Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[O:11])=[C:4]([CH3:27])[CH:3]=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][C:30]=1[C:38]([O:40][CH2:41][CH3:42])=[O:39].N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:41]([O:40][C:38](=[O:39])[C:30]1[CH:31]=[C:32]([O:26][C:23]2[CH:22]=[CH:21][C:20]([CH:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=3[CH3:27])[CH2:9][C:10]([C:12]3[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=3)=[O:11])=[CH:25][CH:24]=2)[CH:33]=[CH:34][C:29]=1[Cl:28])[CH3:42]
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(O)cc1
Reactant: CCOC(=O)c1cc(B(O)O)ccc1Cl
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(Oc2ccc(C(CC(=O)c3ccc(=O)n(C)c3)c3ccc(Cl)cc3C)cc2)ccc1Cl

Procedure:
In analogy to example 222, step 1, 5-[3-(4-chloro-2-methyl-phenyl)-3-(4-hydroxy-phenyl)-propionyl]-1-methyl-1H-pyridin-2-one (example 346, step 1) was reacted with 4-chloro-3-ethoxycarbonylphenylboronic acid in dichloromethane in the presence of copper(II) acetate, pyridine and air to give the title compound as a colourless solid, MS (ESI+): m/z=564.2 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH2:34]([N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]>>[CH2:34]([N:41]1[CH2:42][CH2:43][N:44]([C:1](=[NH:2])[C:3]2[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]3[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([S:29](=[O:31])(=[O:32])[NH2:30])=[CH:25][CH:24]=4)(=[O:20])=[O:19])=[CH:14][CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[CH2:45][CH2:46]1)[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1
Reactant: CCCCCCCN1CCNCC1
Product: CCCCCCCN1CCN(C(=N)c2cccc(NC(=O)Nc3ccc(S(=O)(=O)NCc4ccc(S(N)(=O)=O)cc4)cc3)c2)CC1
Yield: 10 %

Procedure:
The title compound was prepared from 4-(3-(3-cyanophenyl)ureido)-N-(4-sulfamoylbenzyl)benzenesulfonamide following procedure C and using 1.5 equivalents of n-heptylpiperazine as secondary amine. The product was purified by preparative HPLC.
Reaction SMILES: Br[CH2:2][CH3:3].[F:4][C:5]1[CH:6]=[C:7]([CH:15]=[CH:16][CH:17]=1)[CH2:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:2]([N:12]1[CH2:13][CH2:14][CH:9]([CH2:8][C:7]2[CH:15]=[CH:16][CH:17]=[C:5]([F:4])[CH:6]=2)[CH2:10][CH2:11]1)[CH3:3]
Reactant: Fc1cccc(CC2CCNCC2)c1
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN1CCC(Cc2cccc(F)c2)CC1
Reaction time: 20 h

Procedure:
Bromoethane (0.1 mL) was added to a mixture of 4-(3-fluorobenzyl)piperidine (Intermediate 180, 0.259 g) and potassium carbonate (0.204 g) in acetonitrile (10 mL). The mixture was stirred for 20 hours then filtered. The filtrate acidified by addition of few drops of 2M HCl and the solution was passed through a SCX-2 column (10 g). The product was eluted with 2M ammonia in methanol and the residue after evaporation was triturated with diethyl ether. The solid was filtered off and the filtrated was concentrated in vacuo to give 1-ethyl-4-(3-fluorobenzyl)piperidine (0.210 g)
Reaction SMILES: N[C:2]1[C:3]([CH3:13])=[C:4]([NH:9][C:10](=[O:12])[CH3:11])[C:5]([CH3:8])=[CH:6][CH:7]=1.N([O-])=[O:15].[Na+].NC(N)=O>OS(O)(=O)=O.O>[OH:15][C:2]1[C:3]([CH3:13])=[C:4]([NH:9][C:10](=[O:12])[CH3:11])[C:5]([CH3:8])=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1c(C)ccc(N)c1C
Reactant: O=N[O-]
Agent: NC(N)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(=O)Nc1c(C)ccc(O)c1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 40.6 %

