Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][N:10]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21]O)=[CH:17][CH:16]=2)[C:9](=[O:23])[CH:8]=1.P(Br)(Br)[Br:28]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[Br:28][CH2:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][CH2:13][N:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]3[CH:24]=[CH:25][CH:26]=[C:2]([F:1])[CH:3]=3)=[CH:8][C:9]2=[O:23])=[CH:16][CH:17]=1
Reactant: BrP(Br)Br
Reactant: O=c1cc(OCc2cccc(F)c2)ccn1CCc1ccc(CO)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=c1cc(OCc2cccc(F)c2)ccn1CCc1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 250 mg (0.71 mmol) 4-(3-fluoro-benzyloxy)-1-[2-(4-hydroxymethyl-phenyl)-ethyl]-1H-pyridin-2-one (example 8.1a) in 4.0 mL of DCM is added 100 μL (1.06 mmol) phosphorus tribromide. The mixture is stirred 2 h at RT and is diluted with half saturated aqueous NaHCO3-solution. The layers are separated and the aqueous phase is extracted three times with DCM. The organic phase is dried over MgSO4, filtered and the solvent is evaporated to afford the product.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4]([CH:11]=O)=[CH:3]1.[CH3:13][N:14]1C2C(=CC=CC=2)C(C)=C1C=O>>[CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4]([CH2:11][NH:14][CH3:13])=[CH:3]1
Reactant: Cc1c(C=O)n(C)c2ccccc12
Reactant: Cn1cc(C=O)c2cccnc21
Product: CNCc1cn(C)c2ncccc12
Yield: 45 %

Procedure:
According to the procedure of Preparation 13 (c), except substituting 1-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxaldehyde (0.4 g, 2.5 mmole) for the 1,3-dimethyl-1H-indole-2-carboxaldehyde, the title compound (0.2 g, 45%) was prepared as a yellow oil: MS (ES) m/e 176 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:15][C:14](=[O:16])[C:13]2=[C:17]([CH2:25][CH3:26])[N:18]=[C:19]([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[N:12]2[N:11]=1)[CH3:2].[S:27](Cl)([Cl:30])(=[O:29])=[O:28]>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:27]([Cl:30])(=[O:29])=[O:28])=[CH:6][C:5]=1[C:10]1[NH:15][C:14](=[O:16])[C:13]2=[C:17]([CH2:25][CH3:26])[N:18]=[C:19]([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[N:12]2[N:11]=1)[CH3:2]
Reactant: CCOc1ccccc1-c1nn2c(C3CCCC3)nc(CC)c2c(=O)[nH]1
Reactant: O=S(=O)(Cl)Cl
Product: CCOc1ccc(S(=O)(=O)Cl)cc1-c1nn2c(C3CCCC3)nc(CC)c2c(=O)[nH]1

Procedure:
The preparation is carried out analogously to the procedure of Example 27A using 0.34 g (0.96 mmol) of 2-(2-ethoxyphenyl)-5-ethyl-7-cyclopentyl-3H-imidazo-[5,1-f][1,2,4]triazin-4-one (Example 16A). This gives 0.43 g (98%) of sulphonyl chloride as a colourless foam which is directly reacted further.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH2:21][O:22][C:23](OC1C=CC=CC=1)=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH2:21][O:22][C:23]([N:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCC1CN(Cc2ccccc2)CCN1Cc1ccccc1)Oc1ccccc1
Reactant: C1CCNC1
Product: O=C(OCC1CN(Cc2ccccc2)CCN1Cc1ccccc1)N1CCCC1
Yield: 50.1 %

