Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7](I)[CH:6]=[C:5]([Cl:10])[C:3]=1[NH2:4].[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C>[Cl:1][C:2]1[CH:8]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[C:5]([Cl:10])[C:3]=1[NH2:4]
Reactant: OB(O)c1ccccc1
Reactant: Nc1c(Cl)cc(I)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Nc1c(Cl)cc(-c2ccccc2)cc1Cl
Temperature: 25 °C

Procedure:
2,6-Dichloro-4-iodoaniline (10.4 g, 36.0 mmol) is dissolved in toluene (100 mL) and treated with 1.5 equivalents of phenylboronic acid (6.6 g, 54 mmol), and a catalytic amount of tetrakistriphenylphosphine palladium(0) (3.0 g, 2.6 mmol) as a solution in ethanol (20 mL). Sodium carbonate (40 mL of 2 M aqueous solution) is added and the reaction mixture stirred and heated to reflux temperature for 24 hours. After cooling to room temperature, the mixture is partitioned between Et2O (300 mL) and water (150 mL). The organic layer is washed with brine, dried (MgSO4) and concentrated by rotary evaporator. The residual oil is purified by flash chromatography (9:1 hexanes/EtOAc) to give 2,6-dichloro-4-phenylaniline (m.p. 112–113° C.).
Reaction SMILES: C[O:2][C:3](=[O:41])[C@H:4]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[NH:5][C:6](=[O:33])[C:7](=[CH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[NH:8][C:9](=[O:25])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]>CO>[C:15]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:10]1[C:9]([NH:8][C:7]([C:6]([NH:5][C@H:4]([C:3]([OH:41])=[O:2])[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:33])=[CH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:25])([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)C(=Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Solvent: CO
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)O)C(=Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.9 %

Procedure:
There was added 2 ml of N-sodium hydroxide to a solution of 0.556 g (0.001 mole) of N-carbobenzoxy-L-prolyl-dehydrophenylalanyl-L-phenylalanine methyl ester in 10 ml of methanol. The mixture was stirred at room temperature for 2 hours and concentrated in vacuo. The residual aqueous solution was washed with ethyl acetate and after acidification with 4 N-hydrochloric acid, the resulting separated oil was extracted into ethyl acetate and the extracts were dried over anhydrous Na2SO4. The solvent was evaporated in vacuo and the residual oil was purified on a column of silica gel (60-200 mesh) by elution with ether. The oily product was crystallized from ether to yield 0.357 g (66%) of N-carbobenzoxy-L-prolyl-dehydrophenylalanyl-L-phenylalanine, mp 171°-173°, RfA 0.68, [α]D26 =-30.2° (c, 1% in THF); ir (CHCl3) 1730 (Sh, C=O), 1670 (C=O), 1630 cm-1 (Sh, C=C); NMR (CDCl3) δ1.5-2.3 (m, 4H, Pro ring), 3.0-3.5 (m, 2H,>CH--CH2Ph), 3.2-3.7 (m, 2H, Pro ring), 4.2-4.5 (m, 1H>CHCH2Ph), 4.6-5.0 (m, 1H, Pro ring), 5.0 (s, 2H, >N--OCOCH2Ph), 7.0-7.6 (m, 16H, ArH and PhCH=C--), 8.0-8.27 (br, 1H, --NH exchanged by D2O); 9.03-9.5 (br, 2H, --NH or --COOH, exchanged by D2O).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[F:11].[SH:12][C:13]1[N:18]=[C:17]([OH:19])[CH:16]=[C:15]([OH:20])[N:14]=1.[OH-].[K+]>>[F:11][C:4]1[C:5]([O:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][S:12][C:13]1[N:18]=[C:17]([OH:19])[CH:16]=[C:15]([OH:20])[N:14]=1
Reactant: COc1cccc(CBr)c1F
Reactant: Oc1cc(O)nc(S)n1
Agent: [K+]
Agent: [OH-]
Product: COc1cccc(CSc2nc(O)cc(O)n2)c1F

