Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=12.[C:11]([NH:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1)(=[O:13])[CH3:12].C([O-])([O-])=O.[K+].[K+].O>C1(C)C=CC=CC=1.CO.CCO.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[N:4]1[N:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]2=[C:2]([C:19]2[CH:20]=[C:15]([NH:14][C:11](=[O:13])[CH3:12])[CH:16]=[CH:17][CH:18]=2)[CH:3]=1
Reactant: Brc1cnn2ccccc12
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(=O)Nc1cccc(-c2cnn3ccccc23)c1
Temperature: 155 °C
Yield: 19.9 %

Procedure:
A mixture of 3-bromo-pyrazolo[1,5-a]pyridine (197 mg, 1 mmol), (3-acetylaminophenyl)boronic acid (179 mg), K2CO3 (6 eq) and bis(tri-t-butylphosphine)palladium (0) (5 mg) in PhMe (1 ml), MeOH (1 ml), EtOH (1 ml), and H2O (1.8 ml) was stirred and heated at 155° C. in the microwave for 30 minutes. The mixture was partitioned between EtOAc/H2O. The layers were separated and the organic layer was dried, filtered and evaporated. The residue was crystallised from MeOH to give the title compound (50 mg). MS: [M+H]+ 252
Reaction SMILES: C[O:2][C:3]([CH2:5][NH:6][C:7]([C:9]1[C:10]2[CH2:11][C:12]3[N:17]4[CH:18]=[CH:19][N:20]=[C:16]4[C:15](=[O:21])[NH:14][C:13]=3[C:22]=2[CH:23]=[CH:24][CH:25]=1)=[O:8])=[O:4].Cl>O1CCOCC1>[O:21]=[C:15]1[NH:14][C:13]2[C:22]3[CH:23]=[CH:24][CH:25]=[C:9]([C:7]([NH:6][CH2:5][C:3]([OH:4])=[O:2])=[O:8])[C:10]=3[CH2:11][C:12]=2[N:17]2[CH:18]=[CH:19][N:20]=[C:16]12
Reactant: COC(=O)CNC(=O)c1cccc2c1Cc1c-2[nH]c(=O)c2nccn12
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)CNC(=O)c1cccc2c1Cc1c-2[nH]c(=O)c2nccn12
Yield: 83.5 %

Procedure:
A mixture of 1 g 9-(methoxycarbonylmethylcarbamoyl)-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one, 50 ml of dioxane and 15 ml of concentrated hydrochloric acid is heated at reflux for 24 hours. The reaction mixture is concentrated on a rotary evaporator, ethyl ether is added to the evaporation residue and filtration is carried out. The solid obtained is triturated in 20 ml of distilled water, filtered, washed with distilled water (20 ml) and then with ethyl ether and dried at 60° C. under vacuum (1 mm Hg; 0.13 kPa). 0.8 g of N-[(4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-9-yl)carbonyl]glycine is obtained in the form of a yellow solid containing 0.66 mol of hydrochloric acid and melting above 260° C. (Analysis; % Calculated C: 55.13, H: 3.66, Cl: 6.78, N: 16.07, O: 18.36; % Found C: 55.1, H: 3.6, Cl: 6.2, N: 15.8, O: 18.3).
Reaction SMILES: [F:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=[O:14])[NH:6]2.N1CCCCC1.[CH3:21][O:22][C:23]1[CH:27]=[CH:26][NH:25][C:24]=1[CH:28]=O.C(OCC)(=O)C>CC(O)C.O>[F:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:28]/[C:24]1[NH:25][CH:26]=[CH:27][C:23]=1[O:22][CH3:21])/[C:5](=[O:14])[NH:6]2
Reactant: O=C1Cc2c(ccc([N+](=O)[O-])c2F)N1
Reactant: COc1cc[nH]c1C=O
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCNCC1
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(F)c21
Temperature: 0 °C

