Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[CH2:19]1[CH2:28][O:27][C:26]2[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][C:21]=2[O:20]1.C(=O)([O-])[O-].[Na+].[Na+].C1COCC1>C(Cl)(Cl)Cl.[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>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:24]4[CH:23]=[CH:22][C:21]5[O:20][CH2:19][CH2:28][O:27][C:26]=5[CH:25]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Reactant: OB(O)c1ccc2c(c1)OCCO2
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccc5c(c4)OCCO5)cc3CC[C@@H]12
Yield: 80 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg, 0.02 mmol), 3,4-ethylenedioxyphenylboronic acid (140 mg, 0.78 mmol), 0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with chloroform (50 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), to give 189 mg (80%) of the title compound as an amorphous solid. mp 183°-189°. FDMS: m/e=363. α[D]589 =+80.77 (c=1.04, chloroform).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[CH:5][CH:4]=1.[C-:23]#[N:24].[Na+].[I-].[Na+]>CN(C)C=O>[F:22][C:19]1[CH:20]=[CH:21][C:16]([N:13]2[CH2:14][CH2:15][N:10]([CH2:9][C:6]3[CH:7]=[CH:8][C:3]([CH2:2][C:23]#[N:24])=[CH:4][CH:5]=3)[CH2:11][CH2:12]2)=[CH:17][CH:18]=1
Reactant: [C-]#N
Reactant: Fc1ccc(N2CCN(Cc3ccc(CCl)cc3)CC2)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCc1ccc(CN2CCN(c3ccc(F)cc3)CC2)cc1
Temperature: 0 °C
Yield: 67 %

Procedure:
A solution of 4-((4-chloromethylphenyl)methyl)-1-(4-fluorophenyl)piperazine (10.0 g), sodium cyanide (1.72 g) and a catalytic amount of sodium iodide in dimethylformamide (50 ml) was stirred at 70° C. for 3 hr, and poured into ice water (200 ml) and extracted with ethyl acetate (300 ml×2). The ethyl acetate layer was washed with saturated brine and dried over anhydrous sodium sulfate. The obtained residue was purified by silica gel column chromatography (developing solvent; ethyl acetate:hexane=1:2) and recrystallized from ethyl acetate-hexane to give the title compound (6.50 g) as pale-yellow crystals.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]([F:35])=[CH:17][N:18]3[C:23]([C:24]=2[CH3:25])=[C:22]([CH:26]2[CH2:28][CH2:27]2)[CH:21]=[C:20]([C:29]([O:31]CC)=[O:30])[C:19]3=[O:34])=[CH:11][C:10]=1[F:36])=O)(C)(C)C.Cl.[OH-].[Na+]>C1COCC1>[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]([F:35])=[CH:17][N:18]3[C:23]([C:24]=2[CH3:25])=[C:22]([CH:26]2[CH2:28][CH2:27]2)[CH:21]=[C:20]([C:29]([OH:31])=[O:30])[C:19]3=[O:34])=[CH:11][C:10]=1[F:36]
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(NC(=O)OC(C)(C)C)c(F)c3)c(F)cn2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1c(-c2ccc(N)c(F)c2)c(F)cn2c(=O)c(C(=O)O)cc(C3CC3)c12
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 2.6 %

Procedure:
A solution of ethyl 8-(4-(tert-butoxycarbonylamino)-3-fluoro-phenyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (260 mg, 0.52 mmol) in a 4N hydrochloric acid solution (20 mL). The mixture was stirred for 20 min at 50° C. The product was lyophilized and dissolved in a mixture of THF (1 mL) and of an aqueous 4N sodium hydroxide solution (1.31 mL, 5.2 mmol) before being irradiated at 140° C. in a microwave oven for 10 min. The product was purified by preparative HPLC yielding compound 17 8-(4-amino-3-fluoro-phenyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-quinolizine-3-carboxylic acid (5.1 mg, 2.5%).