Procedure:
To a solution of N-(3-amino-2,6-dimethyl-phenyl)acetamide (2 g, 11 mmol, 1.1 eq) in a mixture of H2SO4 (10 mL) and H2O (70 mL) at 0° C. was added a solution of NaNO2 (1 g, 14.6 mmol, 1.3 eq) in H2O (140 mL). The solution was stirred at 0° C. for 30 min then urea (425 mg, 7.1 mmol, 0.63 eq) was added. The reaction was poured into boiling water and the mixture stirred at 100° C. for 2 h. The aqueous phase was extracted with EtOAc, and the combined extracts were dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by column chromatography (MeOH:DCM, 0:1 to 1:20) to give the title compound as a white solid (800 mg, 40%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([S:16][C:17]2[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.ClC1C=C(C=CC=1)C(OO)=[O:33].[OH2:39]>C(Cl)Cl>[CH3:1][C:2]1[C:3]([S:16]([C:17]2[CH:18]=[CH:19][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:26][CH:27]=2)(=[O:33])=[O:39])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1
Reactant: O
Reactant: CCOC(=O)c1ccc(Sc2cc3c(cc2C)C(C)(C)CCC3(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOC(=O)c1ccc(S(=O)(=O)c2cc3c(cc2C)C(C)(C)CCC3(C)C)cc1
Reaction time: 3 h
Yield: 94 %

Procedure:
To a solution of 69 mg (0.18 mmol) of ethyl 4-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthylthio)benzoate (Compound 6) in 2.0 mL of methylene chloride was dropwise added a solution of 87 mg of m-chloroperoxybenzoic acid (0.27 mmol, 50-60%) in 2.0 mL of methylene chloride, and the resulting solution was stirred for 3 h. The reaction was diluted with water and extracted with methylene chloride (2×). The combined organic layers were dried (MgSO4), filtered, and the solvents removed in vacuo to give a white solid. The crude product was purified by flash chromatography on silica gel (9:l/hexane:ethyl acetate) to give the title compound as a white solid (51 mg, 94%):
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:27])=[C:6]([CH:8]2[CH2:13][C:12]([NH:14][NH:15]S(C3C=CC(C)=CC=3)(=O)=O)=[CH:11][C:10](=[O:26])[CH2:9]2)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].CO.Br[CH2:37][C:38](=O)[CH3:39]>COCCOC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:27])=[C:6]([CH:8]2[CH2:13][C:12]3[N:14]=[N:15][CH:37]=[C:38]([CH3:39])[C:11]=3[C:10](=[O:26])[CH2:9]2)[CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)NNC2=CC(=O)CC(c3cc(F)ccc3C)C2)cc1
Reactant: CC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CO
Product: Cc1ccc(F)cc1C1CC(=O)c2c(C)cnnc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.4 %

Procedure:
To a mixture of 5-(5-fluoro-2-methylphenyl)-1-[2-(4-methylphenylsulfonyl)hydrazino]cyclohexen-3-one (1.63 g), anhydrous potassium carbonate (1.45 g), methanol (20 ml) and 1,2-dimethoxyethane (10 ml) was added under ice-cooling 1-bromopropan-2-one (0.75 g), and the mixture was stirred at room temperature for 2 hours and then at 80° C. for 5 hours. Under reduced pressure, the solvent was evaporated, and to the residue were added ethyl acetate (70 ml) and water (30 ml). The mixture was shaken, and the separated upper layer was washed with water and concentrated under reduced pressure. The residue was purified with silica gel column chromatography to give 7-(5-fluoro-2-methylphenyl)-4-methyl-5,6,7,8-tetrahydrocinnolin-5-one (0.265 g) as yellowish brown crystals.
Reaction SMILES: C(Cl)(=O)C.CO.[C:7]([O:11][CH3:12])(=[O:10])[CH2:8][SH:9].[CH:13]1[CH:27]=[C:26]2[C:16]([CH:17](O)[C:18]3[C:23]([CH:24]=[CH:25]2)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][CH:14]=1>C(OCC)(=O)C>[CH:22]1[C:23]2[CH:24]=[CH:25][C:26]3[CH:27]=[CH:13][CH:14]=[CH:15][C:16]=3[CH:17]([S:9][CH2:8][C:7]([O:11][CH3:12])=[O:10])[C:18]=2[CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)CS
Reactant: OC1c2ccccc2C=Cc2ccccc21
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CC(=O)Cl
Product: COC(=O)CSC1c2ccccc2C=Cc2ccccc21
Reaction time: 0.25 h
Yield: 87.2 %

