Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[Br-].[O:13]=[C:14]1[C:23]2[C:18](=[CH:19][C:20]([CH2:24][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:21][CH:22]=2)[CH:17]=[N:16][NH:15]1.O>CS(C)=O>[CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6](/[CH:7]=[CH:24]\[C:20]2[CH:19]=[C:18]3[C:23](=[CH:22][CH:21]=2)[C:14](=[O:13])[NH:15][N:16]=[CH:17]3)=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: O=c1[nH]ncc2cc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)ccc12
Agent: [Br-]
Solvent: O
Solvent: CS(C)=O
Product: CN(C)c1ccc(/C=C\c2ccc3c(=O)[nH]ncc3c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.2 %

Procedure:
4-dimethylaminobenzaldehyde (9 gm) in DMSO (30 ml) was added to a solution of 1-oxo-2H-phthalazin-6-ylmethyl triphenylphosphonium bromide (0.04 mole) in DMSO (100 ml) and stirred overnight at room temperature. The reaction mixture was added to water (1 L), stirred, and the precipitate was filtered to give a solid. The solid was air dried, slurried with acetone (200 ml) and filtered and dried to give a mixture of cis and trans isomers (9.9 gm). The solid was recrystallized from DMF (65 ml) and filtered to give pure cis product (4.8 gm), mp=312°-318° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:6](=[O:7])[CH2:5][C:4]([CH3:9])([CH3:8])[O:3]1.C[O-].[Na+].[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH3:29])=[C:24]([CH:30]=O)[CH:23]=1.Cl>COCCOC>[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH3:29])=[C:24]([CH:30]=[C:5]2[C:4]([CH3:9])([CH3:8])[O:3][C:2]([CH3:10])([CH3:1])[C:6]2=[O:7])[CH:23]=1
Reactant: CC1(C)CC(=O)C(C)(C)O1
Reactant: CCc1ccc(-c2ccc(Cl)cc2Cl)cc1C=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: COCCOC
Product: CCc1ccc(-c2ccc(Cl)cc2Cl)cc1C=C1C(=O)C(C)(C)OC1(C)C
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To an ice-cold solution of 2,2,5,5-tetramethyldihydrofuran-3-one (1.15 g, 0.0081 mol) in 1,2-dimethoxyethane (2 ml) is added sodium methoxide (0.481 g, 0.0089 mol) in one portion. The reaction mixture is then stirred for 5 minutes at this temperature, followed by the addition of a second solution of 2′,4′-dichloro-4-ethylbiphenyl-3-carbaldehyde (2.02 g, 0.0072 mol) in 1,2-dimethoxyethane (2.7 ml). After stirring for an additional 2 hours at 0° C. the reaction mixture is allowed to stand at room temperature overnight. The crude solution is poured into 2M hydrochloric acid and extracted with ether (×3). The organics are combined, washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue is purified by flash column chromatography (5% ethyl acetate in isohexane to 25% ethyl acetate in isohexane) to afford 4-[1-(2′,4′-dichloro-4-ethylbiphenyl-3-yl)-methylidene]-2,2,5,5-tetramethyldihydrofuran-3-one as a yellow gum.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C@H:10]1[O:39][C@H:38]([CH2:40][O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C@@H:29]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@H:20]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C@@H:11]1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH2:49]([O:51][C:52](=[O:58])[C:53](=[N:56][OH:57])[CH2:54]Br)[CH3:50].C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])O.[Na+]>ClCCl>[CH2:49]([O:51][C:52](=[O:58])[C:53](=[N:56][OH:57])[CH2:54][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]=1[C@H:10]1[O:39][C@H:38]([CH2:40][O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C@@H:29]([O:30][CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C@H:20]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C@@H:11]1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:50]
Reactant: CCOC(=O)C(CBr)=NO
Reactant: c1ccc(COC[C@H]2O[C@H](c3cc4ccccc4[nH]3)[C@@H](OCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C(Cc1c([C@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)[nH]c2ccccc12)=NO
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 37.3 %

