Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][CH2:2]1.O=[C:6]1[CH2:23][CH2:22][C:9]2([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH2:8][CH2:7]1.[C-]#N.[K+].[C:27]1([Mg]Br)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CO.C(O)(=O)C.C1COCC1>[N:1]1([C:6]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:23][CH2:22][C:9]3([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]3)[CH2:8][CH2:7]2)[CH2:4][CH2:3][CH2:2]1
Reactant: Br[Mg]c1ccccc1
Reactant: C1CNC1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(=O)CC2)CC1
Agent: [C-]#N
Agent: [K+]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CCC(c1ccccc1)(N1CCC1)CC2
Temperature: 0 °C
Reaction time: 16 h
Yield: 22 %

Procedure:
Azetidine (29.9 mmol, 10 eq) was added to a solution of tert-butyl 9-oxo-3-azaspiro[5.5]undecane-3-carboxylate (2.99 mmol, 1 eq) in methanol (15 ml) and acetic acid (1.5 ml) at 0° C. Then potassium cyanide (7.47 mmol, 2.5 eq) was added to the reaction mixture and it was stirred for another 16 h. The reaction mixture was slowly quenched with NH4OH solution (50 g ice+50 ml ammonia liquor) and stirred at 0° C. for another 30 min. The mixture was extracted with ethyl acetate. The organic layer was washed with water (15 ml), saturated ferrous sulfate solution (15 ml) and brine (20 ml) successively, dried over Na2SO4 and concentrated under reduced pressure to give the crude product. A solution of the crude product (1.1 g) in THF (30 ml) was added to an ice-cold solution of phenyl magnesium bromide (5 eq., 1 M solution in THF) and the resulting reaction mixture was stirred at 25° C. for 16 h under a nitrogen atmosphere. The reaction mixture was quenched with saturated ammonia solution under ice-cold conditions and extracted with ethyl acetate. The organic layer was washed with water (10 ml) and brine (10 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (25% EtOH in hexanes) to yield the desired product. Yield: 22%
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[NH2:10][C@H:11]1[CH2:30][N:15]2[C:16]3[C:21]([C:22]([CH2:23][C:24]([O:26]CCC)=[O:25])=[C:14]2[CH2:13][CH2:12]1)=[CH:20][CH:19]=[CH:18][CH:17]=3.C([BH3-])#N.[Na+].[C:35]([OH:38])(=O)[CH3:36]>CO>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:10]([C:35](=[O:38])[CH2:36][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[C@H:11]2[CH2:30][N:15]3[C:16]4[C:21]([C:22]([CH2:23][C:24]([OH:26])=[O:25])=[C:14]3[CH2:13][CH2:12]2)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: O=Cc1ccc(F)cc1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](N)CC2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: O=C(O)Cc1c2n(c3ccccc13)C[C@H](N(Cc1ccc(F)cc1)C(=O)Cc1ccc(F)cc1)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Fluorobenzaldehyde (43.0 μL) was dissolved in MeOH (3.0 mL) and then propyl [(7R)-7-amino-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate (231 mg) in MeOH (2.0 mL), sodium cyanoborohydride (50.6 mg) and acetic acid (92.0 μL) were added. The reaction mixture was stirred for overnight at room temperature then quenched with NaOH (1N). The aqueous phase was extracted with EtOAc. The organic layers were washed with brine, dried over magnesium sulfate, filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate/hexanes). The resulting benzylamine (48.0 mg) was dissolved in DCM (2.0 mL) and then DMAP (0.743 mg), (4-fluorophenyl)acetyl chloride (32.8 mg) and triethylamine (17.0 μL) were added to the solution under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2 h then quenched with ½(sat.) aqueous ammonium chloride. DCM (4.0 mL) was added and the two phases were separated by using a phase separator. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate/hexanes) to give the title compound as a yellow oil. The resultant material was dissolved in THF (4.0 mL) and MeOH (2.0 mL) then NaOH (0.283 mL, 1N) were added to the solution. The reaction was stirred for 2.5 h at room temperature and then quenched with HCl (1N). DCM was added and the two phases were separated with a phase separator. The organic layers were evaporated under reduced pressure to provide the title compound._MS (+ESI) m/z: 489.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:5]2[C:6]=1[C:7](=[S:13])[NH:8]3.Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]1[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]2[C:21]1=[O:30].C(N(CC)CC)C>CN(C)C=O>[CH3:1][C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:5]2[C:6]=1[C:7]([S:13][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]1[C:21](=[O:30])[C:22]2=[CH:29][CH:28]=[CH:27][CH:26]=[C:23]2[C:24]1=[O:25])=[N:8]3
Reactant: Cc1nc2cccc3[nH]c(=S)c1n23
Reactant: O=C1c2ccccc2C(=O)N1CCCCCBr
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc2cccc3nc(SCCCCCN4C(=O)c5ccccc5C4=O)c1n23
Temperature: 100 °C
Reaction time: 2 h
Yield: 79.5 %

