Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([C@H:10]1[CH2:14][C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@@H:12]([CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([N:28]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=3)=[O:33])[CH2:29][CH:30]=[CH2:31])[CH2:24][CH2:23]2)[CH2:11]1)C(OC(C)(C)C)=O.[C:45]1([S:51](Cl)(=[O:53])=[O:52])[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>>[CH3:1][N:2]([C@H:10]1[CH2:14][C@H:13]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@@H:12]([CH2:21][N:22]2[CH2:23][CH2:24][CH:25]([N:28]([C:32]([O:34][CH2:35][C:36]3[CH:37]=[CH:38][C:39]([N+:42]([O-:44])=[O:43])=[CH:40][CH:41]=3)=[O:33])[CH2:29][CH:30]=[CH2:31])[CH2:26][CH2:27]2)[CH2:11]1)[S:51]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)(=[O:53])=[O:52]
Reactant: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@@H](N(C)C(=O)OC(C)(C)C)C[C@@H]2c2ccccc2)CC1
Reactant: O=S(=O)(Cl)c1ccccc1
Product: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@@H](N(C)S(=O)(=O)c3ccccc3)C[C@@H]2c2ccccc2)CC1

Procedure:
Using essentially the same procedure as in Example 16, Step A and B but substituting 1-(S)-(N-(methyl)-N-(t-butoxycarbonyl)amino)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopentane from Example 31 in Step A and phenylsulfonyl chloride in Step B, the title compound was prepared.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[N:11][N:10]([CH2:13][CH2:14]Br)[C:9](=[O:16])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:17][CH:18]([C:22]1[CH:27]=[CH:26][C:25]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[CH:24][CH:23]=1)[CH2:19][NH:20][CH3:21].C(N(CC)CC)C>C(O)C>[OH:17][CH:18]([C:22]1[CH:23]=[CH:24][C:25]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[CH:26][CH:27]=1)[CH2:19][N:20]([CH3:21])[CH2:14][CH2:13][N:10]1[C:9](=[O:16])[CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:12]=[N:11]1
Reactant: O=c1cc(-c2ccccc2)cnn1CCBr
Reactant: CNCC(O)c1ccc(NS(C)(=O)=O)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN(CCn1ncc(-c2ccccc2)cc1=O)CC(O)c1ccc(NS(C)(=O)=O)cc1

Procedure:
2-[5-Phenyl-2H-pyridazin-3-on-2-yl]ethyl bromide (0.28 g), 2-hydroxy-N-methyl-2-(4-methanesulphonamidophenyl)ethylamine (0.24 g) and triethylamine (0.22 g) were refluxed in ethanol (30 ml) for 4 hours. The solvent was removed and the residue taken up in methylene chloride, washed with water, evaporated and the residue chromatographed on silica [Merck `Kieselgel 60` (Trade Mark)], eluting with ethyl acetate. Collection and evaporation of appropriate fractions gave the title compound as a solid which was recrystallised from diisopropyl ether, yield 0.1 g, m.p. 108°.
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[C:13]([OH:23])[N:14]([C@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:24]>CO>[NH2:24][C:2]1[C:11]2[N:12]=[C:13]([OH:23])[N:14]([C@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: N
Reactant: C[C@@H](c1ccccc1)n1c(O)nc2c(Cl)nc3ccccc3c21
Solvent: CO
Product: C[C@@H](c1ccccc1)n1c(O)nc2c(N)nc3ccccc3c21
Temperature: 135 °C

