Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1([CH3:20])[CH2:10][CH2:9][C:8]2[C:11]([CH3:19])=[C:12]([O:17][CH3:18])[C:13]([CH3:16])=[C:14]([CH3:15])[C:7]=2[O:6]1.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1.Cl>N1C=CC=CC=1>[CH3:18][O:17][C:12]1[C:13]([CH3:16])=[C:14]([CH3:15])[C:7]2[O:6][C:5]([CH2:4][CH2:3][CH2:2][O:1][S:27]([C:24]3[CH:25]=[CH:26][C:21]([CH3:31])=[CH:22][CH:23]=3)(=[O:29])=[O:28])([CH3:20])[CH2:10][CH2:9][C:8]=2[C:11]=1[CH3:19]
Reactant: COc1c(C)c(C)c2c(c1C)CCC(C)(CCCO)O2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: COc1c(C)c(C)c2c(c1C)CCC(C)(CCCOS(=O)(=O)c1ccc(C)cc1)O2
Temperature: 0 °C
Reaction time: 1 h
Yield: 48.9 %

Procedure:
The crude 3,4-dihydro-2-(3-hydroxypropyl)-6-methoxy-2,5,7,8-tetramethyl-2H-benzopyran (5.0 g) obtained in the above manner was dissolved in 50 ml of pyridine and the solution was cooled to 0° C. To the solution was added slowly 3.9 g of p-toluenesulfonyl chloride with vigorous stirring. After stirring at 0° C. for 1 hour, the reaction mixture was poured into 100 ml of dilute hydrochloric acid and extracted with diethyl ether. The ether layer was washed with water and then with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. Low-boiling substances were distilled off from the filtrate under reduced pressure. The residue was purified by silica gel column chromatography to give 3.8 g of 3,4-dihydro-6-methoxy-2-[3-(p-toluenesulfonyloxy)propyl]-2,5,7,8-tetramethyl-2H-benzopyran.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].Cl.[N:16]([O-])=O.[Na+]>O>[CH3:11][O:10][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][C:6]=1[O:8][CH3:9])[N:1]=[N:16][CH:13]=[C:12]2[OH:14]
Reactant: COc1cc(N)c(C(C)=O)cc1OC
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COc1cc2nncc(O)c2cc1OC
Temperature: 2 °C
Reaction time: 1 h