Procedure:
The subtitle compound was prepared as a white solid by the method of Example 39 step i) using 1-(bromomethyl)-2-fluoro-3-methoxybenzene (4.5 g), 2-mercaptopyrimidine-4,6-diol (2.96 g) and potassium hydroxide (1.15 g). Yield: 5.0 g.
Reaction SMILES: [CH2:1]([CH:3]([CH:8]([CH3:10])[CH3:9])[C:4]([O:6][CH3:7])=[O:5])[CH3:2].[CH2:11](Br)[CH:12]=[CH2:13].C([N-]C(C)C)(C)C.[Li+].CN(P(N(C)C)(N(C)C)=O)C>C1COCC1>[CH2:1]([C:3]([CH:8]([CH3:10])[CH3:9])([CH2:13][CH:12]=[CH2:11])[C:4]([O:6][CH3:7])=[O:5])[CH3:2]
Reactant: C=CCBr
Reactant: CCC(C(=O)OC)C(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C=CCC(CC)(C(=O)OC)C(C)C
Yield: 81.7 %

Procedure:
The reaction of methyl 2-ethyl-3-methylbutyrate (23.76 g, 165 mmol), prepared as in Lion C, Dubois J E (1981) supra., with allyl bromide (31.34 g, 259 mmol) in the presence of lithium diisopropylamide (prepared by treating diisopropylamine (25.05 g, 248 mmol) with butyllithium in hexanes (2.5M, 94.4 mL, 236 mmol)) in THF (330 mL) and HMPA (24.7 mL, 142 mmol), as described above in the preparation of Example 7, followed by the vacuum distillation of crude product afforded the pure olefinic ester (24.85 g, 82%) as a colorless liquid: bp 92°-94° C. (20 mmHg).
Reaction SMILES: [CH2:1]([S:4][CH:5]1[N:8]([C:9](=[C:23]([O:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[S:11])[C:7](=[O:39])[CH2:6]1)[CH:2]=[CH2:3].ClC1C=C(C=CC=1)C(OO)=[O:45]>C(OCC)(=O)C>[CH2:1]([S:4]([CH:5]1[N:8]([C:9](=[C:23]([O:30][C:31]2[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=2)[C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=2)=[S:11])[C:7](=[O:39])[CH2:6]1)=[O:45])[CH:2]=[CH2:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCSC1CC(=O)N1C(C(=S)OCc1ccc([N+](=O)[O-])cc1)=C(Oc1ccc(OC)cc1)C(=O)C(C)(C)C
Solvent: CCOC(C)=O
Product: C=CCS(=O)C1CC(=O)N1C(C(=S)OCc1ccc([N+](=O)[O-])cc1)=C(Oc1ccc(OC)cc1)C(=O)C(C)(C)C
Yield: 62 %

Procedure:
To a solution of 0.35 g of 4-nitrobenzyl 2-(4-allylthioazetidin-2-on-1-yl)-3-(4-methoxyphenoxy)-3-trimethylacetylthio-propenate in ethyl acetate at -78° C. was added a solution of 0.128 g of 80% m-chloroperoxybenzoic acid in ethyl acetate over 10 minutes. The reaction mixture was washed with saturated sodium bicarbonate solution, was dried over MgSO4 and evaporated in vacuo to dryness. Chromatography over silica gel and elution with ethyl acetate-hexane mixtures afforded 0.223 g of the title compound as a yellow oil (62% of the theoretical yield).
Reaction SMILES: CSC.B.[NH2:5][C:6]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:7]=1[C:8]#[N:9]>C1COCC1>[NH2:9][CH2:8][C:7]1[CH:10]=[CH:11][C:12]([N+:14]([O-:16])=[O:15])=[CH:13][C:6]=1[NH2:5]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1N
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: NCc1ccc([N+](=O)[O-])cc1N
Reaction time: 3 h
Yield: 74.8 %