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][N:5]1[C:9]2[C:10]([C:14]([O:16][CH3:17])=[O:15])=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[CH:18](C)C.O.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:18][C:6]1[N:5]([CH2:4][CH:3]=[O:2])[C:9]2[C:10]([C:14]([O:16][CH3:17])=[O:15])=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=1
Reactant: COC(=O)c1cccc2nc(C(C)C)n(CC(OC)OC)c12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COC(=O)c1cccc2nc(C)n(CC=O)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
To a stirred solution of methyl 1-(2,2-dimethoxyethyl)-2-isopropyl-1H-benzo[d]imidazole-7-carboxylate from Step A above in methylene chloride were added water and trifluoroacetic acid and the reaction was stirred at room temperature for 2 h and then heated at reflux for 3.5 h. The reaction mixture was concentrated under reduced pressure to remove the excess trifluoroacetic acid, diluted with methylene chloride, washed with saturated aqueous sodium bicarbonate, re-extracted with methylene chloride, dried (Na2SO4), filtered, and concentrated under reduced pressure to give methyl 2-methyl-1-(2-oxoethyl)-1H-benzo[d]imidazole-7-carboxylate (0.4 g, 56%): 1H NMR (500 MHz, DMSO-d6) δ 9.70 (s, 1H), 7.81 (dd, J=8.0, 1.5 Hz, 1H), 7.67 (dd, J=7.5, 1.0 Hz, 1H), 7.25 (t, J=8.0 Hz, 1H), 5.38 (s, 2H), 3.84 (s, 3H), 2.47 (s, 3H); MS (ESI+) m/z 233 (M+H).
Reaction SMILES: I[CH:2]([CH3:4])[CH3:3].[CH:5]1([C:8]2[C:15]([CH:16]3[CH2:18][CH2:17]3)=[CH:14][C:11]([CH:12]=[O:13])=[C:10]([OH:19])[C:9]=2[F:20])[CH2:7][CH2:6]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH:5]1([C:8]2[C:15]([CH:16]3[CH2:18][CH2:17]3)=[CH:14][C:11]([CH:12]=[O:13])=[C:10]([O:19][CH:2]([CH3:4])[CH3:3])[C:9]=2[F:20])[CH2:6][CH2:7]1
Reactant: CC(C)I
Reactant: O=Cc1cc(C2CC2)c(C2CC2)c(F)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1c(C=O)cc(C2CC2)c(C2CC2)c1F
Reaction time: 2 h
Yield: 97.6 %

Procedure:
2-Iodopropane (862 mg) was added at room temperature to a mixture of 4,5-dicyclopropyl-3-fluoro-2-hydroxybenzaldehyde (744 mg), potassium carbonate (934 mg), and DMF (20 mL), and the mixture was stirred at 60 C for 2 hours in a nitrogen atmosphere. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The obtained organic layer was washed with water and saturated saline in this order and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (865 mg).
