Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7](Cl)[N:6]=[C:5]([OH:10])[CH:4]=1)[CH3:2].[CH3:11][CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14][NH:13]1>>[CH2:1]([C:3]1[N:8]=[C:7]([N:13]2[CH2:14][CH2:15][C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:12]2[CH3:11])[N:6]=[C:5]([OH:10])[CH:4]=1)[CH3:2]
Reactant: CCc1cc(O)nc(Cl)n1
Reactant: CC1NCCc2ccccc21
Product: CCc1cc(O)nc(N2CCc3ccccc3C2C)n1
Yield: 80.2 %

Procedure:
In accordance with the same procedure as in Step 2 of Example 57, except that 6-ethyl-2-chloro-4-hydroxypyrimidine (7.0 g, 37.5 mmol) prepared in the above Step 1 and 1-methyl-1,2,3,4-tetrahydroisoquinoline(11.04 g, 75 mmol) were used as starting materials, 8.1 g of the titled compound was prepared. (Yield: 80%)
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[CH:5][CH:6]=1.C([Li])(C)(C)C.CCCCCC.C1COCC1.Br[C:24]1[S:28][C:27]([C:29]2[N:33]3[N:34]=[C:35]([CH3:43])[CH:36]=[C:37]([CH:38]([CH2:41][CH3:42])[CH2:39][CH3:40])[C:32]3=[N:31][C:30]=2[CH3:44])=[C:26]([CH3:45])[CH:25]=1>CCOC(C)=O.[Cl-].[Cl-].[Zn+2].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].CCOCC>[CH2:39]([CH:38]([C:37]1[C:32]2[N:33]([C:29]([C:27]3[S:28][C:24]([C:4]4[O:3][C:2]([CH3:1])=[CH:6][CH:5]=4)=[CH:25][C:26]=3[CH3:45])=[C:30]([CH3:44])[N:31]=2)[N:34]=[C:35]([CH3:43])[CH:36]=1)[CH2:41][CH3:42])[CH3:40]
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(Br)cc3C)c(C)nc12
Reactant: Cc1ccco1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cl-]
Solvent: CCOCC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCC(CC)c1cc(C)nn2c(-c3sc(-c4ccc(C)o4)cc3C)c(C)nc12
Temperature: 0 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
To a 0° C. mixture of 2-methylfuran (0.18 mL, 2.04 mmol) and Et2O (2 mL) is added 1.6 M t-Bu-Li in hexane (1.30 mL, 2.14 mmol). The mixture is heated at a reflux for 30 minutes, cooled to 0° C., and 0.5 M ZnCl2 in THF (4.3 mL, 2.14 mmol) is added and the solution warmed to ambient temperature. 3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.40 g, 1.02 mmol) and PdCl2(dppf) (0.037 g, 0.051 mmol) is added and mixture is stirred at 65° C. overnight, diluted with EtOAc (30 mL), washed with 10% citric acid (15 mL), water (15 mL), brine (15 mL), dried over MgSO4, filtered and concentrated. The residue is purified by ISCO column chromatography (20% EtOAc/hexane gradient) furnish the title compound (0.20 g, 0.51 mmol, 50%). 1H NMR (CDCl3), δ 0.89 (t, J=7.5 Hz, 6H), 1.74-1.92 (m, 4H), 2.12 (s, 3H), 2.35 (s, 3H), 2.48 (s, 3H), 2.51 (s, 3H), 3.29-3.38 (m, 1H), 6.62 (dd, J=3.1, 0.9 Hz, 1H), 6.40 (d, J=3.1 Hz, 1H), 6.66 (s, 1H), 7.12 (s, 1H). LC/MS (m/z): calcd. for C23H27N3OS (M+H)+: 394.3; found: 394.2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8](Br)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[C:10]1([CH2:9][CH2:8][NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: BrCCc1ccccc1
Reactant: Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: c1ccc(CCNc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of aniline (9.1 ml, 100 mmol), phenethylbromide 18.5 g, 100 mmol), potassiumcarbonate (13.8 g, 100 mmol) and 50 ml dimethylsulfoxide is stirred at ambient temperature for 72 hours, and is diluted with 200 ml water. The mixture is extracted three times with diethylether and the combined organic phases is washed with water and brine and dried over magnesium sulphate. The solution is concentrated in vacuo and the crude product is subjected to a vacuum distillation yielding the title compound as a colourless oil dest. 120°-128° C./0.7 mbar.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([NH:36][C:37](=[O:49])[C:38]([NH:41]C(=O)OC(C)(C)C)([CH3:40])[CH3:39])[C:11]([N:13]1[CH2:35][CH2:34][CH2:33][C:15]2([C:19](=[O:20])[N:18]([CH2:21][C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[CH2:17][CH:16]2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:14]1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:41][C:38]([CH3:40])([CH3:39])[C:37]([NH:36][C@H:10]([CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:11]([N:13]1[CH2:35][CH2:34][CH2:33][C:15]2([C:19](=[O:20])[N:18]([CH2:21][C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[CH2:17][CH:16]2[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:14]1)=[O:12])=[O:49]
Reactant: CN(C)C(=O)CN1CC(c2ccccc2)C2(CCCN(C(=O)[C@@H](COCc3ccccc3)NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C2)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)CN1CC(c2ccccc2)C2(CCCN(C(=O)[C@@H](COCc3ccccc3)NC(=O)C(C)(C)N)C2)C1=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A diasteromeric mixture of tert-butyl 1-((2R)-3-(benzyloxy)-1-(2-(2-(dimethylamino)-2-oxoethyl)-1-oxo-4-phenyl-2,7-diazaspiro[4.5]decan-7-yl)-1-oxopropan-2-ylamino)-2-methyl-1-oxopropan-2-ylcarbamate (386 mg; 0.569 mmol) was solubilised in dichloromethane (3 ml) at room temperature. Trifluoroacetic acid (439 ul; 5.69 mmol) was added and mixture stirred at RT for 72 hours. The solvent was removed in vacuo and the crude product was dissolved in methanol and loaded onto a pre-wetted 10 g SCX-2 cartridge. Methanol (50 ml) was passed through the cartridge and the product was eluted with 2M NH3 in methanol. Concentration of the ammonia fraction afforded the title compound as a diastereomeric mixture. Diastereomers were separated by chiral SFC, collecting the second peak.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([O-:5])=O.[K+].[Cl-].[Mg+2].[Cl-].[Cl:14][C:15]1[CH:23]=[CH:22][C:18](C(O)=O)=[CH:17][CH:16]=1.S(Cl)(Cl)=O>C(OCC)(=O)C.C(N(CC)CC)C.CN(C)C=O.C1(C)C=CC=CC=1>[CH2:8]([O:7][C:1](=[O:6])[CH2:2][C:3]([C:18]1[CH:22]=[CH:23][C:15]([Cl:14])=[CH:16][CH:17]=1)=[O:5])[CH3:9]
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: CCOC(=O)CC(=O)[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Mg+2]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(=O)c1ccc(Cl)cc1
Reaction time: 18 h
Yield: 88.4 %