Procedure:
Acetyl chloride (171 μL, 2.4 mmol) is carefully added to 8 mL of dry methanol and the solution is stirred for 15 minutes. Methyl thioglycolate (257 μL, 2.9mmol) and dibenzosuberenol (Aldrich) (0.50 g, 2.4 mmol) are added, and the reaction is stirred for 5 minutes. The reaction is diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate, water, then brine. The organic phase is dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil is chromatographed on silica gel eluting with ethyl acetate:toluene:hexane (3:27:70) to give 0.62 g (87%) of methyl (5H-dibenzo[a,d]cyclohepten-5-yl-thio)acetate: melting point 74°-76° C.
Reaction SMILES: [ClH:1].F[C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)CC1CCNCC1.Cl.[CH2:17]([N:24]1[CH2:29][CH2:28][CH:27]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=2)[CH2:26][CH2:25]1)[C:18]1C=CC=CC=1.C[OH:39]>[Pd]>[ClH:1].[O:39]([CH2:18][CH2:17][N:24]1[CH2:25][CH2:26][CH:27]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=2)[CH2:28][CH2:29]1)[C:3]1[CH:4]=[CH:5][CH:13]=[CH:14][CH:15]=1
Reactant: Fc1cccc(CC2CCN(Cc3ccccc3)CC2)c1
Reactant: Fc1cccc(CC2CCNCC2)c1
Reactant: CO
Agent: [Pd]
Agent: Cl
Product: Fc1cccc(CC2CCN(CCOc3ccccc3)CC2)c1
Yield: 98 %

Procedure:
4-(3-Fluorobenzyl)piperidine hydrochloride. A solution of 1-benzyl-4-(3-fluorobenzyl)piperidine hydrochloride (319 mg, 1.0 mmol) in 10 ml of methanol with 80 mg of 10% Pd/C was hydrogenated at 50 psi to give 228 mg (98%) of the title compound, mp 173-175° C. 1H NMR (CHCl3) 1.613-1.807 (m, 5 H), 2.593 (m, 2 H), 2.785 (m, 2 H), 3.481 (m, 2 H), 6.880 (m, 3 H), 7.25 (m, 1 H), 9.363 (s, 1 H), 9.634 (s, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=2[CH:18]([OH:20])[CH3:19])=[CH:5][CH:4]=1.C[N+]1([O-])CCOCC1>ClCCl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=2[C:18](=[O:20])[CH3:19])=[CH:21][CH:22]=1
Reactant: COc1ccc(COc2cccc([N+](=O)[O-])c2C(C)O)cc1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: COc1ccc(COc2cccc([N+](=O)[O-])c2C(C)=O)cc1
Temperature: 0 °C
Reaction time: 12 h
Yield: 80.1 %

Procedure:
To a cooled (0° C.), stirred solution of 1-{2-[(4-methoxybenzyl)oxy]-6-nitrophenyl}ethanol (0.20 g, 0.659 mmol) in dichloromethane (20 mL) were added molecular sieves 4A (1 g), N-methylmorpholine N-oxide (0.15 g, 1.319 mmol) and tetra-n-propylammonium perruthenate (0.01 g). The mixture was stirred at room temperature for 12 hrs. The reaction mixture was filtered on Celite®, and the filtrate was diluted with ethyl acetate. The organic phase was washed with saturated aqueous ammonium chloride solution and dried over Na2SO4, filtered and concentrated under reduced pressure to give 1-{2-[(4-methoxybenzyl)oxy]-6-nitrophenyl}ethanone as a white solid (0.159 g, yield; 80%). The residue was used for the next step without further purification.
Reaction SMILES: I[CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[CH:26]([NH:27][C:28](=[O:58])/[C:29](=[N:55]\[O:56][CH3:57])/[C:30]3[N:31]=[C:32]([NH:35]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[S:33][CH:34]=3)[C:25](=[O:59])[N:7]2[C:8]=1[C:9]([O:11]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:10].[S:60]1[C:68]2[CH:67]=[CH:66][N:65]=[CH:64][C:63]=2[N:62]=[CH:61]1>CS(C)=O.C(OCC)(=O)C>[NH2:35][C:32]1[S:33][CH:34]=[C:30](/[C:29](=[N:55]/[O:56][CH3:57])/[C:28]([NH:27][CH:26]2[C:25](=[O:59])[N:7]3[C:8]([C:9]([O-:11])=[O:10])=[C:3]([CH2:2][N+:65]4[CH:66]=[CH:67][C:68]5[S:60][CH:61]=[N:62][C:63]=5[CH:64]=4)[CH2:4][S:5][C@H:6]23)=[O:58])[N:31]=1
Reactant: c1cc2scnc2cn1
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CI)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccc4scnc4c3)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21 %