Reaction SMILES: [N:1]1([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25]([O:28]C)[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:12][CH2:11]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.B(Br)(Br)Br>C(Cl)Cl>[N:1]1([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25]([OH:28])[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:12][CH2:11]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cccc2[nH]c(C(=O)NC3CCN(CCN4CCCCCC4)CC3)cc12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(NC1CCN(CCN2CCCCCC2)CC1)c1cc2c(O)cccc2[nH]1
Reaction time: 18 h

Procedure:
The methoxy derivative from example 1 (100 mg, 0.25 mmol) is dissolved in 5 ml of DCM. A solution of BBr3 (1M in DCM, 2.5 ml, 2.5 mmol) is added and the mixture is stirred for 18 hours. It is then poured onto ice and washed with EtOAc (30 ml). The pH of the water layer is adjusted to 9 and extracted twice with EtOAc. The organic layers are combined washed with brine, dried over anhydrous sodium sulfate and evaporated.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([CH2:16][N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:8]=1[N:9]1[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]1)[NH2:5].Cl[C:24]1[C:33]2[C:28](=[CH:29][C:30]([Cl:34])=[CH:31][CH:32]=2)[N:27]=[CH:26][CH:25]=1.Cl>C(#N)C>[Cl:34][C:30]1[CH:29]=[C:28]2[C:33]([C:24]([NH:5][C:4]3[CH:6]=[C:7]([CH2:16][N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[C:8]([N:9]4[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]4)=[C:2]([CH3:1])[CH:3]=3)=[CH:25][CH:26]=[N:27]2)=[CH:32][CH:31]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: Cc1cc(N)cc(CN2CCOCC2)c1N1CCN(C)CC1
Agent: Cl
Solvent: CC#N
Product: Cc1cc(Nc2ccnc3cc(Cl)ccc23)cc(CN2CCOCC2)c1N1CCN(C)CC1
Yield: 61.9 %

Procedure:
3-Methyl-4-(4-methylpiperazin-1-yl)-5-(morpholin-4-ylmethyl)aniline (79 mg, 0.26 mmol) and 4,7-dichloroquinoline (56 mg, 1.1 eq) were refluxed overnight in 5 mL of acetonitrile with 0.78 mL of HCl 1M. The reaction mixture was then evaporated and purified by flash chromatography (DCM/MeOH/NH4OH//9/1/0.1) to yield expected compound as a pale yellow solid (75 mg, 62% yield). m/z (ESI) 466.4 [M+H]+.
Reaction SMILES: C(O[C:6]([N:8]([CH3:25])[CH:9]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[N:17]=[CH:16][CH:15]=2)[CH2:10]1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O.[F:33][C:34]1[CH:39]=[CH:38][C:37]([N:40]=C=O)=[CH:36][CH:35]=1.C(N(CC)CC)C>C(Cl)Cl>[F:33][C:34]1[CH:39]=[CH:38][C:37]([NH:40][C:6]([N:8]([CH3:25])[CH:9]2[CH2:13][CH2:12][N:11]([C:14]3[C:23]4[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=4)[N:17]=[CH:16][CH:15]=3)[CH2:10]2)=[O:7])=[CH:36][CH:35]=1
Reactant: CN(C(=O)OC(C)(C)C)C1CCN(c2ccnc3cc(Cl)ccc23)C1
Reactant: O=C=Nc1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)Nc1ccc(F)cc1)C1CCN(c2ccnc3cc(Cl)ccc23)C1

Procedure:
