Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][N:8]=[C:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:34][CH2:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=1.O>O1CCCC1>[Cl:43][C:40]1[CH:41]=[CH:42][C:37]([O:36][CH2:35][CH2:34][CH:7]([N:8]=[C:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:22])=[CH:38][CH:39]=1
Reactant: Clc1ccc(OCCBr)cc1
Reactant: CC(C)(C)OC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)C(CCOc1ccc(Cl)cc1)N=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
While under a nitrogen atmosphere, a solution of (benzhydrylidene-amino)-acetic acid tert-butyl ester (400 mg, 1.35 mmol) in tetrahydrofuran (7 mL) was cooled to −78° C. and treated with sodium bis(trimethylsilyl)amide (1.49 mL, 1.0 M in tetrahydrofuran, 1.49 mmol) in a dropwise manner. After the addition was complete, stirring was continued for 30 minutes and 1-(2-bromoethoxy)-4-chlorobenzene (398 mg, 1.69 mmol) was slowly added to the reaction mixture. Stirring was continued for 2 more hours, then slowly warmed to room temperature overnight. The resulting solution was poured into water, and extracted with ethyl acetate (3×). The combined organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated. Purification by flash column chromatography (silica gel, 0-20% ethyl acetate in heptane) gave tert-butyl 4-(4-chlorophenoxy)-2-(diphenylmethyleneamino)butanoate as a colorless oil (450 mg. 74%); MS (+CI): m/z for C27H28ClNO3: expected 449.2. found 450.2 (M+H)+, 394.2 (M+H−isobutene)+.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].[CH2:17]([CH2:19][NH2:20])[OH:18].[C:21]([O-:38])(=[O:37])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>[Pd].C(O)C>[NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].[CH2:17]([CH2:19][NH2:20])[OH:18].[C:21]([O-:38])(=[O:37])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: [Pd]
Agent: CCCCCCCCCCCCCCCC(=O)[O-]
Solvent: CCO
Solvent: NCCO
Product: C[C@H](N)C(=O)O

Procedure:
Alanine-Ethanolamine-palmitate (AEP) was prepared by hydrogenation of Z-Ala-Ethanolamine-palmitate in a Parr hydrogenator in the presence of palladium on charcoal (10%) in ethanol. The removal of the benzyloxycarbonyl group was monitored by HPLC (System B). After removing the catalyst by filtration and evaporation of the solvent the title compound was obtained in quantitative yield.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:20][CH2:21][CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[C:14]([NH2:19])[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([O:35][C:36]1[CH:37]=[C:38]2[C:43](=[CH:44][CH:45]=1)[N:42]=[CH:41][C:40]([NH2:46])=[C:39]2[NH:47][CH2:48][CH:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[C:55](OCC)(OCC)(OCC)[CH2:56][CH3:57]>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:20]([CH2:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:28]([CH2:29][CH3:30])=[N:19][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH2:28]([O:35][C:36]1[CH:45]=[CH:44][C:43]2[N:42]=[CH:41][C:40]3[N:46]=[C:55]([CH2:56][CH3:57])[N:47]([CH2:48][CH:49]4[CH2:54][CH2:53][O:52][CH2:51][CH2:50]4)[C:39]=3[C:38]=2[CH:37]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CCOC(CC)(OCC)OCC
Reactant: Nc1cnc2ccc(OCc3ccccc3)cc2c1NCC1CCOCC1
Reactant: Nc1cnc2cc(OCc3ccccc3)ccc2c1NCC1CCOCC1
Product: CCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC1CCOCC1
Product: CCc1nc2cnc3ccc(OCc4ccccc4)cc3c2n1CC1CCOCC1