Procedure:
To a suspension of potassium ethyl malonate (8.2 g) in ethyl acetate (100 mL), triethylamine (17 mL) and magnesium chloride (5.5 g) were added under ice cooling. The temperature of the resultant mixture was returned gradually to room temperature, and the mixture was stirred for 18 hours. In addition, a suspension of 4-chlorobenzoic acid (5.0 g), thionyl chloride (12 mL), N,N-dimethylformamide (1 drop), and toluene (100 mL) was heated under reflux for 1 hour, and the reaction mixture was concentrated. The residue was dissolved in ethyl acetate, and the solution was added dropwise to the above mixture under ice cooling. The temperature of the mixture was gradually returned to room temperature, and the mixture was stirred for 18 hours. 10% Aqueous citric acid was added to the reaction mixture, and the mixture was stirred for 30 minutes, and the organic layer was partitioned. The resultant organic layer was washed with saturated brine, followed by drying over sodium sulfate anhydrate. The solvent was distilled away under reduced pressure. The residue was separated and purified by silica gel column chromatography (chloroform), to thereby give the title compound (6.4 g).
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:11]=2[N:10]=[C:9]1[C@@H:18]([NH:24][C:25](=[O:40])[C:26]1[CH:31]=[CH:30][C:29]([C:32]([N:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)=[O:33])=[C:28]([CH3:39])[CH:27]=1)[CH2:19][CH2:20][C:21]([OH:23])=[O:22])=O)(C)(C)C.FC(F)(F)C(O)=O.ClCl>C(OCC)(=O)C.C(O)C.C(O)(=O)C>[Cl:17][C:15]1[CH:14]=[CH:13][C:12]2[NH:8][C:9]([C@@H:18]([NH:24][C:25](=[O:40])[C:26]3[CH:31]=[CH:30][C:29]([C:32]([N:34]4[CH2:38][CH2:37][CH2:36][CH2:35]4)=[O:33])=[C:28]([CH3:39])[CH:27]=3)[CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[N:10][C:11]=2[CH:16]=1
Reactant: Cc1cc(C(=O)N[C@@H](CCC(=O)O)c2nc3cc(Cl)ccc3n2C(=O)OC(C)(C)C)ccc1C(=O)N1CCCC1
Agent: ClCl
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)N[C@@H](CCC(=O)O)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Yield: 68 %

