Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C@@H:2]1[CH2:6][N:5]([C:7](=[O:12])[C:8]([F:11])([F:10])[F:9])[C@H:4]([C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14])[CH2:3]1.N1C(C)=CC=CC=1C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH2:42]([O:49][NH2:50])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>C(#N)C.C(OCC)(=O)C>[CH2:42]([O:49][NH:50][C@H:2]1[CH2:6][N:5]([C:7](=[O:12])[C:8]([F:11])([F:10])[F:9])[C@H:4]([C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14])[CH2:3]1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: C=CCOC(=O)[C@@H]1C[C@H](O)CN1C(=O)C(F)(F)F
Reactant: NOCc1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: Cc1cccc(C)n1
Solvent: CC#N
Product: C=CCOC(=O)[C@@H]1C[C@@H](NOCc2ccccc2)CN1C(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of allyl (4S)-4-hydroxy-1-(trifluoroacetyl)-L-prolinate (844 mg, 3.16 mmol) in acetonitrile (16 mL) was cooled to −10° C. and 2,6-lutidine (0.62 mL, 5.32 mmol) was added followed by trifluoromethanesulfonic anhydride (0.85 mL, 5.15 mmol). After addition, the temperature was allowed to warm to 0° C. The reaction mixture was stirred at 0° C. for 1 hour then O-benzylhydroxylamine (1 mL, 8.67 mmol) was added followed by 2,6-lutidine (0.62 mL, 5.32 mmol). The reaction mixture was allowed to warm to room temperature overnight. The reaction mixture was then diluted with ethyl acetate and washed with 5% sodium bicarbonate solution and brine, dried over magnesium sulfate, filtered and concentrated under vacuum. The tan oil residue (2.57 g) was chromatographed on silica gel eluted initially with 95:5 dichloromethane:ethyl acetate and finally with 80:20 dichloromethane:ethyl acetate to afford the title compound as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:3]=1[O:4][C:5]1[C:6]([NH:18][S:19]([C:22]2[CH:27]=[CH:26][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:24][N:23]=2)(=[O:21])=[O:20])=[N:7][C:8]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[N:9][C:10]=1[CH3:11].[Se](=O)=[O:38]>O1CCOCC1>[Cl:1][C:2]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:3]=1[O:4][C:5]1[C:6]([NH:18][S:19]([C:22]2[CH:27]=[CH:26][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:24][N:23]=2)(=[O:21])=[O:20])=[N:7][C:8]([N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)=[N:9][C:10]=1[CH:11]=[O:38]
Reactant: O=[Se]=O
Reactant: COc1ccc(Cl)c(Oc2c(C)nc(N3CCOCC3)nc2NS(=O)(=O)c2ccc(C(C)C)cn2)c1
Solvent: C1COCCO1
Product: COc1ccc(Cl)c(Oc2c(C=O)nc(N3CCOCC3)nc2NS(=O)(=O)c2ccc(C(C)C)cn2)c1
Yield: 51.6 %

Procedure:
1 g of the compound obtained in Example 36 and 2.1 g of selenium dioxide in 40 ml of dioxan were stirred in an autoclave at 170° C. for 7 hours. The reaction mixture was filtered and the filtrate was concentrated. The residue was partitioned between ethyl acetate and water. The organic phase was dried, the solvent was evaporated and the residue was purified over silica gel with ethyl acetate/hexane. 0.53 g of 5-isopropyl-pyridine-2-sulphonic acid 5-(2-chloro-5-methoxy-phenoxy)-6-formyl-2-morpholin-4-yl-pyrimidin-4-ylamide, m.p. 194° C., was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].[H-].[Na+].[H][H].[CH2:15]([N:22]([CH2:36][CH2:37]Cl)[CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C=O>[CH2:15]([N:22]([CH2:36][CH2:37][O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: [H][H]
Reactant: O=C(NCCCCN(CCCl)Cc1ccccc1)c1ccccc1
Reactant: O=[N+]([O-])c1ccccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(NCCCCN(CCOc1ccccc1[N+](=O)[O-])Cc1ccccc1)c1ccccc1
Temperature: 67.5 °C
Reaction time: 1.5 h