Procedure:
For examples 229 and 231, 7-benzyloxy-N4-(tetrahydro-2H-pyran-4-ylmethyl)quinoline-3,4-diamine (Example 229) or 6-benzyloxy-N4-(tetrahydro-2H-pyran-4-ylmethyl)quinoline-3,4-diamine (Example 231) can be treated with triethyl orthopropionate according to the general method described in Part G of Example 1 to provide 7-benzyloxy-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinoline (Example 229) or 8-benzyloxy-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinoline (Example 231).
Reaction SMILES: [NH:1]1[C:5](=O)[CH2:4][CH2:3][C:2]1=[O:7].Br[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1>>[N:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][CH:5]1[NH:1][C:2](=[O:7])[CH2:3][CH2:4]1
Reactant: O=C1CCC(=O)N1
Reactant: BrCc1ccccn1
Product: O=C1CCC(Cc2ccccn2)N1

Procedure:
5-(Pyridin-2-ylmethyl)pyrrolidin-2-one is synthesized from pyrrolidine-2,5-dione and 2-(bromomethyl)pyridine according to S. Lebrun et al. (Tetrahedron Asymmetry 2003, 14, 2625-2632).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:12][C@H:13]1[CH2:17][CH2:16][N:15]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:14]1=[O:24].CCN(C(C)C)C(C)C.[Cl:34][C:35]1[CH:40]=[N:39][C:38](Cl)=[CH:37][N:36]=1.C(OCC)C>CN(C=O)C>[Cl:34][C:35]1[N:36]=[CH:37][C:38]([N:21]2[CH2:22][CH2:23][CH:18]([N:15]3[CH2:16][CH2:17][C@H:13]([NH:12][C:3]4[CH:4]=[CH:5][C:6]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:7][C:2]=4[F:1])[C:14]3=[O:24])[CH2:19][CH2:20]2)=[N:39][CH:40]=1
Reactant: CS(=O)(=O)c1ccc(N[C@H]2CCN(C3CCNCC3)C2=O)c(F)c1
Reactant: Clc1cnc(Cl)cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1ccc(N[C@H]2CCN(C3CCN(c4cnc(Cl)cn4)CC3)C2=O)c(F)c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 73.4 %

Procedure:
To a solution of (S)-3-(2-fluoro-4-(methylsulfonyl)phenylamino)-1-(piperidin-4-yl)pyrrolidin-2-one (Preparation E; 3 g, 8.44 mmol) and DIEA (7.35 mL, 42.2 mmol) in DMF (30 mL) was added 2,5-dichloropyrazine (2.51 g, 16.9 mmol). This mixture was degassed with nitrogen for 30 minutes then stirred at 100° C. for 4 hours under nitrogen. The mixture was poured into brine (500 mL) and extracted into ethyl acetate (3×100 mL). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to give an oil. Diethyl ether (200 mL) was added and a precipitate formed overnight. The ether was decanted and the solid was triturated using ethanol (100 mL) at reflux with stirring for 5 minutes. The suspension was filtered and the solid was washed using ethanol to give a solid crystal. This solid was dried over the weekend under high vacuum to provide the title compound (2.9 g, 73% yield). Mass spectrum (apci) m/z=468.1 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[F:17][C:18]1[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][C:21]([NH2:22])=[C:20]([O:28][CH3:29])[CH:19]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CC(O)CCC>C(Cl)Cl>[F:17][C:18]1[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][C:21]([NH:22][C:2]2[N:7]=[C:6]([C:8]3[CH:9]=[N:10][N:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=34)[CH:5]=[CH:4][N:3]=2)=[C:20]([O:28][CH3:29])[CH:19]=1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1N
Reactant: Clc1nccc(-c2cnn3ccccc23)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Solvent: CCCC(C)O
Product: COc1cc(F)c([N+](=O)[O-])cc1Nc1nccc(-c2cnn3ccccc23)n1
Temperature: 125 °C
Yield: 53 %