Procedure:
A mixture of benzhydryl 3-iodomethyl-7-[(Z)-2-methoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-cephem-4-carboxylate [VIIa] (1.50 g, 1.61 mmoles) and thiazolo[4,5-c]-pyridine (300 mg, 2.20 mmoles) in dry dimethylsulfoxide (DMSO) (7.5 mL) was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate (20 mL), washed with water (5 mL), dried and evaporated to dryness. To a solution of the residue in CHCl3 (5 mL) was added ether (50 mL) to give the quaternized blocked cephalosporin [XIIIa] (1.7 g), which was collected by filtration and treated with 90% trifluoroacetic acid [TFA] (17 mL) at room temperature for 1 hour. After evaporation of the solvent, the residue was triturated with ether, filtered and dissolved in CH3OH (2 mL). The solution was treated with 1M sodium 2-ethylhexanoate [SEH] in ethyl acetate (3.2 mL) at room temperature for 30 minutes to afford 774 mg of the crude title compound (Ia), which was purified by HPLC (Column, Lichrosorb RP-18, 8×300 mm; eluted with 0.01M ammonium phosphate buffer, pH 7.2--15% CH3OH) and HP-20 column chromatography (3×30 cm, washed with 1 L of water and eluted with 700 mL of 30% CH3OH). The fractions containing the desired product were collected, concentrated and lyophilized to afford 180 mg (22%) of the title compound (Ia) as a colorless powder, mp 165° C. (dec.).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[NH:12][C:13]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)=[N:14][N:15]=2)=[CH:6][CH:5]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Cl.Cl[C:37]1[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=1.[C:43]([O-])([O-:45])=[O:44].[K+].[K+]>CN(C=O)C.CO>[F:24][C:2]([F:1])([F:23])[C:43]([OH:45])=[O:44].[N:40]1[CH:41]=[CH:42][C:37]([O:22][C:19]2[CH:20]=[CH:21][C:16]([C:13]3[NH:12][C:11]([NH:10][C:7]4[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:23])[F:24])=[CH:9][CH:8]=4)=[N:15][N:14]=3)=[CH:17][CH:18]=2)=[CH:38][CH:39]=1
Reactant: Oc1ccc(-c2nnc(Nc3ccc(OC(F)(F)F)cc3)[nH]2)cc1
Reactant: O=C([O-])[O-]
Reactant: Clc1ccncc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: FC(F)(F)Oc1ccc(Nc2nnc(-c3ccc(Oc4ccncc4)cc3)[nH]2)cc1
Product: O=C(O)C(F)(F)F
Temperature: 80 °C
Yield: 80.1 %

