27 (m, 6H), 6.84-6.81 (dd, 1H), 6.70-6.66 (m, 1H), 4.58-4.57 (d, 2H).
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:17])[C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1.[N:18]1[CH:23]=[CH:22][CH:21]=[C:20](B(O)O)[CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(#N)C>[Cl:17][C:6]1[C:7]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]2)=[C:2]([C:20]2[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=2)[CH:3]=[N:4][CH:5]=1
Reactant: OB(O)c1cccnc1
Reactant: NC(=O)C1CCN(c2c(Cl)cncc2Cl)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: NC(=O)C1CCN(c2c(Cl)cncc2-c2cccnc2)CC1
Yield: 25.1 %

Procedure:
General procedure D was followed using 1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide 23 (24 mg, 0.088 mmol), pyridin-3-yl boronic acid (12 mg, 0.11 mmol), tetrakis(triphenylphosphine)palladium(0) (5 mg, 5 mol %), acetonitrile (1 mL) and 0.5 M sodium carbonate (0.25 mL, 0.12 mmol) for 30 min. The crude product was purified by preparative tlc on silica gel (CH2Cl2, MeOH, 10:1) to furnish the title compound as a white solid (7 mg, 25%), LC-MS (ESI, 3.5 min) Rt 1.06 min, m/z 317 (100%, [M+H]+); m/z (ESI) C16H18ClN4O requires 317.1164 found [M+H]+ 317.1161.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][CH:5]=[C:6]([C:8]2[CH:24]=[CH:23][C:11]([O:12][C:13]3[CH:18]=[CH:17][N:16]=[C:15]([C:19]([NH:21][CH3:22])=[O:20])[CH:14]=3)=[CH:10][CH:9]=2)[N:7]=1.CC([O-])(C)C.[K+].[Cl:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][C:33]=1[C:41]([F:44])([F:43])[F:42]>CN(C=O)C>[Cl:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([NH:1][C:2]2[N:3]=[N:4][CH:5]=[C:6]([C:8]3[CH:9]=[CH:10][C:11]([O:12][C:13]4[CH:18]=[CH:17][N:16]=[C:15]([C:19]([NH:21][CH3:22])=[O:20])[CH:14]=4)=[CH:23][CH:24]=3)[N:7]=2)=[O:37])=[CH:34][C:33]=1[C:41]([F:42])([F:43])[F:44]
Reactant: O=C(Cl)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CNC(=O)c1cc(Oc2ccc(-c3cnnc(N)n3)cc2)ccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(Oc2ccc(-c3cnnc(NC(=O)c4ccc(Cl)c(C(F)(F)F)c4)n3)cc2)ccn1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
108.6 mg (0.337 mmol, 1.0 eq) of 4-[4-(3-amino-[1,2,4]triazin-5-yl)-phenoxy]-N-methylpyridine-2-carboxamide can be dissolved in 2 mL of anhydrous DMF with heating to about 100° C. 45.4 mg (0.405 mmol, 1.2 equivalent) of solid t-BuOK can be added to the solution, followed by 0.405 mmol (1.2 equivalent) of 4-chloro-3-trifluoromethylbenzoyl chloride. It can be allowed to stir at ambient temperature for 1-2 hours. The product can be isolated by a number of methods known to those skilled in the art, such as precipitation or by extraction with a number of solvents, such as ethyl acetate, methylene chloride or diethyl ether or by silica gel column chromatography, or by reverse-phase prep-HPLC chromatography.
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][C:4]([C:7]([NH:9][CH2:10][C:11]2[CH:12]=[C:13]([NH:17]C(=O)OC(C)(C)C)[CH:14]=[CH:15][CH:16]=2)=[O:8])=[CH:3][CH:2]=1.FC(F)(F)C(O)=O.O>C(Cl)Cl>[NH2:17][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[CH2:10][NH:9][C:7]([C:4]1[CH:5]=[CH:6][C:1]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:2][CH:3]=1)=[O:8]
Reactant: CC(C)(C)OC(=O)Nc1cccc(CNC(=O)c2ccc(-c3ccccc3)cc2)c1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1cccc(CNC(=O)c2ccc(-c3ccccc3)cc2)c1
Reaction time: 8 h
Yield: 102 %