Procedure:
Borane-dimethyl sulfide (40 mL, 80 mmol) was added dropwise to a stirring solution of 2-amino-4-nitro-benzonitrile (2.27 g, 14 mmol) in dry THF (50 mL) at room temperature. The mixture was stirred at same temperature for 3 hours, and then carefully quenched with 1N aqueous HCl. The mixture was made basic (pH>11) with 4N sodium hydroxide and extracted with methylene chloride. The organic phase was dried over sodium sulfate, filtered and concentrated to provide 1.75 g of 2-aminomethyl-5-nitro-phenylamine (75%): 1H NMR (300 MHz, CDCl3) δ7.6 (m, 2H), 7.25 (d, 1H), 5.1 (br, 2H), 4.1 (s, 3H); MS (m/e): 168.1 (M+1).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH2:14][CH2:15][NH2:16])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][C:12]#[CH:13].C(N(CC)C(C)C)(C)C.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C:33](=[O:40])[CH2:34][CH:35]([OH:39])[C:36](O)=[O:37])=[CH:29][CH:28]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([C:33](=[O:40])[CH2:34][CH:35]([OH:39])[C:36]([NH:16][CH2:15][CH2:14][C:6]2[CH:7]=[CH:8][C:9]([O:10][CH2:11][C:12]#[CH:13])=[C:4]([O:3][CH3:2])[CH:5]=2)=[O:37])=[CH:31][CH:32]=1
Reactant: O=C(CC(O)C(=O)O)c1ccc(Cl)cc1
Reactant: C#CCOc1ccc(CCN)cc1OC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C#CCOc1ccc(CCNC(=O)C(O)CC(=O)c2ccc(Cl)cc2)cc1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-(3-Methoxy-4-prop-2-ynyloxy-phenyl)-ethylamine hydrochloride (5.4 g, 22 mmol) and N,N-diisopropylethylamine (11 g, 83 mmol) are dissolved in 70 ml of N,N-dimethylformamide. To this solution 4-(4-chloro-phenyl)-2-hydroxy-4-oxo-butyric acid (4.8 g, 21 mmol) and (benzotriazol-1-yloxy)-tris-(dimethylamino)-phosphonium hexafluorophosphate (10 g, 23 mmol) are added successively. The reaction mixture is stirred for 16 hours at room temperature, subsequently poured on ice-water and extracted several times with ethyl acetate. The combined organic layer is washed with brine, dried over sodium sulfate and evaporated in vacuum. The remaining oil is purified by chromatography on silicagel (ethyl acetate/hexane 6:4) to give 4-(4-chloro-phenyl)-2-hydroxy-N-[2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-4-oxo-butyramide (Compound E1.10).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([C:14]#[CH:15])[O:7][C@H:6]1[N:16]1[CH:24]=[N:23][C:22]2[C:17]1=[N:18][CH:19]=[N:20][C:21]=2[NH:25][C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=1[F:33])(=[O:3])[CH3:2].[Br:34][C:35](Br)=[N:36][OH:37].C(=O)(O)[O-].[Na+].O>C(OCC)(=O)C>[C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([C:14]2[O:37][N:36]=[C:35]([Br:34])[CH:15]=2)[O:7][C@H:6]1[N:16]1[CH:24]=[N:23][C:22]2[C:17]1=[N:18][CH:19]=[N:20][C:21]=2[NH:25][C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=1[F:33])(=[O:3])[CH3:2]
Reactant: ON=C(Br)Br
Reactant: C#C[C@H]1O[C@@H](n2cnc3c(Nc4ccc(Cl)cc4F)ncnc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](c2cc(Br)no2)O[C@H]1n1cnc2c(Nc3ccc(Cl)cc3F)ncnc21
Yield: 75.6 %

Procedure:
(2R,3 R,4R,5R)4-(acetyloxy)-2-[6-(4-chloro-2-fluoroanilino)-9H-purin-9-yl]-5-ethynyltetrahydrofuran-3-yl acetate (20 mg) was stirred at 22° C. with dibromoformaldoxime (12.5 mg), sodium bicarbonate (39 mg), water (0.075 ml) and ethyl acetate (1.5 ml) for 88 h. The mixture was partitioned between water (20 ml) and ethyl acetate (3×10 ml), the organic layers were washed with brine and evaporated in vacuo to give a brown gum (19 mg). Purification by chromatography on silica gel (Varian Bondelut cartridge), eluting with ethyl acetate:cyclohexane 20:80-80:20) gave the title compound as a colourless gum (16.8 mg).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[C:6]([F:18])[CH:5]=1.[NH:19]1[CH:23]=[CH:22][N:21]=[C:20]1[C:24]1[C:32]2[C:27](=[N:28][CH:29]=[CH:30][CH:31]=2)[N:26]([CH2:33][C:34](O)=[O:35])[N:25]=1>>[Cl:3][C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([N:12]2[CH2:13][CH2:14][N:15]([C:34](=[O:35])[CH2:33][N:26]3[C:27]4=[N:28][CH:29]=[CH:30][CH:31]=[C:32]4[C:24]([C:20]4[NH:19][CH:23]=[CH:22][N:21]=4)=[N:25]3)[CH2:16][CH2:17]2)=[C:6]([F:18])[CH:5]=1
Reactant: COc1cc(N2CCNCC2)c(F)cc1Cl
Reactant: O=C(O)Cn1nc(-c2ncc[nH]2)c2cccnc21
Agent: Cl
Product: COc1cc(N2CCN(C(=O)Cn3nc(-c4ncc[nH]4)c4cccnc43)CC2)c(F)cc1Cl