Procedure:
First, 2.08 g (3.24 mmol) of (1R)-1,5-anhydro-1-C-(2-indolyl)-2,3,4,6-tetra-O-benzyl-D-mannitol [compound (VII) wherein R1 to R4 are benzyl] was dissolved in dichloromethane (160 ml). Then, 1.36 g (6.49 mmol) of 3-bromo-2-hydroxyiminopropionic acid ethyl ester [compound (VIII) wherein R6 is ethyl] and 1.03 g (9.74 mmol) of sodium carbonate powder were added to the mixture and stirred at room temperature for about 1.5 hours. Then, a saturated aqueous solution of sodium hydrogen carbonate was added to the reaction mixture which was then subjected to extraction with dichloromethane. The extracted solution was washed with water and then dried on anhydrous sodium sulfate. After removal of the solvent by distillation, the residue was fractionated by column chromatography on silica gel [silica gel: Merck Kieselgel 60 (230-400 mesh ASTM); elution solvent: n-hexane and ethyl acetate (3:1)] to give 1.04 g (recovery 50%) of the starting material and 0.93 g (yield 37%) of 2-hydroxyimino-3-[2-(2,3,4,6-tetra-O-benzyl-α-D-mannopyranosyl)indole-3-yl]propionic acid ethyl ester [compound (IX) wherein R1 to R4 are benzyl and R6 is ethyl].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]=3)[CH:11]=2)[CH:6]=[CH:7][C:8]=1[OH:9].[N+:26]([O-])([OH:28])=[O:27]>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:23])[F:24])[N:17]=3)[CH:11]=2)[CH:6]=[C:7]([N+:26]([O-:28])=[O:27])[C:8]=1[OH:9]
Reactant: O=[N+]([O-])O
Reactant: COc1cc(-c2cccc(-c3cccc(C(F)(F)F)n3)c2)ccc1O
Solvent: CC(=O)O
Product: COc1cc(-c2cccc(-c3cccc(C(F)(F)F)n3)c2)cc([N+](=O)[O-])c1O

Procedure:
To a solution of 3-methoxy-3′-(6-(trifluoromethyl)pyridin-2-yl)biphenyl-4-ol (0.476 g, 1.38 mmol) in acetic acid (10 mL) at room temperature was added 60% nitric acid (0.12 mL, 1.52 mmol) dropwise. The resulting mixture was allowed to stir for thirty minutes then poured onto ice-water (100 mL) and the resulting precipitate was filtered off, washed with water and dried. After chromatography over silica gel (petroleum ether/ethyl acetate, 2:1), 3-methoxy-5-nitro-3′-(6-(trifluoromethyl)pyridin-2-yl)biphenyl-4-ol was obtained as a yellow solid, 0.323 g (60%).
Reaction SMILES: [CH3:1][C:2]([CH3:38])([CH3:37])[C@H:3]([NH:8][C:9]([C:11]1[N:12]=[C:13]([C:28]2[CH:33]=[C:32]([F:34])[C:31]([F:35])=[CH:30][C:29]=2[F:36])[N:14]2[CH2:19][CH2:18][N:17]([CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])[CH2:16][C:15]=12)=[O:10])[C:4]([NH:6][CH3:7])=[O:5].[OH-].[K+]>CO.O>[CH3:1][C:2]([CH3:38])([CH3:37])[C@H:3]([NH:8][C:9]([C:11]1[N:12]=[C:13]([C:28]2[CH:33]=[C:32]([F:34])[C:31]([F:35])=[CH:30][C:29]=2[F:36])[N:14]2[CH2:19][CH2:18][N:17]([CH2:20][C:21]([OH:23])=[O:22])[CH2:16][C:15]=12)=[O:10])[C:4]([NH:6][CH3:7])=[O:5]
Reactant: CNC(=O)[C@@H](NC(=O)c1nc(-c2cc(F)c(F)cc2F)n2c1CN(CC(=O)OC(C)(C)C)CC2)C(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CNC(=O)[C@@H](NC(=O)c1nc(-c2cc(F)c(F)cc2F)n2c1CN(CC(=O)O)CC2)C(C)(C)C
Temperature: 100 °C
Yield: 14 %