Procedure:
A mixture of 3-(2-chloropyrimidin-4-yl)pyrazolo[1,5-a]pyridine (Intermediate 152, 1.476 g, 6.40 mmol), 4-fluoro-2-methoxy-5-nitroaniline (Intermediate 23, 1.310 g, 7.04 mmol), p-toluenesulfonic acid monohydrate (1.339 g, 7.04 mmol) and 2-pentanol (45 mL) was heated at 125° C. for 22 h. After cooling, the mixture was filtered. The solid was washed with CH3OH, diethyl ether and then dried on the filter to give a brown solid. The solid was dissolved in CH2Cl2 and this solution was washed with sat. NaHCO3 (×3), water and brine, then dried (MgSO4) and concentrated in vacuo. The resulting residue was triturated in boiling CH3CN and then allowed to cool. The resulting solid was collected by filtration and air dried to give the title compound (1.29 g, 53%) as a brown solid; 1H NMR: 4.03 (3H, s), 7.11 (1H, td), 7.37 (1H, d), 7.41 (1H, d), 7.43-7.48 (1H, m), 8.45 (1H, d), 8.51 (1H, s), 8.58 (1H, d), 8.82-8.84 (2H, m), 9.00 (1H, d); m/z: ES+ MH+ 381.54.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[O:9])[C:5]([OH:19])=[CH:4][CH:3]=1.[C:20]([O-])([O-])=O.[Cs+].[Cs+].ClCI>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:19][CH2:20][N:10]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[C:8](=[O:9])[C:6]=2[N:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(NCc1ccc(Cl)cc1)c1nc(Br)ccc1O
Agent: ClCI
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C1c2nc(Br)ccc2OCN1Cc1ccc(Cl)cc1
Yield: 71.9 %

Procedure:
To a solution of 6-bromo-N-(4-chlorobenzyl)-3-hydroxypicolinamide (200 mg, 0.59 mmol) and Cs2CO3 (516 mg, 2.93 mmol) in DMF (5 mL) was added chloroiodomethane (382 mg, 1.17 mmol) dropwise at 100° C. for 10 minutes. The mixture was concentrated in vacuo and the residue was suspended in water. The mixture was extracted with EtOAc and the organic phase was washed with brine, dried over sodium sulfate and concentrated in vacuo to give the crude 6-bromo-3-(4-chlorobenzyl)-2H-pyrido[2,3-e][1,3]oxazin-4(3H)-one (150 mg, yield: 73%) without further purification. MS (M+H)+: 353/355.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C=O)C.[Cl:18][C:19]1[CH:20]=[C:21]([C:25]2[C:30]([NH2:31])=[C:29]([CH3:32])[N:28]=[C:27]([S:33][CH3:34])[N:26]=2)[CH:22]=[CH:23][CH:24]=1.N1C=CC=CC=1>S(Cl)(Cl)=O>[Cl:18][C:19]1[CH:20]=[C:21]([C:25]2[C:30]([NH:31][C:10](=[O:12])[CH2:9][CH2:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[C:29]([CH3:32])[N:28]=[C:27]([S:33][CH3:34])[N:26]=2)[CH:22]=[CH:23][CH:24]=1
Reactant: CSc1nc(C)c(N)c(-c2cccc(Cl)c2)n1
Reactant: O=C(O)CCCc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CSc1nc(C)c(NC(=O)CCCc2ccccc2)c(-c2cccc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
56.2 mg (0.342 mmol) of 4-phenylbutyric acid was dissolved in 1 ml of thionyl chloride. A catalytic amount of DMF was added and stirred at room temperature for 3 hours. After the solvent was evaporated under reduced pressure, 45.4 mg (0.171 mmol) of 4-(3-chlorophenyl)-6-methyl-2-(methylthio)-5-pyrimidinamine and 1 ml of pyridine were added and stirred at 50° C. overnight. After the solvent was evaporated under reduced pressure, the reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=10/1 to 1/1) to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][C:3]=1[OH:9].[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][C:18]([OH:20])=O.P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:27]N(C=O)C>>[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[C:18](=[O:20])[C:7]2[C:5](=[CH:4][C:3]([OH:9])=[C:2]([Cl:1])[CH:8]=2)[O:6][CH:27]=1
Reactant: O=C(O)Cc1ccccc1Br
Reactant: CN(C)C=O
Reactant: Oc1ccc(Cl)c(O)c1
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: O=c1c(-c2ccccc2Br)coc2cc(O)c(Cl)cc12
Yield: 39.1 %