Procedure:
The title compound was prepared following Protocol A. 1-(4-Chloro-2-fluoro-5-methoxyphenyl)piperazine dihydrochloride and [3-(1H-imidazol-2-yl)-pyrazolo[3,4-b]pyridin-1-yl]-acetic acid were used as the coupling components. The crude product was purified by silica gel chromatography (1% to 10% MeOH in CH2Cl2) to provide 1-[4-(4-chloro-2-fluoro-5-methoxyphenyl)piperazin-1-yl]-2-[3-(1H-imidazol-2-yl)-pyrazolo[3,4-b]pyridin-1-yl]ethanone as a tan solid (27 mg): 1H NMR (CDCl3, 400 MHz) δ 8.79 (dd, 0.6H), 8.67 (dd, 0.4H), 8.57-8.55 (m, 1H), 7.31-7.20 (m, 2H), 7.12-7.06 (m, 2H), 6.49-6.45 (m, 1H), 5.45 (s, 0.6H), 5.43 (s, 1.4H), 3.86 (s, 0.9H), 3.85 (s, 2.1 H), 3.81-3.75 (m, 4H), 3.15-3.08 (m, 4H); LC/MS m/z (M+H)+ 470.4.
Reaction SMILES: OS(O)(=O)=O.[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][C:16]([C:26]#[N:27])([C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][CH:20]=2)[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]>C1COCC1>[C:6]([O:10][C:11]([N:13]1[CH2:14][CH2:15][C:16]([CH2:26][NH2:27])([C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][CH:20]=2)[CH2:17][CH2:18]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccc(I)cc2)CC1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CN)(c2ccc(I)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.7 %

Procedure:
A solution of LiAH4 (8.5 mL of a 1.0M solution in THF, 8.5 mmol, 3.5 eq.) was cooled to 0° C. and concentrated H2SO4 (0.43 mL, 7.6 mmol, 3.2 eq) was added in a drop-wise fashion. The resulting white slurry was stirred at room temperature for 0.5 h then heated to 30° C. for 0.5 h. The reaction was cooled to room temperature and a solution of 4-cyano-4-(4-iodo-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (1 g, 2.43 mmol) in THF (3 mL) was added over 0.25 h. The mixture was heated to 55° C. and monitored by TLC. After 5 h the reaction was cooled to room temperature and quenched by careful addition of H2O (0.323 mL), 1 N NaOH (0.646 mL) and H2O (0.97 mL). This mixture was diluted with CH2Cl2 (25 mL) and stirred vigorously for 1 h and then filtered through a pad of celite®. The salts were washed with CH2Cl2 (5×25 mL) and the combined washings were concentrated by rotary evaporation to give the crude product as a yellow solid (0.597 g) which was purified by flash column chromatography by eluting with 1% MeOH/CH2Cl2 (+1% TEA) to give 4-aminomethyl-4-(4-iodo-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (0.26 g, 26%). 1H NMR (CDCl3): δ 7.81 (d, 2H), 7.17 (d, 2H), 3.82 (m, 2H), 3.145 (m, 2H), 2.86 (s, 2H), 2.24 (m, 2H), 1.80 (m, 2H), 1.65 (br.m, 2H), 1.56 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5](O)=[O:6].O=S(Cl)[Cl:16]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([Cl:16])=[O:6]
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)c1ccc([N+](=O)[O-])c(F)c1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
To a suspension of 3-fluoro-4-nitrobenzoic acid (30 g, 162.0 mmol) in toluene (500 mL) was added SOCl2 (35 mL, 486 mmol). The reaction was heated to 110° C. at which point the reaction became homogeneous. The reaction was stirred at 110° C. for 3 h. The reaction had not gone to completion so an additional portion of SOCl2 (10 mL) was added. The reaction was stirred for an additional 3 h. A small amount of stalling material remained thus a final portion of SOCl2 (10 mL) was added and the reaction was heated for 2 h. The resulting green solution was cooled to room temperature and allowed to stand over night. The reaction mixture was filtered and concentrated in vacuo. Toluene (300 mL) was added to the resulting oil and removed under reduced pressure (2×). The product was used without further purification.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=O)[CH:10]=2)=[CH:7][C:6]([CH2:17][NH:18][C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([NH:29][CH2:30][C:31]3[C:32]([NH:44][CH:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)=[C:33]4[CH:41]=[N:40][N:39]([CH2:42][CH3:43])[C:34]4=[N:35][C:36]=3[CH2:37][CH3:38])=[O:28])[CH:22]=2)=[O:20])=[CH:5][CH:4]=1)#[N:2].[N:51]1(C(OC(C)(C)C)=O)[CH2:57][CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>C(Cl)Cl>[C:1]([C:3]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:51]3[CH2:57][CH2:56][CH2:55][NH:54][CH2:53][CH2:52]3)[CH:10]=2)=[CH:7][C:6]([CH2:17][NH:18][C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([NH:29][CH2:30][C:31]3[C:32]([NH:44][CH:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)=[C:33]4[CH:41]=[N:40][N:39]([CH2:42][CH3:43])[C:34]4=[N:35][C:36]=3[CH2:37][CH3:38])=[O:28])[CH:22]=2)=[O:20])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(C#N)c(-c3cccc(C=O)c3)c2)c1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(C#N)c(-c3cccc(CN4CCCNCC4)c3)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.1 %