Procedure:
3.12 g (7,5 mmol) of 1,4-dibenzyl-2-phenoxycarbonyloxymethylpiperazine are dissolved in 9.4 ml (15 equivalents; 112.8 mmol) of pyrrolidine in a 100 ml ground-necked conical flask on which is fitted a condenser. The mixture is refluxed in a thermostatically controlled oil bath for 60 hours. After cooling and evaporation of the excess amine, the residue is taken up in CH2Cl2 and washed with water until neutral. After drying the organic phase (MgSO4), filtration on paper and evaporation of the solvent, the product is chromatographed on a column of silica gel, eluting with an MeOH/CH2Cl2 mixture (0.5/99.5 v/v). 1.48 g of 1,4-dibenzyl-2-(1′-pyrrolidinocarbonyloxymethyl)piperazine are thus obtained in the form of a viscous product. Yield 50.2%. Rf=0.38 (5/95 v/v MeOH/CH2Cl2).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([NH:6][C:7]([C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[CH:12]=[C:13](N)[CH:14]=1)=[O:8])[CH3:5].N(OCCC(C)C)=O.[I:31]CI>>[CH3:1][O:2][CH2:3][CH:4]([NH:6][C:7]([C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[CH:12]=[C:13]([I:31])[CH:14]=1)=[O:8])[CH3:5]
Reactant: COCC(C)NC(=O)c1cc(N)cc(-c2ccc(C)cc2)c1
Reactant: ICI
Agent: CC(C)CCON=O
Product: COCC(C)NC(=O)c1cc(I)cc(-c2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 158.8 %

Procedure:
A mixture of 5-amino-4′-methyl-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide (5.3 g, 17. 8 mmol), iso-amyl nitrite (13.5 ml, 88.9 mmol) and diiodomethane (8 ml, 106.7 mmol) was stirred at room temperature for 1 hour. The mixture was then heated to 65 ° C. and kept for 8 hours, LC/MS indicated that reaction completed. The reaction mixture was cooled to room temperature and the separation of iodobenzene from excess diiodomethane was effected by addition of the reaction mixture at room temperature to a stirred solution of piperidin-CH3CN (V/V=90 ml/90 ml). A vigorous exothermic reaction ensued. The excess volatile reagents were removed by rotary evaporation at 80° C. The residue was diluted with ethyl acetate, washed with 10% hydrochloric acid, water and brine. The organic layer was separated and dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (ethyl acetate/hexanes=10:1) to yield 5-iodo-4′-methyl-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide as a yellow solid (5.2 g, 83.8%). MS (M+H)=410.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]2[C:4]=1[C@@:5]1([CH3:26])[C@H:14]([CH2:15][S:16]2)[C@:13]2([CH3:23])[C@H:8]([C:9]([CH3:25])([CH3:24])[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1.ClC1C=C(C=CC=1)C(OO)=[O:32]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]2[C:4]=1[C@@:5]1([CH3:26])[C@H:14]([CH2:15][S:16]2=[O:32])[C@:13]2([CH3:23])[C@H:8]([C:9]([CH3:25])([CH3:24])[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1
Reactant: COc1cc(OC)c2c(c1)SC[C@@H]1[C@@]3(C)CCCC(C)(C)[C@@H]3CC[C@@]21C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1cc(OC)c2c(c1)S(=O)C[C@@H]1[C@@]3(C)CCCC(C)(C)[C@@H]3CC[C@@]21C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (1R,10R,11S,16S)-3,5-dimethoxy-1,11,15,15-tetramethyl-8-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene (Compound No. 22) (187 mg, 0.5 mmol) in CH2Cl2 (20 mL) was added 3-chloroperoxybenzoic acid (77%, 112 mg, 0.5 mmol) portionwise at room temperature. The resulting mixture was stirred at room temperature for 2 h. CH2Cl2 (100 mL) was added and the mixture washed with saturated aqueous sodium bicarbonate (20 mL), dried (Na2SO4), and concentrated. Purification by chromatography on silica gel (Hexanes/EtOAc, 1:1) gave (1R,10R,11S,16S)-3,5-dimethoxy-1,11,15,15-tetramethyl-8-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-trien-8-one (Compound No. 24) as separate diastereomers. (Diastereomer 1, white foam, 44 mg; Diastereomer 2, white solid, 290 mg).
Reaction SMILES: Br[C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[F:10].[CH2:11]([S:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1)[CH3:12]>>[CH2:11]([S:13][C:14]1[CH:19]=[C:18]([C:2]2[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=2[F:10])[CH:17]=[CH:16][CH:15]=1)[CH3:12]
Reactant: CCSc1cccc(B(O)O)c1
Reactant: Nc1cc(F)c(Br)c(F)c1
Product: CCSc1cccc(-c2c(F)cc(N)cc2F)c1
Yield: 108.3 %

