Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:6]([CH2:7]Cl)=[CH:5][CH:4]=[C:3]([Cl:9])[CH:2]=1.[CH3:10][NH:11][CH3:12]>O1CCCC1.C(OCC)C>[CH3:10][N:11]([CH2:7][C:6]1[CH:5]=[CH:4][C:3]([Cl:9])=[CH:2][CH:1]=1)[CH3:12]
Reactant: ClCc1ccc(Cl)cc1
Reactant: CNC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN(C)Cc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 48 h

Procedure:
The starting material is prepared as follows: The solution of 141 g of α,p-dichlorotoluene in 200 ml of tetrahydrofuran is added dropwise to an ice-cold saturated solution of dimethylamine in 1 liter of tetrahydrofuran and the mixture stirred for 2 days at 25°. It is diluted with diethyl ether, washed with 2N aqueous sodium hydroxide, the organic layer dried, evaporated, the residue distilled and the fraction boiling at 106°/12 mm Hg collected, to yield the N,N-dimethyl-4-chlorobenzylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[O:19][C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[C:12]=2[NH:20][C:21]([C@H:23]2[CH2:28][CH2:27][C@H:26]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][C:30]3=[O:35])[CH2:25][CH2:24]2)=[O:22])=[O:10])=[N:6][CH:7]=1.[C:36](Cl)(=[O:38])[CH3:37]>>[C:36]([N:32]1[CH2:33][CH2:34][N:29]([C@H:26]2[CH2:27][CH2:28][C@H:23]([C:21]([NH:20][C:12]3[C:13]4=[N:14][CH:15]=[CH:16][CH:17]=[C:18]4[O:19][C:11]=3[C:9]([NH:8][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=3)=[O:10])=[O:22])[CH2:24][CH2:25]2)[C:30](=[O:35])[CH2:31]1)(=[O:38])[CH3:37]
Reactant: CC(=O)Cl
Reactant: O=C(Nc1ccc(Cl)cn1)c1oc2cccnc2c1NC(=O)[C@H]1CC[C@H](N2CCNCC2=O)CC1
Product: CC(=O)N1CCN([C@H]2CC[C@H](C(=O)Nc3c(C(=O)Nc4ccc(Cl)cn4)oc4cccnc34)CC2)C(=O)C1

Procedure:
N-(5-Chloropyridin-2-yl)-3-({[trans-4-(2-oxopiperazin-1-yl)cyclohexyl]carbonyl}amino)furo[3,2-b]pyridine-2-carboxamide (50 mg) obtained in Example 125 and acetyl chloride (9 μl) are treated in a similar manner to Example 122 to give the title compound (41 mg).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]([CH2:14][C:15]3[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=3)[S:12][CH:13]=2)[CH:6]=[CH:7][CH:8]=1.[CH3:27][Si](C)(C)[N-][Si](C)(C)C.[Li+].IC.Cl>O1CCCC1>[F:26][C:2]([F:1])([F:25])[C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]([CH:14]([C:15]3[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=3)[CH3:27])[S:12][CH:13]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1ccc(Cc2nc(-c3cccc(C(F)(F)F)c3)cs2)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(C)c2nc(-c3cccc(C(F)(F)F)c3)cs2)cc1
Yield: 56.8 %

Procedure:
To a solution of the compound (641 mg, 1.70 mmol) obtained in Example 178b in tetrahydrofuran (10 mL) was slowly added dropwise a solution (1.85 mL, 2.041 mmol) of 1.1M lithium hexamethyldisilazide in tetrahydrofuran under ice-cooling. The reaction mixture was stirred under ice-cooling for 5 min, iodomethane (0.16 mL, 2.55 mmol) was added dropwise at the same temperature, and the mixture was further stirred for 5 min. The reaction mixture was acidified with 1N aqueous hydrochloric acid solution, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: silica gel, eluent: hexane-ethyl acetate) to give the title compound (378 mg, 57%) as a colorless oil.
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH2:7][OH:8])=[CH:4][CH:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[C:9]1([C:2]2[O:6][C:5]([CH2:7][OH:8])=[CH:4][CH:3]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OB(O)c1ccccc1
Reactant: OCc1ccc(Br)o1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: OCc1ccc(-c2ccccc2)o1
Temperature: 80 °C
Yield: 34.6 %