Procedure:
N-[(6-Cyano-3′-formyl-3-biphenylyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,3-benzenedicarboxamide (108 mg, 0.000161 mol) in DCM (4 mL) and 1,1-dimethylethyl hexahydro-1H-1,4-diazepine-1-carboxylate (47 mg, 0.00023 mol) were mixed with sodium triacetoxyborohydride (68.3 mg, 0.00032 mol) and AcOH (11.6 mg, 11 μL). This solution was stirred overnight at room temperature. LC-MS showed that the reaction was complete. The reaction was quenched with sat. aq. NaHCO3, then extracted with DCM (2×). Combined extracts were washed with sat. aq. NaCl, dried (Na2SO4) and concentrated to a glassy foam (238.7 mg). The glassy foam was taken up in DCM (10 mL) containing 25% TFA and allowed to stand at room temperature for 3 h. LC-MS showed the reaction to be complete. Solvent was stripped off. Purification was carried out on Gilson instrument with acetonitrile-water (0.1% TFA) gradient; C18-RP column. Fractions containing the clean desired product were combined; diluted with EtOAc; washed with sat. aq. NaHCO3; and the aq. phase was back-extracted with EtOAc. Combined organic layers were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. It was taken up in a small amount of DCM and transferred to a vial and pumped down to afford the title compound as a chalky solid [73 mg (60%)]. LC-MS m/z 754.3 (M+H)+.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([C:30]([F:33])([F:32])[F:31])[CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=4)[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:34][NH2:35]>>[CH3:34][NH:35][CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[C:19]([C:30]([F:33])([F:32])[F:31])[CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=3)[C:15]=2[O:14]1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(C(F)(F)F)cc(-c4ccc(F)c(F)c4)c3O2)cc1
Reactant: CN
Product: CNCC1Cc2cc(C(F)(F)F)cc(-c3ccc(F)c(F)c3)c2O1

Procedure:
The title compound was prepared (0.035 g, 48%) following the general procedure of Example 390 as a white solid, hydrochloride salt from [7-(3,4-difluorophenyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.093 g, 0.19 mmol) and methylamine (0.12 g, 3.9 mmol). mp 235-237° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13](=[O:26])[N:14]([CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])[CH:15]=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13](=[O:26])[N:14]([CH2:18][C:19]([OH:21])=[O:20])[CH:15]=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)Cn1cccc(NC(=O)OCc2ccccc2)c1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)Cn1cccc(NC(=O)OCc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4.00 g of tert-butyl 2-(3-(benzyloxycarbonylamino)-2-oxopyridin-1(2H)-yl)acetate (11.2 mmol) are dissolved in 50 mL of dichloromethane and treated with 50 mL of trifloroacetic acid. It is stirred at RT for 3 h, before the volatile components are removed in vacuo. After drying under high vacuum a brown solid is obtained and it is suitable for the further use without purification.
Reaction SMILES: [CH:1]([CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N+:13]([O-])=O)[CH:11]=2)[N:6]([CH3:16])[C:5]1=[O:17])([CH3:3])[CH3:2].[C:18](O)(=[O:20])[CH3:19]>[Ni]>[CH:1]([CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:13][C:18](=[O:20])[CH3:19])[CH:11]=2)[N:6]([CH3:16])[C:5]1=[O:17])([CH3:3])[CH3:2]
Reactant: CC(=O)O
Reactant: CC(C)C1C(=O)N(C)c2ccc([N+](=O)[O-])cc21
Agent: [Ni]
Product: CC(=O)Nc1ccc2c(c1)C(C(C)C)C(=O)N2C