A solution of 4-[3-[tert-butoxycarbonyl(methyl)amino]pyrrolidin1-yl]-7-chloroquinoline (285 mg, 0.79 mmol) in CH2Cl2 (5 mL) is treated with trifluoroacetic acid (1 mL). After 1 h the reaction mixture is concentrated. The residue is dissolved in CH2Cl2 (10 mL), and 4-fluorophenyl isocyanate (90 μL, 0.79 mmol) and triethylamine (1 mL) are added. The reaction mixture is concentrated, and the residue is purified by column chromatography and an aqueous work-up step yielding the title product.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([C@H:9]([O:11][C:12](=[O:28])[NH:13][C:14]2[C:15]([CH2:26][CH3:27])=[N:16][O:17][C:18]=2[C:19]2[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=2)[CH3:10])[CH:6]=[CH:7][CH:8]=1.[CH2:31]([O:33][C:34]([C:36]1([C:39]2[CH:44]=[CH:43][C:42](B3OC(C)(C)C(C)(C)O3)=[CH:41][CH:40]=2)[CH2:38][CH2:37]1)=[O:35])[CH3:32]>>[CH2:31]([O:33][C:34]([C:36]1([C:39]2[CH:44]=[CH:43][C:42]([C:22]3[CH:23]=[CH:24][C:19]([C:18]4[O:17][N:16]=[C:15]([CH2:26][CH3:27])[C:14]=4[NH:13][C:12]([O:11][C@@H:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:30])([F:29])[F:1])[CH:4]=4)[CH3:10])=[O:28])=[CH:20][CH:21]=3)=[CH:41][CH:40]=2)[CH2:37][CH2:38]1)=[O:35])[CH3:32]
Reactant: CCc1noc(-c2ccc(Br)cc2)c1NC(=O)O[C@H](C)c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(CC)c4NC(=O)O[C@H](C)c4cccc(C(F)(F)F)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 6 using [5-(4-bromo-phenyl)-3-ethyl-isoxazol-4-yl]-carbamic acid (R)-1-(3-trifluoromethyl-phenyl)-ethyl ester and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][C:10]3=[N:12][N:13]=[C:14]([S:15][CH3:16])[N:9]3[CH:8]=[CH:7][C:6]=2[CH:17]=1.[Se](=O)=[O:19]>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:19])[C:10]3=[N:12][N:13]=[C:14]([S:15][CH3:16])[N:9]3[CH:8]=[CH:7][C:6]=2[CH:17]=1
Reactant: CSc1nnc2n1C=Cc1cc(C)ccc1C2
Reactant: O=[Se]=O
Product: CSc1nnc2c(=O)c3ccc(C)cc3ccn12

Procedure:
By a procedure similar to that described in Examples 13, the reaction of 8-methyl-3-methylthio-11H-s-triazolo[3,4-b][3]benzazepine with selenium dioxide gave 8-methyl-3-methylthio-11H-s-triazolo[3,4-b][3]benzazepin-11-one as crystals. Recrystallization from methanol yielded colorless platelets melting at 178°-179° C.
Reaction SMILES: I.[NH2:2][C:3]1[C:4]([C:11]([NH:13][C:14](=[NH:17])SC)=[O:12])=[N:5][C:6]([Cl:10])=[C:7]([NH2:9])[N:8]=1.C(N(CC)CC)C.[C:25]([O:29][C:30](=[O:48])[NH:31][CH2:32][CH2:33][NH:34][C:35](=[O:47])[C:36]1[CH:41]=[CH:40][C:39]([CH2:42][CH2:43][CH2:44][CH2:45][NH2:46])=[CH:38][CH:37]=1)([CH3:28])([CH3:27])[CH3:26]>CO>[C:25]([O:29][C:30](=[O:48])[NH:31][CH2:32][CH2:33][NH:34][C:35](=[O:47])[C:36]1[CH:41]=[CH:40][C:39]([CH2:42][CH2:43][CH2:44][CH2:45][NH:46][C:14]([NH2:17])=[N:13][C:11]([C:4]2[C:3]([NH2:2])=[N:8][C:7]([NH2:9])=[C:6]([Cl:10])[N:5]=2)=[O:12])=[CH:38][CH:37]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Reactant: CC(C)(C)OC(=O)NCCNC(=O)c1ccc(CCCCN)cc1
Agent: I
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCNC(=O)c1ccc(CCCCNC(N)=NC(=O)c2nc(Cl)c(N)nc2N)cc1
Reaction time: 2 h
Yield: 86.8 %

Procedure:
1-(3,5-Diamino-6-chloropyrazinoyl)-2-methylisothiourea hydriodide (0.32 g, 0.82 mmol) and triethylamine (0.27 mL, 1.64 mmol) were sequentially added into a solution of 33 (0.39 g, 0.82 mmol) in 5 mL of methanol. The reaction mixture was stirred in the boiling solvent for 2 h. The solvent was evaporated and the residue was separated by Flash™ (BIOTAGE, Inc) (90 g silica gel cartridge 40M, 6:1:0.1 chloroform/ethanol/concentrated ammonium hydroxide) to provide 34 (0.39 g, 62%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 1.07 (t, 2H), 1.38 (s, 9H), 1.52 (m, 2H), 1.65 (m, 2H), 2.66 (m, 2H), 3.10 (m, 2H), 3.28 (m, 2H), 4.39 (m, 1H), 6.65 (br s, 1H), 6.94 (m, 1H), 7.28 (m, 2H), 7.75 (d, 2H), 8.49 (m, 1H).