Procedure:
tert-Butyl 3-{[(1,1′-biphenyl-4-ylcarbonyl)amino]methyl}phenylcarbamate (250 mg, 0.6 mmol) was dissolved in DCM (10 ml). Trifluoroacetic acid (0.2 ml) was added. The mixture was stirred overnight. HPLC showed that more than 50% of the starting material was not reacted. More trifluoroacetic acid (0.3 ml) was added. The mixture was stirred overnight again. Water was added into the mixture. The phases were not clear. DCM was evaporated in vacuum Ethyl acetate was added to the residue. The obtained organic phase was washed with water (×3) and dried with magnesium sulphate. The solvent was then evaporated. Solid product (185 mg) was obtained, yield 99%.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:28]=[CH:27][C:9]([C:10]([N:12]([CH3:26])[C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:23][CH2:22][CH:21]([NH:24][CH3:25])[CH2:20]3)=[CH:15][CH:14]=2)=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[CH3:29][N:30]([CH3:35])[CH2:31][C:32](O)=[O:33]>>[CH2:1]([O:5][C:6]1[CH:28]=[CH:27][C:9]([C:10]([N:12]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:23][CH2:22][CH:21]([NH:24][CH2:25][C:32](=[O:33])[CH2:31][N:30]([CH3:35])[CH3:29])[CH2:20]3)=[CH:15][CH:14]=2)[CH3:26])=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CN(C)CC(=O)O
Reactant: CCCCOc1ccc(C(=O)N(C)c2ccc(N3CCC(NC)C3)cc2)cc1
Product: CCCCOc1ccc(C(=O)N(C)c2ccc(N3CCC(NCC(=O)CN(C)C)C3)cc2)cc1

Procedure:
4-Butoxy-N-methyl-N-[4-(3-methylaminopyrrolidin-1-yl)phenyl]benzamide was reacted with N,N-dimethylglycine by method E. This resulted in the product with the molecular weight of 466.63 (C27H38N4O3); MS (ESI): 467 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH:13]=[CH2:14])=[C:11]([NH2:15])[N:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[N:9]=2)=[CH:4][CH:3]=1>[Pd].CCO>[CH2:13]([C:12]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[N:9][N:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[C:11]=1[NH2:15])[CH3:14]
Reactant: C=Cc1c(-c2ccc(F)cc2)nn(-c2ccccc2C)c1N
Agent: [Pd]
Solvent: CCO
Product: CCc1c(-c2ccc(F)cc2)nn(-c2ccccc2C)c1N
Yield: 76.7 %

Procedure:
To a mixture of wet palladium on carbon (10 wt %, 10 mg) in EtOH (5 mL) was added 3-(4-fluorophenyl)-1-(2-methylphenyl)-4-vinyl-1H-pyrazol-5-amine (87 mg, 0.30 mmol) in EtOH (5 mL). The reaction was mixed on a Parr shaker under H2 atmosphere (55 psi) for 16 h. The palladium catalyst was filtered through Celite® and rinsed with EtOH (3×20 mL). The solution was concentrated under reduced pressure to afford the title compound (68 mg, 77%) containing trace impurities. This material was used in subsequent reactions without further purification: ES-MS m/z 296.2 (MH+); HPLC RT (min) 2.65.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:10]([CH3:13])[C:8](=[O:9])[C:7]2=[CH:14][CH:15]=1)([O-])=O.[H][H]>N.O[V](=O)=O.[O-2].[O-2].[Ti+4].[Pd].O>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:10]([CH3:13])[C:8](=[O:9])[C:7]2=[CH:14][CH:15]=1
Reactant: [H][H]
Reactant: CN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O
Agent: O=[V](=O)O
Agent: [Pd]
Agent: [Ti+4]
Solvent: O
Product: CN1C(=O)c2ccc(N)cc2C1=O
Temperature: 63 °C
Reaction time: 75 h
Yield: 94.3 %