Procedure:
To a suspension of 2.03 g (10.7 mmol) of 1,2-dihydro-3-methyl-1,4,7b-triazacyclopent[cd]inden-2-thione in 50 ml of N,N-dimethylformamide were added 3.18 g (10.7 mmol) of N-(5-bromopentyl)phthalimide and 2.24 ml (16.1 mmol) of triethylamine. The mixture was stirred for two hours at 100° C. After cooling, the resulting precipitates were collected by filtration, washed with N,N-dimethylformamide, ethanol, and diethylether, successively, dried to afford 3.44 g of the desired compound (79.3%, a pale brown solid).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([CH3:9])[CH:3]=1.CN1CC(=O)OB(/[CH:20]=[CH:21]/[CH3:22])OC(=O)C1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>C(OCC)(=O)C.O.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>[CH3:9][C:4]1[CH:3]=[C:2](/[CH:20]=[CH:21]/[CH3:22])[N:7]=[C:6]([NH2:8])[CH:5]=1
Reactant: C/C=C/B1OC(=O)CN(C)CC(=O)O1
Reactant: Cc1cc(N)nc(Br)c1
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: C/C=C/c1cc(C)cc(N)n1
Temperature: 150 °C
Yield: 59.6 %

Procedure:
6-bromo-4-methylpyridin-2-amine (500 mg, 2.67 mmol), (E)-6-methyl-2-(prop-1-enyl)-1,3,6,2-dioxazaborocane-4,8-dione (1.05 g, 5.35 mmol), cesium carbonate (2.61 g, 8.02 mmol) and tetrakis(triphenylphosphine)palladium (0) (309 mg, 267 μmol) were combined with dioxane (7.4 mL and water (1.5 mL) and the mixture was heated to 150° C. for 60 min in the microwave. The reaction mixture was cooled and then diluted with ethyl acetate and water. The phases were separated and the organic phase was washed with water and brine. The organic phase was concentrated in vacuo and then purified by chromatography (silica, 20% to 60% ethyl acetate in hexanes) to give a residue that was triturated with methanol to obtain a yellow precipitate. This precipitate was collected by filtration and dried to give (E)-4-methyl-6-(prop-1-enyl)pyridin-2-amine (235 mg, 1.59 mmol, 59%) as a yellow oil. MS (EI/CI) m/z: 148.8 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]2[N:7]([CH3:26])[C:8](=[O:25])[N:9]([CH2:10][C@H:11]3[CH2:16][CH2:15][C@H:14]([C:17]([N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)=[O:18])[CH2:13][CH2:12]3)[C:5]=2[CH:4]=1.C(N(CC)CC)C.[C:36](Cl)(=[O:38])[CH3:37]>C(Cl)Cl>[C:36]([N:22]1[CH2:21][CH2:20][N:19]([C:17]([C@H:14]2[CH2:15][CH2:16][C@H:11]([CH2:10][N:9]3[C:5]4[CH:4]=[C:3]([O:2][CH3:1])[CH:28]=[CH:27][C:6]=4[N:7]([CH3:26])[C:8]3=[O:25])[CH2:12][CH2:13]2)=[O:18])[CH2:24][CH2:23]1)(=[O:38])[CH3:37]
Reactant: CC(=O)Cl
Reactant: COc1ccc2c(c1)n(C[C@H]1CC[C@H](C(=O)N3CCNCC3)CC1)c(=O)n2C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)n(C[C@H]1CC[C@H](C(=O)N3CCN(C(C)=O)CC3)CC1)c(=O)n2C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Methoxy-1-methyl-3-[trans-4-(piperazine-1-carbonyl)-cyclohexylmethyl]-1,3-dihydro-benzoimidazol-2-one (85 mg, 0.22 mmol) was dissolved in anhydrous DCM (4 ml). Triethyl amine (0.12 ml, 0.66 mmol) and acetyl chloride (0.02 ml, 0.26 mmol) were added and the mixture was stirred at room temperature overnight. The solution was washed with saturated NaHCO3 the organic phase was concentrated and the crude product purified on silica column using EtOAc as eluent to give the titled compound (60 mg, 64%).
Reaction SMILES: Br[C:2]1[C:3]([O:28][CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[C:4]([CH:10]([NH:12][C:13]2[N:21]=[CH:20][N:19]=[C:18]3[C:14]=2[N:15]=[CH:16][N:17]3C2CCCCO2)[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].[CH3:37][S:38]([C:41]1[CH:46]=[CH:45][C:44](B(O)O)=[CH:43][CH:42]=1)(=[O:40])=[O:39].C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])[O-].[K+].[K+]>>[Cl:9][C:6]1[CH:5]=[C:4]([CH:10]([NH:12][C:13]2[N:21]=[CH:20][N:19]=[C:18]3[C:14]=2[N:15]=[CH:16][NH:17]3)[CH3:11])[C:3]([O:28][CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[C:2]([C:44]2[CH:45]=[CH:46][C:41]([S:38]([CH3:37])(=[O:40])=[O:39])=[CH:42][CH:43]=2)[C:7]=1[CH3:8]
Reactant: Cc1c(Cl)cc(C(C)Nc2ncnc3c2ncn3C2CCCCO2)c(OCCN2CCOCC2)c1Br
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Product: Cc1c(Cl)cc(C(C)Nc2ncnc3[nH]cnc23)c(OCCN2CCOCC2)c1-c1ccc(S(C)(=O)=O)cc1
Yield: 27 %

