Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:42])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]3[CH2:41][C:25]5([CH2:28][C:27]([C:35]([O:37]C(C)C)=[O:36])([C:29]([O:31]C(C)C)=[O:30])[CH2:26]5)[CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:43]([C:46]([CH3:48])=[CH2:47])[CH2:44][CH2:45][C@:5]1([NH:49][CH2:50][CH2:51][N:52]([C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[S:53]([C:56]([F:59])([F:58])[F:57])(=[O:55])=[O:54])[CH2:4][CH2:3]2.[OH-].[Na+].Cl>O1CCOCC1.CO>[CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:42])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:21])([CH3:22])[C:14]([C:23]3[CH2:41][C:25]5([CH2:26][C:27]([C:35]([OH:37])=[O:36])([C:29]([OH:31])=[O:30])[CH2:28]5)[CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:43]([C:46]([CH3:48])=[CH2:47])[CH2:44][CH2:45][C@:5]1([NH:49][CH2:50][CH2:51][N:52]([C:60]1[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=1)[S:53]([C:56]([F:57])([F:58])[F:59])(=[O:55])=[O:54])[CH2:4][CH2:3]2
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN(c3ccccc3)S(=O)(=O)C(F)(F)F)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC7(C6)CC(C(=O)OC(C)C)(C(=O)OC(C)C)C7)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: C=C(C)[C@@H]1CC[C@]2(NCCN(c3ccccc3)S(=O)(=O)C(F)(F)F)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC7(C6)CC(C(=O)O)(C(=O)O)C7)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 50 °C
Reaction time: 3 h
Yield: 42 %

Procedure:
To a solution of diisopropyl 6-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-((2-(1,1,1-trifluoro-N-phenylmethylsulfonamido)ethyl)amino)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)spiro[3.3]hept-5-ene-2,2-dicarboxylate (15 mg, 0.016 mmol) in dioxane (2 mL) and MeOH (1 mL) was added 1N NaOH (1 mL, 1 mmol). The mixture was stirred at 50° C. for 3 h. The mixture was neutralized by 1N HCl (1 mL) to pH ˜6 and solids formed were collected by filtration. The crude product was purified by preparative HPLC using method 14 to give 6-((1R,3 aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-((2-(1,1,1-trifluoro-N-phenylmethylsulfonamido)ethyl)amino)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)spiro[3.3]hept-5-ene-2,2-dicarboxylic acid in 42% yield as a solid. MS: m/e 841.5 (M+H)+, 2.52 min (method 4). 1H NMR (400 MHz, METHANOL-d4) δ 7.52-7.43 (m, 5H), 5.93 (s, 1H), 5.56-5.52 (m, 1H), 4.72 (d, J=1.8 Hz, 1H), 4.60 (s, 1H), 3.99 (s., 2H), 2.77-2.65 (m, 4H), 2.63-2.51 (m, 5H), 2.15 (dd, J=17.8, 6.5 Hz, 1H), 1.92-1.83 (m, 2H), 1.78-0.94 (m, 19H), 1.69 (s, 3H), 1.16 (s, 3H), 1.11 (s, 3H), 1.09 (s, 3H), 0.98 (s, 3H), 0.87 (s, 3H). 19F NMR (376 MHz, METHANOL-d4) δ −75.37 (s., 3F).
Reaction SMILES: C(N(CC)CC)C.[CH:8]1([NH:11][CH2:12][C:13]2[CH:14]=[C:15]([C:19]3[CH:20]=[CH:21][C:22]4[O:26][N:25]=[C:24]([NH:27][CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:23]=4[CH:33]=3)[CH:16]=[CH:17][CH:18]=2)[CH2:10][CH2:9]1.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(Cl)Cl>[CH:8]1([N:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:20]=[CH:21][C:22]4[O:26][N:25]=[C:24]([NH:27][CH2:28][C:29]([CH3:30])([CH3:32])[CH3:31])[C:23]=4[CH:33]=3)[CH:14]=2)[C:34](=[O:41])[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)CNc1noc2ccc(-c3cccc(CNC4CC4)c3)cc12
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)CNc1noc2ccc(-c3cccc(CN(C(=O)c4ccccc4)C4CC4)c3)cc12
Temperature: -70 °C
Reaction time: 15 h
Yield: 76.9 %