Procedure:
The title compound (500 mg) was prepared from 4-bromo-3,5-difluoroaniline (300 mg, 1.74 mmol) and 3-(ethylthio)phenylboronic acid (340 mg, 1.86 mmol) as a yellow liquid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:23](=[CH:24][CH:25]=1)[C:7]1=[CH:8][C:9]3[C:10](=O)[C:11]4[CH:12]=[C:13]([Br:21])[CH:14]=[CH:15][C:16]=4[C:17](=O)[C:18]=3[CH:19]=[C:6]1[C:5]2([CH3:27])[CH3:26].I.O.II>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:23](=[CH:24][CH:25]=1)[C:7]1=[CH:8][C:9]3[CH:10]=[C:11]4[C:16](=[CH:17][C:18]=3[CH:19]=[C:6]1[C:5]2([CH3:27])[CH3:26])[CH:15]=[CH:14][C:13]([Br:21])=[CH:12]4
Reactant: CC1(C)c2cc(Br)ccc2-c2cc3c(cc21)C(=O)c1ccc(Br)cc1C3=O
Agent: I
Agent: II
Solvent: O
Solvent: CC(=O)O
Product: CC1(C)c2cc(Br)ccc2-c2cc3cc4cc(Br)ccc4cc3cc21
Reaction time: 48 h
Yield: 60.3 %

Procedure:
2,8-dibromo-13,13-dimethyl-13H-indeno[1,2-b]anthracene-6,11-dione (20 g, 0.04 mol) was dissolved in acetic acid (200 ml), and added with 57% HI (50 ml), followed by reflux-stirring for 48 hours. After the reaction was completed, the resultant solution was added with distilled water (500 ml). The produced solid was filtered and dissolved in toluene (200 ml) and iodine (4.05 g, 0.016 mol) was added thereto, followed by reflux-stirring for 3 hours. After the reaction was completed, through extraction and column chromatography, 2,8-dibromo-13,13-dimethyl-13H-indeno[1,2-b]anthracene (10.9 g, yield 59%) was obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH3:10])[N:5]=[C:4]([C:11]2[N:12]=[C:13]([CH3:16])[S:14][CH:15]=2)[N:3]=1.[CH3:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:26])=[C:23]([CH:25]=1)[NH2:24]>>[CH3:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:26])=[C:23]([CH:25]=1)[NH:24][C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH3:10])[N:5]=[C:4]([C:11]2[N:12]=[C:13]([CH3:16])[S:14][CH:15]=2)[N:3]=1
Reactant: COc1ccc(C)c(N)c1
Reactant: COCc1cc(Cl)nc(-c2csc(C)n2)n1
Product: COCc1cc(Nc2cc(OC)ccc2C)nc(-c2csc(C)n2)n1

Procedure:
The title compound was prepared from a mixture of 4-chloro-6-(methoxymethyl)-2-(2-methyl-1,3-thiazol-4-yl)pyrimidine (50 mg, 0.196 mmol) and 5-methoxy-2-methylaniline (27 mg, 0.196 mmol) similar to Example 13 and isolated as a tan oil (42 mg, 60%). 1H NMR (CDCl3): 8.12 (s, 1H), 7.19 (d, J=8.4 Hz, 1H), 6.99 (d, J=2.4 Hz, 1H), 6.89 (s, 1H), 6.75 (dd, J=3.0, 8.7 Hz, 1H), 6.56 (s, 1H), 4.50 (s, 2H), 3.80 (s, 3H), 3.44 (s, 3H), 2.83 (s, 3H), 2.21 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)=[O:11])[N:5]=[C:4](OCC)[C:3]=1[C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.C1(N)CC1>CN(C=O)C>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:14][CH2:15]2)=[O:11])[N:5]=[CH:4][C:3]=1[C:23](=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOc1nn(-c2cc(C(=O)NC3CC3)ccc2C)c(N)c1C(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: NC1CC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)c2ccccc2)c1N
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 66.2 %