Procedure:
The desired compound was prepared according to the procedure of Example 125, step D, using N-{1-[3-bromo-5-chloro-4-methyl-2-(2-morpholin-4-ylethoxy)phenyl]ethyl}-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine, [4-(methylsulfonyl)phenyl]boronic acid, and sodium carbonate (instead of potassium carbonate) as the starting materials in 27% yield. LCMS for C27H32ClN6O4S (M+H)+: m/z=571.2. Found: 571.3; 1H NMR (400 MHz, DMSO-d6): δ 12.9 (s, 1H), 8.17-8.07 (m, 3H), 8.00 (d, J=7.9 Hz, 2H), 7.67 (s, 1H), 7.64 (d, J=7.2 Hz, 1H), 7.55 (d, J=7.4 Hz, 1H), 5.80 (s, 1H), 4.15-3.84 (m, 1H), 3.42-3.37 (m, 4H), 3.28 (s, 3H), 2.32-2.25 (m, 2H), 2.17-2.12 (m, 2H), 2.08-2.00 (m, 2H), 1.98 (s, 3H), 1.50 (d, J=6.9 Hz, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[OH:14])[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2].[C:15](OC)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1.[H-].[Na+].C(O)(=O)C>O1CCOCC1.O>[OH:14][C:13]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[C:1]([CH2:2][C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1)=[O:3]
Reactant: COC(=O)c1cccnc1
Reactant: COC(=O)c1ccc(O)c(C(C)=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1ccc(O)c(C(=O)CC(=O)c2cccnc2)c1
Reaction time: 6 h
Yield: 69.8 %