Procedure:
1,3-Dihydro-4-fluoro-5-nitro-2H-indol-2-one (5.25 g, 26.8 mmol) (Starting Material 9) was suspended in 110 mL solution of 1.35% piperidine in 2-propanol (Aldrich). 3-Methoxy-2-pyrrolecarboxaldehyde (3.68 g, 29.4 mmol, 1.1 eq.)(Bellamy, supra) was added and this mixture heated at 60° C. for 3.5 hours (TLC: 50% ethyl acetate in hexanes). The reaction mixture was poured into 1 L ice and water mixture and the solid precipitate filtered, washed with water and dried at 50° C. under high vacuum to give (Z)-1,3-dihydro-4-fluoro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5-nitro-2H-indol-2-one as an orange-brown solid. (Yield 6.6 g, 81%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([F:12])[C:9](B2OC(C)(C)C(C)(C)O2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Br[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.C(=O)([O-])[O-].[K+].[K+].O>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:11]=[C:10]([F:12])[C:9]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: Brc1ccccn1
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(F)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(-c2ccccn2)c(F)cc1Cl
Temperature: 25 °C
Yield: 67.1 %

Procedure:
To a solution of methyl 2-chloro-4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (212 mmol) in THF (400 mL), was added 2-bromopyridine (33.4 g, 211 mmol), potassium carbonate (117 g, 848 mmol) and water (64 mL). The mixture was degassed with argon for 30 minutes. To this mixture was added tetrakis(triphenylphosphine)palladium (12.2 g, 10.6 mmol) and the mixture heated at reflux for 1.5 h. The mixture was cooled to room temperature and filtered through Celite, washing with EtOAc (1.2 L) and water (800 mL). The filtrate was diluted with saturated aqueous brine solution (200 mL) and the aqueous layer separated and extracted with EtOAc (600 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography over silica gel, eluting with EtOAc:hexane (3:17 to 1:4) and concentrated in vacuo to a slurry, which was diluted with heptane (100 mL) and cooled to 0° C. The solid was collected by filtration to afford the title compound (37.6 g, 67%).
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([O:13][CH:14]([F:16])[F:15])=[C:9]([F:12])[CH:10]=2)[N:5]([CH:17]2[CH2:20][CH2:19][CH2:18]2)[C:4]=1[C:21]1[N:26]=[CH:25][C:24]([S:27]([NH:30][C@@H:31]([CH3:36])[C:32]([F:35])([F:34])[F:33])(=[O:29])=[O:28])=[CH:23][CH:22]=1)#[N:2].[Br:37]Br.OS([O-])=O.[Na+]>[Fe].ClCCCl>[Br:37][C:10]1[C:9]([F:12])=[C:8]([O:13][CH:14]([F:15])[F:16])[CH:7]=[C:6]2[C:11]=1[C:3]([C:1]#[N:2])=[C:4]([C:21]1[N:26]=[CH:25][C:24]([S:27]([NH:30][C@@H:31]([CH3:36])[C:32]([F:34])([F:35])[F:33])(=[O:28])=[O:29])=[CH:23][CH:22]=1)[N:5]2[CH:17]1[CH2:18][CH2:19][CH2:20]1
Reactant: C[C@H](NS(=O)(=O)c1ccc(-c2c(C#N)c3cc(F)c(OC(F)F)cc3n2C2CCC2)nc1)C(F)(F)F
Reactant: BrBr
Agent: [Fe]
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: C[C@H](NS(=O)(=O)c1ccc(-c2c(C#N)c3c(Br)c(F)c(OC(F)F)cc3n2C2CCC2)nc1)C(F)(F)F
Temperature: 50 °C
Yield: 46.3 %