Procedure:
To compound 69B (20 mg, 0.037 mmol) in 1 mL of a 3:1 mixture of MeOH/water was added KOH (6.3 mg, 0.112 mmol). The reaction vessel was capped and heated in the microwave at 100° C. for 10 minutes. The reaction mixture was quenched with 1N HCl and evaporated to dryness. The residue was purified by automated preparative LC/MS to provide 2.5 mg (13% yield) of a white solid. LCMS (+ESI) m/z 482.6 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH3:23])[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH:13]2[O:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)[CH2:7]1)=[O:5])[CH3:2].[CH2:24](I)C>>[CH2:1]([O:3][C:4]([C:6]1([CH2:23][CH3:24])[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH:13]2[O:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(C)CCCN(CC2COc3ccccc3O2)C1
Reactant: CCI
Product: CCOC(=O)C1(CC)CCCN(CC2COc3ccccc3O2)C1

Procedure:
Prepared according to the procedure described above for 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpiperidine-3-carboxylic acid ethyl ester except that ethyl iodide was used instead of methyl iodide.
Reaction SMILES: [NH2:1][C@:2]1([CH3:15])[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[O:5][CH2:4][C@@H:3]1[CH2:13][OH:14].[C:16]([N:24]=[C:25]=[S:26])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[F:12][C:8]1[CH:7]=[C:6]2[C:11]([C@:2]([NH:1][C:25]([NH:24][C:16](=[O:23])[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[S:26])([CH3:15])[C@@H:3]([CH2:13][OH:14])[CH2:4][O:5]2)=[CH:10][CH:9]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: C[C@@]1(N)c2ccc(F)cc2OC[C@@H]1CO
Solvent: C1CCOC1
Product: C[C@@]1(NC(=S)NC(=O)c2ccccc2)c2ccc(F)cc2OC[C@@H]1CO
Yield: 93.9 %

Procedure:
A solution of ((3S,4S)-4-amino-7-fluoro-4-methylchroman-3-yl)methanol from step F3 (795 mg, 3.76 mmol), and benzoyl isothiocyanate (614 mg, 3.76 mmol) in THF (50 mL) was stirred at rt for 1.5 h. The resulting mixture was concentrated in vacuo. The crude residue was purified using silica gel column chromatography (95:5 chloroform/MeOH) to afford rel-N-(((3S,4S)-7-fluoro-3-(hydroxymethyl)-4-methylchroman-4-yl)carbamothioyl)benzamide (1.32 g, 3.53 mmol, 94% yield). LCMS (M+Na)+=397.2. 1H NMR (500 MHz, DMSO-d6) δ 11.45 (s, 1H), 11.26 (s, 1H), 7.91 (dd, J=8.4, 1.2 Hz, 2H), 7.68-7.58 (m, 1H), 7.57-7.41 (m, 3H), 6.86 (td, J=8.5, 2.7 Hz, 1H), 6.70 (dd, J=10.4, 2.7 Hz, 1H), 4.84 (t, J=4.7 Hz, 1H), 4.56 (dd, J=11.4, 3.1 Hz, 1H), 4.20 (dd, J=11.4, 1.6 Hz, 1H), 3.64-3.52 (m, 1H), 3.26-3.12 (m, 2H), 2.07 (s, 2H).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])([OH:3])=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:49]([O:51][C:52](=[O:65])[C@H:53]([OH:64])[C@H:54]([NH2:63])[CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1[Cl:62])[CH3:50]>C(Cl)Cl>[Cl:62][C:57]1[CH:58]=[CH:59][CH:60]=[CH:61][C:56]=1[CH2:55][C@@H:54]([NH:63][C:1]([CH2:4][CH2:5][CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])=[O:3])[C@H:53]([C:52]([O:51][CH2:49][CH3:50])=[O:65])[OH:64]
Reactant: CCOC(=O)[C@H](O)[C@H](N)Cc1ccccc1Cl
Reactant: O=C(O)CCCc1ccccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)[C@H](O)[C@@H](Cc1ccccc1Cl)NC(=O)CCCc1ccccc1C(=O)O
Yield: 27.9 %