Procedure:
A solution consisting of methyl 3-acetyl-4-hydroxy-benzoate (16 g) and methyl nicotinate (23 g) in dioxane (100 ml) was slowly added at room temperature under stirring to a suspension of sodium hydride 50% (12 g) in dioxane (60 ml). The solution was kept for 6 hours at 80° C, then cooled, diluted with petroleum ether (200 ml), and filtered. The product obtained was dissolved in water and treated with acetic acid; the precipitate obtained was washed with water and crystallised with methylene chloride/methanol to give (2-hydroxy-5-carbomethoxy-benzoyl)-nicotinoylmethane (17.2 g; m.p. 200°-202° C) which was then treated with ethanol (300 ml) containing concentrated hydrochloric acid 1% at reflux temperature for 2 hours. After concentration under vacuum, dilution with water, neutralisation with sodium acetate, the precipitate was filtered. The raw 6-carbomethoxy-2-(3'-pyridyl)-chromone (15.1 g) was hydrolysed with the stoichiometric quantity of potassium hydroxide 1% in ethanol 95% at reflux temperature for an hour. After cooling, dilution with water (600 ml), neutralisation with acetic acid, the precipitate was collected, to obtain, after crystallisation from dimethylformamide, 6-carboxy-2-(3'-pyridyl)-chromone (9.8 g; m.p. > 350° C); I.R. (KBr): νC=O (carboxy) 1680 cm-1, νC=O (chromone) 1630 cm-1, 1610 cm-1, γC-H (meta-substituted pyridine) 770 cm-1, 696 cm-1.
Reaction SMILES: [C:1]1([C@H:7]2[CH2:11][O:10][C:9](=[O:12])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[CH3:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23]([CH2:28][CH2:29][C:30](O)=[O:31])=[CH:22]2.CC(C)(C)C(Cl)=O.C[N+]1(C)[C@H]2CC3C=CC(O)=C4O[C@H]5[C@@H](O)C=C[C@@H]2[C@]5(C=34)CC1>C1COCC1>[CH3:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23]([CH2:28][CH2:29][C:30]([N:8]1[C@@H:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:11][O:10][C:9]1=[O:12])=[O:31])=[CH:22]2
Reactant: O=C1N[C@@H](c2ccccc2)CO1
Reactant: Cc1ccc2[nH]c(CCC(=O)O)cc2c1
Agent: CC(C)(C)C(=O)Cl
Agent: C[N+]1(C)CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@@H]1C5
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc2[nH]c(CCC(=O)N3C(=O)OC[C@@H]3c3ccccc3)cc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
To the suspension of (4S)-4-phenyl-1,3-oxazolidin-2-one (6.85 g, 42 mmol) in anhydrous THF (130 mL) was added BuLi (26.3 mL, 42 mmol) at −78° C. and the mixture was stirred under argon (0.5 h). To the above suspension was added a solution of active ester prepared by reacting 3-(5-methylindolyl)propanoic acid 7 (10.23 g, 50.39 mmol) in anhydrous THF (130 mL) and trimethylacetyl chloride (5.10 g, 50.39 mmol) in the presence of N-methyl morphine (6.06 g, 50.39 mmol) at 0° C. under argon, followed by stirring at −78° C. (1 h). The combined reaction mixture was stirred at −78° C. for an additional 2 h, then the solution was warmed to room temperature and stirred overnight. The reaction was quenched by the addition of ice-cold saturated NH4Cl solution (120 mL), extracted with EtOAc, washed with brine and dried (Na2SO4). Evaporation provided a residue, which was purified by silica gel flash chromatography to provide 8 as colorless oil. (12.7 g, 87% yield). 1H NMR (d6-DMSO) δ 7.36-7.23 (m, 8H), 6.94 (dd, 1H, J=1.5 Hz & 8.5 Hz), 6.28 (dd, 1H, J=0.8 Hz & 3.1 Hz), 5.43: (dd, 1H, J=3.5 Hz & 8.6 Hz), 4.70 (t, 1H, J=8.8), 4.40 (s, 1H), 4.40-4.37 (m, 2H), 4.15 (dd, 1H, J=3.5 Hz & 8.8 Hz), 3.41-3.30 (m, 2H), 2.36 (s, 3H). FABMS (+Ve) m/z 348 [M+], 349 [MH+]. Anal. Calcd for C21H20N2O3 C, 72.40; H, 5.79; N, 8.04. Found C, 72.33; H, 5.77; N, 8.15.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH2:11][CH2:12][OH:13].C[S:15](Cl)(=[O:17])=[O:16].N1C=CC=C[CH:20]=1>>[CH3:20][O:16][S:15](=[O:17])[O:13][CH2:12][CH2:11][NH:10][C:2]1[O:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: c1ccncc1
Reactant: OCCNc1nc2ccccc2o1
Product: COS(=O)OCCNc1nc2ccccc2o1
Temperature: 25 °C