Procedure:
To a stirred solution of acid 4 (46 g, 0.143 mol, 1.0 equiv) in DMF (1.9 L) was added EDCI (57.5 g, 0.299 mol, 2.09 equiv), HOBt (41.4 g, 0.306, 2.14 equiv) and diisopropylethylamine (76.6 g, 0.59 mol, 4.15 equiv) and the solution was stirred for 20 minutes at room temperature. Then it was cooled to 15-20° C. and cyclopropylamine (20.6 g, 0.36 mol, 2.51 equiv) was added and stirred at room temperature. The reaction was monitored by TLC. After 14 hours, since the reaction was not complete and additional cyclopropylamine (9.36 g, 0.16 mol, 1.14 equiv) was added and stirring was continued for two hours. DMF was removed under reduced pressure at 50-55° C. To the residue EtOAc (1 L) and water (500 ml) were added and the mixture was stirred for 10 minutes. The mixture was extracted and the organic layer was collected. The aqueous layer was extracted with EtOAc (2×250 ml). The combined organic layer was washed with sodium bicarbonate (2×500 ml) and brine (2×500 ml), dried over anhydrous sodium sulfate and concentrated. To the residue EtOAc/dichloromethane /hexane (50 ml/50 ml/50 ml) was added, the mixtue was stirred for 10 minutes, and filtered to provide the product (34.1 g, 65.7%) as an off white crystalline solid. HPLC (Waters X-Terra 5 micron C18 column 4.6 mm×250 mm, 1.0 mL/min, mobile phase: 0.1% TEA in H2O/acetonitrile 50/50, 30 min elution) tR 5.53 min, 99.3% purity; MS m/z 360 [M]+; 1H NMR (DMSO-d6, 400 MHz) is consistent with Example 4.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([NH2:10])=[O:9])[N:5]([CH3:7])[CH:6]=1.[C:11]([O:14][CH2:15][C:16]1[C:21](B2OC(C)(C)C(C)(C)O2)=[CH:20][CH:19]=[CH:18][C:17]=1[N:31]1[N:40]([CH3:41])[CH2:39][C:38]2[C:33](=[CH:34][CH:35]=[C:36]([C:42]([CH3:45])([CH3:44])[CH3:43])[CH:37]=2)[C:32]1=[O:46])(=[O:13])[CH3:12].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O.O1CCOCC1>[C:11]([O:14][CH2:15][C:16]1[C:21]([C:2]2[CH:3]=[C:4]([C:8](=[O:9])[NH2:10])[N:5]([CH3:7])[CH:6]=2)=[CH:20][CH:19]=[CH:18][C:17]=1[N:31]1[N:40]([CH3:41])[CH2:39][C:38]2[C:33](=[CH:34][CH:35]=[C:36]([C:42]([CH3:45])([CH3:44])[CH3:43])[CH:37]=2)[C:32]1=[O:46])(=[O:13])[CH3:12]
Reactant: Cn1cc(Br)cc1C(N)=O
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1C(=O)c2ccc(C(C)(C)C)cc2CN1C
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)OCc1c(-c2cc(C(N)=O)n(C)c2)cccc1N1C(=O)c2ccc(C(C)(C)C)cc2CN1C
Temperature: 125 °C
Yield: 15.6 %