Procedure:
0.005 g of ammonium vanadate and 2.5 g 1% by weight of titanium dioxide extrudate containing metallic palladium and having a particle size of 3 mm (from Johnson Matthey) are added to a suspension consisting of 250 ml of water and 10.3 g of 4-nitro-N-methylphthalimide. After displacing the air with nitrogen, the latter is replaced by hydrogen at atmospheric pressure and the suspension is stirred at 63° C. for 75 hours. During this time, 104% of the theoretical amount of hydrogen, based on the 4-nitro-N-methylphthalimide, is absorbed. The resulting suspension is then sieved through a sieve having a mesh width of 1 mm. The material remaining on the sieve is washed with 50 ml of water and the combined aqueous phases are then filtered through a paper filter and washed with 50 ml of water. Drying at 80° C. under reduced pressure (125 mbar) gives 8.3 g (94%) of 4-amino-N-methylphthalimide. The purity determined by high pressure liquid chromatography is 98%.
Reaction SMILES: CC(C([NH:7][C:8]1[N:17]=[C:16]([NH:18]C(C(C)(C)C)=O)[C:15]2[CH2:14][C:13](=[N:25][O:26][C:27]3[CH:32]=[C:31]([Cl:33])[CH:30]=[C:29]([Cl:34])[CH:28]=3)[CH2:12][CH2:11][C:10]=2[N:9]=1)=O)(C)C.Cl.O>O1CCCC1>[NH2:7][C:8]1[N:17]=[C:16]([NH2:18])[C:15]2[CH2:14][C:13](=[N:25][O:26][C:27]3[CH:32]=[C:31]([Cl:33])[CH:30]=[C:29]([Cl:34])[CH:28]=3)[CH2:12][CH2:11][C:10]=2[N:9]=1
Reactant: CC(C)(C)C(=O)Nc1nc2c(c(NC(=O)C(C)(C)C)n1)CC(=NOc1cc(Cl)cc(Cl)c1)CC2
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Nc1nc(N)c2c(n1)CCC(=NOc1cc(Cl)cc(Cl)c1)C2
Temperature: 25 °C

Procedure:
A suspension of 2.5 grams (0.005 mole) of 2,4-di[(1,1-dimethylethyl)carbonylamino]-6-(3,5-dichlorophenoxyimino)-5,6,7,8-tetrahydroquinazoline in 40 mL of tetrahydrofuran is stirred, and a methanolic solution saturated with hydrogen chloride is added portionwise until a clear solution is obtained. After this time about 2 mL of water is added, and the reaction mixture is heated to reflux where it is stirred for about 4 hours. The reaction mixture is then cooled to ambient temperature and is washed with acetone. The reaction mixture is concentrated under reduced pressure, yielding 2,4-diamino-6-(3,5-dichlorophenoxyimino)-5,6,7,8-tetrahydroquinazoline.
Reaction SMILES: [C:1]([N:8]([CH2:10][C:11]([OH:13])=O)[CH3:9])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:47][C:48]([F:57])([F:56])[C:49]1[CH:50]=[C:51]([CH:53]=[CH:54][CH:55]=1)[NH2:52]>CCOC(C)=O.CN(C=O)C>[C:4]([O:3][C:1](=[O:2])[N:8]([CH3:9])[CH2:10][C:11](=[O:13])[NH:52][C:51]1[CH:53]=[CH:54][CH:55]=[C:49]([C:48]([F:47])([F:56])[F:57])[CH:50]=1)([CH3:5])([CH3:6])[CH3:7]
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(CC(=O)Nc1cccc(C(F)(F)F)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.8 %