Procedure:
2-nitrophenol (0.56 g, 0.004 mole) is added in portions to a stirred suspension of sodium hydride (160 mg of a dispersion at 60% in oil, 0.004 mole) in dry dimethylformamide (10 ml) in a nitrogen atmosphere. When the hydrogen evolution is completed, while stirring, a solution of N-[4-{benzyl (2-chloroethyl)amino}butyl]benzamide (1.6 g, 0.0046 mole) in dry dimethylformamide (5 ml) is added dropwise. The reaction mixture is heated to 65-70 degrees C. for 1.5 hours, cooled back to ambient temperature, and poured over crushed ice. The mixture is extracted with ether (50 ml); the organic phase is separated and washed with water (3×20 ml) before being dried over magnesium sulfate. Filtration and evaporation of the solvent at reduced pressure yield 1.3 g of an oil which is purified by flash chromatography over silica gel by using a mixture of ethyl acetate/heptane (3/1) as eluant. The expected compound is obtained in the form of oil (0.94 g, 52%).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][CH:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[CH:3]=1.[CH3:21][O:22][C:23]1[CH:29]=[C:28]([N:30]2[CH2:35][CH2:34][P:33]([CH3:37])(=[O:36])[CH2:32][CH2:31]2)[CH:27]=[CH:26][C:24]=1[NH2:25].Cl>COCCO.C(O)C>[CH3:21][O:22][C:23]1[CH:29]=[C:28]([N:30]2[CH2:31][CH2:32][P:33]([CH3:37])(=[O:36])[CH2:34][CH2:35]2)[CH:27]=[CH:26][C:24]=1[NH:25][C:2]1[N:7]=[N:6][CH:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[CH:3]=1
Reactant: COc1cc(N2CCP(C)(=O)CC2)ccc1N
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1cnnc(Cl)c1
Agent: Cl
Solvent: CCO
Solvent: COCCO
Product: COc1cc(N2CCP(C)(=O)CC2)ccc1Nc1cc(Nc2ccccc2S(=O)(=O)C(C)C)cnn1

Procedure:
To a solution of 6-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyridazin-4-amine (prepared in Example 73: 0.02 mmol) and 2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)aniline (0.7 mmol) in 1 mL of 2-Methoxy ethanol, is added 1 mL of 2.5M HCl in Ethanol. The reaction mixture is heated in a sealed tube at 140 degree until formation of the desired compound. The reaction mixture is filtered through a syringe filter and can be purified by Prep-HPLC.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:14])[CH:11]=NO)[CH:5]=[CH:6][C:7]=1[CH3:8].S(=O)(=O)(O)[OH:16]>>[F:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]2[C:3]=1[C:11](=[O:16])[C:10](=[O:14])[NH:9]2.[F:1][C:2]1[CH:3]=[C:4]2[C:5]([C:11](=[O:16])[C:10](=[O:14])[NH:9]2)=[CH:6][C:7]=1[CH3:8]
Reactant: O=S(=O)(O)O
Reactant: Cc1ccc(NC(=O)C=NO)cc1F
Product: Cc1cc2c(cc1F)NC(=O)C2=O
Product: Cc1ccc2c(c1F)C(=O)C(=O)N2
Temperature: 80 °C

Procedure:
Add of N-(3-Fluoro-4-methyl-phenyl)-2-hydroxyimino-acetamide (2.96 g, 15.10 mmol) in small portions at 65° C. to concentrated sulfuric acid (15 mL) and heat the mixture at 80° C. for 10 minutes. Cool to room temperature, pour into ice water (100 mL) and filter the precipitate and wash with water. Dry the solid to yield 4-Fluoro-5-methyl-1H-indole-2,3-dione and 6-Fluoro-5-methyl-1H-indole-2,3-dione.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH2:9])=[CH:4][CH:3]=1.Cl[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].C([O-])([O-])=O.[K+].[K+]>O1CCCC1.O>[I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:11](=[O:12])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(NCc1ccc(I)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of (4-iodophenyl)methanamine (5 g, 18.5 mmol) and benzyl chloroformate (3.47 g) in a mixture of tetrahydrofuran (20 mL) and H2O (50 mL) was added K2CO3 (10.2 g, 74 mmol) at 5° C. The reaction mixture was stirred at room temperature for 5 hours, and partitioned between ethyl acetate and brine. The organic phase was washed with brine, dried over MgSO4, filtered, and concentrated to afford the title compound. LC-MS (ESI): m/z 368 (M+H), RT: 2.25 min; 1H NMR (400 MHz, CDCl3): δ 4.32 (d, J=6.0 Hz, 2H), 5.13 (s, 2H), 7.03 (d, J=7.6 Hz, 2H), 7.32-7.36 (m, 5H), 7.65 (d, J=8.0 Hz, 2H).
Reaction SMILES: [C:1]1([C@@H:7]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:8]([O:10][C@@H:11]2[CH:16]3[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]3)[CH2:12]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:26][CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH3:36])=[O:29]>CCOC(C)=O>[Br-:26].[O:29]=[C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH3:36])[CH2:27][N+:13]12[CH2:14][CH2:15][CH:16]([CH2:17][CH2:18]1)[C@@H:11]([O:10][C:8](=[O:9])[C@@H:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:12]2
Reactant: Cc1ccccc1C(=O)CBr
Reactant: O=C(O[C@H]1CN2CCC1CC2)[C@H](Nc1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Product: Cc1ccccc1C(=O)C[N+]12CCC(CC1)[C@@H](OC(=O)[C@H](Nc1ccccc1)c1ccccc1)C2
Product: [Br-]
Temperature: 25 °C
Reaction time: 15 h
Yield: 86.4 %