Procedure:
1-(2-Amino-4,5-dimethoxyphenyl)ethanone (105 g, 0.538 mol) was dissolved in concentrated HCl (2000 mL, 20 mol) at ambient temperature. The solution was then cooled to 0-4° C., and sodium nitrite (37.5 g, 0.543 mol) was added dropwise over 45 minutes as a solution in water (200 mL). The reaction mixture was stirred at 0-4° C. for one hour during which time it turned dark brown and became homogenous. The reaction mixture was then heated to 60-70° C. for four hours, and a yellow solid formed. After cooling the reaction mixture to 10° C., the solid was collected by filtration. The wet solid was suspended in 1500 mL of water, and the pH was adjusted to 12 with 4N NaOH to give a brown solution, followed by adjusting the pH to 7 with concentrated hydrochloric acid (78 mL). 6,7-Dimethoxycinnolin-4-ol precipitated as an off-white solid, which was filtered, washed with water (3×300 mL), and dried in a vacuum overnight at 50° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:65][S:66][C:67]1[CH:72]=[CH:71][C:70]([NH2:73])=[CH:69][CH:68]=1>C(Cl)Cl>[CH3:65][S:66][C:67]1[CH:72]=[CH:71][C:70]([NH:73][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10]2)=[O:30])=[CH:69][CH:68]=1
Reactant: CSc1ccc(N)cc1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ccc(NC(=O)C2NC(CC(C)(C)C)C(C#N)(c3ccc(Cl)cc3F)C2c2cccc(Cl)c2F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (250 mg, 0.44 mmol) in methylene chloride (10 mL), HATU (Aldrich, 332 mg, 0.88 mmol) was added followed by the addition of DIPEA (0.230 mL, 1.31 mmol) and 4-amino-phenyl methyl sulfide (Aldrich, 122 mg, 0.88 mmol). The mixture was stirred at rt for 2 hr. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (50 g column, eluent EtOAc/Hexanes, 5-10%) to give a white solid. 135 mg.
Reaction SMILES: [Br-].[Li+].[Br-].[CH2:4]([O:6][C:7](=[O:14])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][Zn+])[CH3:5].Cl[C:16]1[N:25]=[C:24]2[C:19]([CH:20]=[C:21]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:23]2)=[CH:18][CH:17]=1.CN1C(=O)N(C)CC1>C1COCC1>[C:32]1([C:21]2[CH:20]=[C:19]3[C:24](=[N:23][C:22]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:25]=[C:16]([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:7]([O:6][CH2:4][CH3:5])=[O:14])[CH:17]=[CH:18]3)[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: Clc1ccc2cc(-c3ccccc3)c(-c3ccccc3)nc2n1
Reactant: CCOC(=O)CCCCC[Zn+]
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN1CCN(C)C1=O
Product: CCOC(=O)CCCCCc1ccc2cc(-c3ccccc3)c(-c3ccccc3)nc2n1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
A mixture comprising lithium bromide (307 mg, 3.54 mmol) and PEPPSi-iPr catalyst (75 mg, 0.110 mmol) in THF (2 ml) was stirred at room temperature for 15 minutes until a solution formed. (6-Ethoxy-6-oxohexyl)zinc(II) bromide (13.26 ml of a 0.5M solution in THF, 6.62 mmol) was added and the mixture was cooled to 0° C. A solution of 7-chloro-2,3-diphenyl-1,8-naphthyridine (step 1) (350 mg, 1.105 mmol) in THF (3 ml)/DMI (1 ml) was added and the resulting mixture was stirred at room temperature for 24 h. The reaction mixture was partitioned between EtOAc and water and the organic portion was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. Purification of the crude product by chromatography on silica eluting with 0-50% EtOAc in iso-hexane afforded the title product as a yellow oil;
Reaction SMILES: [NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].[Cl:7][C:8]1[CH:9]=[C:10]([CH2:14][C:15](O)=[O:16])[CH:11]=[CH:12][CH:13]=1>>[Cl:7][C:8]1[CH:9]=[C:10]([CH2:14][C:15]([NH:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3])=[O:16])[CH:11]=[CH:12][CH:13]=1
Reactant: C[C@H](N)C(=O)O
Reactant: O=C(O)Cc1cccc(Cl)c1
Product: C[C@H](NC(=O)Cc1cccc(Cl)c1)C(=O)O

Procedure:
The title compound was prepared using L-alanine (Nova Biochem) and 3-chlorophenyl acetic acid (Aldrich) by following General Procedures BF or BG, followed by hydrolysis using General Procedure BD.
Reaction SMILES: [CH3:1][C:2]1[C:3]([OH:11])=[C:4]([CH3:10])[C:5]([CH3:9])=[C:6]([CH:8]=1)[OH:7].B(F)(F)F.CCOCC.[CH:21]([C:23]1(O)[CH2:26][CH2:25][CH2:24]1)=[CH2:22]>O1CCOCC1>[C:23]1(=[CH:21][CH2:22][C:8]2[C:6]([C:5]([CH3:9])=[C:4]([CH3:10])[C:3](=[O:11])[C:2]=2[CH3:1])=[O:7])[CH2:26][CH2:25][CH2:24]1
Reactant: Cc1cc(O)c(C)c(C)c1O
Reactant: C=CC1(O)CCC1
Agent: FB(F)F
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC1=C(C)C(=O)C(CC=C2CCC2)=C(C)C1=O
Yield: 46.3 %

Procedure:
To a solution of trimethyl hydroquinone (3 g) in 100 mL dioxane at room temperature, was added BF3.Et2O (4.26 g). While stirring, a solution of 1-vinylcyclobutanol (1.96 g) in 20 mL dioxane was added dropwise to the mixture. The reaction was stirred for 1 h and quenched by pouring onto ice (50 g). The aqueous layer was saturated with NaCl and extracted with 3:1 hexane/EtOAc. The combined organic phase was washed with brine and NaHCO3 solution, concentrated and diluted with EtOH (30 mL). 10% FeCl3 aqueous solution (40 mL) was added to the solution and the mixture was stirred for 2 h at room temperature. The mixture was diluted with hexane/EtOAc (4:1, 80 mL) and the aqueous layer was saturated with NaCl. After layer separation, the organic layer was washed with brine, dried over Na2SO4 and concentrated. The crude product was chromatographed to afford 2-(2-cyclobutylideneethyl)-3,5,6-trimethylbenzo-1,4-quinone (2.1 g). MS m/z=231 (M−OH).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[C:10]([Br:12])[CH:9]=[CH:8][C:7]=1[Cl:13].O.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[C:16]([NH:2][CH2:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[C:10]([Br:12])[CH:9]=[CH:8][C:7]=1[Cl:13])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCC(=O)Cc1cc(Br)ccc1Cl
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(CNC(=O)c1ccccc1)Cc1cc(Br)ccc1Cl
Reaction time: 3 h