Procedure:
This compounds was synthesised in the same manner as described above. 4-Chlororesorcinol (2.0 g, 13.8 mmol), 2-bromophenyl acetic acid (2.98 g, 13.8 mmol), BF3Et2O (8 ml), PCl5 (4.3 g, 20.6 mmol), DMF (8 ml and 12 ml). The precipitate formed was filtered and re-crystallized from methanol to give 3-(2-Bromo-phenyl)-6-chloro-7-hydroxy-chromen-4-one as a white solid (1.9 g, 39.1%); Rf 0.85 ethyl acetate/hexane (75/25).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:19]=[C:18]([C:20]([OH:22])=O)[O:17][N:16]=1.F[B-](F)(F)F.[N:28]1(OC(N(C)C)=[N+](C)C)[C:32]2[CH:33]=[CH:34][CH:35]=CC=2N=[N:29]1.C(N(CC)C(C)C)(C)C.Cl.NN1CCCC1>CN(C=O)C>[N:28]1([NH:29][C:20]([C:18]2[O:17][N:16]=[C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=4)=[N:5][O:6][C:2]=3[CH3:1])[CH:19]=2)=[O:22])[CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: Cc1onc(-c2ccccn2)c1COc1cc(C(=O)O)on1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Agent: NN1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccccn2)c1COc1cc(C(=O)NN2CCCC2)on1
Reaction time: 4 h
Yield: 57.4 %

Procedure:
To a solution of 3-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid (100 mg, 0.33 mmol) in DMF (5 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (160 mg, 0.5 mmol), N,N-diisopropyl ethyl amine (280 μL, 1.7 mmol) and N-aminopyrrolidine HCl (61 mg, 0.50 mmol). The resulting reaction mixture was for 4 h at room temperature. Concentration and purification by chromatography (silica, dichloromethane:methanol=1:0 to 8.5:1.5) afforded the title compound (70 mg, 57%) as a white solid. MS: m/e=370.2 [M+H]+.
Reaction SMILES: Cl[CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.[Mg].[Cl:10][C:11]1[CH:19]=[C:18]2[C:14]([CH2:15][C:16]([CH3:22])([CH3:21])[C:17]2=[O:20])=[CH:13][CH:12]=1.[Cl-].[NH4+]>O1CCCC1>[Cl:10][C:11]1[CH:19]=[C:18]2[C:14]([CH2:15][C:16]([CH3:22])([CH3:21])[C:17]2([CH:2]2[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]2)[OH:20])=[CH:13][CH:12]=1
Reactant: CC1(C)Cc2ccc(Cl)cc2C1=O
Reactant: CN1CCC(Cl)CC1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN1CCC(C2(O)c3cc(Cl)ccc3CC2(C)C)CC1

Procedure:
A Grignard reagent is prepared from 14.0 g 4-chloro-N-methylpiperidine and 2.6 g magnesium in 200 ml boiling tetrahydrofuran. After cooling, a solution of 10.0 g 6-chloro-2,2-dimethyl-indanone in 50 ml tetrahydrofuran is added dropwise at 5°-10°, and the reaction mixture is refluxed for 6 hours. After cooling, a 10% aqueous solution of ammonium chloride is added and the mixture is extracted with toluene. The toluene phase is dried and evaporated, to give 6-chloro-2,2-dimethyl-1-(1-methyl-4-piperidinyl)indan-1-ol (m.p. 181°-182°).
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[F:20][C:21]1[CH:22]=[CH:23][C:24]([C:30]([F:33])([F:32])[F:31])=[C:25]([CH:29]=1)[C:26]([OH:28])=O.CCN=C=NCCCN(C)C.Cl.[C:46]([O:50][C:51]([N:53]1[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1)=[O:52])([CH3:49])([CH3:48])[CH3:47]>CN(C=O)C.O>[C:46]([O:50][C:51]([N:53]1[CH2:58][CH2:57][N:56]([C:26](=[O:28])[C:25]2[CH:29]=[C:21]([F:20])[CH:22]=[CH:23][C:24]=2[C:30]([F:33])([F:32])[F:31])[CH2:55][CH2:54]1)=[O:52])([CH3:49])([CH3:47])[CH3:48]
Reactant: O=C(O)c1cc(F)ccc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(F)ccc2C(F)(F)F)CC1
Temperature: 10 °C
Reaction time: 8 h
Yield: 88.9 %