Procedure:
4-Chloro-1-[(1S)-1-phenylethyl]-1H-imidazo[4,5-c]quinolin-2-ol (4.0 g, 12 mmol) and ammonia (65 mL of a 7 N solution in methanol) were added to a high-pressure vessel, which was sealed and heated in an oven at 135° C. over two nights. The volatiles were removed under reduced pressure. The crude product was purified twice by automated flash chromatography (silica cartridge, eluting with aqueous ammonium hydroxide:methanol:dichloromethane in a gradient from 0:0:100 to 0.2:3.8:96). The chromatographed product was washed with acetonitrile and diethyl ether several times and dried in a vacuum oven to provide 260 mg of 4-amino-1-[(1S)-1-phenylethyl]-1H-imidazo[4,5-c]quinolin-2-ol as an off-white solid, mp 292-295° C.
Reaction SMILES: C[N:2]([CH3:17])[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1)=O.[NH2:18][C:19]1[C:23](C#N)=[C:22]([C:26]#[N:27])[NH:21][N:20]=1>C(O)(=O)C>[C:19]([C:23]1[C:22]([C:26]#[N:27])=[N:21][N:20]2[C:5]([C:7]3[CH:8]=[C:9]([C:13]([F:14])([F:15])[F:16])[CH:10]=[CH:11][CH:12]=3)=[CH:4][CH:3]=[N:2][C:17]=12)#[N:18]
Reactant: CN(C)C=CC(=O)c1cccc(C(F)(F)F)c1
Reactant: N#Cc1[nH]nc(N)c1C#N
Solvent: CC(=O)O
Product: N#Cc1nn2c(-c3cccc(C(F)(F)F)c3)ccnc2c1C#N

Procedure:
A mixture of 4.86 g. of 3-dimethylamino-3'-(trifluoromethyl)acrylophenone, 50 ml. of glacial acetic acid and 2.66 g. of 3-aminopyrazole-4,5-dicarbonitrile is refluxed for 10 hours and the solvent removed under reduced pressure. The residue is treated with trifluoroacetic anhydride to give the product of the example. cl EXAMPLE 44
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH2:9][C:10]#[N:11])=[C:4]([CH3:12])[CH:3]=1.[CH2:13](N)[CH2:14][NH2:15].[S]>>[F:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([CH2:9][C:10]2[NH:15][CH2:14][CH2:13][N:11]=2)=[C:6]([CH3:8])[CH:7]=1
Reactant: NCCN
Reactant: Cc1cc(F)cc(C)c1CC#N
Agent: [S]
Product: Cc1cc(F)cc(C)c1CC1=NCCN1
Temperature: 200 °C

Procedure:
A mixture of 1.30 g (8 mmol) (4-fluoro-2,6-dimethyl-phenyl)-acetonitrile, 3.83 g (4.27 ml, 64 mmol) ethylene diamine and 0.128 g (4 mmol) sulfur in a pressurized glass tube was heated under microwave irradiation to 200° C. for 20 min. The cooled reaction mixture was poured onto water, extracted with methylene chloride, the combined extracts washed with brine, dried over Na2SO4, filtered and evaporated. Purification of the residue by flash-chromatography over silica gel with a ethyl acetate/methanol gradient containing 1% conc. ammonia provided 2-(4-fluoro-2,6-dimethyl-benzyl)-4,5-dihydro-1H-imidazole as light yellow solid: MS (EI): 206.1 ((M+.), 100%).
Reaction SMILES: C(N1CCCC(C(OCC)=O)C1)(=O)C1C=CC=CC=1.[CH3:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH:22]1[C:27]([O:29][CH2:30][CH3:31])=[O:28].C(N(C(C)C)CC)(C)C.[S:41]1[CH:45]=[CH:44][CH:43]=[C:42]1[CH2:46][C:47](Cl)=[O:48]>>[S:41]1[CH:45]=[CH:44][CH:43]=[C:42]1[CH2:46][C:47]([N:24]1[CH2:25][CH2:26][CH:21]([CH3:20])[CH:22]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:23]1)=[O:48]
Reactant: O=C(Cl)Cc1cccs1
Reactant: CCOC(=O)C1CNCCC1C
Agent: CCOC(=O)C1CCCN(C(=O)c2ccccc2)C1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CN(C(=O)Cc2cccs2)CCC1C
Yield: 74.1 %