Procedure:
The 5-bromo-2-hydroxymethylfuran prepared in Example 327A (1.012 g, 5.72 mmol) was dissolved in 10 mL of DMF and PdCl2 (PPh3)2 (401 mg, 0.57 mmol) was added followed by phenylboronic acid (1.39 g, 11.4 mmol) and Cs2CO3 (3.71 g, 11.4 mmol) and the reaction was heated at 80° C. under N2 for 12 hours. The reaction mixture was taken up in ethyl acetate and washed with water (3×) and brine (3×), dried over Na2SO4, filtered and evaporated to a brown oil that was purified by flash chromatography (50% ethyl acetate-hexanes) to give the desired compound (345 mg, 35%) as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[CH2:11]([CH2:15][C:16](=O)[CH3:17])[C:12]([CH3:14])=O.C1(C)C=CC=CC=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[CH3:17][C:16]1[N:1]([C:2]2[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=2)[C:5]([OH:7])=[O:6])[C:12]([CH3:14])=[CH:11][CH:15]=1
Reactant: Nc1cccc(C(=O)O)c1
Reactant: CC(=O)CCC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(C)n1-c1cccc(C(=O)O)c1
Yield: 89.7 %

Procedure:
In a reaction vessel equipped with a Dean-Stark trap was placed 13.7 grams (0.10 mole) of 3-aminobenzoic acid, 11.4 grams (0.10 mole) of acetonylacetone, 0.10 gram of p-toluenesulfonic acid and 150 ml of toluene. The stirred reaction mixture was heated under reflux for 15.5 hours during which time the theoretical amount of by-product water was collected in the Dean-Stark trap. The reaction mixture was cooled and placed in a separatory funnel where it was washed with two portions of 50 ml each of aqueous 2N sodium hydroxide. The combined base washes were backwashed with 50 ml of toluene then acidified with aqueous 2 N hydrochloric acid. A solid precipitate was collected by filtration and recrystallized from heptane to give 19.3 grams of 3-(2,5-dimethylpyrrol-1-yl)benzoic acid; mp 148°-150° C.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].O1CCCCC1[N:34]1[C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][CH:36]=[N:35]1>CCO.CC#N>[OH:27][C@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:36]3[NH:35][N:34]=[CH:38][CH:37]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@H](O)C2)c(Br)c1
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Solvent: CCO
Solvent: CC#N
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@H](O)C2)c(-c2ccn[nH]2)c1

Procedure:
The title compound was prepared in analogous fashion to that described in Example 8 using (S)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 34.1) and 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole to afford an off-white powder. HPLC (Condition 4) tR=4.42 min, HPLC Chiral (CHIRALPAK® AD-H, 250×4.6 mm, eluent:EtOH/MeCN (98:2), 0.5 mL/min, UV 210 nm) tR=28.27 min, UPLC-MS (Condition 3) tR=0.91 min, m/z=434.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.63-1.88 (m, 2H) 2.92 (d, J=11.73 Hz, 1H) 3.19-3.29 (m, 2H) 3.34-3.47 (m, 1H) 4.18 (br. s, 1H) 4.80 (d, J=3.13 Hz, 1H) 6.37 (s, 1H) 7.31 (d, J=8.99 Hz, 2H) 7.75-7.89 (m, 3H) 8.00 (d, J=2.35 Hz, 1H) 8.71 (d, J=2.35 Hz, 1H) 10.16 (s, 1H) 12.85-13.12 (m, 1H).
Reaction SMILES: [CH:1]1([CH:4]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[C:12]([O:17]C)[CH:11]=2)[CH2:5][C:6]([O:8][CH3:9])=[O:7])[CH2:3][CH2:2]1.B(Br)(Br)Br.O>ClCCl>[CH:1]1([CH:4]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[C:12]([OH:17])[CH:11]=2)[CH2:5][C:6]([O:8][CH3:9])=[O:7])[CH2:2][CH2:3]1
Reactant: COC(=O)CC(c1ccc(F)c(OC)c1)C1CC1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: COC(=O)CC(c1ccc(F)c(O)c1)C1CC1
Reaction time: 2 h
Yield: 52.9 %