Procedure:
Triethylamine (0.18 mL, 1.29 mmol, 1.5 equiv.) was added to a solution of 5-(3-((cyclopropylamino)methyl)phenyl)-N-neopentylbenzo[d]isoxazol-3-amine (exemplary compound 51) (0.30 g, 0.86 mmol, 1 equiv.) in DCM (10 mL) and the mixture was subsequently cooled to −70° C. Benzoylchloride (0.12 mL, 1.03 mmol, 1.2 equiv.) was added in drops and the mixture was slowly heated to RT and stirred for 15 hours. The reaction mixture was diluted with DCM (80 mL) and extracted with sat. aq. sodium hydrogen carbonate sol. (1×15 mL) and sat. aq. NaCl solution (1×15 mL), dried (MgSO4) and the solvent removed in a vacuum. After column-chromatographic purification (EtOAc/hexane; 10:1), the desired product (0.30 g, 77%) is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[O:17])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[C:6](Cl)[CH:7]=1.BrC1C=CC([F:25])=C(Cl)C=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[O:17])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[F:25]
Reactant: O=C(Cc1ccccc1)c1cc(Cl)cc(Cl)c1
Reactant: Fc1ccc(Br)cc1Cl
Product: O=C(Cc1ccccc1)c1ccc(F)c(Cl)c1
Yield: 20 %

Procedure:
Prepared following the procedure described in Intermediate 13, starting from 4-bromo-2-chloro-1-fluorobenzene, where the crude product was purified by column chromatography (PE: EtOAc=100:1) to afford Intermediate 17 (110 mg, yield 20.0%).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:16].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](Cl)=[O:26])=[CH:20][CH:19]=1>>[C:12]([C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:16])[N:2]([NH:1][C:25](=[O:26])[CH2:24][C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=2)[N:11]=1)([CH3:13])([CH3:15])[CH3:14]
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: CC(C)(C)c1nn(N)c(=O)c2ccccc12
Product: CC(C)(C)c1nn(NC(=O)Cc2ccc(Cl)cc2)c(=O)c2ccccc12

Procedure:
The product from Example 62A and 2-(4-chlorophenyl)acetyl chloride were treated using a method similar to that described in Example 1C to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 11.54 (s, 1H), 8.38 (d, J=8.3 Hz, 1H), 8.37 (dd, J=7.7, 1.6 Hz, 1H), 7.94-8.00 (m, 1H), 7.84-7.90 (m, 1H), 7.41 (s, 4H), 3.68 (s, 2H), 1.47 (s, 9H); MS (ESI+) M/Z 370 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[CH2:7][C:8]1([CH2:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[O:12][N:11]=[C:10]([C:13]2[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:14]=2[CH2:20][CH2:21][C:22]([OH:24])=[O:23])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(N(CC)C(C)C)(C)C.Cl>CN(C=O)C>[C:28]([O:27][C:26](=[O:32])[CH2:25][C:8]1([CH2:7][C:6](=[O:33])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[O:12][N:11]=[C:10]([C:13]2[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:14]=2[CH2:20][CH2:21][C:22]([O:24][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:23])[CH2:9]1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)CC1(CC(=O)OC(C)(C)C)CC(c2cc(O)ccc2CCC(=O)O)=NO1
Reactant: BrCc1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CC1(CC(=O)OC(C)(C)C)CC(c2cc(O)ccc2CCC(=O)OCc2ccccc2)=NO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-(2-(5,5-bis(2-tert-butoxy-2-oxoethyl)-4,5-dihydro-1,2-oxazol-3-yl)-4-hydroxyphenyl)propanoic acid (413 mg), (bromomethyl)benzene (0.117 mL), N,N-diisopropylethylamine (0.342 mL), and DMF (4 mL) was stirred overnight at room temperature. To the reaction mixture, 0.1 M hydrochloric acid was added, followed by extraction with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (227 mg).
Reaction SMILES: [N:1](OCC(C)C)=[O:2].[CH2:8]([N:13]([C@:20]1([OH:35])[C@H:26]([OH:27])[C@@H:25]([CH2:28][OH:29])[O:24][C@:22]([CH2:30][CH:31]([CH3:33])[CH3:32])([OH:23])[C@@H:21]1[OH:34])[C:14](=[O:19])[NH:15][CH2:16][CH2:17][Cl:18])[CH2:9][CH:10]([CH3:12])[CH3:11].O1CCCC1.Cl>C(O)C>[CH2:8]([N:13]([C@:20]1([OH:35])[C@H:26]([OH:27])[C@@H:25]([CH2:28][OH:29])[O:24][C@:22]([CH2:30][CH:31]([CH3:33])[CH3:32])([OH:23])[C@@H:21]1[OH:34])[C:14](=[O:19])[N:15]([CH2:16][CH2:17][Cl:18])[N:1]=[O:2])[CH2:9][CH:10]([CH3:11])[CH3:12]
Reactant: CC(C)CCN(C(=O)NCCCl)[C@]1(O)[C@H](O)[C@@H](CO)O[C@@](O)(CC(C)C)[C@@H]1O
Reactant: CC(C)CON=O
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)CCN(C(=O)N(CCCl)N=O)[C@]1(O)[C@H](O)[C@@H](CO)O[C@@](O)(CC(C)C)[C@@H]1O
Yield: 67.3 %