Procedure:
Prepared analogously to Example 17 from N-[(1S)-1-(1-tert-butoxycarbonyl-5-chlorobenzimidazol-2-yl)-3-hydroxycarbonylpropyl]-3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzamide and trifluoroacetic acid. Yield: 68%; Rf value: 0.50 (silica gel; ethyl acetate/ethanol/acetic acid=85:15:5); C24H25ClN4O4 (468.94); mass spectrum: (M+H)+=469/471 (chlorine isotope).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:9]/[CH:10]=[CH:11]/[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.[N+:20]([C:23]1[CH:28]=[CH:27][C:26](O)=[CH:25][CH:24]=1)([O-:22])=[O:21].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:20]([C:23]1[CH:28]=[CH:27][C:26]([O:13][C:12](=[O:14])/[CH:11]=[CH:10]/[CH:9]=[C:8](/[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)\[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:25][CH:24]=1)([O-:22])=[O:21]
Reactant: CCCCC/C(=C\C=C\C(=O)O)c1ccc(F)cc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCC/C(=C\C=C\C(=O)Oc1ccc([N+](=O)[O-])cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 69.6 %

Procedure:
As in Example 115, (E,E)-5-(4-fluorophenyl)-2,4-decadienoic acid (4.78 g) and 4-nitrophenol (3.14 g) in 20 mL of dichloromethane was treated with 1,3- dicyclohexylcarbodiimide (3.8 g) and the mixture was stirred at room temperature for 3 days. After the usual work up. crystallization of the crude ester from 2-propanol-hexane gave 4.86 g of (E,E)-5-(4-fluorophenyl)-2,4-decadienoic acid 4-nitrophenyl ester, mp 71°-72,5° C.
Reaction SMILES: C(OC([N:8]1[C:14]2[CH:15]=[CH:16][C:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][O:28][CH2:29][CH3:30])=[CH:21][CH:20]=3)=[CH:18][C:13]=2[CH:12]=[C:11]([C:31]([O:33][CH3:34])=[O:32])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.[OH-].[Na+]>C(OCC)(=O)C>[CH2:29]([O:28][CH2:27][CH2:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([C:17]2[CH:16]=[CH:15][C:14]3[NH:8][CH2:9][CH2:10][C:11]([C:31]([O:33][CH3:34])=[O:32])=[CH:12][C:13]=3[CH:18]=2)=[CH:24][CH:23]=1)[CH3:30]
Reactant: CCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3C(=O)OC(C)(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1
Temperature: 80 °C
Reaction time: 0.75 h
Yield: 81 %