Procedure:
A mixed solution of the above 1-(3-amino-2-oxopropyl)-5-bromo-2-chlorobenzene.hydrochloride (1.70 g) in ethyl acetate (30 ml)-water (15 ml) was cooled to 0° C. Added thereto were benzoyl chloride (0.99 ml) and sodium hydrogen carbonate (2.39 g), and the mixture was stirred at the same temperature for 3 hours. The organic layer was washed with brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:ethyl acetate=95:5) to give 1-(3-benzoylamino-2-oxopropyl)-5-bromo-2-chlorobenzene (710 mg) as a colorless solid. APCI-Mass m/Z 366/368 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)[O:3]1.[N:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][NH2:27])=[CH:21][CH:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[N:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][NH:27][C:13](=[O:15])[C:12]2[CH:11]=[CH:10][C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:1])([CH3:18])[O:3]3)=[CH:17][CH:16]=2)=[CH:21][CH:20]=1
Reactant: CC1(C)OB(c2ccc(C(=O)O)cc2)OC1(C)C
Reactant: NCCc1ccncc1
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: CC1(C)OB(c2ccc(C(=O)NCCc3ccncc3)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 118.3 %

Procedure:
A solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (150 mg, 0.60 mmol) in 30 mL of DCM were added 2-(pyridin-4-yl)ethanamine (110 mg, 0.9 mmol), HATU (274 mg, 0.72 mmol) and DIEA (232 mg, 1.80 mmol) at room temperature. Then the reaction mixture was stirred at room temperature overnight. The solution was washed with sat NaHCO3 (2×20 mL), brine (20 mL), then dried over anhydrous sodium sulfate, concentrated under reduce pressure to give crude N-(2-(pyridin-4-yl)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (250 mg) and used without further purification. LC-MS: 353 [M+H]+, tR=1.22 min
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[O:14]1[CH:19]=[CH:18][CH2:17][CH2:16][CH2:15]1.CC1C=CC(S(O)(=O)=O)=CC=1.N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([N+:11]([O-:13])=[O:12])[C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][O:14]1)[CH:6]=2
Reactant: O=[N+]([O-])c1cc(Br)cc2[nH]ncc12
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cc(Br)cc2nn(C3CCCCO3)cc12
Temperature: 25 °C
Yield: 96.5 %

Procedure:
A mixture of 6-bromo-4-nitro-1H-indazole (available from Sinova, 10 g, 0.041 mol), 3,4-dihydro-2H-pyran (7.85 g, 8.52 ml, 0.093 mol) and pyridine 4-methylbenzenesulfonate (0.125 g, 0.496 mol) in dichloromethane (150 ml) was heated at reflux for 4.5 hours. The reaction was allowed to cool to room temperature and was poured onto saturated aqueous sodium bicarbonate (200 ml). The layers were separated and the aqueous layer extracted with dichloromethane (2×100 ml). The combined organic layers were washed with 5% aqueous citric acid (w/v, 100 ml) and brine (100 ml) and dried over magnesium sulphate. Solvent was removed in vacuo to give the title compound (12.9 g) as a dark orange solid.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:10]1([N:16]=[C:17]=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1COCC1>[CH2:1]([NH:9][C:17]([NH:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=C=Nc1ccccc1
Reactant: CCCCCCCCN
Solvent: C1CCOC1
Product: CCCCCCCCNC(=O)Nc1ccccc1
Yield: 98.3 %