Procedure:
Isobutyl nitrite (3.5 ml) was dropped into a solution of 3-isopentyl-3-(isobutyl α-D-glucopyranose-3-yl)-1-(2-chloroethyl)urea (3.48 g, 8.47 mmol) in a mixture of ethanol (50 ml), tetrahydrofuran (150 ml), and 2N hydrochloric acid (30 ml) with well stirring at 0° to 5° C. Thereafter, 2.51 g of 3-isopentyl-3-(isobutyl α-D-glucopyranose-3-yl)-1-(2-chloroethyl)-1-nitrosourea was obtained by the same operations of Example 63(2); yield 67.3%, m.p. 69°-71° C., [α]D20 +45.8° (C 1.0, methanol).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[NH:10][N:11]=[C:12]([CH3:14])[CH:13]=2)[N:5]=[C:4]([S:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([CH:25]3[CH2:27][CH2:26]3)=[O:24])=[CH:18][CH:17]=2)[N:3]=1.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([C:2]2[CH:7]=[C:6]([NH:8][C:9]3[NH:10][N:11]=[C:12]([CH3:14])[CH:13]=3)[N:5]=[C:4]([S:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([CH:25]4[CH2:27][CH2:26]4)=[O:24])=[CH:18][CH:17]=3)[N:3]=2)[CH2:31][CH2:30]1
Reactant: Cc1cc(Nc2cc(Cl)nc(Sc3ccc(NC(=O)C4CC4)cc3)n2)[nH]n1
Reactant: CN1CCNCC1
Product: Cc1cc(Nc2cc(N3CCN(C)CC3)nc(Sc3ccc(NC(=O)C4CC4)cc3)n2)[nH]n1
Reaction time: 2 h

Procedure:
Compound D (2.373 g, 5.92 mmol) was treated with N-methylpiperazine (10 ml) and the mixture stirred at 110° for 2 hours. The excess N-methylpiperazine was removed in vacuo then the residue was dissolved in ethyl acetate, washed with aqueous sodium bicarbonate solution, dried over magnesium sulphate, and concentrated. The residue was crystallised from methanol to give colourless crystals of desired product V-1 (1.82 g, 66%), 1H-NMR DMSO-d6, δ 0.81 (4H, d), 1.79 (1H, m), 2.01 (3H, s), 2.18 (3H, s), 2.30 (4H, m), 3.35 (masked signal), 5.42 (1H, s), 6.02 (1H, br s), 7.47 (2H, d), 7.69 (2H, d), 9.22 (1H, s), 10.39 (1H, s), 11.69 (1H, s).
Reaction SMILES: [F:1][C:2]1([F:7])[CH2:5][CH:4]([NH2:6])[CH2:3]1.Cl.CCN(C(C)C)C(C)C.[F:18][C:19]([F:42])([F:41])[C@H:20]1[CH2:25][CH2:24][C@H:23]([NH:26][C:27](=[O:40])[C:28]2[CH:33]=[C:32]([N+:34]([O-:36])=[O:35])[C:31]([NH:37][CH3:38])=[CH:30][C:29]=2F)[CH2:22][CH2:21]1>CC#N>[F:18][C:19]([F:41])([F:42])[C@H:20]1[CH2:25][CH2:24][C@H:23]([NH:26][C:27](=[O:40])[C:28]2[CH:33]=[C:32]([N+:34]([O-:36])=[O:35])[C:31]([NH:37][CH3:38])=[CH:30][C:29]=2[NH:6][CH:4]2[CH2:5][C:2]([F:7])([F:1])[CH2:3]2)[CH2:22][CH2:21]1
Reactant: NC1CC(F)(F)C1
Reactant: CNc1cc(F)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1[N+](=O)[O-]
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CNc1cc(NC2CC(F)(F)C2)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1[N+](=O)[O-]
Reaction time: 16 h