Procedure:
(rac)-3-Isopropyl-1-methyl-5-nitro-1,3-dihydro-indol-2-one (3.40 g) is dissolved in acetic acid (30 ml) and subjected to a catalytic hydrogenation with Raney-nickel (0.5 g) at 3 bar. After completion of the hydrogenation the mixture is filtered and evaporated. The residue is treated with acetic anhydride (10 ml) for 2 h at RT. The mixture is concentrated in vacuo to give the crude acetamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][N:8]3[C:14]([C:17]([F:20])([F:19])[F:18])=[N:15][N:16]=[C:7]3[C:6]=2[CH:21]=1.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][CH3:12])=[C:6]([C:7]2[N:8]([CH2:9][C:10](=[O:13])[N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:14]([C:17]([F:20])([F:18])[F:19])=[N:15][N:16]=2)[CH:21]=1
Reactant: C1COCCN1
Reactant: CN1C(=O)Cn2c(nnc2C(F)(F)F)-c2cc(Cl)ccc21
Product: CNc1ccc(Cl)cc1-c1nnc(C(F)(F)F)n1CC(=O)N1CCOCC1

Procedure:
4.8 g. (0.0152 mole) of 10-chloro-7-methyl-3-(trifluoromethyl)-5H-s-triazolo[4,3-d][1,4]benzodiazepin-6(7H)-one from example 1a are dissolved in 40 ml. of morpholine and the resulting solution is refluxed for 3 days. The morpholine is removed under vacuum, 3N aqueous NaOH is added, and the mixture is extracted with benzene. The benzene solution is dried over Na2SO4, decanted from drying agent, and the solvent removed under vacuum to yield a gum. This gum is chromatographed on silica gel plates with chloroform/ethyl acetate, 6:4. The largest band is isolated, extracted with chloroform, the chloroform is evaporated, and the residue is recrystallized from ethanol to yield 3-[5-chloro-2-(methylamino)phenyl]-4-[2-oxo-2-(4-morpholinyl)ethyl]-5-(trifluoromethyl)-1,2,4-triazole; m.p. 152°-153°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30](=[O:43])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=2)[CH:32]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30](=[O:43])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=2)[CH:32]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccccn2)c1
Product: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccccn3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-ethoxy-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J8) (240 mg, 0.75 mmol) and 3-oxo-3-(3-pyridin-2-yl-phenyl)-propionic acid tert-butyl ester (Example K3) (223 mg, 0.75 mmol) according to the general procedure M. Obtained as an off-white solid (234 mg).
Reaction SMILES: [NH3:1].Cl([O-])(=O)(=O)=O.[C:7]([N+:11]1[O:12][C:13]([CH3:16])=[CH:14][CH:15]=1)([CH3:10])([CH3:9])[CH3:8]>C(Cl)Cl>[C:13]([C:14]1[C:15]([NH:11][C:7]([CH3:10])([CH3:9])[CH3:8])=[N:1][C:15]([NH:11][C:7]([CH3:10])([CH3:9])[CH3:8])=[CH:14][C:13]=1[CH3:16])(=[O:12])[CH3:16]
Reactant: N
Reactant: Cc1cc[n+](C(C)(C)C)o1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: ClCCl
Product: CC(=O)c1c(C)cc(NC(C)(C)C)nc1NC(C)(C)C
Temperature: -30 °C
Reaction time: 96 h

Procedure:
About 60 ml. of anhydrous ammonia were condensed into a flask containing 60 ml. of methylene chloride. The reaction mixture was maintained at a temperature not in excess of -30° C. under nitrogen and a solution of 50 g. of 2-t-butyl-5-methylisoxazolium perchlorate in 100 ml. of methylene chloride was added rapidly. The reaction mixture was allowed to come to room temperature and stirred for 4 days at room temperature. The methylene chloride was then removed at reduced pressure to obtain a gummy solid which was triturated with water to obtain a yellow solid. Recrystallization of the yellow solid from methanol/water yielded the product, m.p. 128°-129° C. Its spectra were identical with those of the product of Example 4(a).