Procedure:
2-(3-Carboxy-propyl)benzoic acid (50 mg, 240 μmol 1.0 eq.) was combined with DIPEA (134 μL, 3.2 eq.) and HATU (91.3 mg, 240 μmol, 1.0 eq.) in DCM (5 mL). (2R,3R)-3-Amino-4-(2-chloro-phenyl)-2-hydroxy-butyric acid ethyl ester (69.9 mg, 240 μmol, 1.0 eq.) was added and the mixture was stirred. The reaction was quenched after 1 hour by adding saturated NH4Cl and the product was extracted with DCM, dried and evaporated. The product was purified using preparative HPLC to yield the title compound (30 mg, 100% purity). MS m/z [M+H]+ calc'd for C23H26ClNO6, 448.14. found 448.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.[CH3:12][O:13][C:14](=[O:18])[C@@H:15]([CH3:17])[NH2:16].C(N(CC)CC)C>CO>[CH3:12][O:13][C:14](=[O:18])[C@@H:15]([CH3:17])[NH:16][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: COC(=O)[C@@H](C)N
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](C)Nc1ncccc1[N+](=O)[O-]
Yield: 5.9 %

Procedure:
A suspension of 2-chloro-3-nitropyridine (37.76 g, 0.239 mole), (R)-alanine methyl ester hydrochloride (50 g, 0.358 mole) and triethylamine (60.3 g, 0.597 mole) in methanol (370 ml) was refluxed overnight under nitrogen. The solvents were removed under reduced pressure and the resulting solid was triturated in ethyl acetate (300 ml), filtered, and rinsed with additional ethyl acetate. The filtrate and washings were combined and washed once with water. The aqueous wash was extracted with ethyl acetate and the combined organic layers were washed several times with water, dried over sodium sulfate, filtered and evaporated under reduced pressure to give an oil weighing 45.6 g (85%). Elution of a portion of the oil with 1:6 tetrahydrofuran/hexane through a silica gel column gave 3.2 g of product after evaporation of solvent. Drying of a portion of the solid under high vacuum at room temperature gave 0.98 g of title compound, mp 39°-40° C.
Reaction SMILES: [NH2:1][C@@:2]([CH3:15])([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13]C)=[CH:9][CH:8]=1)[C:3](N)=[O:4].C1(CC(N)=[O:24])C=CC=CC=1.Br>O>[CH3:15][C@@:2]([NH2:1])([C:3]([OH:24])=[O:4])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1
Reactant: NC(=O)Cc1ccccc1
Reactant: COc1ccc(C[C@](C)(N)C(N)=O)cc1
Agent: Br
Solvent: O
Product: C[C@](N)(Cc1ccc(O)cc1)C(=O)O
Temperature: 120 °C
Reaction time: 0.25 h
Yield: 84 %