Procedure:
HOBt (163 mg, 1.2 mmol) and DIEA (373 mg, 2.9 mmol) were added to a stirred solution of 5-fluoro-2-trifluoromethyl-benzoic acid (200 mg, 0.9 mmol) in DMF (1.0 mL) and the resulting mixture was cooled to 10° C. EDCI.HCl (231 mg, 1.2 mmol) followed by piperazine-1-carboxylic acid tert-butyl ester (197 mg, 1.0 mmol) were then added and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and the product extracted with ethyl acetate. The ethyl acetate layer was washed with brine solution, dried over Na2SO4 and concentrated under reduced pressure to afford the crude residue, which was purified by column chromatography using silica gel 60-120 mesh (30% ethyl acetate in hexane) to afford 301 mg (83%) of 4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazine-1-carboxylic acid tert-butyl ester, LCMS purity: 99.5%.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH2:6][CH:5]([CH:8]=[N:9][OH:10])[CH2:4][CH2:3]1.[Cl:12]N1C(=O)CCC1=O>>[OH:10][N:9]=[C:8]([Cl:12])[CH:5]1[CH2:4][CH2:3][C:2]([CH3:11])([CH3:1])[CH2:7][CH2:6]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC1(C)CCC(C=NO)CC1
Product: CC1(C)CCC(C(Cl)=NO)CC1

Procedure:
N-Hydroxy-4,4-dimethylcyclohexanecarbimidoyl chloride (I-9D) was prepared by reaction of 4,4-dimethylcyclohexanecarbaldehyde oxime and N-chloro succinimide following the same protocol as described for I-6B. MS m/z 190.1 (M+1).
Reaction SMILES: [O:1]=[C:2]1[CH2:9][C:6]([CH3:8])([CH3:7])[CH2:5][C:4]([CH3:10])=[CH:3]1.Br[CH2:12][CH2:13][CH2:14][CH3:15].[OH-].[K+].O>CN1CCCC1=O.C(OCC)(=O)C>[CH2:12]([C:3]1[C:2](=[O:1])[CH2:9][C:6]([CH3:8])([CH3:7])[CH2:5][C:4]=1[CH3:10])[CH2:13][CH2:14][CH3:15]
Reactant: CCCCBr
Reactant: CC1=CC(=O)CC(C)(C)C1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCC1=C(C)CC(C)(C)CC1=O
Temperature: 70 °C
Yield: 44.9 %

Procedure:
In 60 ml of 1-methyl-2-pyrrolidone were dissolved 10.0 g (72.36 mmol) of isophorone and 14.9 g (95.6 mmol) of 1-bromobutane. To this mixture was added 8.1 g (144.4 mmol) of powdered potassium hydroxide and the mixture was stirred with heating at 70° C. for 6 hours. After the reaction mixture was added to water, extraction with ethyl acetate, washing with a saturated saline solution, drying over anhydrous sodium sulfate, and concentration were performed. The residual liquid was purified by silica gel column chromatography to give 6.31 g of a yellow oily matter (yield: 44.9%).
Reaction SMILES: ClC1C=C([N+]([O-])=O)C(N)=NC=1.[F:12][C:13]([F:20])([CH:17]([F:19])[F:18])[C:14](Cl)=[O:15].[Cl:21][C:22]1[CH:23]=[C:24]([N+:30]([O-:32])=[O:31])[C:25]([NH2:29])=[N:26][C:27]=1[Cl:28].C(N(CC)CC)C>O1CCCC1>[Cl:21][C:22]1[CH:23]=[C:24]([N+:30]([O-:32])=[O:31])[C:25]([NH2:29])=[N:26][C:27]=1[Cl:28].[Cl:21][C:22]1[CH:23]=[C:24]([N+:30]([O-:32])=[O:31])[C:25]([NH:29][C:14](=[O:15])[C:13]([F:20])([F:12])[CH:17]([F:19])[F:18])=[N:26][C:27]=1[Cl:28]
Reactant: O=C(Cl)C(F)(F)C(F)F
Agent: Nc1nc(Cl)c(Cl)cc1[N+](=O)[O-]
Agent: Nc1ncc(Cl)cc1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1nc(Cl)c(Cl)cc1[N+](=O)[O-])C(F)(F)C(F)F
Yield: 94 %