Procedure:
In a 10 ml microwave vial, 4-bromo-1-methyl-1H-pyrrole-2-carboxamide (82.5 mg, 406 μmol, Eq: 1.00), [prepared in Example 12, Step 1], 2-(6-tert-butyl-3-methyl-1-oxo-3,4-dihydrophthalazin-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate (200 mg, 406 μmol, Eq: 1.00), X-phos (19.4 mg, 40.6 μmol, Eq: 0.10), and potassium phosphate tribasic (259 mg, 1.22 mmol, Eq: 3.00) were combined with 1,4-dioxane (5 ml) and water (0.5 ml) to give a dark brown suspension. The reaction mixture was stirred while purging with argon for 10 min. The reaction mixture was heated at 125° C. in the microwave for 30 min. The reaction mixture was diluted with 50 mL of dichloromethane and dried (MgSO4). Concentrated in vacuo. The crude material was purified by flash chromatography (silica, 20%-100% ethyl acetate/hexanes gradient) to give 2-(6-tert-butyl-3-methyl-1-oxo-3,4-dihydrophthalazin-2(1H)-yl)-6-(5-carbamoyl-1-methyl-1H-pyrrol-3-yl)benzyl acetate (31 mg, 16%): 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.37 (s, 9H) 1.98 (s, 3H) 2.68 (s, 3H) 3.99 (s, 2H) 5.28 (s, 2H) 6.72 (d, J=1.89 Hz, 1H) 6.84-6.94 (m, 1H) 7.23 (d, J=1.51 Hz, 1H) 7.27-7.52 (m, 5H) 7.61 (s, 1H) 8.04 (d, J=7.93 Hz, 1H).
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:58]1[CH2:63][CH2:62][CH:61]([NH2:64])[CH2:60][CH2:59]1>>[CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:64][CH:61]5[CH2:62][CH2:63][O:58][CH2:59][CH2:60]5)=[O:29])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Reactant: NC1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)NC2CCOCC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and tetrahydro-2H-pyran-4-amine. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.08-1.43 (m, 3H) 1.49-1.90 (m, 11H) 3.19-3.32 (m, 3H) 3.32-3.46 (m, 2H) 3.84-3.92 (m, 2H) 3.94 (d, J=9.0 Hz, 3H) 3.97-4.08 (m, 1H) 4.07-4.23 (m, 2H) 4.38-4.58 (m, 1H) 7.42-7.61 (m, 2H) 8.06-8.17 (m, 1H) 8.24 (br. s., 2H) 8.62 (br. s., 1H). [M+H] calc'd for C27H34F2N6O4 545. found 545.
Reaction SMILES: [NH2:1][C:2]1[C:7]([S:8]([CH2:11][C@@H:12]([CH3:15])[CH2:13][OH:14])(=[O:10])=[O:9])=[CH:6][C:5](Br)=[CH:4][N:3]=1.[CH3:17][O:18][C:19]1[CH:28]=[C:27]2[C:22]([C:23]([N:29]3[CH2:35][C:34]4[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][C:33]=4[O:32][CH2:31][CH2:30]3)=[N:24][CH:25]=[N:26]2)=[CH:21][CH:20]=1>>[NH2:1][C:2]1[C:7]([S:8]([CH2:11][C@@H:12]([CH3:15])[CH2:13][OH:14])(=[O:10])=[O:9])=[CH:6][C:5]([C:37]2[CH:38]=[CH:39][C:33]3[O:32][CH2:31][CH2:30][N:29]([C:23]4[C:22]5[C:27](=[CH:28][C:19]([O:18][CH3:17])=[CH:20][CH:21]=5)[N:26]=[CH:25][N:24]=4)[CH2:35][C:34]=3[CH:36]=2)=[CH:4][N:3]=1
Reactant: C[C@@H](CO)CS(=O)(=O)c1cc(Br)cnc1N
Reactant: COc1ccc2c(N3CCOc4ccc(B(O)O)cc4C3)ncnc2c1
Product: COc1ccc2c(N3CCOc4ccc(-c5cnc(N)c(S(=O)(=O)C[C@@H](C)CO)c5)cc4C3)ncnc2c1