Procedure:
A solution of octyl amine (22.79 g, 176 mmol) and phenyl isocyanate (21 g, 176 mmol) in THF (200 ml) at 0° C. was stirred for 2 hours. The solvent was evaporated in vacuo and the residue was triturated with hexane to give 43 g of final product (173 mmol).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:20][CH:19]=3)=[C:12]2[C:8]=1[CH2:9][NH:10][C:11]2=[O:39])(=O)=O.[C:42](=[O:45])([O-])[O-].[K+].[K+].O>C(COC)OC>[OH:45][CH2:42][C:7]1[CH:15]=[CH:14][C:13]([C:7]2[CH:15]=[CH:14][C:13]([C:16]3[N:17]([C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[C:18]4[C:23]([CH:24]=3)=[CH:22][C:21]([CH2:25][N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:20][CH:19]=4)=[C:12]3[C:8]=2[CH2:9][NH:10][C:11]3=[O:39])=[CH:12][CH:8]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)C(F)(F)F)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)n1c(-c2ccc(-c3ccc(CO)cc3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 128.1 %

Procedure:
In a similar manner to Step 1 of Example 152, 4-trifluoromethanesulfonyloxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (80.0 mg, 0.135 mmol) was dissolved in dimethoxyethane (9.6 mL), and the solution was treated with 4-(hydroxymethyl)phenylborate (62.0 mg, 0.405 mmol), [bis(diphenylphosphino)ferrocene]dichloropalladium (22 mg, 0.027 mmol), potassium carbonate (93.0 mg, 0.675 mmol) and water (0.098 mL), followed by purification by preparative thin-layer chromatography (chloroform/methanol=6/1) to obtain 4-[4-(hydroxymethyl)phenyl]-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (47.7 mg, yield 64%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11]([C:13]2[N:14]=[N:15][C:16](Cl)=[CH:17][CH:18]=2)=[O:12])=[CH:4][CH:3]=1.[N:20]1([C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:37])([F:36])[F:35])=[O:27])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11]([C:13]2[N:14]=[N:15][C:16]([N:23]3[CH2:24][CH2:25][N:20]([C:26](=[O:27])[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]([F:37])([F:35])[F:36])[CH2:21][CH2:22]3)=[CH:17][CH:18]=2)=[O:12])=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Reactant: O=C(NCCc1ccc(Cl)cc1)c1ccc(Cl)nn1
Product: O=C(NCCc1ccc(Cl)cc1)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid [2-(4-chlorophenyl)ethyl]amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(2-trifluoromethylphenyl)methanone, the title compound was obtained as a light yellow powder (46.5% yield). 1H NMR (500 MHz, CDCl3) δ 8.10, 7.95, 7.75, 7.65, 7.58, 7.35, 7.25, 7.15, 7.00, 4.10, 3.95-3.66, 3.38, 2.90.
Reaction SMILES: C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[C:12]([OH:20])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CN1C=CN=C1.O[C@H:28]1[CH2:33][CH2:32][C@H:31]([CH2:34][C:35]#[N:36])[CH2:30][CH2:29]1>C(#N)C>[C:35]([CH2:34][C@H:31]1[CH2:32][CH2:33][C@H:28]([O:19][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:29][CH2:30]1)#[N:36]
Reactant: N#CC[C@H]1CC[C@H](O)CC1
Reactant: O=C(O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cn1ccnc1
Solvent: CC#N
Product: N#CC[C@H]1CC[C@H](OC(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of p-toluenesulfonyl chloride (4.71 g), benzoic acid (2.52 g), N-methylimidazole (4.9 mL), and acetonitrile (50 mL), an acetonitrile (50 mL) solution of trans-(4-hydroxy-cyclohexyl)-acetonitrile (2.87 g) obtained in Example (41a) was added at 0° C. The reaction mixture was warmed to room temperature, then stirred overnight, and then concentrated. The residue was diluted with ethyl acetate, then washed with water and saturated brine, and then concentrated. The residue was purified by column chromatography (hexane/ethyl acetate) to obtain the title compound (4.42 g, 88%) as a white solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl-].[N+:7]([C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[C:18]([O:20][CH3:21])=[O:19])[CH2:13][NH3+:14])([O-:9])=[O:8].C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([NH:14][CH2:13][C:12]1[CH:15]=[CH:16][C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:10]([N+:7]([O-:9])=[O:8])[CH:11]=1)(=[O:4])=[O:3]
Reactant: COC(=O)c1ccc(C[NH3+])cc1[N+](=O)[O-]
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(CNS(C)(=O)=O)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h