Procedure:
5,6-Dichloro-2-amino-3-nitropyridine was prepared by chlorination of 5-chloro-2-amino-3-nitropyridine and was subsequently reacted with 2,2,3,3-tetrafluoropropionyl chloride. More particularly, 5,6-dichloro-2-amino-3-nitropyridine (3.0 grams; 0.15 mole) was taken up in tetrahydrofuran (20 ml.) and triethylamine (2 ml.) was added. Then 2,2,3,3-tetrafluoropropionyl chloride was added portionwise until all the starting material had reacted. The reaction yielded 5.3 grams (94 percent yield) of 5,6-dichloro-2-(2,2,3,3-tetrafluoropropionamido)-3-nitropyridine as an oil. Its identity was confirmed by infrared spectroscopy.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][P:25]([CH3:29])(=[O:28])[CH2:24][CH2:23]3)=[CH:18][C:17]=2[O:30][CH3:31])=[N:4][C:5]([NH:8][CH2:9][C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[N:6][CH:7]=1.NCC1SC=CC=1[S:39]([N:42]([CH2:45][CH3:46])[CH2:43][CH3:44])(=[O:41])=[O:40]>>[Cl:1][C:2]1[C:3]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][P:25]([CH3:29])(=[O:28])[CH2:24][CH2:23]3)=[CH:18][C:17]=2[O:30][CH3:31])=[N:4][C:5]([NH:8][CH2:9][C:10]2[S:11][CH:12]=[CH:13][C:14]=2[S:39]([N:42]([CH2:45][CH3:46])[CH2:43][CH3:44])(=[O:41])=[O:40])=[N:6][CH:7]=1
Reactant: CCN(CC)S(=O)(=O)c1ccsc1CN
Reactant: COc1cc(N2CCP(C)(=O)CC2)ccc1Nc1nc(NCc2cccs2)ncc1Cl
Product: CCN(CC)S(=O)(=O)c1ccsc1CNc1ncc(Cl)c(Nc2ccc(N3CCP(C)(=O)CC3)cc2OC)n1

Procedure:
The compound can be prepared as in Example 32 by reacting 2,5-dichloro-N-[2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)phenyl]pyrimidin-4-amine (as described in Example 47) with 2-(aminomethyl)-N,N-diethylthiophene-3-sulfonamide.
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][N:5]2[C:6](=[O:18])[CH2:7][CH2:8][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][C@H:4]2[CH2:3]1.CC(C)([O-])C.[K+].Br[C:27]1[CH:32]=[N:31][C:30]([CH:33]2[CH2:35][CH2:34]2)=[CH:29][N:28]=1.CO>O1CCCC1>[CH:33]1([C:30]2[N:31]=[CH:32][C:27]([O:1][C@H:2]3[CH2:19][N:5]4[C:6](=[O:18])[CH2:7][CH2:8][N:9]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:10][C@H:4]4[CH2:3]3)=[N:28][CH:29]=2)[CH2:35][CH2:34]1
Reactant: Brc1cnc(C2CC2)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)N2C[C@H](O)C[C@@H]2C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=O)N2C[C@H](Oc3cnc(C4CC4)cn3)C[C@@H]2C1
Reaction time: 0.08 h
Yield: 58.1 %