Procedure:
To a solution of methyl 3-cyclopropyl-3-(4-fluoro-3-methoxyphenyl)propanoate (800 mg) in dichloromethane (20 mL) was added dropwise a 1.0 M solution of boron tribromide in dichloromethane (3.8 mL) at −5° C. over 20 min, and thereafter the mixture was stirred for 2 hr. Water (20 mL) was added dropwise to the reaction mixture, and the mixture was extracted with dichloromethane. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (400 mg) as a yellow oil.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH:5]([NH:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]#[C:30][CH3:31])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Br:16])[CH:14]=2)[NH:9][CH:8]=1)C.CO.[OH-].[Na+].Cl>O1CCCC1>[Br:16][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:6][CH:5]([NH:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]#[C:30][CH3:31])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[C:4]([OH:32])=[O:3]
Reactant: CC#CCOc1ccc(S(=O)(=O)NC(Cc2c[nH]c3ccc(Br)cc23)C(=O)OCC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC#CCOc1ccc(S(=O)(=O)NC(Cc2c[nH]c3ccc(Br)cc23)C(=O)O)cc1
Reaction time: 10 h
Yield: 93.9 %

Procedure:
2-(4-But-2-ynyloxy-benzenesulfonylamino)-3-(5-bromo-1H-indol-3-yl)-propionic acid ethyl ester (0.100 g, 0.193 mmol) was dissolved in 0.5 mL tetrahydrofuran. To the solution was added MeOH (0.5 mL) and 1 N NaOH (0.4 mL, 0.4 mmol). The reaction mixture was placed in a shaker for 10 hours at room temperature. The solution was acidified with 1N HCl and extracted with ethyl acetate (3×3 mL). The organic solution was concentrated and the residue was purified by RP-HPLC to give 0.089 g (94%) of the title compound as a pale yellow solid. 1H NMR (DMSO-d6): 400 MHz δ 12.65 (bs, 1H), 11.01 (s, 1H), 8.08 (d, J=8.8 Hz, 1H), 7.48 (m, 3H), 7.26 (d, J=8.8 Hz, 1H), 7.13 (m, 2H), 6.89 (d, J=9.2 Hz, 2H), 4.77 (q, J=2.8 Hz, 2H), 3.82 (q, J=8.4 Hz, 1H), 3.01 (dd J=14.6, 6.4 Hz, 1H), 2.82 (dd J=14.6, 8.0 Hz, 1H), 1.83 (t, J=2.4 Hz, 3H); HRMS: calcd for C21H20BrN2O5S (ESI+, Br79, [M+H]1+), 491.0271; found 491.0287; LCMS m/z (ESI) [M−H] 489 (Br79), retention time=2.75 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[N:12][C:13](S(C)=O)=[N:14][CH:15]=2)[N:10]2[CH:22]=[CH:23][N:24]=[C:9]12.[NH2:25][C:26]1[CH:35]=[C:34]2[C:29]([CH2:30][CH2:31][N:32]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:33]2)=[CH:28][CH:27]=1>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[CH:15]=[N:14][C:13]([NH:25][C:26]3[CH:35]=[C:34]4[C:29]([CH2:30][CH2:31][N:32]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:33]4)=[CH:28][CH:27]=3)=[N:12][C:11]=2[N:10]2[CH:22]=[CH:23][N:24]=[C:9]12
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(N)cc2C1
Reactant: CS(=O)c1ncc2c(=O)n(-c3ccccc3Cl)c3nccn3c2n1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2ccc(Nc3ncc4c(=O)n(-c5ccccc5Cl)c5nccn5c4n3)cc2C1