Procedure:
This reaction was run in the same manner as ethyl 1-benzoyl-3-piperidinecarboxylate, starting with ethyl 4-methyl-3-piperidinecarboxylate (531.8 mg; 3.11 mmol), diisopropylethylamine (600 μl; 3.44 mmol), and thiopheneacetyl chloride (382 μl; 3.11 mmol). The crude product was purified by chromatography on silica eluting with 50% ethyl acetate/50% hexane, giving ethyl 1-(2-thiopheneacetyl)-4-methyl-3-piperidinecarboxylate (681.2 mg) as a yellow oil. MS m/z (positive ion) 397 (MH++Et3N; 70), 296 (MH+; 100).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH:9]1[CH:13]=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:11]=[N:10]1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:2]([N:9]1[CH:13]=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:11]=[N:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cnn(Cc2ccccc2)c1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
Bromomethyl-benzene (610 mg, 3.57 mmol) was suspended in Acetone (25 ml), ethyl 1H-pyrazole-4-carboxylate (500 mg, 3.57 mmol) and K2CO3 (2465 mg, 17.84 mmol) were added. The suspension was stirred 16 h at 50° C. The reaction mixture was filtrated and evaporated in vacuum to give the title compound which was used for the next step without further purification. HPLC/MS (Method A) RtA=1.82 min, MS [M+H]+=230.9.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:19][O:20][C:21](=[O:61])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([CH2:58][CH3:59])([C:38]3[CH:43]=[CH:42][C:41]([C:44]#[C:45][C:46]4([O:52][Si](C)(C)C)[CH2:51][CH2:50][S:49][CH2:48][CH2:47]4)=[C:40]([CH3:57])[CH:39]=3)[CH2:36][CH3:37])=[CH:31][C:30]=2[CH3:60])=[CH:25][CH:24]=1.O>O1CCCC1>[CH3:19][O:20][C:21](=[O:61])[CH2:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([CH2:36][CH3:37])([C:38]3[CH:43]=[CH:42][C:41]([C:44]#[C:45][C:46]4([OH:52])[CH2:51][CH2:50][S:49][CH2:48][CH2:47]4)=[C:40]([CH3:57])[CH:39]=3)[CH2:58][CH3:59])=[CH:31][C:30]=2[CH3:60])=[CH:27][CH:28]=1
Reactant: CCC(CC)(c1ccc(C#CC2(O[Si](C)(C)C)CCSCC2)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)cc2)c(C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(C#CC2(O)CCSCC2)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)cc2)c(C)c1
Reaction time: 0.5 h
Yield: 71.9 %

Procedure:
Tetrabutylammonium fluoride (1 M solution in tetrahydrofuran, 0.13 mL, 0.13 mmol) was added to a solution of (4′-{1-ethyl-1-[3-methyl-4-(4-trimethylsilanyloxy-tetrahydro-thiopyran-4-ylethynyl)-phenyl]-propyl}-2′-methyl-biphenyl-4-yl)-acetic acid methyl ester (Example 136-(5); 53 mg, 0.09 mmol) in tetrahydrofuran (1 mL) at 0° C., and the mixture was stirred at the same temperature for 30 minutes. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=1:1) to give the target compound as a colorless oil (35 mg, 78%).
Reaction SMILES: [F:1][C:2]([F:20])([CH:17]([F:19])[F:18])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[N:14][NH:13][C:12]2=[O:16])=[CH:7][CH:6]=1.[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[C:29](=[O:40])[C@@H:30](OS(C(F)(F)F)(=O)=O)[CH3:31]>CN1CCCC1=O.[H-].[Na+].O1CCCC1.C(O)(=O)C.C(OCC)(=O)C>[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[C:29](=[O:40])[C@H:30]([N:13]1[C:12](=[O:16])[N:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][C:2]([F:1])([F:20])[CH:17]([F:19])[F:18])=[CH:6][CH:7]=2)[CH:15]=[N:14]1)[CH3:31]
Reactant: C[C@H](OS(=O)(=O)C(F)(F)F)C(=O)c1ccc(F)cc1F
Reactant: O=c1[nH]ncn1-c1ccc(OCC(F)(F)C(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@H](C(=O)c1ccc(F)cc1F)n1ncn(-c2ccc(OCC(F)(F)C(F)F)cc2)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 55.5 %