Procedure:
In ethyl acetate (50 ml) was dissolved methyl 1-(t-butoxycarbonyl)-7-[4-(2-ethoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (1.1 g). To the solution was added 6N hydrochloric acid (20 ml), and the mixture was stirred at 80° C. for 45 minutes, neutralized with 1N sodium hydroxide solution and was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give methyl 7-[4-(2-ethoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.7 g) as yellow crystals.
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:19]=[C:20]([C:23]([OH:25])=[O:24])[S:21][CH:22]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH2:26]([O:28][CH2:29][CH2:30]O)[CH3:27].B(F)(F)F.CCOCC>C1(C)C=CC=CC=1>[CH2:1]([NH:17][C:18]1[CH:19]=[C:20]([C:23]([O:25][CH2:27][CH2:26][O:28][CH2:29][CH3:30])=[O:24])[S:21][CH:22]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCOCCO
Reactant: CCCCCCCCCCCCCCCCNc1csc(C(=O)O)c1
Agent: FB(F)F
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCNc1csc(C(=O)OCCOCC)c1
Reaction time: 120 h

Procedure:
A solution of 11.8 g. of 4-(hexadecylamino)-2-thiophenecarboxylic acid, 1.00 g. of 2-ethoxyethanol and 5.35 ml. of boron trifluoride etherate in 200 ml. of toluene is stirred under reflux for 48 hours. The solution is treated with an additional 5.35 ml. of boron trifluoride etherate and refluxing is continued for 120 hours. Dilution with water and methylene chloride followed by filtration affords 2-ethoxyethyl 4-(hexadecylamino)-2-thiophenecarboxylate as a white solid.
Reaction SMILES: O=[C:2]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:4]2([CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:11])[CH2:6][CH2:5]2)[CH2:3]1.[NH2:26][OH:27].Cl.CC([O-])=O.[Na+]>CCO>[OH:27][N:26]=[C:2]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:4]2([CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:11])[CH2:6][CH2:5]2)[CH2:3]1
Reactant: NO
Reactant: O=C1CC2(CCN(C(=O)OCc3ccccc3)CC2)c2ccccc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C(OCc1ccccc1)N1CCC2(CC1)CC(=NO)c1ccccc12
Yield: 87 %

Procedure:
A solution of benzyl 3-oxo-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate (3 g, 10.3 mmol) in EtOH (30 mL) containing NH2OH.HCl (1.43 g, 20.6 mmol) and NaOAc (1.52 g, 18.53 mmol) was heated under reflux for 1.5 h. The solvent was removed by evaporation and the residue was partitioned between CH2Cl2 and water. The organic phase was washed with brine, dried over Na2SO4, and concentrated to provide benzyl 3-(hydroxyimino)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate (3.14 g, yield 99%), which was used directly in the next step.
Reaction SMILES: C([N:4]([C@@H:19]([CH3:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C@@H:5]([C:14]1[O:15][CH:16]=[CH:17][CH:18]=1)[CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])C=C.C(OC(C)(C)C)(=O)C=CC=C.C(N([C@@H](C)C1C=CC=CC=1)[C@@H](C=CC1C=CC=CC=1)CC(OC(C)(C)C)=O)C=C.C(N([C@@H](C)C1C=CC=CC=1)[C@@H](C1C=CC=CC=1)[C@H](O)C(OC(C)(C)C)=O)C=C>C(Cl)(Cl)Cl>[CH3:26][C@H:19]([NH:4][C@@H:5]([C:14]1[O:15][CH:16]=[CH:17][CH:18]=1)[CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:11])[CH3:12])=[O:8])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: C=CCN([C@H](CC(=O)OC(C)(C)C)c1ccco1)[C@@H](C)c1ccccc1
Agent: C=CC=CC(=O)OC(C)(C)C
Agent: C=CCN([C@@H](C)c1ccccc1)[C@@H](c1ccccc1)[C@H](O)C(=O)OC(C)(C)C
Agent: C=CCN([C@@H](C=Cc1ccccc1)CC(=O)OC(C)(C)C)[C@@H](C)c1ccccc1
Solvent: ClC(Cl)Cl
Product: C[C@H](N[C@H](CC(=O)OC(C)(C)C)c1ccco1)c1ccccc1