Procedure:
A mixture of Example 1E (0.900 g, 2.501 mmol) and tert-butyl 7-amino-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.994 g, 4.00 mmol) was heated in a capped vial at 90° C. for 1 hour. The reaction mixture were suspended and stirred in ethyl acetate. The solids were filtered and washed with ethyl acetate. The filter cake was stirred in saturated aqueous NaHCO3, filtered, washed with water, and oven-dried to provide the title compound. The filtrate was diluted with ethyl acetate and washed with saturated NaHCO3. The organic layer was dried over MgSO4, filtered, concentrated, and purified on an 80 g column using the ISCO Companion flash system eluting with CH2Cl2/ethyl acetate (6:4 to 5:5) to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.44 (s, 9H), 2.77 (t, J=5.75 Hz, 2H), 3.58 (t, J=5.75 Hz, 2H), 4.54 (s, 2H), 7.07 (d, J=1.59 Hz, 1H), 7.21 (d, J=8.72 Hz, 1H), 7.53-7.66 (m, 5H), 7.69-7.74 (m, 1H), 7.76 (d, J=1.59 Hz, 1H), 9.12 (s, 1H), 10.71 (s, 1H). MS (ESI+) m/z 544.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[CH:16]=[C:17]([C:20](O)=[O:21])[NH:18][N:19]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[CH:4][CH:3]=1.[NH3:24]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[CH:16]=[C:17]([C:20]([NH2:24])=[O:21])[NH:18][N:19]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: N
Reactant: Cc1onc(-c2ccc(F)cc2)c1/C=C/c1cc(C(=O)O)[nH]n1
Product: Cc1onc(-c2ccc(F)cc2)c1/C=C/c1cc(C(N)=O)[nH]n1
Yield: 32 %

Procedure:
As described for example 132, 5-{(E)-2-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-vinyl}-2H-pyrazole-3-carboxylic acid was converted, using ammonia instead of morpholine, to the title compound (12 mg, 32%) which was obtained as an off white solid. MS: m/e=313.2 [M+H]+.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:20]2[CH:25]=[CH:24][C:23]([CH:26]=[O:27])=[CH:22][CH:21]=2)[C:10]2[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[C:12]([O:18]C)[CH:11]=2)=[CH:5][CH:4]=1)=[O:2].[Cl-].[Al+3].[Cl-].[Cl-].O>ClCCl>[CH:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:20]2[CH:21]=[CH:22][C:23]([CH:26]=[O:27])=[CH:24][CH:25]=2)[C:10]2[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[C:12]([OH:18])[CH:11]=2)=[CH:5][CH:4]=1)=[O:2]
Reactant: COc1cc(N(c2ccc(C=O)cc2)c2ccc(C=O)cc2)ccc1C=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: O=Cc1ccc(N(c2ccc(C=O)cc2)c2ccc(C=O)c(O)c2)cc1
Yield: 87.7 %

Procedure:
A solution of compound 9 (310 mg, 860 μmol) in dichloromethane (5 mL) is added dropwise to a suspension of aluminium chloride (AlCl3, 575 mg, 4.31 mmol, 5 eq.) in dichloromethane (10 mL) at −10° C. The mixture is stirred under reflux for 24 hours. It is then poured into a mixture of water and ice, and it is then vigorously stirred for 10 minutes. It is extracted with dichloromethane. The organic phase is washed with water and with brine, dried and concentrated to give a solid which is triturated in hexane to give 260 mg (754 μmol) of compound 10 in the form of a yellow powder (yield: 87%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][N:7]2[N:9]=[C:10]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][CH:16]=3)[C:11]([C:12]([NH2:14])=[O:13])=[C:6]2[NH:5][CH2:4]1.[C:28](Cl)(=[O:31])[CH:29]=[CH2:30]>>[C:28]([NH:1][CH2:2][CH:3]1[CH2:8][N:7]2[N:9]=[C:10]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][CH:16]=3)[C:11]([C:12]([NH2:14])=[O:13])=[C:6]2[NH:5][CH2:4]1)(=[O:31])[CH:29]=[CH2:30]
Reactant: NCC1CNc2c(C(N)=O)c(-c3ccc(Oc4ccccc4)cc3)nn2C1
Reactant: C=CC(=O)Cl
Product: C=CC(=O)NCC1CNc2c(C(N)=O)c(-c3ccc(Oc4ccccc4)cc3)nn2C1