Reaction SMILES: O[CH2:2][C@H:3]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH:12]([CH3:16])[CH2:13][CH2:14][CH3:15])=[CH:6][CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:45]>O1CCCC1>[Br:45][CH2:2][C@H:3]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH:12]([CH3:16])[CH2:13][CH2:14][CH3:15])=[CH:6][CH:5]=1
Reactant: BrC(Br)(Br)Br
Reactant: CCCC(C)COc1ccc([C@H](CO)NC(=O)OC(C)(C)C)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCC(C)COc1ccc([C@H](CBr)NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
To a solution of t-butyl (1R)-2-hydroxy-1-(4-(2-methylpentyloxy)phenyl)ethylcarbamate (15 g, 44.5 mmol), prepared according to the procedure described in example 1, in anhydrous tetrahydrofuran (200 mL) was added triphenylphosphine (17.49 g, 66.7 mmol) and carbon tetrabromide (22.11 g, 66.7 mmol). The reaction mixture was stirred at room temperature for 2 h. The mixture was filtered through a pad of diatomaceous earth (Celite®) and the filtrate was concentrated to afford yellow residue which was purified by column chromatography on silica gel (20→30% ethyl acetate in hexanes) to afford t-butyl (1R)-2-bromo-1-(4-(2-methylpentyloxy)phenyl)ethylcarbamate (17.8 g, 100% yield) as a colorless solid: 1H NMR (400 MHz, CDCl3) δ 7.18 (d, J=8.8 Hz, 2H), 6.86 (d, J=8.6 Hz, 2H), 5.05 (br. s., 1H), 4.91 (br. s., 1H), 3.78 (dd, J=8.8, 5.8 Hz, 1H), 3.68 (dd, J=9.1, 6.8 Hz, 1H), 3.65 (d, J=5.0 Hz, 1H), 1.86-1.97 (m, 1H), 1.60 (d, J=7.3 Hz, 1H), 1.42 (s, 9H), 1.14-1.51 (m, 4H), 0.99 (d, J=6.5 Hz, 3H), 0.90 (t, J=7.3 Hz, 3H); LRMS (ESI) m/e 400.2 [(M+H)+, calcd for C19H31NO3Br 400.1].
Reaction SMILES: [CH3:1][S:2]([O-:5])(=O)=[O:3].[CH2:6]([C@@:9]1([CH3:35])[CH2:14][C@H:13]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([Cl:22])[CH:16]=2)[C@@H:12]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[N+:11]2[C@@H:30]([CH2:33][CH3:34])[CH2:31][O:32][C:10]1=2)[CH:7]=[CH2:8].CS(O)=O.[Na]>CC#N>[CH2:6]([C@@:9]1([CH3:35])[CH2:14][C@H:13]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([Cl:22])[CH:16]=2)[C@@H:12]([C:23]2[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=2)[N:11]([C@@H:30]([CH2:33][CH3:34])[CH2:31][S:2]([CH3:1])(=[O:5])=[O:3])[C:10]1=[O:32])[CH:7]=[CH2:8]
Reactant: CS(=O)(=O)[O-]
Reactant: C=CC[C@@]1(C)C[C@H](c2cc(F)cc(Cl)c2)[C@@H](c2ccc(Cl)cc2)[N+]2=C1OC[C@@H]2CC
Agent: CS(=O)O
Agent: [Na]
Solvent: CC#N
Product: C=CC[C@@]1(C)C[C@H](c2cc(F)cc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CS(C)(=O)=O)C1=O
Temperature: 114 °C
Reaction time: 48 h

Procedure:
To a solution of (3S,5S,6R,8S)-8-allyl-6-(3-chloro-5-fluorophenyl)-5-(4-chlorophenyl)-3-ethyl-8-methyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-ium methanesulfonate (Example 395, step A, 100 mg, 0.184 mmol) in MeCN (1.8 mL) was added methanesulfinic acid, sodium salt (56.5 mg, 0.553 mmol). The mixture was heated to 114° C. After heating for 24 hours, the mixture was cooled to room temperature and stirred for 2 days. The mixture was partitioned between EtOAc and aq. NH4Cl. The organic layer was washed with brine, dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by flash chromatography on silica gel (eluent: 20 to 60% EtOAc/hexanes, gradient elution) to afford the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:23]3=[CH:24][C:25]([CH2:26][OH:27])=[C:21]4[N:22]3[C:17](=[CH:18][CH:19]=[CH:20]4)[C:16]=2[CH2:28][CH3:29])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].CC(C)([O-])C.