Procedure:
tert-Butyl (8R,9aR)-8-hydroxy-5-oxohexahydro-1H-pyrrolo[1,2-a][1,4]diazepine-2(3H)-carboxylate (60 mg, 0.222 mmol, 1.0 equivalent, Example 46, Part D) was dissolved in tetrahydrofuran (1.0 mL). Potassium tert-butoxide (0.311 mL, 0.311 mmol, 1 M in tetrahydrofuran, 1.4 equivalents) was added at room temperature, and the resulting yellow solution was stirred for five minutes. Then 2-bromo-5-cyclopropylpyrazine (57.4 mg, 0.289 mmol, 1.3 equivalents) was added as a solution in tetrahydrofuran (0.5 mL), and the reaction mixture was stirred for 16 hours at the same temperature. The reaction mixture was quenched with 1 drop of saturated sodium bicarbonate, the solvent was removed in vacuo, and the crude material was loaded onto a 12 g silica column with 5% methanol/dichloromethane and eluted with 100:0 to 95:5 dichloromethane:methanol over 20 minutes to give the titled compound (50 mg, 0.129 mmol, 58.0% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.02 (s, 1H), 7.94 (d, J=1.1 Hz, 1H), 5.38 (br s, 1H), 4.23 (br s, 2H), 3.95 (t, J=7.2 Hz, 1H), 3.90-3.73 (m, 2H), 3.00 (br s, 2H), 2.71-2.45 (m, 3H), 2.18-1.86 (m, 2H), 1.47 (s, 9H), 1.05-0.85 (m, 4H); MS (ESI+) m/z 333.0 (M-tBu+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10](=[O:20])[O:11][C:12]3[C:17]([C:18]=2[OH:19])=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:5][CH:4]=1.[O:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28]Cl)[CH2:23][CH2:22]1>>[O:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][O:19][C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[O:11][C:10](=[O:20])[C:9]=2[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:23][CH2:22]1
Reactant: ClCCN1CCOCC1
Reactant: COc1ccc(-c2c(O)c3ccccc3oc2=O)cc1
Product: COc1ccc(-c2c(OCCN3CCOCC3)c3ccccc3oc2=O)cc1
Yield: 82.5 %

Procedure:
Obtained according to the method of Example 8, from 12.1 g. (0.045 mol) of 3-(4'-methoxyphenyl)-4-hydroxy-coumarin and 8.7 g. (0.058 mol) of 2-morpholino-1-chlorethane. After recrystallisation from ethanol, there are obtained 14.7 g. of a beige product; M.P. 104° C. Yield 82.5% (theoretical yield 17.1 g.).
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[CH:10]=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:17][CH:16]2[C:35]([OH:37])=O)[CH:12]=[CH:13][CH:14]=1.[NH2:38][C:39]1[CH:48]=[CH:47][C:42]([C:43]([O:45][CH3:46])=[O:44])=[CH:41][CH:40]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:46][O:45][C:43](=[O:44])[C:42]1[CH:47]=[CH:48][C:39]([NH:38][C:35]([C@H:16]2[C@H:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([Br:8])[CH:10]=3)[C@:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[C@H:18]([CH2:30][C:31]([CH3:32])([CH3:34])[CH3:33])[NH:17]2)=[O:37])=[CH:40][CH:41]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Br)c2)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Br)c2)cc1
Yield: 36.6 %

Procedure:
In a manner similar to the method described in Examples 1e, rac-(2R,3R,4R,5S)-3-(3-bromo-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 66c (0.44 g, 0.74 mmol) was reacted with methyl 4-aminobenzoate (0.1 g, 1.32 mmol), HATU (0.3 g, 0.4 mmol) and iPr2NEt (0.32 mL, 1.8 mmol) in CH2Cl2 at room temperature to give rac-4-{[(2R,3R,4R,5S)-3-(3-bromo-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid methyl ester as a white solid (0.17 g, 37%).