Procedure:
4-[5-(4-trifluoromethoxy-phenylamino)-4H[1,2,4]triazol-3-yl]-phenol (106.0 mg, 0.315 mmol) was dissolved in 2 mL of anhydrous DMF in a 5 mL microwave vial (Personal Chemistry). Solid potassium bis(trimethylsilyl)amide (157.2 mg, 0.788 mmol) was added and the reaction mixture was stirred with heating at 80° C. for 15 min, then 4-chloropyridine hydrochloride (56.7 mg, 0.378 mmol) was added, followed by anhydrous K2CO3 (44.0 mg, 0.315 mmol). Then the vial was capped and microwaved at 250° C. for 20 min. Then the reaction mixture was diluted with ca. 1 mL of MeOH, filtered through 0.22 μm syringe filter and purified by reverse-phase preparative HPLC in acetonitrile/water system with 0.01% TFA. The product was isolated as a TFA salt (66.5 mg of off-white solid).
Reaction SMILES: OS(O)(=O)=O.[Br:6][C:7]1[CH:8]=[CH:9][C:10]([CH:14]2[CH2:16][CH2:15]2)=[C:11]([CH:13]=1)N.N([O-])=[O:18].[Na+]>O>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([CH:14]2[CH2:16][CH2:15]2)=[C:11]([OH:18])[CH:13]=1
Reactant: O=N[O-]
Reactant: Nc1cc(Br)ccc1C1CC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Oc1cc(Br)ccc1C1CC1
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
An ice-cold solution of H2SO4 (0.23 mL, 4.31 mmol) in water (2 mL) was added to 5-bromo-2-cyclopropylaniline (300 mg, 1.42 mmol) at 0° C. The reaction was stirred for 10 min, then sodium nitrite (98 mg, 1.415 mmol) in 2 mL cold water was added dropwise. The reaction was stirred at 0° C. for 1 h and then heated at 100° C. for 1 h. Reaction was extracted with EtOAc. Combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated to afford the title compound, which was used without further purification. LC-MS calculated for C9H9BrO 211.98, no ionization, (Rt: 1.57/4 min.).
Reaction SMILES: [CH:1]1([CH:7]([N:19]2[C:23]3[CH:24]=[C:25]([F:29])[C:26]([F:28])=[CH:27][C:22]=3[N:21]=C2C2C(OC)=NC(OC)=CC=2)[CH2:8][O:9]C2C=CC(C(O)=O)=CN=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:40][C:41]1[CH:49]=[CH:48][C:44]([C:45](O)=O)=[C:43]([CH3:50])[CH:42]=1.C1(C=O)CCCCC=1.[CH2:59]([N+:66]#[C-])[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1.Cl>CO.O1CCOCC1>[CH2:59]([NH:66][C:8](=[O:9])[CH:7]([N:19]1[C:23]2[CH:24]=[C:25]([F:29])[C:26]([F:28])=[CH:27][C:22]=2[N:21]=[C:45]1[C:44]1[CH:48]=[CH:49][C:41]([Cl:40])=[CH:42][C:43]=1[CH3:50])[CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1
Reactant: COc1ccc(-c2nc3cc(F)c(F)cc3n2C(COc2ccc(C(=O)O)cn2)C2CCCCC2)c(OC)n1
Reactant: [C-]#[N+]Cc1ccccc1
Reactant: Cc1cc(Cl)ccc1C(=O)O
Agent: Cl
Agent: O=CC1=CCCCC1
Solvent: CO
Solvent: C1COCCO1
Product: Cc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1C(C(=O)NCc1ccccc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the solution of 1.5 g (6.145 mmol) 2-amino-4,5-difluoro-phenyl)-carbamic acid tert-butyl ester (Example 73, intermediate g), 1.080 g (6.145 mmol) 4-chloro-2-methyl-benzoic acid (commercially available), 985.5 ul (7.375 mmol) cyclohexenecarbaldehyde (commercially available) and 763.5 ul (6.145 mmol) benzyl isocyanide (commercially available) were dissolved in 15 ml methanol and the light brown solution was stirred at room temperature overnight. Then 15.00 ml (60.0 mmol) 4M hydrochloric acid in dioxane (commercially available) were added and the reaction mixture was stirred at room temperature for 4.5 h and then evaporated. The residue was taken up in ethyl acetate and aqueous saturated sodium bicarbonate solution, the phases were separated, the organic phase extracted a second time with ethyl acetate and the combined organic layers washed with water and brine to give, after evaporation, the compound as yellow foam which was pure enough for the next step without further purification. MS (ESI): m/z=508.02 (M+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C:8]1([CH3:17])[CH2:13][CH:12]([NH2:14])[CH2:11][C:10]([CH3:16])([CH3:15])[NH:9]1.F[C:19]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:20]=1[C:21]#[N:22].[CH3:31]I>CN(C=O)C>[CH3:31][N:9]1[C:10]([CH3:16])([CH3:15])[CH2:11][CH:12]([NH:14][C:19]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:20]=2[C:21]#[N:22])[CH2:13][C:8]1([CH3:17])[CH3:7]
Reactant: CI
Reactant: CC1(C)CC(N)CC(C)(C)N1
Reactant: N#Cc1ccc(C(F)(F)F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1C(C)(C)CC(Nc2cc(C(F)(F)F)ccc2C#N)CC1(C)C
Temperature: 60 °C
Reaction time: 12 h

Procedure:
Potassium carbonate and 2,2,6,6-tetramethylpiperidine-4-amine were added to a DMF solution of 2-fluoro-4-(trifluoromethyl)benzonitrile. After stirring at 60° C. for 12 hours, methyl iodide and potassium carbonate were added thereto, followed by stirring at room temperature for 1 day. By post-treating the reaction liquid, 2-[(1,2,2,6,6-pentamethylpiperidin-4-yl)amino]-4-(trifluoromethyl)benzonitrile was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:14]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:41][I:42]>>[I-:42].[CH3:41][N+:36]1[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=1[CH2:34][N:11]([S:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:14]=1
Reactant: CCCCCCCCCCCCCCOc1cccc(CN(Cc2ccccn2)S(=O)(=O)c2ccc(C)cc2)c1
Reactant: CI
Product: CCCCCCCCCCCCCCOc1cccc(CN(Cc2cccc[n+]2C)S(=O)(=O)c2ccc(C)cc2)c1
Product: [I-]
Temperature: 100 °C
Yield: 92.6 %