Procedure:
Prepared according to the method of example 5 by using (2S)-3-[(2-amino-5-bromopyridin-3-yl)sulfonyl]-2-methylpropan-1-ol (reagent preparation 41) and {4-[7-(methyloxy)quinazolin-4-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}boronic acid (reagent preparation 23) in step 1. 1H NMR (400 MHz, Methanol-d4): 8.42 (s, 1H), 8.34 (br, 1H), 8.07 (br, 1H), 7.89 (d, 1H), 7.44 (s, 1H), 7.35 (d, 1H), 7.08 (m, 2H), 6.94 (d, 1H), 4.96 (s, 2H), 4.34 (m, 2H), 4.14 (m, 2H), 3.84 (s, 3H), 3.41 (m, 2H), 3.31 (dd, 1H), 2.98 (dd, 1H), 2.12 (m, 1H), 0.99 (d, 3H); MS (EI) for C27H20N5O5S: 536 (MH+).
Reaction SMILES: [CH2:1]([P:3]([C:14]1[CH:19]=[C:18]([O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=2[Cl:31])[CH:17]=[CH:16][C:15]=1[N+:32]([O-])=[O:33])([O:5][N:6]=[C:7]([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:4])[CH3:2].NN>O1CCCC1.[Rh]>[CH2:1]([P:3]([C:14]1[CH:19]=[C:18]([O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:29])([F:30])[F:28])=[CH:23][C:22]=2[Cl:31])[CH:17]=[CH:16][C:15]=1[NH:32][OH:33])([O:5][N:6]=[C:7]([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:4])[CH3:2]
Reactant: CCOC(=O)C(C)=NOP(=O)(CC)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Agent: [Rh]
Agent: NN
Solvent: C1CCOC1
Product: CCOC(=O)C(C)=NOP(=O)(CC)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1NO
Reaction time: 2 h

Procedure:
To a solution of ethyl 2-[P-ethyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinyloxyimino]propionate (500 mg) in tetrahydrofuran (10 ml) is added hydrazine (1 eq.) and 5% rhodium on activated charcoal (50 mg) at 15°-25°, with stirring for 2 hours. The reaction is then filtered and the filtrate is diluted with methylene chloride, washed, dried and concentrated to dryness to give ethyl 2-[P-ethyl-2-hydroxyamino-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinyloxyimino]propionate.
Reaction SMILES: C(CC(O[NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][C:11]=1[OH:18])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[C:16]([C:13]1[CH:14]=[CH:15][C:10]([NH2:9])=[C:11]([OH:18])[CH:12]=1)#[N:17]
Reactant: CC(C)(C)CC(=O)ONc1ccc(C#N)cc1O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(N)c(O)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 97.5 %

Procedure:
To a solution of N-t-butylacetoxy-4-cyano-2-hydroxyl aniline (3.1 g, 13 mmol) in methylene chloride (100 mL) at 0° C. was added trifluoroacetic acid and the reaction mixture was allowed to warm to rt. After 2.5 h, the reaction was quenched with water (100 mL) and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude material was purified by flash column chromatography (50% ethyl acetate/hexanes) to give 1.7 g (96%) of 4-cyano-2-hydroxyl aniline as a tan solid. 1H NMR (400 MHz, DMSO) δ 7.0 (d, 1H), 6.85 (s, 1H), 6.65 (d, 1H); MS(EI) m/e 134 (M+).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[Cl:14])=[N+:2]=[N-:3].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([O:25][CH3:26])=[C:20]([CH2:22][C:23]#[N:24])[CH:21]=1.C[O-].[Na+]>C(O)C.C(OCC)(=O)C>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([O:25][CH3:26])=[C:20]([C:22]2[N:3]=[N:2][N:1]([C:4]3[CH:9]=[CH:8][C:7]([C:10]([F:12])([F:13])[F:11])=[CH:6][C:5]=3[Cl:14])[C:23]=2[NH2:24])[CH:21]=1
Reactant: [N-]=[N+]=Nc1ccc(C(F)(F)F)cc1Cl
Reactant: COc1ccc(Cl)cc1CC#N
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(Cl)cc1-c1nnn(-c2ccc(C(F)(F)F)cc2Cl)c1N
Temperature: 0 °C
Reaction time: 8 h
Yield: 49.5 %