Procedure:
To a solution of (R)—((R)-quinuclidin-3-yl) 2-phenyl-2-(phenylamino)acetate (diastereomer 1 of I2) (55 mg, 0.16 mmol) in EtOAc (5 ml), was added 2-bromo-1-o-tolylethanone (41.8 mg, 0.20 mmol), and the reaction was stirred at room temperature for 15 hours. The precipitate was collected by suction filtration to obtain (R)-1-(2-oxo-2-o-tolylethyl)-3-((R)-2-phenyl-2-(phenylamino)acetoxy)-1-azoniabicyclo[2.2.2]octane bromide (76.0 mg, 85% yield).
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:17]=[C:18]1[C:23]2=[CH:24][NH:25][C:26]([CH:27]=O)=[C:22]2[CH2:21][CH2:20][O:19]1>>[O:16]=[C:12]1[C:11](=[CH:27][C:26]2[NH:25][CH:24]=[C:23]3[C:18](=[O:17])[O:19][CH2:20][CH2:21][C:22]=23)[C:10]2[C:14](=[CH:15][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][CH:9]=2)[NH:13]1
Reactant: O=C1Cc2ccc(-c3ccccc3)cc2N1
Reactant: O=Cc1[nH]cc2c1CCOC2=O
Product: O=C1Nc2cc(-c3ccccc3)ccc2C1=Cc1[nH]cc2c1CCOC2=O

Procedure:
6-Phenyl-1,3-dihydro-indol-2-one was condensed with 4-oxo-2,4,6,7 tetrahydro-pyrano[3,4-c]pyrrole-1-carbaldehyde to give the title compound.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][CH2:13][NH2:14].[C:15]([C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=1)(=[O:17])[CH3:16].Cl>ClCCl.C(N(CC)CC)C.O>[C:15]([C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH:14][CH2:13][CH2:12][O:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[O:23])=[CH:20][CH:19]=1)(=[O:17])[CH3:16]
Reactant: NCCOc1ccc2ccccc2c1
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)c1ccc(C(=O)NCCOc2ccc3ccccc3c2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 53.9 %

Procedure:
A stirred mixture of 2-(2-naphthalenyloxy)ethanamine (4.9 g) in dichloromethane (25 mL) and triethylamine (5 mL) was chilled to 0° C. and treated with the acid chloride prepared from 4-acetyl benzoic acid (4.3 g) and then the mixture was stirred at room temperature for 10 minutes. The mixture was diluted with water and acidified with excess 2N hydrochloric acid, extracted with dichloromethane and the organic layer was washed in turn with sodium bicarbonate solution and saturated sodium chloride solution. The organic layer was dried (Na2SO4), filtered, and evaporated to give crude material which was purified by HPLC (ethyl acetate-dichloromethane; 1:9) and crystallized from ethyl acetate to provide 4.7 g of 4-acetyl-N-[2-(2-naphthalenyloxy)ethyl]benzamide as a colorless solid, mp 131°-132° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([CH2:16][O:17][CH3:18])[O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=1.[NH2:19][C:20]1[C:25]2[CH:26]=[C:27]([CH2:29][CH:30]([NH:40]S(C3C=CC(OC4CCOCC4)=CC=3)(=O)=O)[C:31]([N:33]3[CH2:38][CH2:37][CH:36]([CH3:39])[CH2:35][CH2:34]3)=[O:32])[S:28][C:24]=2[CH:23]=[CH:22][N:21]=1>>[NH2:19][C:20]1[C:25]2[CH:26]=[C:27]([CH2:29][CH:30]([NH:40][S:12]([C:9]3[CH:10]=[CH:11][C:6]([O:5][CH:4]([CH2:16][O:17][CH3:18])[CH2:3][O:2][CH3:1])=[CH:7][CH:8]=3)(=[O:14])=[O:13])[C:31]([N:33]3[CH2:34][CH2:35][CH:36]([CH3:39])[CH2:37][CH2:38]3)=[O:32])[S:28][C:24]=2[CH:23]=[CH:22][N:21]=1
Reactant: COCC(COC)Oc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1CCN(C(=O)C(Cc2cc3c(N)nccc3s2)NS(=O)(=O)c2ccc(OC3CCOCC3)cc2)CC1
Product: COCC(COC)Oc1ccc(S(=O)(=O)NC(Cc2cc3c(N)nccc3s2)C(=O)N2CCC(C)CC2)cc1