Procedure:
2-(Benzooxazol-2-ylamino)-ethanol [compound of Step II] (9.76 g, 55 mmol) was taken in dry pyridine (40 mL) and to this solution, methanesulfonyl chloride (4.6 mL, 60 mmol) was added under stirring at room temperature. The reaction mixture was stirred for 15 hours, then diluted with ice water and extracted with dichloromethane (3×200 mL). The dichloromethane layer was washed with water and brine, dried over anhydrous sodium sulfate and was concentrated to give a crude material (18 g). The crude material obtained was purified using a silica gel column and 80% ethyl acetate in petroleum ether to yield sulfurous acid 2-(benzooxazol-2-ylamino)-ethyl ester methyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[NH2:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:12]([NH2:14])=[O:13])=[CH:7][C:8]=1[C:9]([NH:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1)=[O:11]
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Reactant: Nc1ccc2ccccc2n1
Product: COc1ccc(C(N)=O)cc1C(=O)Nc1ccc2ccccc2n1

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and 2-aminoquinoline by the same procedure as in the manufacturing method described in step C of Example 1-3-1.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([NH:17][C:18](=[O:20])[CH3:19])=[N:14][C:13]=2[CH3:21])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[Na+].[CH3:23][S:24]([O-:26])=[O:25].FC1C=C(C=CC=1S(C)(=O)=O)C=O>>[CH3:23][S:24]([C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([NH:17][C:18](=[O:20])[CH3:19])=[N:14][C:13]=2[CH3:21])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9])(=[O:26])=[O:25]
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)c(F)c2)s1
Reactant: CS(=O)[O-]
Agent: CS(=O)(=O)c1ccc(C=O)cc1F
Agent: [Na+]
Product: CC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)c(S(C)(=O)=O)c2)s1

Procedure:
This is isolated as a minor by product in the synthesis of N-[5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 64) when excess methane sulfinic acid sodium salt is added in the first step of the synthesis (64a). The resulting aldehyde is converted into the title compound by the procedure described in parts 64b-d.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C:11]1[CH:20]=[C:19]2[C:14]([CH2:15][CH2:16][NH:17][CH2:18]2)=[CH:13][CH:12]=1)=[O:10].[C:21]1([CH2:27][CH2:28][N:29]=[C:30]=[O:31])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.C(N(CC)CC)C>[C:21]1([CH2:27][CH2:28][NH:29][C:30]([N:17]2[CH2:16][CH2:15][C:14]3[C:19](=[CH:20][C:11]([C:9]([NH:8][O:7][CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)=[O:10])=[CH:12][CH:13]=3)[CH2:18]2)=[O:31])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(NOC1CCCCO1)c1ccc2c(c1)CNCC2
Reactant: O=C=NCCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(NOC1CCCCO1)c1ccc2c(c1)CN(C(=O)NCCc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.9 %

Procedure:
A mixture of 200 mg N-(tetrahydro-2H-pyran-2-yloxy)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide, 117 mg phenylethyl-isocyanat, 98 mg HOBt, 278 mg EDC, 0.6 ml triethylamine and 8 ml DMF is stirred overnight at ambient temperature. The mixture is evaporated. The residue is purified by silica gel flash chromatography. 208 mg of the title compound are obtained after drying as colorless foam.
Reaction SMILES: CN.[Br:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[C:13]([CH3:16])([CH3:15])[CH3:14])[C:7]([OH:9])=O.O[N:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2N=N1.[CH3:27][N:28]([CH3:37])[CH2:29][CH2:30]CN=C=NCC>CN(C)C=O>[CH3:27][N:28]1[CH2:29][CH2:30][C:25]2[C:24](=[CH:23][C:22]([NH:18][C:7](=[O:9])[C:6]3[CH:10]=[CH:11][C:12]([C:13]([CH3:16])([CH3:15])[CH3:14])=[C:4]([Br:3])[CH:5]=3)=[CH:21][CH:26]=2)[CH2:37]1
Reactant: On1nnc2ccccc21
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)c1ccc(C(=O)O)cc1Br
Agent: CN
Solvent: CN(C)C=O
Product: CN1CCc2ccc(NC(=O)c3ccc(C(C)(C)C)c(Br)c3)cc2C1
Reaction time: 48 h
Yield: 92.9 %