Procedure:
4-[4-(2,2,3,3-Tetrafluoropropoxy)phenyl]-3(2H,4H)-1,2,4-triazolone (6.12 g) was dissolved in 60 ml of 1-methyl-2-pyrrolidone, to which 60% of sodium hydride in oil (0.80 g) was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was ice-cooled and added dropwise under nitrogen atmosphere over the period of 25 minutes to a solution of 7.32 g of (2S)-2',4'-difluoro-2-trifluoromethanesulfonyloxypropiophenone in 180 ml of tetrahydrofuran which was cooled to -50° C. Then, the reaction temperature was raised to -30° C. over the period of 10 minutes. After stirring for 30 minutes, the reaction solution was diluted with 10 ml of acetic acid and 500 ml of ethyl acetate, washed with water (300 ml×2), 0.5N-hydrochloric acid (400 ml×2) and 300 ml of a saturated aqueous solution of sodium chloride successively, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (silica gel: 250 g, eluent; hexane:ethyl acetate:acetic acid=3:1:0.04), and dissolved in 12 ml of diisopropyl ether. The solution was allowed to stand for 1 hour with ice cooling. The deposited insoluble substance was removed by filtration and the solution was concentrated under reduced pressure to give 5.36 g of 2-[(1R)-2-(2,4-difluorophenyl)-2-oxo-1-methylethyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-3(2H,4H)-1,2,4-triazolone as a pale yellow viscous substance.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][C:3]=1[F:12].ClC1C=C2C(C=C[N+]([O-:24])=C2)=CC=1F>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N+:8]([O-:24])=[CH:9]2)=[CH:4][C:3]=1[F:12]
Reactant: [O-][n+]1ccc2cc(F)c(Cl)cc2c1
Reactant: Fc1cc2ccncc2cc1Br
Product: [O-][n+]1ccc2cc(F)c(Br)cc2c1

Procedure:
Starting from 7-bromo-6-fluoro-isoquinoline (15), the title compound was prepared following the method described for 7-chloro-6-fluoro-isoquinoline 2-oxide (5). Rt=0.93 min (Method C). Detected mass: 242.2/244.2 (M+H+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:14][CH:13]3[O:15][CH:10]([CH2:11][CH2:12]3)[CH2:9]2)[CH:5]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)[N:3]=1.Cl.[CH:26]12[O:33][CH:30]([CH2:31][CH2:32]1)[CH2:29][NH:28][CH2:27]2.C(N(CC)CC)C.CCN(C(C)C)C(C)C>O1CCOCC1.C(OCC)(=O)C>[N+:22]([C:19]1[CH:20]=[CH:21][C:16]([C:4]2[N:3]=[C:2]([N:28]3[CH2:27][CH:26]4[O:33][CH:30]([CH2:31][CH2:32]4)[CH2:29]3)[N:7]=[C:6]([N:8]3[CH2:14][CH:13]4[O:15][CH:10]([CH2:11][CH2:12]4)[CH2:9]3)[CH:5]=2)=[CH:17][CH:18]=1)([O-:24])=[O:23]
Reactant: C1CC2CNCC1O2
Reactant: O=[N+]([O-])c1ccc(-c2cc(N3CC4CCC(C3)O4)nc(Cl)n2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(-c2cc(N3CC4CCC(C3)O4)nc(N3CC4CCC(C3)O4)n2)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 65.6 %