Procedure:
9.4 ml (0.244 mol) of methanesulfonyl chloride are metered over 30 minutes with ice-cooling to a solution of 30.1 g (0.122 mol) of 3-nitro-4-methoxycarbonyl-benzylammonium chloride and 34 ml (0.244 mol) of triethylamine in 300 ml of dichloromethane, and stirring of the mixture is continued for one hour. For work-up, the reaction mixture is treated with ice water, the phases are separated, and the aqueous phase is reextracted twice more with dichloromethane. After drying (Na2SO4), filtration and concentration, 31.3 g (89%) of methyl 4-methanesulfonylaminomethyl-2-nitrobenzoate remain as a syrupy oil.
Reaction SMILES: COC1C=CC(C[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([NH:21][C:22]([C:24]4[CH:25]=[CH:26][C:27]([C:34]5[C:39]([Cl:40])=[C:38]([O:41][CH3:42])[CH:37]=[C:36]([O:43][CH3:44])[C:35]=5[Cl:45])=[C:28]5[C:33]=4[N:32]=[CH:31][CH:30]=[CH:29]5)=[O:23])=[N:19][CH:20]=3)[CH2:10][CH2:9]2)=CC=1>C(Cl)Cl.CO>[N:11]1([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:22]([C:24]3[CH:25]=[CH:26][C:27]([C:34]4[C:35]([Cl:45])=[C:36]([O:43][CH3:44])[CH:37]=[C:38]([O:41][CH3:42])[C:39]=4[Cl:40])=[C:28]4[C:33]=3[N:32]=[CH:31][CH:30]=[CH:29]4)=[O:23])=[N:19][CH:20]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: COc1ccc(CN2CCN(Cc3ccc(NC(=O)c4ccc(-c5c(Cl)c(OC)cc(OC)c5Cl)c5cccnc45)nc3)CC2)cc1
Solvent: ClCCl
Solvent: CO
Product: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(CN4CCNCC4)cn3)c3ncccc23)c1Cl
Temperature: 120 °C
Reaction time: 1 h