Procedure:
This compound was prepared from 0.75 mmol of 4-(2-methoxy-1-methoxymethyl-ethoxy)-benzenesulfonyl chloride and 210 mg (0.5 mmol) of 30a using the procedure described for 58c. Yield: 120 mg (oil), EI-MS: 576 (M+).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH2:3]1.[CH2:12]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20](Cl)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13]1.[I-].[Na+].C(N(CC)CC)C>O1CCOCC1>[CH:15]1[C:14]2[CH2:13][CH2:12][C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH:20]([N:2]3[CH2:7][CH2:6][CH:5]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH2:3]3)[C:19]=2[CH:18]=[CH:17][CH:16]=1
Reactant: ClC1c2ccccc2CCc2ccccc21
Reactant: COC(=O)C1=CCCNC1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COC(=O)C1=CCCN(C2c3ccccc3CCc3ccccc32)C1
Temperature: 90 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
A mixture of methyl 1,2,5,6-tetrahydropyridine-3-carboxylate hydrochloride (crude, 150 mmol), 5-chlorodibenzosuberane (41 g, 180 mmol, 1.2 eq), sodium iodide (2.2 g, 15 mmol, 0.1 eq) and triethylamine (63 mL, 450 mmol, 3.0 eq) in dioxane (300 mL) was stirred at 90° C. overnight. The reaction mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over MgSO4, and concentrated. The crude product was passed through a silica gel plug, eluting with CH2Cl2. After concentration, the resulting solid was triturated with ether to yield 27 g (55%) of methyl 1-(10,11-dihydro5H-dibenzo[a,d][7]annulen-5-yl)-1,2,5,6-tetrahydropyridine-3-carboxylate.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=4)[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(N(CC)CC)C.[F:35][C:36]([F:51])([S:47](F)(=[O:49])=[O:48])[C:37]([F:46])([F:45])[C:38]([F:44])([F:43])[C:39]([F:42])([F:41])[F:40]>C(#N)C>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH:20][C:21]4[CH:22]=[CH:23][C:24]([O:27][S:47]([C:36]([F:35])([F:51])[C:37]([F:45])([F:46])[C:38]([F:43])([F:44])[C:39]([F:42])([F:41])[F:40])(=[O:49])=[O:48])=[CH:25][CH:26]=4)[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(Nc4ccc(O)cc4)nc23)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(-c2cccn3nc(Nc4ccc(OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc4)nc23)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 4-[8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-phenol (100.0 mg, 0.2629 mmol) and triethylamine (55.0 L, 0.395 mmol) in acetonitrile (1 mL) was added 1,1,2,2,3,3,4,4,4-nonafluoro-butane-1-sulfonyl fluoride (60.0 L, 0.341 mmol). The mixture was stirred for 1 hour at room temperature then partitioned between water (25 mL) and ethyl acetate (25 mL). The organic was rinsed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and evaporated. The residue was purified via chromatography using silica gel column (12 g) and ethyl acetate:hexane solvent gradient. The title compound was isolated as a pale yellow foam (0.128 g, 73%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.51 (d, J=6.6 Hz, 1H), 8.22 (d, J=7.5 Hz, 2H), 8.09 (d, J=7.8 Hz, 2H), 7.71-7.64 (m, 3H), 7.29-7.25 (m, 2H), 7.11 (s, 1H), 7.08 (t, J=7.0 Hz, 1H), 3.10 (s, 3H). MS=663 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:15]3=[C:16]([S:18](=[O:22])(=[O:21])[CH2:19][CH2:20][N:14]3[C@H:13]3[CH2:23][CH2:24][N:25](C(OC(C)(C)C)=O)[CH2:26][C@@H:12]23)[CH:17]=1.C>>[ClH:1].[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:15]3=[C:16]([S:18](=[O:21])(=[O:22])[CH2:19][CH2:20][N:14]3[C@H:13]3[CH2:23][CH2:24][NH:25][CH2:26][C@@H:12]23)[CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(-c3ccc(Cl)cc3Cl)cc3c1N2CCS3(=O)=O
Agent: C
Product: Cl
Product: O=S1(=O)CCN2c3c(cc(-c4ccc(Cl)cc4Cl)cc31)[C@@H]1CNCC[C@@H]12
Yield: 162.6 %