Procedure:
A solution of the amine D5 (162 mg; 1.0 mmol) and 3-bromo-4-tert-butylbenzoic acid (257 mg; 1.0 mmol) in anhydrous N,N-dimethylformamide (7 ml), was treated with 1-hydroxybenzotriazole (135 mg; 1.0 mmol) and 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (192 mg; 1.0 mmol) at 25° C. The mixture was shaken for 48 h before extracting the product into dichloromethane and washing with 10% aqueous NaHCO3, water and finally brine. The organic layer was dried over MgSO4 and evaporated in vacuo to afford 373 mg of the title compound in 93% yield.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].[CH:13]1[CH:14]=[CH:15][N:16]2[C:21]=1[CH:20]=[CH:19][CH:18]=[CH:17]2.C(OCC)(=O)C.O>ClCCl>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([C:15]1[N:16]2[C:21]([CH:20]=[CH:19][CH:18]=[CH:17]2)=[CH:13][CH:14]=1)=[O:8])([O-:3])=[O:2]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: c1ccn2cccc2c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: O=C(c1cccc([N+](=O)[O-])c1)c1ccc2ccccn12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.9 %

Procedure:
A mixture of 3-nitrobenzoyl chloride (4.50 g) and indolizine (2.84 g) in dichloromethane (30 ml) was stirred at room temperature for 30 minutes. The reaction mixture was poured into a mixture of ethyl acetate and water. The organic phase was separated, washed with brine, dried over magnesium sulfate and concentrated. The resultant solid was collected and washed with ethyl acetate to give 3-(3-nitrobenzoyl)indolizine (4.51 g).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[Mg+].[C:25]([O:31][CH2:32][CH3:33])(=[O:30])[CH2:26]C([O-])=O.Cl>O1CCCC1.O.C(OCC)(=O)C>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](=[O:6])[CH2:26][C:25]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: O=C(O)c1ccc(F)cc1F
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Mg+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CC(=O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 124 %

Procedure:
To a solution of 2,4-difluorobenzoic acid (10 g, 63.3 mmol) in tetrahydrofuran (150 ml) was added 1,1′-carbonylbis-1H-imidazole (11.3 g, 69.6 mmol) and the mixture was stirred at room temperature for 30 min. Monoethyl malonate magnesium salt (10 g, 34.8 mmol) was added to the reaction solution and the mixture was stirred at room temperature for 2 hrs. To the reaction solution were added ethyl acetate (50 ml) and water (50 ml), and conc. hydrochloric acid was added until the aqueous layer showed acidic pH. The reaction solution was extracted with ethyl acetate (200 ml×2). The extract-was washed with saturated brine, dried-over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give ethyl 3-(2,4-difluorophenyl)-3-oxopropionate (9.85 g, 74%) as a brown oil.
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:30]=[CH:29][C:10]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25](Br)[CH:26]=4)[CH2:21][CH2:20]3)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1.CN(C)[CH:33]=[O:34].[Cl-].[NH4+]>CCCCCC.O1CCCC1.C(OCC)(=O)C>[F:6][C:7]1[CH:30]=[CH:29][C:10]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([CH:33]=[O:34])[CH:26]=4)[CH2:21][CH2:20]3)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1
Reactant: CN(C)C=O
Reactant: Fc1ccc(CCN2CCC(N3CCc4ccc(Br)cc43)CC2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=Cc1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Reaction time: 0.17 h

Procedure:
A 2.5 M solution (50 ml) of n-butyllithium in hexane was added dropwise at −78° C. into a solution of 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-bromoindoline (40 g) in tetrahydrofuran (1 l) over 10 min. After 10 min, dimethylformamide (11.6 ml) was added thereto and the resultant mixture was warmed to room temperature. Next, a saturated aqueous solution of ammonium chloride (200 ml) and ethyl acetate (500 ml) were added thereto and the layers were separated. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the crude title compound (37.5 g). A portion of this crude product was purified by silica gel column chromatography (ethyl acetate/ethanol system) to give the title compound as a yellow powder.