Procedure:
The title compound (33) was prepared from compound (14) of Example 5 using the above-described procedure. [α]D21 -1.5 (c 1.74, CHCl3); νmax (CHCl3)/cm-1 1729 s (C=O); δH (300 MHz; CDCl3) 7.32-7.20 (6H, m, Ph, OCH=CH), 6.28 (1H, dd, J=3.2 and 1.9, OCH=CH), 6.15 (1H, d, J=3.2, OCH=CH), 4.19 (1H, t, J=6.9, NCHCH2), 3.76 (1H, q, J=6.5, PhCHCH3); δC (50 MHz; CDCl3) 170.93 (C=O), 156.00 (OC=CH), 146.15 (Ph:Cipso), 141.78 (OCH=CH), 128.61, 126.81 (Ph:Cortho, Cmeta), 127.14 (Ph:Cpara), 110.10 (OCH=CH), 106.40 (OC=CH), 80.55 (C(CH3)3), 54.97, 50.83 (CHN), 40.72 (CH2CO), 27.96 (C(CH3)3), 23.04 (NCHCH3); m/z (CI) 316 (MH+, 100%), 260 (25), 200 (25), 154 (20), 120 (25), 105 (27); (Found: C, 72.37; H, 8.04; N, 4.31. C19H25NO3 requires C, 72.35; H, 7.99; N, 4.44%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].CN1CCOCC1.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][N:11]([C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(Cl)c1ccccc1
Reactant: OCCC1(c2ccc(Cl)c(Cl)c2)CCNC1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=C(c1ccccc1)N1CCC(CCO)(c2ccc(Cl)c(Cl)c2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 70.8 %

Procedure:
3-(3,4-Dichloro-phenyl)-3-(2-hydroxy-ethyl)-pyrrolidine (6.37 g, 24.5 mmol) was dissolved in dichloromethane (100 mL) at -78° C. and treated with 4-methylmorpholine (5.5 mL, 50 mmol, 2.0 eq.) and benzoyl chloride (3.0 mL, 25.8 mmol, 1.05 eq. ). The solution was allowed to warm to 0° C. and stir for 2 hours. The reaction mixture was washed with 1N HCl and 5% NaHCO3, and the organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel (300 g) with a gradient from ethyl acetate to 10% methanol in dichloromethane to give 6.32 g (71%) of the title compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:11](=[O:13])[NH:10][C@H:9]3[CH2:14][NH:15][CH2:16][C@@H:8]3[C:7]=2[CH:6]=[C:5]([CH2:17][CH3:18])[CH:4]=1>CO.[Pd]>[ClH:2].[CH2:17]([C:5]1[CH:4]=[CH:3][C:12]2[C:11](=[O:13])[NH:10][C@H:9]3[CH2:14][NH:15][CH2:16][C@@H:8]3[C:7]=2[CH:6]=1)[CH3:18]
Reactant: CCc1cc(Cl)c2c(c1)[C@H]1CNC[C@@H]1NC2=O
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCc1ccc2c(c1)[C@H]1CNC[C@@H]1NC2=O

Procedure:
To a solution of (3aR,9bS)-6-chloro-8-ethyl-2,3,3a,4-tetrahydro-1H-pyrrolo[3,4-c]isoquinolin-5(9bH)-one hydrochloride (the title compound of Example 29) (36 mg, 0.12 mmol) in 5 mL of methanol was added 10% Pd/C catalyst (2.5 mg). The mixture was stirred at room temperature under 1 atm of hydrogen maintained by a balloon for 3 h. The reaction mixture was filtered through a pad of Celite and concentrated in vacuo. The resulting solid was triturated with ether and dried in vacuo to afford 25 mg (80%) of the title compound of Example 40 as an off-white solid. 1H NMR (CD3OD): δ 7.91 (d, 1H, J=8.3 Hz), 7.32 (d, 1H, J=7.7 Hz), 7.10 (s, 1H), 4.10-4.03 (m, 1H), 3.80-3.68 (m, 2H), 3.47-3.39 (m, 2H), 3.30-3.25 (m, 1H), 2.72 (q, 2H, J=7.5 Hz), 1.25 (t, 3H, J=7.7 Hz). LRMS (ESI): 217.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([O:12][Si](C)(C)C)=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:2].[F:17]OC(F)(F)F>C(Cl)(Cl)(Cl)F>[F:17][CH:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:12]
Reactant: CCOC(=Cc1ccccc1)O[Si](C)(C)C
Reactant: FOC(F)(F)F
Solvent: FC(Cl)(Cl)Cl
Product: CCOC(=O)C(F)c1ccccc1
Temperature: 25 °C
Yield: 76.4 %