Procedure:
A mixture of (S)-6-(3-cyano-1-cyclobutyl-6-(difluoromethoxy)-5-fluoro-1H-indol-2-yl)-N-(1,1,1-trifluoropropan-2-yl)pyridine-3-sulfonamide (500 mg, 0.94 mmol), Fe powder (700 mg, 13 mmol), Br2 (300 μL, 5.9 mmol), and 1,2-dichloroethane (3 mL) was heated at 50° C. for 3 hours. The reaction mixture was then poured into aq. NaHSO3 solution. This was extracted into CH2Cl2. The organic layer was dried over MgSO4 and filtered, and the filtrate was concentrated under vacuum. Purification by silica gel chromatography (ethyl acetate in hexanes, 20% to 30%) yielded (S)-6-(4-bromo-3-cyano-1-cyclobutyl-6 (difluoromethoxy)-5-fluoro-1H-indol-2-yl)-N-(1,1,1-trifluoropropan-2-yl)pyridine-3-sulfonamide (266 mg, 46%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([C:27]2[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=2)[C:6]=1[C:7]1[C:8](=[O:26])[N:9]([CH3:25])[C:10](=[O:24])[N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[C:12]=1[CH3:13].C(N(CC)C(C)C)(C)C.O.[C:45]([O:48]CC)(=[O:47])C>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:31]([C:30]1[CH:33]=[CH:34][C:27]([N:5]2[C:6]([C:7]3[C:8](=[O:26])[N:9]([CH3:25])[C:10](=[O:24])[N:11]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=4)[C:12]=3[CH3:13])=[C:2]([C:45]([OH:48])=[O:47])[CH:3]=[N:4]2)=[CH:28][CH:29]=1)#[N:32]
Reactant: Cc1c(-c2c(Br)cnn2-c2ccc(C#N)cc2)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: CCOC(C)=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: O
Product: Cc1c(-c2c(C(=O)O)cnn2-c2ccc(C#N)cc2)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
To a solution of 4-(4-bromo-5-(3,6-dimethyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile (prepared in Example 93) (139.8 mg) in 1,4-dioxane (2.0 ml) were added tetrakis(triphenylphosphine)palladium (30.7 mg),N,N-diisopropylethylamine (46.8 μl) and water (0.5 ml) and the resulting mixture was stirred at 100° C. under carbon monoxide atmosphere for four hours. To the reaction mixture was added ethyl acetate (100 ml) and the mixture was washed with 1M hydrochloric acid (30 ml) and saturated saline (30 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol) to afford 1-(4-cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-carboxylic acid (24.5 mg) as brown solid.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@@H:9]([C:16]([O:18][CH3:19])=[O:17])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[O:7])([CH3:4])[CH3:3].[Li+].[CH3:21][Si]([N-][Si](C)(C)C)(C)C.CI>C(=O)=O.CC(C)=O.C1COCC1>[CH3:4][C:2]([O:5][C:6]([NH:8][C@@H:9]([C:16]([O:18][CH3:19])=[O:17])[CH2:10][C@@H:11]([CH3:21])[C:12]([O:14][CH3:15])=[O:13])=[O:7])([CH3:1])[CH3:3]
Reactant: COC(=O)CC[C@@H](NC(=O)OC(C)(C)C)C(=O)OC
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C=O
Agent: [Li+]
Solvent: CI
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: COC(=O)[C@H](C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)OC
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Into a 250 mL RB flask was added dimethyl N-{[(1,1-dimethylethyl)oxy]carbonyl}-D-glutamate (4 g, 14.53 mmol) and cool in Dry Ice/Aceton −78° C. bath. By cannulation was added by drop wise 1M LiHMDS in THF (30.5 mL, 30.5 mmol. After addition the mixture was let stir at −78° C. for 0.5 hours. Then methyl iodide (1.817 mL, 29.1 mmol) was added as rapidly as possible, and the solution was stirred at −78° C. for 4.5 hours. The reaction was then quenched with 1N HCl solution (40 mL), and extracted with EtOAc (3×50 mL). The organics were combined and washed with saturated NaHCO3, brine, then dried over Na2SO4 and concentrated to give a red amber color oil. The oil was then purified on a Biotage SNAP 50 g column with a gradient of 0 to 35% gradient EtOAc in Hexane over 35 minutes. The fractions with product were combined to isolate the title compound (1.37 g) as a clear oil. 1H NMR (400 MHz, DMSO-d6): δ 1.08 (d, J=7.1 Hz, 3H), 1.38 (s, 9H), 1.71 (ddd, J=13.6, 8.3, 5.1 Hz, 1H), 1.94 (ddd, J=13.9, 10.1, 6.1 Hz, 1H), 2.43-2.49 (m, 1H), 3.60 (s, 3H), 3.62 (s, 3H), 4.01 (ddd, J=9.9, 8.4, 5.2 Hz, 1H), 7.29 (d, J=8.3 Hz, 1H).
Reaction SMILES: [CH:1]1([CH:7]([N:11]2[C:15]3[CH:16]=[C:17]([F:21])[C:18]([F:20])=[CH:19][C:14]=3[N:13]=[C:12]2[C@@H:22]([O:29][CH3:30])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:8](O)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.S(Cl)(Cl)=O.[NH2:41][C:42]1[CH:52]=[CH:51][C:45]([C:46]([O:48][CH2:49][CH3:50])=[O:47])=[CH:44][CH:43]=1>ClCCl>[CH2:49]([O:48][C:46](=[O:47])[C:45]1[CH:51]=[CH:52][C:42]([NH:41][C:8](=[O:9])[CH:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[N:11]2[C:15]3[CH:16]=[C:17]([F:21])[C:18]([F:20])=[CH:19][C:14]=3[N:13]=[C:12]2[C@@H:22]([O:29][CH3:30])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:43][CH:44]=1)[CH3:50]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CO[C@@H](c1ccccc1)c1nc2cc(F)c(F)cc2n1C(C(=O)O)C1CCCCC1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)c1ccc(NC(=O)C(C2CCCCC2)n2c([C@@H](OC)c3ccccc3)nc3cc(F)c(F)cc32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of cyclohexyl-[5,6-difluoro-2-((S)-methoxy-phenyl-methyl)-benzoimidazol-1-yl]-acetic acid (160 mg, 0.39 mmol, 1.0 equiv.) in dichloromethane (2 ml) was added pyridine (0.046 ml, 1.5 equiv.). Thionyl chloride (0.034 ml, 1.2 eq) was added dropwise. The mixture was stirred 1 h at room temperature. A solution of ethyl 4-amino-benzoate (64 mg, 0.95 equiv., [CAS RN 94-09-7]) and pyridine (0.031 ml, 1.1 equiv.) in dichloromethane (2 ml) was added and the mixture stirred overnight at room temperature. The mixture was applied to a 5 g silica gel column (Biotage) and the product eluted with EtOAc to afford the title compound as an orange solid that was used without further purification. MS (ISP): 562.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]([OH:12])=O)[CH:7]([CH3:9])[CH3:8])=[O:4].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[CH3:34][N:35]1[CH2:40][CH2:39][N:38]([C:41]2[CH:46]=[CH:45][C:44]([CH2:47][N:48]([NH:61][C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[CH2:49][C@H:50]([OH:60])[C@@H:51]([NH2:59])[CH2:52][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)=[CH:43][CH:42]=2)[CH2:37][CH2:36]1>CN(C=O)C>[CH3:34][N:35]1[CH2:36][CH2:37][N:38]([C:41]2[CH:46]=[CH:45][C:44]([CH2:47][N:48]([NH:61][C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[CH2:49][C@H:50]([OH:60])[C@@H:51]([NH:59][C:10](=[O:12])[C@H:6]([CH:7]([CH3:8])[CH3:9])[NH:5][C:3]([O:2][CH3:1])=[O:4])[CH2:52][C:53]3[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=3)=[CH:43][CH:42]=2)[CH2:39][CH2:40]1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: CN1CCN(c2ccc(CN(C[C@H](O)[C@@H](N)Cc3ccccc3)NC(=O)OC(C)(C)C)cc2)CC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(Cc1ccc(N2CCN(C)CC2)cc1)NC(=O)OC(C)(C)C)C(C)C
Reaction time: 0.33 h