Procedure:
To a 100 mL flask with a reflux condenser was charged amide 4 (5.50 g of a mixture containing 4 (3.37 g, 16.1 mmol) and phenylacetamide (2.13 g)) and 48% HBr (30 mL). The solution was heated for 5 h at 120° C. and was cooled to room temperature. H2O (60 mL) was added and the solution was washed with EtOAc (3×35 mL). The aqueous phase was concentrated in vacuo to provide a beige paste. The paste was dissolved in H2O (15 mL) and the resulting mixture was heated to 65° C. Activated carbon (300 mg, Type NORIT SX) was added and the mixture was stirred for 15 min, was filtered and the filter pad was washed with water (2×4 mL). The combined filtrates were heated to 55° C. and the pH was adjusted to 5-6 using 32% aq. NH3. The mixture was cooled to 0° C., was stirred for 15 min and was filtered. The collected solids were washed with cold water (2×5 mL) and were dried in vacuo to provide (−)-α-methyl-L-tyrosine (or metyrosine) 1 (2.65 g, 84%) as a white solid. HPLC (Zorbax C18, NaH2PO4 10 mM pH=3/MeCN (100:0) 10 min, (100:0) to (0:100) 15 min, 0:100 5 min) tR=10.1 min. Chiral HPLC (Nucleosil Chiral-1, CuSO4 10 mM/MeCN 10:1) tR=16.9 min. m.p.=320-321° C. [α]546=+201° (c=0.5 Copper complex solution) (lit.2+185-190° Copper complex solution preparation: Solution A (anhydrous NaOAc dissolved in H2O (150 mL) in 250 mL volumetric flask, glacial acetic acid (50 mL) added and diluted to volume with H2O) mixed with Solution B (cupric sulfate (62.5 g) diluted to volume with H2O in a 200 mL volumetric flask) in a 1 L volumetric flask and was diluted to volume with H2O. Metyrosine solution (5 mg/mL) was prepared in this solution.
Reaction SMILES: [F:1][C:2]1[C:7](=[O:8])[NH:6][C:5]([CH2:9][C:10]([O-:12])=O)=[N:4][C:3]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[Na+].[CH3:20][CH:21]1[CH2:29][C:28]2[C:23](=[CH:24][C:25]([F:30])=[CH:26][CH:27]=2)[NH:22]1>>[F:1][C:2]1[C:7](=[O:8])[NH:6][C:5]([CH2:9][C:10]([N:22]2[C:23]3[C:28](=[CH:27][CH:26]=[C:25]([F:30])[CH:24]=3)[CH2:29][CH:21]2[CH3:20])=[O:12])=[N:4][C:3]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: CC1Cc2ccc(F)cc2N1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)c(F)c(=O)[nH]1
Agent: [Na+]
Product: CC1Cc2ccc(F)cc2N1C(=O)Cc1nc(N2CCOCC2)c(F)c(=O)[nH]1
Yield: 52.5 %

Procedure:
The product is prepared by following the procedure described in example 1a (step 5a) using 123 mg of sodium (5-fluoro-4-morpholin-4-yl-6-oxo-1,6-dihydropyrimidin-2-yl)acetate obtained in step 2a of example 6a and 62 mg of (+)-2-methyl-6-fluoro-2,3-dihydro-1H-indole (reference example 6a). After silica column purification: eluent 98/02 dichloromethane/methanol, 84 mg of 5-fluoro-2-[2-((−)-6-fluoro-2-methyl-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one are obtained in the form of a solid, the characteristics of which are the following:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.CO.Cl[CH2:17]Cl.C[Si](C=[N+]=[N-])(C)C>C1COCC1>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:17])=[O:12])=[CH:6][CH:7]=1
Reactant: ClCCl
Reactant: Nc1ccc(CCCC(=O)O)cc1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)CCCc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28 %

Procedure:
To a solution of 4-(4-aminophenyl)butanoic acid (180 mg, 1 mmol) in a mixture of THF (4 ml), MeOH (1 ml) and dichloromethane (1 ml) in a 20-mL vial was added dropwise (trimethylsilyl)diazo-methane (1 ml, 2N in hexane) at 0° C. After the addition was complete, the resulting mixture was stirred at room temperature for 1 hr. The volatile material was removed under reduced pressure and the residue was purified by chromatography on silica gel using hexane/dichloromethane (2:1) followed by dichloromethane as eluent to give methyl 4-(4-aminophenyl)butanoate as an yellowish oil (55 mg, 28% yield).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH2:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[F:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH2:25][NH:26][CH2:27]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[F:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH2:25][N:26]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[C:9]([NH2:17])[C:10]=1[F:16])[CH2:27]2
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: Fc1cccc2c1CNC2
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: Nc1c(F)c(N2Cc3cccc(F)c3C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 21.2 %