Procedure:
The title compound was prepared in analogy to the procedure described in Example 105 but using 5-(2,6-dichloro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylic acid {5-[4-(4-methoxy-benzyl)-piperazin-1-ylmethyl]pyridin-2-yl}-amide (Example 166) and stirring the reaction mixture for 1 h at 120° C. Title compound: ESI-MS: 552.1 [M+H]+; TLC: Rf=0.12 (DCM/MeOH, 9:1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[NH:12][C:11]([C:15]3[CH:22]=[CH:21][C:18]([C:19]#N)=[CH:17][CH:16]=3)=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(C1C=CC(C(=O)C(O)=[O:33])=CC=1)#N.Cl.ClC1C=C(NN)C=CC=1Cl.Cl>O>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[NH:12][C:11]([C:15]3[CH:22]=[CH:21][C:18]([CH:19]=[O:33])=[CH:17][CH:16]=3)=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: N#Cc1ccc(-c2nn(-c3ccc(Cl)c(Cl)c3)c(=O)[nH]2)cc1
Reactant: N#Cc1ccc(C(=O)C(=O)O)cc1
Agent: Cl
Agent: NNc1ccc(Cl)c(Cl)c1
Solvent: O
Product: O=Cc1ccc(-c2nn(-c3ccc(Cl)c(Cl)c3)c(=O)[nH]2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
4-[1-(3,4-Dichloro-phenyl)-5-oxo-4,5-dihydro-1H-[1,2,4]triazol-3-yl]-benzonitrile. A suspension of 4-cyanophenyl-oxo-acetic acid (100 mg, 0.571 mmol), (3,4-dichlorophenyl)hydrazine hydrochloride (122 mg, 0.571 mmol), 12.1 N HCl (5 uL, 0.057 mmol), and H2O (˜10 mL) in a 25 mL reaction vial was stirred vigorously at ambient temperature for 24 h. The hydrazone was obtained by vacuum filtration and placed into a 100 mL round bottom flask with a magnetic stir bar. The flask was then supplemented with triethylamine (0.08 mL, 0.571 mmol), diphenylphosphoryl azide (157 mg, 0.571 mmol), and toluene (20 mL) before heating at 110° C. for 1 h. Upon cooling the contents were quenched with 10% NaOH (aq) and made acidic (pH 1) with conc. HCl. Precipitation was allowed for 15 min before the intermediate was obtained by vacuum filtration and dried overnight in a 45° C. vacuum oven (16 mg, 8%). The nitrile was reduced to the aldehyde using DIBAL under conditions previously described.
Reaction SMILES: [CH:1]1([N:6]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[C:7](=[O:23])[CH2:8][NH:9][CH:10]2[CH:15]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:14]=[CH:13][CH:12]=[CH:11]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:32](Cl)(=[O:37])[CH2:33][C:34](Cl)=[O:35]>C1COCC1>[CH:1]1([N:6]([C:24]2[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)[C:7](=[O:23])[CH2:8][N:9]2[C:34](=[O:35])[CH2:33][C:32](=[O:37])[N:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(N(C(=O)CNC2C=CC=CC2Nc2ccccc2)C2CCCC2)cc1
Reactant: O=C(Cl)CC(=O)Cl
Solvent: C1CCOC1
Product: COc1ccc(N(C(=O)CN2C(=O)CC(=O)N(c3ccccc3)c3ccccc32)C2CCCC2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
To a stirred solution of 419 mg (1.01 mmol) N-Cyclopentyl-N-(4-methoxy-phenyl)-2-(6-phenylamino-cyclohexa-2,4-dienylamino)-acetamide, prepared as in Part B, in 5 mL THF is added 170 mg (1.21 mmol, 1.2 equiv) Malonyl dichloride dissolved in 2 mL THF dropwise at 0° C. The reaction is stirred 1 h at 0° C. followed by 18 h at ambient temperature. The solvent is removed in vacuo and the residue purified by flash chromatography on 15 g silica gel eluted with EtOAc/Hexanes (1:1, 300 mL). Appropriate fractions were combined and concentrated in vacuo to give 249 mg (0.515 mmol) of N-Cyclopentyl-2-(2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-(4-methoxy-phenyl)-acetamide as a clear glass: 1H NMR (CDCl3, 300 MHz) δ7.43-7.20 (m, 8H), 7.09 (m, 2H), 6.97 (m, 3H), 4.95 (m, 1H), 4.38 (d, 1H, J=16.4), 4.06 (d, 1H, J=16.3), 3.84 (s, 3H), 3.59 (d, 1H, J=12.0), 3.49 (d, 1H, J=11.9), 1.90 (m, 2H), 1.52 (m, 4H), 1.35 (m, 2H); TLC Rf =0.16 (EtOAc/Hexanes, 1:1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])=O.[CH2:18]([O:20][C:21](=[O:28])[CH2:22][C:23](=O)[CH:24]([CH3:26])[CH3:25])[CH3:19]>>[CH2:18]([O:20][C:21]([C:22]1[C:23]([CH:24]([CH3:26])[CH3:25])=[N:1][C:2]2[C:3]([C:9]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])=[CH:4][CH:5]=[C:6]([Cl:8])[CH:7]=2)=[O:28])[CH3:19]
Reactant: Nc1cc(Cl)ccc1C(=O)c1ccccc1F
Reactant: CCOC(=O)CC(=O)C(C)C
Product: CCOC(=O)c1c(C(C)C)nc2cc(Cl)ccc2c1-c1ccccc1F

Procedure:
The title compound was prepared in analogy to example 6 step A from a mixture of (2-amino-4-chloro-phenyl)-(2-fluoro-phenyl)-methanone and 4-methyl-3-oxo-pentanoic acid ethyl ester. White solid. MS (ESI): 372.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][CH:4]=[CH2:5])[CH3:2].[Br:6][CH:7]([CH3:17])[C:8]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)=[O:9]>C1(C)C=CC=CC=1.C(O)(C(F)(F)F)=O>[Br:6][CH:7]([CH3:17])[C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH:1]([O:3][CH2:4][CH3:5])[CH3:2])=[CH:12][CH:11]=1)=[O:9]
Reactant: CC(Br)C(=O)c1ccc(O)cc1
Reactant: C=COCC
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(C)Oc1ccc(C(=O)C(C)Br)cc1
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 103.9 %

Procedure:
Ethoxyethene (3.148 g, 43.655 mmol) and TFA (0.249 g, 2.183 mmol) was added to a suspension of 2-bromo-1-(4-hydroxyphenyl)propan-1-one (5.000 g, 21.827 mmol) in toluene (50 ml) at rt. The reaction mixture was stirred at 30° C. for 2 h and 30 min. The solvent was evaporated to yield the product as an oil (6.83 g, 100%).