Procedure:
A solution of 21.28 g (0.09 mol) of β-ethoxy-β-trimethylsiloxystyrene (from above) in 200 ml of CFCl3 was cooled to -70° C. and 9.4 g (0.09 mol) of trifluoromethyl hypofluorite were passed into the solution over a period of 3 hours. The reaction mixture was warmed to room temperature and then distilled to give 12.52 g (77% yield) of ethyl α-fluorobenzeneacetate as a colorless liquid: bp 96°-98° C. (4.8 mm); 19F NMR (CFCl3) δ-180.1 ppm (d,J=48 Hz); 1H NMR (CFCl3) δ 1.10 ppm (t,J=7 Hz, 2H), 4.10 ppm (q,J=7 Hz, 2H), 5.66 ppm (d,J=48 Hz, 1H) and 7.1-7.6 ppm (m, 5H). Anal. Calcd. for C10H11FO2 : C, 65.92; H, 6.07; F, 10.43; Found: C, 66.09; H, 6.13; F, 10.33.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.C(Cl)[Cl:11].S(Cl)(Cl)=O>N1C=CC=CC=1>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([Cl:11])=[O:9]
Reactant: O=C(O)c1cnccn1
Reactant: ClCCl
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: O=C(Cl)c1cnccn1
Temperature: 30 °C

Procedure:
A mixture of 68.2 g (0.55 moles) 2-pyrazine carboxylic acid and methylene chloride (about 200 ml) containing a catalytic amount of pyridine was warmed (to about 30° C.). To that mixture, 78.5 g (0.66 mole) thionyl chloride was added dropwise. The reaction mixture was refluxed for 24 hours. The methylene chloride was removed under reduced pressure and heat to give the 2-pyrazine carboxylic acid chloride which was used in step (b) without further isolation.
Reaction SMILES: CN(C=O)C.FC(F)(F)C(O)=O.[F:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([NH:21][C:22]2[N:27]=[C:26]([NH:28][C:29]3[CH:30]=[CH:31][C:32]4[O:36][C:35](=[O:37])[NH:34][C:33]=4[CH:38]=3)[C:25]([CH3:39])=[CH:24][N:23]=2)=[CH:16][C:15]=1[O:40][CH3:41].C([O-])([O-])=O.[Cs+].[Cs+].[P:48]([O:60][CH2:61]Cl)([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49]>O>[P:48]([O:60][CH2:61][N:34]1[C:33]2[CH:38]=[C:29]([NH:28][C:26]3[C:25]([CH3:39])=[CH:24][N:23]=[C:22]([NH:21][C:17]4[CH:18]=[C:19]([CH3:20])[C:14]([F:13])=[C:15]([O:40][CH3:41])[CH:16]=4)[N:27]=3)[CH:30]=[CH:31][C:32]=2[O:36][C:35]1=[O:37])([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])([O:55][C:56]([CH3:57])([CH3:58])[CH3:59])=[O:49]
Reactant: CC(C)(C)OP(=O)(OCCl)OC(C)(C)C
Reactant: COc1cc(Nc2ncc(C)c(Nc3ccc4oc(=O)[nH]c4c3)n2)cc(C)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(Nc2ncc(C)c(Nc3ccc4oc(=O)n(COP(=O)(OC(C)(C)C)OC(C)(C)C)c4c3)n2)cc(C)c1F
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
With reference to Scheme (XI), A DMF (300 mL) suspension of 5-(2-(4-fluoro-3-methoxy-5-methylphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one trifluoroacetate (prepared as described in Example 3)(40.38 g, 79 mmol) and Cs2CO3 (78.3 g, 238 mmol) was stirred at rt under Nitrogen atmosphere, after 2.5 h, di-tert-butyl chloromethyl phosphate (26.6 g, 103 mmol) was added and stirring was continued at room temperature. After 49 h, by LC-MS, the reaction was >90% complete (note: due to relatively poor quality of alkylating agent of this batch, additional ˜7 g of di-tert-butyl chloromethyl phosphate was added). With stirring, the reaction mixture was poured into 1.2 L of H2O, ppt formed and was a bit lumpy, additional 500 mL of H2O was added to ensure the formation of non-sticky solid. Precipitate was collected by filtration, washed with water, and was further dried under high vac. Compound di-tert-butyl (5-(2-(4-fluoro-3-methoxy-5-methylphenylamino)-5-methylpyrimidin-4-ylamino)-2-oxobenzo[d]oxazol-3(2H)-yl)methyl phosphate was obtained as a light brown solid and was used directly in the next reaction.
Reaction SMILES: C(OC(=O)[N:7]([CH:15]1[CH2:17][CH2:16]1)[C@H:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[F:14])(C)(C)C.Cl[C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=1>>[CH:15]1([NH:7][C@H:8]2[CH2:13][CH2:12][N:11]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=3)[CH2:10][C@H:9]2[F:14])[CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)N(C1CC1)[C@H]1CCNC[C@H]1F
Reactant: FC(F)(F)c1ccc(Cl)nc1
Product: F[C@@H]1CN(c2ccc(C(F)(F)F)cn2)CC[C@@H]1NC1CC1