Procedure:
200 mg of 1-cyclopropyl-5-amino-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 101 mg of 4-fluoroisoindoline, 200 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 59 mg of the target compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(N(CC)CC)C.[NH2:18][C:19]1[CH:40]=[CH:39][C:22]([C:23]([N:25]2[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[CH2:29][N:28]3[CH:36]=[CH:37][CH:38]=[C:27]3[CH2:26]2)=[O:24])=[CH:21][CH:20]=1>C(Cl)Cl>[CH2:38]1[C:27]2=[CH:26][N:25]([C:23]([C:22]3[CH:21]=[CH:20][C:19]([NH:18][C:4](=[O:5])[C:3]4[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=4[F:1])=[CH:40][CH:39]=3)=[O:24])[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[CH2:29][N:28]2[CH:36]=[CH:37]1
Reactant: O=C(Cl)c1ccccc1F
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)N2C=C3CC=CN3Cc3ccccc32)cc1)c1ccccc1F
Reaction time: 0.05 h
Yield: 88.4 %

Procedure:
To a solution of 314 mg of 2-fluorobenzoyl chloride in 5 ml of methylene chloride at 0° C. is added 346 μl of triethylamine. After stirring for 3 minutes, 500 mg of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo-[2,1-c][1,4]benzodiazepine is added. The bath is removed and the reaction mixture stirred at room temperature for 18 hours. The volatiles are concentrated in vacuo to give a residue which is dissolved in methylene chloride, washed with water, 2N citric acid, 1M NaHCO3 and brine. The organic layer is dried with Na2SO4, filtered and concentrated in vacuo to give 620 mg of the desired product as a crystalline solid, m.p. 257°-260° C.
Reaction SMILES: [CH3:1][P:2]([C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[Cl:23])[CH:9]=[CH:8][C:7]=1[C:24]#[N:25])(=[O:5])[O:3]C.C[Si](Br)(C)C.CO>C(Cl)Cl>[CH3:1][P:2]([C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[Cl:23])[CH:9]=[CH:8][C:7]=1[C:24]#[N:25])(=[O:3])[OH:5]
Reactant: COP(C)(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1C#N
Agent: C[Si](C)(C)Br
Solvent: CO
Solvent: ClCCl
Product: CP(=O)(O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1C#N
Reaction time: 2 h

Procedure:
To a solution of methyl P-methyl-2-cyano-5-(2-chloro-4-trifluoromethylphenoxy)-phenylphosphinate (0.46 g) in 10 ml of methylene chloride is added trimethylsilyl bromide (0.75 ml) dropwise. The mixture is stirred for 2 hours, after which methanol is added. The reaction is stripped and evaporated under vacuum to give P-methyl-2-cyano-5-(2-chloro-4-trifluoromethyl-phenoxy)phenylphosphinic acid, m/s 375 (M+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7]([NH:9][C:10]2[CH:15]=[C:14]([C:16](=[O:21])[NH:17][CH:18]3[CH2:20][CH2:19]3)[CH:13]=[CH:12][C:11]=2[CH3:22])=[O:8])[S:5][CH:6]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1>>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[CH:3]=[C:4]([C:7]([NH:9][C:10]3[CH:15]=[C:14]([C:16](=[O:21])[NH:17][CH:18]4[CH2:20][CH2:19]4)[CH:13]=[CH:12][C:11]=3[CH3:22])=[O:8])[S:5][CH:6]=2)=[CH:26][CH:25]=1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(Br)cs1
Reactant: OB(O)c1ccc(Cl)cc1
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(-c2ccc(Cl)cc2)cs1