Procedure:
1.60 g (9.16 mmol) of N-methoxycarbonyl-(L)-valine, 3.29 g (17.16 mmol) of EDC and 1.54 g (11.4 mmol) of HOBT are dissolved, under a N2 atmosphere, in 49 ml of DMF. After 20 min at RT, 4.8 ml (34.4 mmol) of triethylamine are added. 2.77 g (5.7 mmol) of 1-[p-(4-methylpiperazin-1-yl)phenyl]-4(S)-hydroxy-2-(tert-butyloxycarbonyl)amino-5(S)-amino-6-phenyl-2-azahexane in 24 ml of DMF are then added and the whole is thoroughly stirred overnight. The reaction mixture is evaporated under HV and the residue is dissolved in methylene chloride and a little methanol; this solution is then washed with sat. NaHCO3 solution, water and brine. The aqueous phases are extracted twice with methylene chloride. The combined organic phases are dried (Na2SO4) and concentrated by evaporation. Precipitating with DIPE from a concentrated solution in boiling methylene chloride results in the title compound:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=2[C:13]([NH2:15])=[O:14])(=[O:10])=[O:9])=[CH:4][C:3]=1[CH3:20].[F:21][C:22]1[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/B(O)O)=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:2]2[CH:7]=[CH:6][C:5]([S:8]([C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13]([NH2:15])=[O:14])(=[O:10])=[O:9])=[CH:4][C:3]=2[CH3:20])=[CH:24][CH:23]=1
Reactant: OB(O)/C=C/c1ccc(F)cc1
Reactant: Cc1cc(S(=O)(=O)c2ccccc2C(N)=O)ccc1Br
Product: Cc1cc(S(=O)(=O)c2ccccc2C(N)=O)ccc1/C=C/c1ccc(F)cc1