Procedure:
The desired product was prepared form 6-(aminomethyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide and acryloyl chloride using the procedure similar to that for compound 8. 1H NMR (400 MHz, DMSO-d6) δ 8.31 (t, J=5.6 Hz, 1H), 7.51 (d, J=8.8 Hz, 2H), 7.46-7.38 (m, 2H), 7.17 (t, J=7.6 Hz, 1H), 7.08 (d, J=7.6 Hz, 2H), 7.04 (d, J=8.8 Hz, 2H), 6.61 (s, 1H), 6.25 (dd, J=17.1, 10.1 Hz, 1H), 6.11 (dd, J=17.1, 2.2 Hz, 1H), 5.62 (dd, J=10.1, 2.2 Hz, 1H), 4.07 (dd, J=12.4, 6.0 Hz, 1H), 3.73 (dd, J=12.4, 8.0 Hz, 1H), 3.41-3.34 (m, 1H), 3.27-3.21 (m, 2H), 3.09-2.96 (m, 1H), 2.37-2.24 (m, 1H). MS (ESI) m/e [M+1]+ 417.9.
Reaction SMILES: C(N(CC)C(C)C)(C)C.Cl[C:11]1[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][N:14]=[C:13]([S:22][CH3:23])[N:12]=1.Cl.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32][NH2:33]>O1CCCC1>[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32][NH:33][C:11]1[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][N:14]=[C:13]([S:22][CH3:23])[N:12]=1
Reactant: NNc1ccccc1Cl
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnc(SC)nc1NNc1ccccc1Cl

Procedure:
At room temperature, 16.2 mL of N,N-diisopropylethylamine was added to tetrahydrofuran (300 mL) solution of 9.4 g of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate and 8.3 g of 2-chlorophenylhydrazine hydrochloride, and heated under reflux for 18 hours. The solvent was concentrated under reduced pressure, water was added to this, and extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated saline water, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure to obtain crude ethyl 4-[2-(2-chlorophenyl)hydrazino]-2-(methylthio)pyrimidine-5-carboxylate as a yellow oily substance.
Reaction SMILES: [C:1](Cl)(=O)[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][CH2:16][CH2:17]C.C[C:22]1(C)[O:29][C:27](=[O:28])[CH2:26][C:24](=[O:25])O1.N1C=CC=CC=1>C(Cl)Cl>[O:25]=[C:24]([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])[CH2:26][C:27]([O:29][CH3:22])=[O:28]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCC(=O)CC(=O)OC

Procedure:
270 ml of stearoyl chloride were added dropwise at a maximum of 150° C. to a solution of 117 g of Meldrum's acid and 131 ml of pyridine in 1.5 l of methylene chloride. After stirring the reaction mixture was washed with 4N hydrochloric acid, the aqueous phase was back-extracted with methylene chloride and the methylene chloride phase was dried and concentrated. The residue was taken up in methanol and stirred under reflux. After cooling the separated crystals were filtered off, dissolved in methylene chloride and chromatographed on silica gel with methylene chloride. There were obtained 175 g of methyl 3-oxoeicosanoate, m.p. 52°-54° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][N:12](CC3C=CC=CC=3)[CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>C(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]2[CH:14]([CH2:13][NH:12][CH2:11]2)[CH2:15]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC2CN(Cc3ccccc3)CC2C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC2CNCC2C1
Temperature: 25 °C
Yield: 83.3 %