Procedure:
The title compound (37 mg, 80%) was prepared from tert-butyl(6bR,10aS)-5-(2,4-dichlorophenyl)-1,2,6b,9,10,10a-hexahydropyrido[4,3-b][1,4]thiazino[2,3,4-hi]indole-8(7H)-carboxylate 3,3-dioxide (52 mg) using the procedure described in Example 448 Step B. 1H NMR (CD3OD, 500 MHz) δ2.20-2.25 (m, 1H), 2.25-2.35 (m, 1H), 3.00 (t, 1H, 12.5 Hz), 3.18-3.38 (m, 3H), 3.45-3.75 (m, 5H), 3.83-3.95 (m, 2H), 7.35 (d, 1H, J=6.8 Hz), 7.40 (m, 1H), 7.49 (m, 1H), 7.51 (m, 1H), 7.59 (m, 1H) ppm. CIMS (Methane) m/z=410 [C19H18Cl2N2O2S+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[CH:9](=O)/[CH:10]=[CH:11]/[CH3:12]>>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:3]=1[N:4]=[C:11]([CH3:12])[CH:10]=[CH:9]2
Reactant: C/C=C/C=O
Reactant: Nc1ccccc1Cl
Product: Cc1ccc2cccc(Cl)c2n1
Yield: 57 %

Procedure:
The procedure described in Example 1 was followed, except that 130 g/hour of 2-chloroaniline and 84 g/hour of crotonaldehyde were employed. Distillation from the oil bed under 5 mbar until the bottom temperature reached 250° C., and crystallization of the distillate with xylene, gave 101 g (57% of theory) of 8-chloro-2-methylquinoline of melting point 64° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:14][NH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].ClN1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=[CH:19]C1.[CH:27]([N:30](C(C)C)CC)(C)C>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:14][NH:15][C:27]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=[CH:19][N:30]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: ClN1CC=Nc2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1CN
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1CNc1ncnc2ccccc12