Procedure:
To a 25 mL round bottomed flask was added Boc-sarcosine (378 mg, 2.0 mmol, 1.0 eq.), DMF (10.0 mL), DIEA (0.35 mL, 2.0 mmol, 2.0 eq.), HATU (836 mg, 2.2 mmol, 2.2 eq.) and 3-trifluoromethylaniline (0.4 mL, 3.0 mmol, 1.5 eq.). The reaction was allowed to stir at RT overnight before quenching with H2O (20 mL) and EtOAc (100 mL). The organic layer was then washed 2× with 10% LiCl, washed with brine, dried with Na2SO4, and concentrated to give an oil. Further drying on high vacuum then gave a solid. Column chromatography on silica gel with 60:40 EtOAc:Hex gave methyl-[(3-trifluoromethyl-phenylcarbamoyl)-methyl]-carbamic acid tert-butyl ester (431 mg, 64%). LC/MSD (HP Series 1100 MSD): Expected MW: 332, Observed M−H: 331, Retention time: 1.6 min. 1H-NMR (d6-DMSO): 10.35 (d, 1H), 8.10 (d, 1H), 7.75 (dd, 1H), 7.55 (t, 1H), 7.40 (d, 1H), 4.00 (d, 2H), 2.88 (d, 3H), 1.40 (d, 9H) ppm.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[C:10]([CH3:19])([CH3:18])[CH2:9]2)=[CH:3][CH:2]=1.[CH2:20]([N:26]=[C:27]=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>>[CH2:20]([NH:26][C:27](=[O:28])[O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)[CH2:9][C:10]2([CH3:19])[CH3:18])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CC1(C)CN(Cc2ccncc2)c2ccc(O)cc21
Reactant: CCCCCCN=C=O
Product: CCCCCCNC(=O)Oc1ccc2c(c1)C(C)(C)CN2Cc1ccncc1

Procedure:
The title compound was synthesized from 1-(4-pyridylmethyl)-3,3-dimethylindolin-5-ol (20.0 mg, 0.09 mmol) using the same procedure employed for Example 2 (2), but with n-hexylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained as a white solid (10.4 mg, 35%) having the following characteristics.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([C:18]3[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH:19]=3)[CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].[C:26]([C:28]1[CH:29]=[C:30]([C:33](O)=[O:34])[NH:31][CH:32]=1)#[N:27].Cl.CN(C)CCCN=C=NCC.OC1C2N=NNC=2C=CC=1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:1][O:2][C:3]([C:5]1([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:33]([C:30]3[NH:31][CH:32]=[C:28]([C:26]#[N:27])[CH:29]=3)=[O:34])=[C:13]([C:18]3[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH:19]=3)[CH:12]=2)[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1)=[O:4]
Reactant: COC(=O)C1(c2ccc(N)c(C3=CCC(C)(C)CC3)c2)CCOCC1
Reactant: N#Cc1c[nH]c(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)C1(c2ccc(NC(=O)c3cc(C#N)c[nH]3)c(C3=CCC(C)(C)CC3)c2)CCOCC1
Yield: 49.8 %

Procedure:
A solution of 4-[4-amino-3-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-tetrahydro-pyran-4-carboxylic acid methyl ester (as prepared in Example 16, step (d), 68.7 mg, 0.200 mmol), 4-cyano-1H-pyrrole-2-carboxylic acid (Canadian J. Chem. 59, 2673 (1981), 40.8 mg, 0.300 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (57.5 mg, 0.300 mmol), hydroxybenzotriazole (HOBt) (40.5 mg, 0.300 mmol) and DIEA (105 μL, 0.600 mmol) in 2.5 mL of DMF was stirred at RT for 2 d under Ar. The resulting mixture was treated with H2O (20 mL) and extracted with EtOAc (2×25 mL). The combined organic layers were washed with H2O (10 mL) and brine (10 mL). After drying over Na2SO4 and concentrating in vacuo, the residue was purified by silica gel chromatography (10-20% EtOAc/DCM) to afford the title compound (46 mg, 50%) as a white solid. Mass spectrum (ESI, m/z): Calcd. for C27H31N3O4, 462.2 (M+H). found 462.2.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Br:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(N(CC)CC)C.[C:20](Cl)(=[O:22])[CH3:21]>ClCCl>[C:20]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([Br:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8])(=[O:22])[CH3:21]
Reactant: COC(=O)c1cc(N)ccc1Br
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc(NC(C)=O)ccc1Br
Temperature: 0 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
Methyl 5-amino-2-bromobenzoate (Reference Compound No. 1-(1), 21.0 g, 91.2 mmol) was dissolved in anhydrous dichloromethane (450 mL), triethylamine (19.0 mL, 137 mmol) and acetyl chloride (13.0 mL, 182 mmol) were added dropwise over 30 minutes successively, and then the mixture was stirred at 0° C. for 2 hours. The reaction mixture was washed with water (200 mL, 2 times), saturated aqueous sodium hydrogen carbonate solution (200 mL, 2 times), and saturated brine (200 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was filtered with hexane-ethyl acetate (20:1) to give the titled reference compound (24.2 g) as a pale yellow solid. (Yield 98%)
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-])=O)=[CH:4][C:3]=1[O:12][CH3:13]>C(O)C.C(N(CC)CC)C.[Pd]>[F:8][C:6]1[CH:7]=[CH:2][C:3]([O:12][CH3:13])=[CH:4][C:5]=1[NH2:9]
Reactant: COc1cc([N+](=O)[O-])c(F)cc1Cl
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc(F)c(N)c1
Yield: 71.7 %