Procedure:
The title compound is prepared from cyclopropyl-[(3R,4S)-3-fluoro-piperidin-4-yl]-carbamic acid tert-butyl ester and 2-chloro-5-trifluoromethyl-pyridine following a procedure analogous to that described for Intermediate 73.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([OH:20])=O)[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:54]([CH2:56][CH2:57][NH:58][CH2:59][CH2:60][CH2:61][C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1)#[N:55]>O1CCCC1>[C:54]([CH2:56][CH2:57][N:58]([CH2:59][CH2:60][CH2:61][C:62]1[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=1)[C:18](=[O:20])[C@H:9]([CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])#[N:55]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCc1ccccc1)C(=O)O
Reactant: N#CCCNCCCc1ccccc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](CCc1ccccc1)C(=O)N(CCC#N)CCCc1ccccc1
Reaction time: 8 h

Procedure:
A solution of Boc-homophenylalanine (136 mg, 0.49 mmol), diisopropylethylamine (169 μl mg, 0.97 mmol), and tetrahydrofuran (3 ml) was treated with PyBrop (248 mg, 0.63 mmol) at 0° C. (2-cyanoethyl)-3-phenylpropylamine (109 mg, 0.58 mmol) in tetrahydrofuran (2 ml) was added dropwise and the reaction mixture was stirred overnight. The solid was filtered and rinsed with ethyl acetate, and the filtrate was concentrated and purified by chromatography to give Boc-homophenylalanine (2-cyanoethyl)-3-phenylpropylamide. A mixture of above product (200 mg), 10% palladium-on-carbon (20 mg), and methanol (40 ml) was hydrogenated on a Parr hydrogenator (40 psi) overnight. The catalyst was removed by filtration through Celite and the filtrate was concentrated in vacuo. The residue was then treated with trifluoroacetic acid for 30 min. The solvent was removed in vacuo and the product was purified by reverse phase HPLC to give white solid: 1H NMR (400 MHz, D2O) δ1.8-2.1 (m, 6H), 2.5-2.8 (m, 4H), 3.0-3.3 (m, 4H), 3.3-3.7 (m, 2H), 4.0-4.1 (m, 1H), and 7.3-7.5 (m, 10H).