Procedure:
A mixture of 3,3-difluoro-cyclobutylamine×HCl (49 mg, 0.34 mmol), DIPEA (0.26 ml, 1.5 mmol), N-(trans-4-trifluoromethyl-cyclohexyl)-2-fluoro-4-methylamino-5-nitro-benzoic acid amide (125 mg, 0.34 mmol, prepared according to WO2010/100249) and MeCN (5 mL) is stirred for 16 h at reflux. Then the mixture is concentrated, diluted with EtOAc, washed with water, concentrated, dried and directly used in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH:13]2[CH2:18][CH2:17][CH:16]([N:19]([CH3:21])[CH3:20])[CH2:15][CH2:14]2)=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[CH2:7]2.N[C:23]1C=CC(C2CCC(=O)CC2)=C2C=1C(=O)N(C)C2.C(NC)C>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH:13]2[CH2:18][CH2:17][CH:16]([N:19]([CH2:21][CH3:23])[CH3:20])[CH2:15][CH2:14]2)=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[CH2:7]2
Reactant: CN1Cc2c(C3CCC(N(C)C)CC3)ccc(N)c2C1=O
Reactant: CN1Cc2c(C3CCC(=O)CC3)ccc(N)c2C1=O
Agent: CCNC
Product: CCN(C)C1CCC(c2ccc(N)c3c2CN(C)C3=O)CC1

Procedure:
The title product was prepared according to the procedure for Compound 233A using 7-amino-2-methyl-4-(4-oxocyclohexyl)-2,3-dihydro-1H-isoindol-1-one and ethyl-methylamine. Used without purification in the next step.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:23])([F:22])[F:21])[NH:11][N:10]=1.[CH3:26]I>>[CH3:26][N:10]1[C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:2]([F:1])([F:24])[F:25])=[N:13][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:21])([F:22])[F:23])=[N:11]1
Reactant: CI
Reactant: FC(F)(F)c1ccccc1-c1n[nH]c(-c2ccccc2C(F)(F)F)n1
Product: Cn1nc(-c2ccccc2C(F)(F)F)nc1-c1ccccc1C(F)(F)F

Procedure:
starting from 3,5-di(o-trifluoromethyl-phenyl)-1H-1,2,4-triazole and methyl iodide there is obtained 1-methyl-3,5-di(o-trifluoromethyl-phenyl)-1H-1,2,4-triazole, m.p. 108°-111° C.;
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[CH2:26][CH2:25][C:24]3[N:23]=[C:22]([CH3:27])[O:21][C:20]=3[C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]2=3)=[O:16])=[CH:11][C:10]=1[CH3:32])(C)(C)C.[ClH:34].O1CCOCC1>CO>[ClH:34].[NH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[CH2:26][CH2:25][C:24]3[N:23]=[C:22]([CH3:27])[O:21][C:20]=3[C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]2=3)=[O:16])=[CH:11][C:10]=1[CH3:32]
Reactant: Cc1nc2c(o1)-c1ccccc1N(C(=O)c1ccc(CNC(=O)OC(C)(C)C)c(C)c1)CC2
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1nc2c(o1)-c1ccccc1N(C(=O)c1ccc(CN)c(C)c1)CC2
Yield: 100 %

Procedure:
[2-Methyl-4-(2-methyl-4,5-dihydro-1-oxa-3,6-diaza-benzo[e]azulene-6-carbonyl)-benzyl]-carbamic acid tert-butyl ester from Example E119.1 (62 mg, 0.14 mmol) in methanol (0.5 ml) was reacted with 4N HCl/dioxan using an analogous procedure to that described for Example E4.2 to yield the title compound (53 mg, 100%).
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:6]([CH2:7][O:8][C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:5][C@@H:4]([N:28]2[CH:35]=[CH:34][C:32](=[O:33])[NH:31][C:29]2=[O:30])[CH2:3]1.[C:36](OC(=O)C)(=[O:38])[CH3:37].C(N(CC)CC)C>C(Cl)Cl>[C:36]([NH:1][C@@H:2]1[C@@H:6]([CH2:7][O:8][C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:5][C@@H:4]([N:28]2[CH:35]=[CH:34][C:32](=[O:33])[NH:31][C:29]2=[O:30])[CH2:3]1)(=[O:38])[CH3:37]
Reactant: CC(=O)OC(C)=O
Reactant: N[C@H]1C[C@H](n2ccc(=O)[nH]c2=O)O[C@@H]1COC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N[C@H]1C[C@H](n2ccc(=O)[nH]c2=O)O[C@@H]1COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.5 %