Procedure:
The title compound was prepared by coupling 4-bromo-N-(5-(cyclopropylcarbamoyl)-2-methylphenyl)thiophene-2-carboxamide a with commercially available 4-chlorophenylboronic acid using the method described in Step B of Example 136 to afford a white solid (Example 203). HPLC Ret time=3.66 min. LCMS [M+H]+ 411.21.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:17])[C:5]([NH:8][N:9]=[CH:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])=[N:6][CH:7]=1.[C:18]([C:22](=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:23])(OC)=[O:19]>O1CCOCC1.CCCCCC>[Cl:1][C:2]1[CH:3]=[C:4]([F:17])[C:5]([N:8]2[C:18](=[O:19])[C:22]([CH3:23])=[C:11]([C:12]([F:15])([F:14])[F:13])[CH:10]=[N:9]2)=[N:6][CH:7]=1
Reactant: COC(=O)C(C)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(C=NNc1ncc(Cl)cc1F)C(F)(F)F
Solvent: CCCCCC
Solvent: C1COCCO1
Product: Cc1c(C(F)(F)F)cnn(-c2ncc(Cl)cc2F)c1=O
Temperature: 50 °C

Procedure:
A solution of 8.09 g 3((5-chloro-3-fluoro-pyridine-2-yl) -hydrazono)-1,1,1-trifluoro-propan-2-one and 11.5 g 1-carbomethoxyethylidene triphenylphosphine in 200 ml dioxane was stired for 30 min. at 20° C. and then heated until complete conversion at 50° C. The reaction mixture was diluted with hexane, filtered from solid triphenylphosphine oxide through silicagel and evaporated. Further purification of the residue on silicagel (ethyl acetate-hexane 3:7) led to the desired product with m.p. 91-93° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:18][C:19]2[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:10]2[CH2:15][CH2:14][N:13]([C:16]#[N:17])[CH2:12][CH2:11]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[NH2:26][OH:27].Cl.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:18][C:19]2[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:10]2[CH2:15][CH2:14][N:13]([C:16]([NH:26][OH:27])=[NH:17])[CH2:12][CH2:11]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: NO
Reactant: Cc1cccnc1CN(Cc1ncccc1C)C1CCN(C#N)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccnc1CN(Cc1ncccc1C)C1CCN(C(=N)NO)CC1
Temperature: 60 °C
Reaction time: 16 h
Yield: 24.9 %

Procedure:
To a solution of 4-[bis-(3-methyl-pyridin-2-ylmethyl)-amino]-piperidine-1-carbonitrile (0.2413 g, 0.72 mmol) in DMF (7 mL) was added NH2OH.HCl (0.1127 g, 1.44 mmol) and DIPEA (0.25 mL, 1.44 mmol), and stirred at 60° C. for 16 hours. Saturated NaHCO3 (15 mL) was added and extracted with CH2Cl2 (3×50 mL). The combined organic extracts were washed with brine (2×50 mL), dried (Na2SO4), filtered, and concentrated. Purification of the crude material by column chromatography on silica gel (20:1:1 CH2Cl2-MeOH—NH4OH) provided 66.1 mg (58%) of COMPOUND 286 as a yellow solid. 1H NMR (CD3OD) 1.70-1.87 (m, 4H), 2.15 (s, 6H), 2.36-2.58 (m, 3H), 3.71 (d, 2H), 3.82 (s, 4H), 7.19-7.24 (m, 2H), 7.53 (d, 2H, J=7.5 Hz), 8.25 (d, 2H, J=4.8 Hz). 13C NMR (CD3OD) δ 18.70, 28.15, 48.19, 55.78, 59.90, 124.62, 136.04, 140.60, 146.72, 158.48, 160.89. ES-MS m/z 369.3 (M+H). Anal. Calcd. for C20H28N6O.0.9H2O: C, 62.44; H, 7.81; N, 21.85. Found: C, 62.60; H, 7.82; N, 21.74.