Procedure:
In a 100 mL round-bottomed flask was placed 3-[2-chloro-6-(4-nitro-phenyl)-pyrimidin-4-yl]-8-oxa-3-aza-bicyclo[3.2.1]octane (14, 110 mg, 0.32 mmol) in dioxane (5 ml). 8-Oxa-3-azabicyclo[3.2.1]octane, HCl (2, 0.15 g, 1 mmol) and triethylamine (0.28 ml, 2 mmol) were added. The mixture was stirred at 80° C. for 16 hours. DIPEA was added (0.3 mL) and stirring was continued at 80° C. for 64 hours. The reaction mixture was diluted with ethyl acetate and washed with sat NaHCO3. The solids between the organic phase and aqueous phase were dissolved in dichloromethane and washed with saturated NaHCO3. The combined organic phases were dried over MgSO4, filtered and concentrated. The crude product was added to a silica gel column and eluted with ethyl acetate in hexanes (10-40%) to give 89 mg of the title compound (0.21 mmol, 65%).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Cl:14])[CH:12]=2)[N:7](C(OCC)=O)[C:6]=1[C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:3])[CH3:2]>C(OCC)(=O)C>[C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Cl:14])[CH:12]=2)[NH:7][C:6]=1[C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)n1c(C(=O)c2ccccc2)c(NC(C)=O)c2cc(Cl)ccc21
Solvent: CCOC(C)=O
Product: CC(=O)Nc1c(C(=O)c2ccccc2)[nH]c2ccc(Cl)cc12

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 2 (Method A) and from 3-acetylamino-2-benzoyl-5-chloro-1-(ethoxycarbonyl)indole (step 2). m.p.: 200-201° C. (ethyl acetate)
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[CH:22]=[C:21]([C@@H:23]3[CH2:27][CH2:26][CH2:25][N:24]3[C@@H](C3C=CC(OC)=CC=3)C)[CH:20]=[CH:19][N:18]=2)=[CH:9]1)=O)(C)(C)C>C(O)(C(F)(F)F)=O>[NH:24]1[CH2:25][CH2:26][CH2:27][C@H:23]1[C:21]1[CH:20]=[CH:19][N:18]=[C:17]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[NH:8][CH:9]=2)[CH:22]=1
Reactant: COc1ccc([C@@H](C)N2CCC[C@H]2c2ccnc(-c3cn(C(=O)OC(C)(C)C)c4ccccc34)c2)cc1
Solvent: O=C(O)C(F)(F)F
Product: c1ccc2c(-c3cc([C@@H]4CCCN4)ccn3)c[nH]c2c1

Procedure:
A solution of 3-(4-{(S)-1-[(R)-1-(4-Methoxy-phenyl)-ethyl]-pyrrolidin-2-yl}-pyridin-2-yl)-indole-1-carboxylic acid tert-butyl ester (160 mg, 0.31 mmol) in TFA (5 mL) is heated in microwave at 100° C. for 30 min and concentrated down to give crude 3-((S)-4-pyrrolidin-2-yl-pyridine-2-yl)-1H-indole (15), which is used in next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:46])=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:12][C:13]([N:15]([CH3:44])[CH:16]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([NH:36]C(=O)OC(C)(C)C)[CH:31]=4)=[CH:26][CH:25]=3)[CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[O:14])[C:6]=2[CH:45]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:36][C:32]1[CH:31]=[C:30]([C:27]2[CH:28]=[CH:29][C:24]([CH:16]([N:15]([CH3:44])[C:13](=[O:14])[CH2:12][N:7]3[C:6]4[CH:45]=[C:2]([Cl:1])[C:3]([Cl:46])=[CH:4][C:5]=4[O:10][CH2:9][C:8]3=[O:11])[CH2:17][N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)=[CH:25][CH:26]=2)[CH:35]=[CH:34][CH:33]=1
Reactant: CN(C(=O)CN1C(=O)COc2cc(Cl)c(Cl)cc21)C(CN1CCOCC1)c1ccc(-c2cccc(NC(=O)OC(C)(C)C)c2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)CN1C(=O)COc2cc(Cl)c(Cl)cc21)C(CN1CCOCC1)c1ccc(-c2cccc(N)c2)cc1
Reaction time: 0.25 h
Yield: 50.4 %