Procedure:
Compound 31 (0.10 g, 0.213 mmol) was suspended in DCM (5 ml), and to this was added acetic anhydride (0.047 g, 0.044 ml, 0.469 mmol) and triethylamine (0.065 ml, 0.469 mmol). The mixture was stirred at room temperature for 3 hours. After this time the solvent was evaporated to give a white solid. The product was purified by column chromatography (MeOH/DCM 2%→6%), and evaporation of the solvent gave the title compound as a white solid (0.103 g, 95%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[N:18]([CH3:19])[CH:17]=[N:16][CH:15]=3)=[O:13])[CH:10]=2)[N:5]=[C:4]([O:20][CH3:21])[C:3]=1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1.[CH3:33]C#N.C(=O)=O.[Li]C>C1COCC1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[N:18]([CH3:19])[CH:17]=[N:16][CH:15]=3)([OH:13])[CH3:33])[CH:10]=2)[N:5]=[C:4]([O:20][CH3:21])[C:3]=1[CH2:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]([F:30])([F:32])[F:31])=[CH:27][CH:28]=1
Reactant: COc1nc2ccc(C(=O)c3cncn3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Reactant: CC#N
Agent: O=C=O
Agent: [Li]C
Solvent: C1CCOC1
Product: COc1nc2ccc(C(C)(O)c3cncn3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Reaction time: 0.5 h

Procedure:
To a flask containing (4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanone (400 mg, 0.87 mmol, Intermediate 12: step b) was added THF (20 mL) and the solution was cooled to −43° C. (CH3CN—CO2). MeLi (1.6 M in Et2O, 0.63 mL, 1.01 mmol) was then introduced. After 30 minutes, the reaction mixture was quenched with saturated aqueous NH4Cl solution. The aqueous portion was extracted with EtOAc (4×30 mL) and the combined organics were washed with brine, dried over MgSO4, filtered and concentrated to dryness. Chromatography on silica gel (30% CH3CN-DCM increasing to 3% MeOH-DCM) provided the title compound as a white amorphous solid. 1H NMR (400 MHz, CDCl3) δ 8.24 (d, J=1.9 Hz, 1H), 7.77 (d, J=8.9 Hz, 1H), 7.49 (dd, J=8.6, 2.2 Hz, 3H), 7.40 (d, J=8.1 Hz, 2H), 7.34 (s, 1H), 7.17 (d, J=0.8 Hz, 1H), 4.35 (s, 2H), 4.07 (s, 3H), 3.25 (s, 3H), 3.0 (br. s, 1H), 1.99 (s, 3H); MS (ESI): mass calcd. for C24H21ClF3N3O2, 475.1, m/z found 475.9 [M+H]+. 1-(4-Chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)-1-(1-methyl-1H-imidazol-5-yl)ethanol was purified by chiral SFC: (Stationary phase: CHIRALCEL OD-H, 5 μm, 250×20 mm), Mobile phase: 70% CO2, 30% MeOH), to give 2 enantiomers. The first eluting enantiomer was Example 9b and the second eluting enantiomer was Example 9c.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:47][C:48]1[CH:55]=[CH:54][C:53]([F:56])=[CH:52][C:49]=1[CH2:50][NH2:51]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([NH:51][CH2:50][C:49]4[CH:52]=[C:53]([F:56])[CH:54]=[CH:55][C:48]=4[F:47])=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: NCc1cc(F)ccc1F
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)NCc2cc(F)ccc2F)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with 2,5-difluorobenzylamine (Aldrich) to give the title product. LC-MS (ES+) 790 [(M+H)+].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].N1(C2C=CN=CC=2)CCCC1.[C:23](O)([CH3:26])([CH3:25])[CH3:24]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:10]
Reactant: CC(C)(C)O
Reactant: O=C(O)Cc1ccccc1Br
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Cc1ccccc1Br
Temperature: 25 °C
Reaction time: 4 h
Yield: 8.7 %

