Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7](O)[CH2:8][C:9]#[C:10][CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:13]([C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1)([O-:15])=[O:14].[F:24][C:25]([F:35])([F:34])[S:26]([O:29][Si](C)(C)C)(=[O:28])=[O:27].C([O-])(O)=O.[Na+]>C(Cl)Cl.C(OCC)C>[F:24][C:25]([F:35])([F:34])[S:26]([O:29]/[C:10](=[C:9]1/[C@H:20]([C:19]2[CH:18]=[CH:17][C:16]([N+:13]([O-:15])=[O:14])=[CH:23][CH:22]=2)[O:21][C@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8]/1)/[CH3:11])(=[O:28])=[O:27]
Reactant: CC#CCC(O)c1ccccc1
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: C/C(OS(=O)(=O)C(F)(F)F)=C1/C[C@@H](c2ccccc2)O[C@H]1c1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 22.6 %

Procedure:
1-Phenylpent-3-yn-1-ol (50 mg, 0.31 mmol) and 4-nitrobenzaldehyde (0.057 mg, 0.37 mmol) were dissolved in methylene chloride (3.0 mL). After the temperature was lowered to −78° C., trimethylsilyl trifluoromethanesulfonate (TMSOTf) (170 mL, 0.93 mmol) was added, and the solution was stirred for one hour at the same temperature. The temperature was slowly elevated to room temperature for about 3 hours, and the solution was further stirred for another one hour at room temperature. The solution was added with an aqueous NaHCO3 solution and diluted with diethylether. The organic layer was washed with water and brine, dried with MgSO4, filtered and condensed. A pure target compound (31 mg) was obtained with a yield of 77% by using column chromatography.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]4[CH:17]([C:5]=3[C:4]=2[CH:3]=1)[CH2:16][CH2:15][CH2:14]4.P([O-])([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O.Br[CH:35]=[C:36]([C:38]1[CH:39]=[CH:40][C:41]([CH3:44])=[N:42][CH:43]=1)[CH3:37]>CN(C=O)C>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH:35]=[C:36]([C:38]3[CH:43]=[N:42][C:41]([CH3:44])=[CH:40][CH:39]=3)[CH3:37])[C:6]3[CH2:11][CH2:12][N:13]4[CH:17]([C:5]=3[C:4]=2[CH:3]=1)[CH2:16][CH2:15][CH2:14]4
Reactant: CC(=CBr)c1ccc(C)nc1
Reactant: Cc1ccc2[nH]c3c(c2c1)C1CCCN1CC3
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=Cn1c2c(c3cc(C)ccc31)C1CCCN1CC2)c1ccc(C)nc1
Temperature: 120 °C
Reaction time: 18 h

Procedure:
To a degassed solution of 10-methyl-2,3,5,6,7,11c-hexahydro-1H-indolizino[7,8-b]indole (50 mg, 0.22 mmol), potassium phosphate (93 mg, 0.44 mmol), L-proline (2 mg, 0.01 mmol) and Cu(I)iodide (8 mg, 0.04 mmol) in DMF (1 mL) was added 5-(1-bromoprop-1-en-2-yl)-2-methylpyridine (93 mg, 0.44 mmol). The reaction mixture was stirred at 120° C. for 18 h. The progress of reaction was monitored by TLC and LCMS. The reaction mixture was filtered through Celite and the filtrate was diluted with water (50 mL), extracted with EtOAc (2×50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase HPLC to yield 10-methyl-7-(2-(6-methylpyridin-3-yl)prop-1-enyl)-2,3,5,6,7,11c-hexahydro-1H-indolizino[7,8-b]indole. 1H NMR, (CD3OD, formate salt) δ (ppm): 8.65 (s, 1H), 8.0 (d, 1H), 7.4 (d, 1H), 7.35 (s, 1H), 7.15 (d, 1H), 7.08 (d, 2H), 5.0 (t, 1H), 3.6 (m, 3H), 3.4 (m, 1H), 3.09 (q, 2H), 2.85 (m, 1H), 2.6 (s, 3H), 2.42 (s, 3H), 2.2 (m, 3H), 2.0 (s, 3H). Chiral HPLC provided the enantiomers 193a and 193b.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][C:9]=1[NH:10][CH:11]1[CH2:13][CH2:12]1)=[O:4].N#N.[Cl:22][C:23]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26]>ClC(Cl)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][C:9]=1[N:10]([CH:11]1[CH2:13][CH2:12]1)[C:25](=[O:26])[C:24]1[CH:28]=[CH:29][C:30]([Cl:32])=[CH:31][C:23]=1[Cl:22])=[O:4]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: COC(=O)c1sc(-c2ccccc2)cc1NC1CC1
Agent: N#N
Solvent: CC(Cl)Cl
Product: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)c1ccc(Cl)cc1Cl)C1CC1
Reaction time: 16 h
Yield: 100.2 %