Procedure:
To a solution of 1,1-dimethylethyl {4′-[1-[[(6,7-dichloro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)acetyl](methyl)amino]-2-(4-morpholinyl)ethyl]-3-biphenylyl}carbamate (1.55 g, 2.3 mmol) in dichloromethane (8 mL) was added trifluoro acetic acid (8 mL). The resultant mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by using a Gilson preparative HPLC (Phenomenex, 100×50 mm, 10 micron, 90 mL/min, A: acetonitrile, 0.1% TFA B: water, 0.1% TFA, A: 10 to 90% over 15 min, UV detection at 214 nm) to give 0.66 g (50%) of the title compound as tan solid MS (ES) m/e 569.1 [M+H]+
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][CH:10](O)[CH:9]1[CH2:20][O:21][Si:22]([C:35]([CH3:38])([CH3:37])[CH3:36])([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].N(C1C=CC=CC=1)(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O.[F:92][C:93]1[CH:98]=[CH:97][C:96]([F:99])=[CH:95][C:94]=1B(O)O>C(Cl)Cl.C1COCC1.CCOC(C)=O.O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[C:10]([C:94]2[CH:95]=[C:96]([F:99])[CH:97]=[CH:98][C:93]=2[F:92])[CH:9]1[CH2:20][O:21][Si:22]([C:35]([CH3:38])([CH3:37])[CH3:36])([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: OB(O)c1cc(F)ccc1F
Reactant: CC(C)(C)OC(=O)N1C(c2ccccc2)CC(O)C1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: [Pd]
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C(c2cc(F)ccc2F)=CC1c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of the carbinol 1-6 (36 g, 67.7 mmol) in CH2Cl2 (400 mL) was treated with Dess-Martin periodinane (29 g, 67.7 mmol). After stirring for 1 h at rt the reaction was quenched with a 1:1 (200 mL) solution of Na2S2O3/NaHCO3 and the mixture stirred vigorously for 2 h. The reaction was extracted with CH2Cl2 (2×200 mL) and the combined organic solutions dried over MgSO4, filtered, and concentrated. The residue (35.5 g, 67.0 mmol) was dissolved in THF (500 mL) and cooled to −78° C. The solution was treated with NaHMDS (83.0 mL of a 1M soln in THF, 83 mmol) and stirred at −78° C. for 1 h. Neat Tf2NPh (28.7 g, 80.4 mmol) was added to the reaction and the reaction was stirred with gradual warming to rt for 12 h. The reaction was diluted with EtOAc and washed with satd aq NH4Cl and brine. The organic solution was dried over MgSO4, filtered and concentrated. The residue (44.3 g, 66.9 mmol) was dissolved in dioxane (300 mL) and 2M Na2CO3 (100 mL). The mixture was degassed with a flow of N2 (g) for 30 min and treated with 2,5-difluorophenylboronic acid (13.7 g, 87 mmol) and tetrakis(triphenylphosphine)-palladium (3.8 g, 3.3 mmol). The yellow mixture was heated at 90° C. for 90 min, cooled to rt, and diluted with EtOAc (300 mL). The organic solution was washed with satd aq NH4Cl (150 mL), dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (SiO2; 20/80 CH2Cl2/hexanes to 10% EtOAc/hexanes) to provide the desired product diastereomers 1-7 as a yellow foam. LRMS (m/z) M+1 expected 627, found 627.
Reaction SMILES: [C:1]([C:6]1[CH:22]=[CH:21][C:9]([O:10][CH:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:12](O)=[O:13])=[C:8]([Cl:23])[CH:7]=1)([CH2:4][CH3:5])([CH3:3])[CH3:2].S(Cl)([Cl:26])=O>C1(C)C=CC=CC=1>[C:1]([C:6]1[CH:22]=[CH:21][C:9]([O:10][CH:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:12]([Cl:26])=[O:13])=[C:8]([Cl:23])[CH:7]=1)([CH2:4][CH3:5])([CH3:3])[CH3:2]
Reactant: CCCCCCC(Oc1ccc(C(C)(C)CC)cc1Cl)C(=O)O
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CCCCCCC(Oc1ccc(C(C)(C)CC)cc1Cl)C(=O)Cl
Temperature: 60 °C