Procedure:
A mixture of 2-bromophenylacetic acid (5.02 g), N,N-dicyclohexylcarbodiimide (5.3 g), 4-pyrrolidinopyridine (0.4 g) and t-butanol (1.74 g) in DCM (120 ml) was stirred at room temperature, under nitrogen, for 4 h. The mixture was left to stand for 18 h, then ER (150 ml) was added and the mixture was filtered and washed with ER. The filtrate was evaporated in vacuo to leave a yellow suspension. F.C.C. (A) eluting with hexane gave a white semisolid, which was further chromatographed eluting with hexane, then 1% ER in hexane, and finally 2% gave a colorless liquid. Vacuum distillation by Kugelrohr at 0.4 mmHg and at 140°-150° gave the title compound as a colorless oil (0.55 g). T.l.c. (A) hexane:ER (3:1) Rf 0.68.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.O=[C:22]([CH2:26][N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1)[C:23]([OH:25])=[O:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:22]([C:23]([OH:25])=[O:24])[CH2:26][N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1
Reactant: O=C(O)C(=O)CN1CCCC1
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Product: O=C(O)C(CN1CCCC1)=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1

Procedure:
In the manner given in Example 13, 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine can be stirred with 2-oxo-3-pyrrolidinopropionic acid at room temperature to give 7-chloro-2-[(1-carboxy-2-pyrrolidinoethylidene)-hydrazino]-5-phenyl-3H-1,4-benzodiazepine.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:37](=[O:38])[N:13]3[C:14]([C:21]([O:23][CH:24]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:22])=[C:15]([C:18](Cl)=[O:19])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:39]([Li])[CH2:40][CH2:41][CH3:42].O1CCCC1.Cl>C(OCC)(=O)C>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:37](=[O:38])[N:13]3[C:14]([C:21]([O:23][CH:24]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:22])=[C:15]([C:18](=[O:19])[CH2:39][CH2:40][CH2:41][CH3:42])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [Li]CCCC
Reactant: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C(=O)Cl)CS[C@H]12
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCC(=O)C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2SC1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
The reaction of these carbanionic reagents with activated 3-carboxycephem intermediates (acid chlorides and mixed anhydrides) is carried out under the same conditions as discussed hereinabove for the process of this invention. A typical procedure is illustrated by reaction of benzhydryl 7-phenylacetamido-3-chlorocarbonyl-3-cephem-4-carboxylate with n-butyllithium. A ethereal solution of 3 equivalents of n-butyllithium is added to a solution of 1 mmole of benzhydryl 7-phenylacetamido-3-chlorocarbonyl-3-cephem-4-carboxylate in 30 ml. of tetrahydrofuran at -73° C. After approximately 5 minutes 10 ml. of 1N. hydrochloric acid is added, and the acidified mixture is then allowed to warm to about 0° C. Ethyl acetate is added, and the resulting mixture is washed with dilute hydrochloric acid and brine and dried over anhydrous sodium sulfate. Chromatographic purification provides benzhydryl 7-phenylacetamido-3-valeroyl-3-cephem-4-carboxylate.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Li]CCCC.[CH2:17]([N:24]1[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1.CCOCC>[CH2:17]([N:24]1[CH2:29][CH2:28][C:27]([C:2]2[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])([OH:30])[CH2:26][CH2:25]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(O)c1cc(Br)ccc1Br
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(O)c1cc(Br)ccc1C1(O)CCN(Cc2ccccc2)CC1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 2,5-dibromobenzoic acid (27.8 g, 100 mmol, 1.00 equiv) in THF/Et2O (450/50 mL) under nitrogen at −78° C. was added dropwise n-BuLi (2.5M) (88 mL, 2.20 equiv). After 2 h at −78° C., was added 1-benzylpiperidin-4-one (26.5 g, 140 mmol, 1.40 equiv). The resulting solution was stirred for 0.5 h at −78° C. and then warmed to room temperature, and stiffed overnight. The reaction was quenched by carefully adding 200 mL of water. The pH of the mixture was adjusted to 2-3 with hydrogen chloride (aq., 2 M). The aqueous phase was extracted with 3×500 mL of ethyl acetate and 3×500 mL of tetrahydrofuran. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield 38.9 g (crude) of the title compound as a yellow solid.