Procedure:
A mixture of compound 4 (130 mg), Pd/C (100 mg, 10%) and ammonium formate (160 mg) in ethanol (10 mL) was heated to reflux for 2 hours and then allowed to cool to room temperature. The solid was filtered off and the filtrate was concentrated in vacuo. The residue was purifed by preparative HPLC to provide title compound 5 as a pale yellow oil (76 mg, 84%). LCMS: Rf: 0.371 min, M+H+: 213.
Reaction SMILES: CC(C[AlH]CC(C)C)C.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20](/[CH:23]=[CH:24]/[C:25](OC)=[O:26])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].CO>C(Cl)Cl>[OH:26][CH2:25]/[CH:24]=[CH:23]/[CH:20]1[CH2:21][CH2:22][N:17]([C:15]([O:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:16])[CH2:18][CH2:19]1
Reactant: COC(=O)/C=C/C1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(/C=C/CO)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1 M DiBAl—H in dichloromethane (42 mL, 2.2 eq.) was added slowly, via an addition funnel, over 20 min to a well stirred solution of the α,β-unsaturated ester from step 1 of this example (5.14 gram, 1 eq.) in anhydrous DCM (100 mL) under argon atmosphere at −78° C. The resulting solution was warmed to 0° C. after completion of addition and was kept at that temperature for 30 min. The reaction was cooled back to −78° C. and 4 mL MeOH was added slowly to quench the excess DiBAl-H. The cold solution was further stirred at −78° C. for 10 min before pouring into 150 mL saturated aqueous Rochelle (sodium potassium tartrate) salts solution. The mixture was vigorously stirred at room temperature for 3 hours until it turned clear. The organic layer was separated, dried over sodium sulfate, filtered and concentrated i. vac. The residue was further purified by column chromatography using acetone/hexanes (20%, isocratic) to give the desired product as colorless oil.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:11](=[O:12])[C@@H:10]([NH:13][C:14](=[O:21])[C@@:15]([F:20])([CH3:19])[C:16](O)=[O:17])[C:9]3[CH:22]=[CH:23][CH:24]=[CH:25][C:8]=3[C:7]3[CH:26]=[CH:27][CH:28]=[CH:29][C:6]2=3)[CH2:3][CH2:2]1.[F:30][C:31]([F:39])([C:35]([F:38])([F:37])[F:36])[CH2:32][CH2:33][NH2:34]>>[CH:1]1([CH2:4][N:5]2[C:11](=[O:12])[C@@H:10]([NH:13][C:14](=[O:21])[C@@:15]([F:20])([CH3:19])[C:16]([NH:34][CH2:33][CH2:32][C:31]([F:39])([F:30])[C:35]([F:38])([F:37])[F:36])=[O:17])[C:9]3[CH:22]=[CH:23][CH:24]=[CH:25][C:8]=3[C:7]3[CH:26]=[CH:27][CH:28]=[CH:29][C:6]2=3)[CH2:2][CH2:3]1
Reactant: C[C@@](F)(C(=O)O)C(=O)N[C@@H]1C(=O)N(CC2CC2)c2ccccc2-c2ccccc21
Reactant: NCCC(F)(F)C(F)(F)F
Product: C[C@@](F)(C(=O)NCCC(F)(F)C(F)(F)F)C(=O)N[C@@H]1C(=O)N(CC2CC2)c2ccccc2-c2ccccc21

Procedure:
(S)-N-((S)-5-cyclopropylmethyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-2-fluoro-2-methyl-malonamic acid was coupled with 3,3,4,4,4-pentafluoro-butylamine in analogy to the procedure described for example 73 to yield (R)-N-((S)-5-cyclopropylmethyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-2-fluoro-2-methyl-N′-(3,3,4,4,4-pentafluoro-butyl)-malonamide as white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH2:28]OC(=O)C(C)(C)C)[C:22]3[N:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[CH:17][CH:16]=2)[C:10](=[O:36])[C:9]1=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:38]([OH:42])(=[O:41])[CH2:39][OH:40].Cl.C(O)C>C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH2:28][O:40][CH2:39][C:38]([OH:42])=[O:41])[C:22]3[N:23]=[CH:24][CH:25]=[CH:26][N:27]=3)=[CH:17][CH:16]=2)[C:10](=[O:36])[C:9]1=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CO
Reactant: CC(C)(C)C(=O)OCN(c1ccc(CN2CCN(Cc3ccccc3)C(=O)C2=O)cc1)c1ncccn1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(O)COCN(c1ccc(CN2CCN(Cc3ccccc3)C(=O)C2=O)cc1)c1ncccn1
Yield: 52.7 %

Procedure:
In 30 ml of ethyl acetate was dissolved 1 g of 1-benzyl-4-{4-[N-pivaloyloxymethyl-N-(2-pyrimidinyl)-amino]benzyl}-2,3-dioxopiperazine, and 1 g of glycolic acid and 0.02 ml of N hydrogen chloride-ethanol solution were added, after which the resulting mixture was subjected to reaction at room temperature for 3 hours with stirring. After the completion of the reaction, the solvent was removed by distillation under reduced pressure, and the residue thus obtained was extracted with 100 ml of methylene chloride. The methylene chloride layer was washed with 30 ml of water and then 30 ml of saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate, after which the solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by a column chromatography (Wakogel C-200, eluted with chloroformethanol), and recrystallized from ethyl acetate-diisopropyl ether, to obtain 0.5 g (52.8% yield) of 1-benzyl-4-{4-[N-carboxymethoxymethyl-N-(2-pyrimidinyl)amino]benzyl}-2,3-dioxopiperazine having a melting point of 85° to 90° C.