[K+].Cl.Cl[CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1>CN(C)C=O.O.C(O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:23]3=[CH:24][C:25]([CH2:26][O:27][CH2:40][CH2:41][N:42]4[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]4)=[C:21]4[N:22]3[C:17](=[CH:18][CH:19]=[CH:20]4)[C:16]=2[CH2:28][CH3:29])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCc1c(-c2ccc(OCc3ccccc3)cc2)c2cc(CO)c3cccc1n32
Reactant: ClCCN1CCCCC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [H-]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: O
Product: CCc1c(-c2ccc(OCc3ccccc3)cc2)c2cc(COCCN3CCCCC3)c3cccc1n32
Yield: 81.4 %

Procedure:
2-(4-Benzyloxyphenyl)-1-ethyl-4-hydroxymethylpyrrolo[2,1,5-cd]indolizine (0.88 g, 1.26 mmol) was dissolved in 40 ml of dry dimethylformamide under a nitrogen atmosphere. Sodium hydride (80% in oil) (0.24 g, 8.0 mmol) and potassium tert-butoxide (0.1 g, 0.9 mmol) was added in portions and stirring was continued for ten minutes. 1-(2-chloroethyl)piperidine hydrochloride (0.74 g, 4 mmol) was added, and the solution was stirred for four hours. Ethanol (10 ml) was added dropwise, and the reaction mixture was diluted with 200 ml of water. The organic material was extracted into toluene (3×50 ml), and the combined organic layers were dried over magnesium sulfate. The solvent was evaporated and the crude product was purified by column chromatography over silica gel 60, using 10% of methanol in dichloromethane as the eluent to afford 0.505 g (81%) of 2-(4-benzyloxyphenyl)-1-ethyl-4-((2-piperidinoethoxy)methyl)pyrrolo[2,1,5-cd]indolizine as a yellow oil. MS(SP): m/z 492 (M+). 1H-NMR (CDCl3, 300 MHz) δ: 1.35-1.50 (m, 5H); 1.68 (m, 4H); 2.63 (m, 4H); 2.76 (t, 2H); 3.23 (q, 2H); 3.79 (t, 2H); 5.01 (s, 2H); 5.12 (s, 2H); 7.13 (d, 2H); 7.30-7.50 (m, 5H); 7.52 (s, 1H); 7.62 (t, 1H); 7.70 (d, 2H); 7.88 (d, 1H); 7.97 (d, 1H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[NH:13]([C:15](=[O:28])[CH2:16][O:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1)[NH2:14]>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:14][NH:13][C:15](=[O:28])[CH2:16][O:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: COC(=O)c1ccc(OCC(=O)NN)cc1
Solvent: CC(=O)O
Product: COC(=O)c1ccc(OCC(=O)NN=C2C(=O)Nc3ccc(I)cc32)cc1
Temperature: 100 °C
Yield: 77 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added methyl 4-(2-hydrazino-2-oxoethoxy)benzoate. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 185 mg of the title compound (77%) as a yellow solid in 99.1% purity by HPLC (Rt: 5.34, gradient of 10 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C@H:7]([NH2:9])[CH3:8])=[CH:3][CH:2]=1.C([O:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][N:30]2[C:38]3[C:33](=[CH:34][C:35]([C:39](O)=[O:40])=[CH:36][CH:37]=3)[C:32]([CH3:42])=[C:31]2[CH3:43])=[CH:25][CH:24]=1)=[O:16])(C)(C)C>>[CH3:43][C:31]1[N:30]([CH2:29][C:26]2[CH:27]=[CH:28][C:23]([C:18]3[C:17]([C:15]([OH:16])=[O:14])=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:24][CH:25]=2)[C:38]2[C:33]([C:32]=1[CH3:42])=[CH:34][C:35]([C:39](=[O:40])[NH:9][C@@H:7]([C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)[CH3:8])=[CH:36][CH:37]=2