Procedure:
A solution of 5.63 g of 2-chloro-4-fluoro-5-nitroanisole in 90 ml of ethanol and 5 ml of triethylamine was hydrogenated at room temperature under 60 pounds per square inch with 1.0 g of 5% palladium on carbon for four hours. The catalyst was filtered off and the solvent was evaporated. The residue was slurried in chloroform and filtered thourough a plug of silica gel and then evaporated. This residue was chromatographed on silica gel using hexane/chloroform mixtures to afford 2.77 g (72%) of the subtitle compound. mp. 253-254° C. NMR (300 MHz, CDCl3): δ 6.88 (dd, J=10.6, 8.9, 1H); 6.32 (dd, J=7.4, 3.0, 1H); 6.20 (dt, J=8.9, 3.2,1H); 3.73 (s, 3H); 3.72 (br, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([CH:12]([CH3:17])[C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:18][Si]([N-][Si](C)(C)C)(C)C.[Li+].IC.O>C1COCC1.CCOCC>[CH3:17][C:12]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]2)([CH3:18])[C:13]([O:15][CH3:16])=[O:14]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COC(=O)C(C)c1cccc2ccc(C)nc12
Agent: [Li+]
Solvent: CCOCC
Solvent: CI
Solvent: O
Product: COC(=O)C(C)(C)c1cccc2ccc(C)nc12
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 43.9 %

Procedure:
To a mixture of NaH (0.58 g, 14.43 mmol) in DMSO (15 mL) at 20-35° C. was slowly added a solution of methyl 2-(2-methylquinolin-8-yl)acetate (1.35 g, 6.272 mmol) and iodomethane (1.08 ml, 17.25 mmol) in THF (5 mL). The reaction mixture was stirred at ambient temperature for 20 hours. Brine (20 mL) and ether (50 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure to give methyl 2-(2-methylquinolin-8-yl)propanoate (1.44 g, 100%) as an oil. The methyl 2-(2-methylquinolin-8-yl)propanoate (1.44 g, 6.28 mmol) was taken up in THF (10 mL) and 1 N lithium bis(trimethylsilyl)amide (12.56 mL, 12.56 mmol) in THF was added at 0° C. After addition, the reaction mixture was stirred at ambient temperature for 40 minutes. Iodomethane (0.78 mL, 12.56 mmol) was added dropwise and the reaction mixture was stirred at ambient temperature for 18 hours. Water (10 mL) and ether (50 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (8:1 hexane/ethyl acetate) to give methyl 2-methyl-2-(2-methylquinolin-8-yl)propanoate (0.67 g, 43.9%) as an oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:35])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[Cl:34])[CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C1(C)C=CC=CC=1>Cl.C(O)C>[Cl:34][C:28]1[CH:29]=[C:30]([Cl:33])[CH:31]=[CH:32][C:27]=1[CH2:26][CH2:25][O:24][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=1[O:22][CH3:23])[C:15]([NH:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)=[O:35]
Reactant: COc1ccc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)cc1OCCc1ccc(Cl)cc1Cl
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(C(=O)NC2CCNCC2)cc1OCCc1ccc(Cl)cc1Cl

Procedure:
1.4 g 4-{3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-benzoylamino}-piperidine-1-carboxylic acid tert-butyl ester was suspended in 20 ml HCl in ethanol at RT. After 2 h a clear solution was obtained. Addition of 50 ml toluene followed by evaporation of the solvent and repeatedly coevaporation of the residue with toluene yielded the product as a white foam.