Procedure:
The title compound was prepared from 2-[(4-bromo-3-methylphenyl)sulfonyl]benzamide (Step 1) and [(E)-2-(4-fluorophenyl)vinyl]boronic acid according to the method of Example 1 Step 4. m/z (ES+) 379 [(M−NH2)+].
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C:10]([CH2:14][N:15]([CH3:17])[CH3:16])([OH:13])[CH2:9]1)C1C=CC=CC=1>CO.[Pd]>[CH3:16][N:15]([CH2:14][C:10]1([OH:13])[CH2:11][CH2:12][NH:8][CH2:9]1)[CH3:17]
Reactant: CN(C)CC1(O)CCN(Cc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CN(C)CC1(O)CCNC1

Procedure:
9.4 g (39 mmol) of 1-benzyl-3-dimethylaminomethyl-3-hydroxypyrrolidine in 60 ml of methanol are hydrogenated using 2 g of palladium/active carbon (5%) at 100°C. and 90 bar. The catalyst is filtered off, the filtrate is concentrated and the residue is distilled.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[C:8]([F:13])[CH:7]=1.C(N(CC)CC)C.C(OCC)(=O)C>O1CCCC1.C(O)C>[Cl:5][C:6]1[CH:12]=[CH:11][C:9]([NH:10][C:1](=[O:3])[CH3:2])=[C:8]([F:13])[CH:7]=1
Reactant: Nc1ccc(Cl)cc1F
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acetyl chloride (24.2 mL, 0.34 mol) is added slowly to a solution of 4-chloro-2-fluoroaniline (49.4 g, 0.34 mol), and triethylamine (47 mL, 0.34 mol) in tetrahydrofuran while maintaining the reaction mixture temperature below 20° C. After the addition is complete, the reaction mixture is stirred overnight at room temperature, and poured into ethyl acetate. The organic solution is washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain an off-white solid. A mixture of the solid in ethanol is stirred for several minutes, and filtered to give the tilte product as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.Cl.Cl.[CH2:13]([CH:15]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[CH2:16][CH3:17])[CH3:14].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.[OH-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:21]2[CH2:22][CH2:23][N:18]([CH:15]([CH2:16][CH3:17])[CH2:13][CH3:14])[CH2:19][CH2:20]2)=[O:8])=[CH:9][CH:10]=1
Reactant: CCC(CC)N1CCNCC1
Reactant: O=C(O)c1ccc(Br)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CN1CCOCC1
Product: CCC(CC)N1CCN(C(=O)c2ccc(Br)cc2)CC1
Yield: 74.7 %