Procedure:
A mixture of 1.01 g of product from Example 80 and 12.69 g of methyl iodide is heated, in a sealed tube, at 100° C. for 5 hours. The reaction is concentrated to give 1.17 g of the desired product as a yellow-green foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:20][CH3:21])=[CH:5][C:6]2[C:7](=[O:19])[N:8]3[N:15]=[C:14]([C:16]([OH:18])=[O:17])[CH:13]=C3NC=2[CH:12]=1.[C:22](=O)([O-])[O-].[K+].[K+].CI.[CH3:30][N:31]([CH:33]=O)[CH3:32]>>[CH3:1][O:2][C:3]1[C:4]([O:20][CH3:21])=[CH:5][C:6]2[C:7](=[O:19])[N:8]3[N:15]=[C:14]([C:16]([O:18][CH3:22])=[O:17])[CH:13]=[C:33]3[N:31]([CH3:30])[C:32]=2[CH:12]=1
Reactant: O=C([O-])[O-]
Reactant: CN(C)C=O
Reactant: COc1cc2[nH]c3cc(C(=O)O)nn3c(=O)c2cc1OC
Agent: [K+]
Solvent: CI
Product: COC(=O)c1cc2n(C)c3cc(OC)c(OC)cc3c(=O)n2n1

Procedure:
From 4,9-dihydro-6,7-dimethoxy-9-oxo-pyrazolo[5,1-b]-quinazoline-2-carboxylic acid (1.5 g; 5.2 mmole), anhydrous potassium carbonate (3.0 g; 22 mmole), methyl iodide (15 ml) and DMF (50 ml), following the procedure of Example 11, there is obtained 4,9-dihydro-6,7-dimethoxy-4-methyl-9-oxo-pyrazolo[5,1-b]quinazoline-2-carboxylic acid, methyl ester (1.8 g); mp 301°-303° (d). The crude methyl ester (1.8 g) is hydrolyzed with 1(N) sodium hydroxide solution (50 ml) as in Example 11 to give 4,9-dihydro-6,7-dimethoxy-4-methyl-9-oxo-pyrazolo-[5,1-b]quinazoline-2-carboxylic acid (0.95 g) mp 284°-5° (d), after crystallization from DMF/methanol.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)O1.Br[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1.[OH-].[Na+]>C1COCC1.[Pd].C(OCC)(=O)C>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)=[CH:21][CH:22]=1
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Reactant: Clc1ccc(Br)cc1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Clc1ccc(-c2cccc3[nH]ccc23)cc1
Temperature: 70 °C
Reaction time: 15 h
Yield: 88.7 %

Procedure:
To a mixture of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (3, 2.43 g, 10 mmol), and 4-bromochlorobenzene (2.87 g, 15 mmol) in THF (34 mL)) were added Palladium catalyst Pd(PPh3)4 (347 mg, 0.3 mmol) and the freshly prepared sodium hydroxide solution (1.20 g, 30 mmol in 14 mL water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 70° C. oil bath for 15 hours. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed by brine, dried over Na2SO4, and concentrated. The crude product was purified by a silica gel column eluting with hexanes—EtOAc (9:1) to provide 2.02 g (89%) of the product 4-(4-chloro-phenyl)-1H-indole as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.C(O)(=O)C>[Fe].O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: CN1CCN(c2ccc([N+](=O)[O-])c(Cl)c2)CC1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(N)c(Cl)c2)CC1
Temperature: 35 °C
Yield: 24.7 %

Procedure:
1-(3-Chloro-4-nitro-phenyl)-4-methyl-piperazine (2.016 g, 7.885 mmol) was combined with Tetrahydrofuran (30 mL). The resulting mixture was filtered. The filtrate was combined with Acetic acid (40 mL, 700 mmol), then at room temperature Iron (2932 mg, 52.50 mmol) was added neat and the mixture was warmed to 35° C. under a nitrogen atmosphere. After 16 h filtered mixture and concentrated resulting filtrate under reduced pressure. The concentrated residue was partitioned between CHCl3 (2×) and saturated aqueous NaHCO3. Combined organics, dried over Na2SO4, filtered, and concentrated under reduced pressure to yield 0.44 g (25%) of 2-Chloro-4-(4-methyl-piperazin-1-yl)-phenylamine as a yellow tinted oil, which crystallized on sitting. This material was used without further manipulation for the subsequent step. LC/MS (E/I+) 226.05 (M+H).