Procedure:
(S)-2-Aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (1.0 g), 4-chloroquinoxaline (0.768 g) and diisopropylethylamine (0.816 ml) were dissolved in tetrahydrofuran (75 ml) and heated to reflux for 6 hours under an atmosphere of argon. After cooling, the reaction solution was partitioned between ethyl acetate and water. The organic layer was washed with saturated sodium hydrogen carbonate solution, saturated brine, dried and evaporated. The residue was chromatographed over silica gel, eluting with a gradient of 50 to 100% ethyl acetate in hexane. The title compound was obtained as a white foam (1.44 g).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:21]([CH2:28][CH2:29][CH:30]3[CH2:34][CH2:33][CH2:32][N:31]3[CH3:35])C(=O)C(F)(F)F)=[C:7]([C:13]3[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[CH:14]=3)[C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1[N+:36]([O-:38])=[O:37].C(=O)([O-])[O-].[K+].[K+]>CO.O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:21][CH2:28][CH2:29][CH:30]3[CH2:34][CH2:33][CH2:32][N:31]3[CH3:35])=[C:7]([C:13]3[CH:14]=[C:15]([CH3:20])[CH:16]=[C:17]([CH3:19])[CH:18]=3)[C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1[N+:36]([O-:38])=[O:37]
Reactant: Cc1cc(C)cc(-c2c(N(CCC3CCCN3C)C(=O)C(F)(F)F)c3cc([N+](=O)[O-])c(Cl)cc3[nH]c2=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1cc(C)cc(-c2c(NCCC3CCCN3C)c3cc([N+](=O)[O-])c(Cl)cc3[nH]c2=O)c1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a solution of N-[7-chloro-3-(3,5-dimethylphenyl)-6-nitro-2-oxo-1,2-dihydroquinolin-4-yl]-2,2,2-trifluoro-N-[2-(1-methylpyrrolidin-2-yl)-ethyl]acetamide (50 mg in a mixture of 1.0 mL methanol and 0.10 mL water) was added 25 mg potassium carbonate and the mixture heated to 60° C. After 4 hours, the mixture was cooled to room temperature and the solvent removed in vacuo. The residue was dissolved in ethyl acetate and washed sequentially with water and brine then dried over sodium sulfate. Purification of the concentrate by flash chromatography on silica gel (chloroform:methanol:ammonium hydroxide, 90:10:1) gave the title compound (31 mg). MASS: 455 (M+H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH:9]([CH:11]2[CH2:13][CH2:12]2)O)=[C:4]([F:14])[CH:3]=1.FC(F)(F)C(O)=O.[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[C:30]([CH2:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH:31]=1)[NH:28][CH:27]=[CH:26]2>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH:9]([CH:11]2[CH2:13][CH2:12]2)[C:26]2[C:25]3[C:29](=[C:30]([CH2:32][S:33]([CH3:36])(=[O:34])=[O:35])[CH:31]=[C:23]([F:22])[CH:24]=3)[NH:28][CH:27]=2)=[C:4]([F:14])[CH:3]=1
Reactant: CS(=O)(=O)Cc1cc(F)cc2cc[nH]c12
Reactant: OC(c1c(F)cc(Cl)cc1F)C1CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)Cc1cc(F)cc2c(C(c3c(F)cc(Cl)cc3F)C3CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
96 mg (0.44 mmol) of the compound from Example 156A and 0.04 ml (0.53 mmol) of trifluoroacetic acid were added to 100 mg (0.44 mmol) of the compound from Example 87A in 3 ml of dichloromethane. The reaction mixture was stirred at RT for 45 min, the solvent was removed in vacuo, and the crude product was then purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 162 mg (86% of theory) of the title compound were obtained.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:8][C:9]=1[NH:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[C:16]([O:28][CH3:29])[CH:15]=1)=[S:12])=O.[C:36](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[CH3:29][O:28][C:16]1[CH:15]=[C:14]([N:13]2[C:3](=[O:2])[C:5]3[S:6][C:7]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:8][C:9]=3[N:10]=[C:11]2[S:12][CH3:36])[CH:19]=[CH:18][C:17]=1[O:20][CH2:21][CH2:22][N:23]1[CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: COC(=O)c1sc(-c2ccccc2)cc1NC(=S)Nc1ccc(OCCN2CCCC2)c(OC)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cc(-n2c(SC)nc3cc(-c4ccccc4)sc3c2=O)ccc1OCCN1CCCC1
Yield: 50 %

Procedure:
This ester (300 mg, 0.56 mmol) and potassium carbonate (162 mg, 1.17 mmol) were suspended in dry DMF (5 ml) and treated with a solution of methyl iodide (83 mg, 0.59 mmol) in DMF (1 ml). When the addition was complete, the mixture was evaporated. The residue was purified by chromatography on silica gel (eluting with dichloromethane-methanol) giving the title compound in 50% yield;
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[CH2:12]([C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17])[CH3:13].O.O=[CH:23][C:24]([OH:26])=[O:25]>C(#N)C>[CH2:12]([C:14]1[CH:15]=[C:16]([NH:17][CH:23]([C:6]2[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:24]([OH:26])=[O:25])[CH:18]=[CH:19][CH:20]=1)[CH3:13]
Reactant: O=CC(=O)O
Reactant: CCc1cccc(N)c1
Reactant: COc1ccc(B(O)O)cn1
Solvent: CC#N
Solvent: O
Product: CCc1cccc(NC(C(=O)O)c2ccc(OC)nc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.7 %

Procedure:
A mixture of 6-methoxypyridin-3-ylboronic acid (200 mg, 1.31 mmol), 3-ethylaniline (163 μl, 1.31 mmol), and 2-oxoacetic acid hydrate (120 mg, 1.31 mmol) in acetonitrile (20 ml) was stirred at room temperature overnight. The solvent was evaporated, and the crude product was purified by flash-chromatography (DCM/MeOH=9/1) to obtain 2-(3-ethylphenylamino)-2-(6-methoxypyridin-3-yl)acetic acid (265 mg, 70.8% yield).