Procedure:
To a solution of 4-bromobenzoic acid (500 mg) and the product of Example 7 (710 mg) in DCM (20 mL) was added 1-{3-(dimethylamino) propyl}-3-ethylcarbodiimide hydrochloride (713 mg), 1-hydroxybenzotriazole hydrate (570 mg), and N-methyl morpholine (1.64 mL). After 16 h the reaction mixture was treated with 1 N NaOH (25 mL) and extracted with DCM (3×75 mL). The organic layers were dried (Na2SO4), concentrated, and chromatographed on silica gel (1-3% 2 M methanolic ammonia/DCM) to give the title compound as white-yellow solid (630 mg).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10](O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(C1C=CC(C)=CC=1)([O-])(=O)=O.[F-:25].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([F:25])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [F-]
Reactant: O[C@@H]1CCN(Cc2ccccc2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: O
Solvent: C1CCOC1
Product: F[C@H]1CCN(Cc2ccccc2)C1
Reaction time: 1.5 h
Yield: 71 %

Procedure:
To a solution of (R)-1-benzyl-3-pyrrolidinol-tosylate (3.06 g, 9.24 mmol) in THF (30 ml) was added 1.0M solution of tetrabutylammonium fluoride in THF (37.0 ml, 37.0 mmol) at room temperature. After 1.5 h stirring at reflux temperature water (150 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate (100 ml×2). The combined extract was washed with water, brine, dried (Na2SO4), and concentrated to give brown oil, which was purified by column chromatography (silica gel: 80 g, CH2Cl2/MeOH:50/1) to afford 1.18 g (71%) of brown oil.
Reaction SMILES: [CH2:1]([O:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].Br[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1>>[CH:11]1([CH2:10][O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Reactant: C=CCCCCCCOCC1CCCCC1
Product: O=[N+]([O-])c1ccc(CCCCCCCCOCC2CCCCC2)cc1
Yield: 48 %

Procedure:
General procedure M was used to convert 4.56 mmol of 11c and 5.02 mmol of 1-bromo-4-nitrobenzene to 2.19 mmol (48%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:10][CH:11]1[NH:13][CH2:12]1>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([CH3:8])[CH:7]=1)[O:9][CH2:10][CH:11]([NH2:13])[CH3:12]
Reactant: CC1CN1
Reactant: Cc1cc(C)cc(O)c1
Solvent: ClC(Cl)Cl
Product: Cc1cc(C)cc(OCC(C)N)c1
Reaction time: 3 h
Yield: 32.5 %