Procedure:
A mixture of 46 g of 2-(4-t-amyl-2-chlorophenoxy)octanoic acid and 46 ml of toluene was heated to 60° C., and 20.3 ml of thionyl chloride was slowly added thereto dropwise while stirring. After allowing the mixture to react at that temperature for 2 hours, the excess thionyl chloride and toluene were removed by distillation under reduced pressure to obtain 48 g of 2-(4-t-amyl-2-chlorophenoxy)octanoic acid chloride.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][NH:16][CH2:15]2)[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22].[OH:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](O)=[O:31]>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][N:16]([C:30](=[O:31])[C:29]3[CH:33]=[CH:34][CH:35]=[C:27]([OH:26])[CH:28]=3)[CH2:15]2)[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)c1c(C)nc2cccc(OCC3CCCNC3)c2c1N
Reactant: O=C(O)c1cccc(O)c1
Product: CCOC(=O)c1c(C)nc2cccc(OCC3CCCN(C(=O)c4cccc(O)c4)C3)c2c1N

Procedure:
Prepared as in Example 24a from ethyl 4-amino-2-methyl-5-(piperidin-3-ylmethoxy)-quinoline-3-carboxylate (Example 110b) and 3-hydroxybenzoic acid as a white solid (34%). MS 464 (MH+).
Reaction SMILES: I[CH3:2].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:29]2[N:30]=[CH:31][NH:32][CH:33]=2)[C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[N:17]([CH3:21])[C:16](=[O:22])[CH:15]=[C:14]3[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:6][CH:5]=1.O>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C1COCC1.[OH-].[Na+]>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:29]2[N:30]=[CH:31][N:32]([CH3:2])[CH:33]=2)[C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[N:17]([CH3:21])[C:16](=[O:22])[CH:15]=[C:14]3[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:6][CH:5]=1
Reactant: CI
Reactant: Cn1c(=O)cc(-c2ccccc2)c2cc(C(c3ccc(Cl)cc3)c3c[nH]cn3)ccc21
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1cnc(C(c2ccc(Cl)cc2)c2ccc3c(c2)c(-c2ccccc2)cc(=O)n3C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
Iodomethane (1.4 ml) was added to a mixture of (±)-6-[(4-chlorophenyl)-1H-imidazol-4-ylmethyl]-1-methyl-4-phenyl-2(1H)-quinolinone (7.5 g) and benzyltriethylammonium chloride (2 g) in THF (75 ml) and sodium hydroxide (75 ml) and the mixture was stirred at room temperature for 1 hour. Water was added and the mixture was extracted with ethyl acetate. The organic layer was dried (MgSO4), filtered off and evaporated till dryness. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 98.5/1.5/0.1). The pure fractions were collected and evaporated. Fraction 1 (3.5 g) was recrystallized from diethyl ether, yielding 3.3 g (42%) of (±)-6-[(4-chlorophenyl)(1-methyl-1H-imidazol-4-yl)methyl]-1-methyl-4-phenyl-2(1H)-quinolinone; mp. 149.9° C. (comp. 44). Fraction 2 was recrystallized from 2-propanone, methanol and diethyl ether, yielding 1.6 g (20%) of (±)-6-[(4chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-4-phenyl-2(1H)-quinolinone (comp. 2, mp. 96.8° C.).