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: C[C@@H](N)c1ccncc1
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@H](C)c3ccncc3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (R)-1-(pyridin-4-yl)ethanamine and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 504 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([CH3:13])[CH:8]=[CH:9][C:10]=2[Cl:12])[N:5]=[C:4]([CH3:14])[CH:3]=1.[NH:15]1[CH:19]=[N:18][CH:17]=[N:16]1.S(=O)(=O)(O)O.[OH-].[NH4+]>O>[N:15]1([C:2]2[C:11]3[C:6](=[C:7]([CH3:13])[CH:8]=[CH:9][C:10]=3[Cl:12])[N:5]=[C:4]([CH3:14])[CH:3]=2)[CH:19]=[N:18][CH:17]=[N:16]1
Reactant: c1nc[nH]n1
Reactant: Cc1cc(Cl)c2c(Cl)ccc(C)c2n1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(-n2cncn2)c2c(Cl)ccc(C)c2n1
Temperature: 70 °C
Reaction time: 3 h
Yield: 77.3 %

Procedure:
A mixture of 2.26 g of 4,5-dichloro-2,8-dimethyl-quinoline, 1.38 g of 1,2,4-triazole and 0.1 g of 96% sulfuric acid is stirred at 70° C. for 3 hours. The reaction mixture is poured into 50 ml of water and neutralized with 1 ml of a concentrated ammonium hydroxide solution. The precipitated product is filtered and washed with water. Thus 2.0 g of the desired compound are obtained, yield 77.4%. Mp.: 117°-118° C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][C@@H:6]1[NH:11][CH2:10][CH2:9][N:8]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:7]1=[O:20])=[O:4].[CH2:21]([O:28][C:29]([NH:31][C@H:32]([C:34](O)=[O:35])[CH3:33])=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl.C(N=C=NCCCN(C)C)C.S([O-])(O)(=O)=O.[K+]>C(#N)C>[CH2:21]([O:28][C:29]([NH:31][C@@H:32]([CH3:33])[C:34]([N:11]1[CH2:10][CH2:9][N:8]([CH2:12][C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[C:7](=[O:20])[C@@H:6]1[CH2:5][C:3]([O:2][CH3:1])=[O:4])=[O:35])=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)C[C@@H]1NCCN(CC(=O)OC(C)(C)C)C1=O
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=S(=O)([O-])O
Solvent: CC#N
Product: COC(=O)C[C@H]1C(=O)N(CC(=O)OC(C)(C)C)CCN1C(=O)[C@H](C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 74.4 %

Procedure:
tert-Butyl (S)-(3-methoxycarbonylmethyl-2-oxo-piperazin-1-yl)acetate (3.0 g) and benzyloxycarbonyl-L-alanine (2.61 g) were dissolved in acetonitrile (40 ml). While stirring the solution at room temperature, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.45 g) was added to the solution, and the mixture was stirred for 3 hours at room temperature. The reaction mixture was poured into a 5% aqueous solution of potassium hydrogen sulfate and the solution was extracted with ethyl acetate, washed with a saturated aqueous solution of sodium hydrogen carbonate and dried over anhydrous magnesium sulfate (MgSO4). The solution was concentrated under reduced pressure. The residue was purified by means of a silica gel column chromatography (eluent:hexane:ethyl acetate=1:4) to give the titled compound (3.83 g) as a pale yellow amorphous powdery product.