Procedure:
The reaction according to the method described in a known literature [J. Am. Chem. Soc., 73 2584 (1951)] was carried out by the use of the same starting materials as those used in Example 17. That is, 24.4 g (0.20 mol) of 3,5-dimethylphenol was dissolved in 100 ml of chloroform, and the resultant mixture was refluxed under atmospheric pressure. A solution prepared by dissolving 3.8 g (0.067 mol) of propyleneimine in 20 ml of chloroform was added dropwise over 30 minutes, and the refluxing was further continued for 3 hours. The reaction product was subjected to extraction with 50 ml of 5% hydrochloric acid three times, and then the water layer of the product was neutralized with sodium hydroxide. The water layer was subjected to extraction with 50 ml of ether three times. The ether layer was washed with water and dried. Then, ether was distilled off, and the residue was distilled under reduced pressure to give 3.9 g of 1-(3,5-dimethylphenoxy)- 2-propylamine. Its yield was as low as 33%.
Reaction SMILES: [CH:1]1([C:4]2[C:15]3[O:14][C:11]4([CH2:13][CH2:12]4)[CH2:10][C:9]([CH3:17])([CH3:16])[C:8]=3[CH:7]=[C:6]([C:18]#[C:19][Si](C)(C)C)[CH:5]=2)[CH2:3][CH2:2]1.CO.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CCCCCC>[CH:1]1([C:4]2[C:15]3[O:14][C:11]4([CH2:13][CH2:12]4)[CH2:10][C:9]([CH3:16])([CH3:17])[C:8]=3[CH:7]=[C:6]([C:18]#[CH:19])[CH:5]=2)[CH2:3][CH2:2]1
Reactant: CC1(C)CC2(CC2)Oc2c(C3CC3)cc(C#C[Si](C)(C)C)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CO
Product: C#Cc1cc(C2CC2)c2c(c1)C(C)(C)CC1(CC1)O2

Procedure:
Following general procedure E, and 8-cyclopropyl-3,4-dihydro-4,4-dimethyl-6-(trimethylsilanyl)ethynylspiro[2H-1-benzopyran-2,1′-cyclopropane] (Intermediate 43, 0.62 g, 1.9 mmol), methanol and potassium carbonate (0.5 g, 3.6 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 1-2% ethyl acetate in hexane as the eluent, the title compound was obtained as an oil (0.5 g, 100%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:9])([CH3:8])[S:6](=[O:11])(=[O:10])[CH2:5][C@@:4]([CH2:19][F:20])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[N:3]=1.S(=O)(=O)(O)O.[N+:26]([O-])([O-:28])=[O:27].[K+].[OH-].[NH4+]>O>[NH2:1][C:2]1[C:7]([CH3:9])([CH3:8])[S:6](=[O:11])(=[O:10])[CH2:5][C@:4]([C:12]2[CH:17]=[C:16]([N+:26]([O-:28])=[O:27])[CH:15]=[CH:14][C:13]=2[F:18])([CH2:19][F:20])[N:3]=1
Reactant: O=[N+]([O-])[O-]
Reactant: CC1(C)C(N)=N[C@](CF)(c2ccccc2F)CS1(=O)=O
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [NH4+]
Solvent: O
Product: CC1(C)C(N)=N[C@](CF)(c2cc([N+](=O)[O-])ccc2F)CS1(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101.4 %

Procedure:
To a solution of (S)-5-amino-3-(fluoromethyl)-3-(2-fluorophenyl)-6,6-dimethyl-3,6-dihydro-2H-1,4-thiazine 1,1-dioxide (1.98 g, 6.55 mmol) in sulfuric acid (8.73 mL, 0.16 mol) at 0° C. was added potassium nitrate (0.69 g, 6.88 mmol) portion wise. When the addition was completed, the reaction mixture was allowed to warm to room temperature and the mixture was stirred at room temperature for 30 min. The reaction mixture was carefully poured over ice-water (100 mL) and neutralized by the addition of aqueous ammonium hydroxide. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated under vacuum to give the title compound (2.27 g, 6.64 mmol) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.43 (dd, J=3.03, 6.75 Hz, 1H), 8.25 (td, J=3.55, 8.95 Hz, 1H), 7.51 (dd, J=9.00, 11.35 Hz, 1H), 6.58 (br. s., 2H), 4.59 (q, J=8.80 Hz, 1H), 4.48 (q, J=8.80 Hz, 1H), 3.68-3.87 (m, 2H), 1.61 (s, 3H), 1.47 (s, 3H). LC/MS (ESI+) m/z=348 (M+H).