Procedure:
To an ice-cooled and stirred mixture of 1-azido-2-chloro-4-trifluoromethyl-benzene (0.500 g, 1 eq) and commercial (5-chloro-2-methoxy-phenyl)-acetonitrile (0.492 g, 1.2 eq) in ethanol (4 ml) kept under nitrogen, a solution of sodium methoxide (0.183 g, 1.5 eq) in ethanol (2 ml) is added drop-wise (15 min). After the addition, the reaction mixture is allowed to reach room temperature spontaneously and stirring is then continued overnight at room temperature. The resulting reaction mixture is diluted with ethyl acetate (25 ml), washed with water (2×25 ml), dried over MgSO4 and evaporated to dryness. The yellow solid residue (0.610 g) is purified by crystallization from a mixture of dichloromethane and hexane (1:1), to afford the title compound as white solid (0.450 g, 50% yield). M.p. 152.8-153.3° C.
Reaction SMILES: Cl[C:2](=[N:9][OH:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:11]([C:16]1[N:17]([CH2:44][CH2:45][CH3:46])[N:18]=[C:19]2[C:28]=1[C:27]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:21]=[C:20]2[N:29]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:12][CH2:13][C:14]#[CH:15].C(N(CC)CC)C>ClCCl>[C:3]1([C:2]2[CH:15]=[C:14]([CH2:13][CH2:12][CH2:11][C:16]3[N:17]([CH2:44][CH2:45][CH3:46])[N:18]=[C:19]4[C:28]=3[C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N:21]=[C:20]4[N:29]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:37]([O:39][C:40]([CH3:42])([CH3:43])[CH3:41])=[O:38])[O:10][N:9]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C#CCCCc1c2c(nn1CCC)c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc1ccccc12
Reactant: ON=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCn1nc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc3ccccc3c2c1CCCc1cc(-c2ccccc2)no1
Yield: 80 %

Procedure:
α-Chlorobenzaldoxime (0.64 g, 4.1 mmol) was added to a solution of di(tert-butyl) 1-pent4-ynyl-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonate (prepared as described in Parts A-E of Example 57, 1.36 g, 2.76 mmol) and triethylamine (0.60 mL, 4.14 mmol) in dichloromethane (10 mL). The solution was heated at 40° C. for 19 hours, during which time additional α-chlorobenzaldoxime (0.65 g) was added. The reaction was worked up as described in Part B of Example 595. The crude product was purified by chromatography (silica gel, sequential elution with 20% then 40% ethyl acetate in hexanes) to provide 1.35 g of di(tert-butyl) 1-[3-(3-phenylisoxazol-5-yl)propyl]-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonate as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.[CH3:30][O:31][C:32](=[O:42])[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40]Br)=[CH:36][CH:35]=1>>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[O:1][CH2:40][C:37]1[CH:38]=[CH:39][C:34]([CH:33]([CH2:40][C:37]3[CH:36]=[CH:35][C:34]([CH2:33][C:32]([O:31][CH3:30])=[O:42])=[CH:39][CH:38]=3)[C:32]([O:31][CH3:30])=[O:42])=[CH:35][CH:36]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Reactant: COC(=O)Cc1ccc(CBr)cc1
Product: COC(=O)Cc1ccc(CC(C(=O)OC)c2ccc(COc3cccc(-c4c(C(=O)c5ccccc5)cnc5c(C(F)(F)F)cccc45)c3)cc2)cc1

Procedure:
The title compound was prepared from [4-(3-hydroxyphenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and (4-bromomethyl-phenyl)-acetic acid methyl ester according to the procedure of Example 41. MS (ESI) m/z 718; HRMS: calcd for C43H34F3NO6+H+, 718.24110; found (ESI, [M+H]+), 718.2444.