Procedure:
To a solution of 3-Cyclopropylamino-5-phenyl-thiophene-2-carboxylic acid methyl ester (52 mg, 0.19 mmol) in dichloroethane (10 ml) in an atmosphere of N2 was added 2,4-dichlorobenzoyl chloride (45 mg, 0.21 mmol). The reaction mixture was stirred for 16 h at reflux. Then, the solvent was removed and the residue was purified by flash chromatography (8:2 Hexane/EtOAc) to obtain 85 mg (99%) of 3-[Cyclopropyl-(2,4-dichloro-benzoyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester. NMR 1H (CDCl3, 400 MHz): 7.64 ppm (d, 2H, Haro); 7.47 ppm (m, 2H, Haro); 7.44-7.33 ppm (m, 3H, Haro); 7.21-7.12 ppm (m, 2H, Haro); 3.89 ppm (s, 3H); 3.33 ppm (m, minor rotamer); 3.13 ppm (m, 1H, major rotamer) 1.01-0.49 ppm (m, 4H).
Reaction SMILES: [CH3:1][N:2]([CH3:24])[CH2:3][CH2:4][CH2:5][NH:6][C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[S:12][C:11]=2[C:10]([CH:22]=O)=[CH:9][CH:8]=1.C(O)=O.[OH-].[Na+].[CH:30]([NH2:32])=[O:31]>O>[CH3:24][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][NH:6][C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[S:12][C:11]=2[C:10]([CH2:22][NH:32][CH:30]=[O:31])=[CH:9][CH:8]=1
Reactant: NC=O
Reactant: CN(C)CCCNc1ccc(C=O)c2sc3ccccc3c(=O)c12
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Solvent: O
Product: CN(C)CCCNc1ccc(CNC=O)c2sc3ccccc3c(=O)c12
Reaction time: 8 h
Yield: 79.4 %

Procedure:
A solution of 1-[[3-(dimethylamino)propyl]amino]-9-oxothioxanthen-4-carboxaldehyde (3.6 g; 10.57 mmol) in 50 mL of formamide containing 3.6 g of formic acid was refluxed for 1.5 h and then was allowed to stand at room temperature overnight. The reaction mixture was diluted with water (400 ml), basified with 3 mL of 5N NaOH solution, stirred rapidly for 30 rain, and the precipitated solid was filtered, washed with water, and dried, yielding 3.1 g (79%) of N-[[1-[[3-(dimethylamino)propyl]amino]-9-oxothioxanthen-4-yl]methyl]formamide (Formula I: R1 =R2 =Me; Q=CH2NHCHO; R8 =H; n=3), as a yellow powder.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=O)[CH3:2].[CH3:10][O:11][C:12]1[C:13]([NH2:18])=[CH:14][CH:15]=[CH:16][CH:17]=1.C1C=CC=CC=1>O>[CH3:2][C:1](=[N:18][C:13]1[C:12](=[CH:17][CH:16]=[CH:15][CH:14]=1)[O:11][CH3:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COc1ccccc1N
Reactant: CC(=O)c1ccccc1
Solvent: c1ccccc1
Solvent: O
Product: COc1ccccc1N=C(C)c1ccccc1

Procedure:
A solution of acetophenone (120 ml), o-anisidine (123 ml), benzene (100 ml) was refluxed with continuous removal of water. The crude product was purified by crystallizing it from ethanol to give N-(αmethyl benzylidene)-o-anisidine (IX) (90 C). It was then hydrogenated using 5% Pd/C as the catalyst and 95% ethanol as the solvent to give N-(α-methyl benzyl)-o-anisidine (X). X had a boiling point of 117° C. at 0.3 millimeter.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([NH2:15])=[O:14].O.[C:17]1(C)[CH:22]=CC(S(O)(=O)=O)=C[CH:18]=1.CC(C)=O>C1(C)C=CC=CC=1>[CH3:18][C:17]1([CH3:22])[NH:1][C:2]2[CH:6]=[C:5]([C:7]3[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=3)[S:4][C:3]=2[C:13](=[O:14])[NH:15]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: NC(=O)c1sc(-c2ccncc2)cc1N
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)NC(=O)c2sc(-c3ccncc3)cc2N1
Yield: 190.7 %

Procedure:
A mixture of 3-amino-5-(pyridin-4-yl)thiophene-2-carboxamide (150 mg, 0.68 mmol), p-toluenesulfonic acid monohydrate (50 mg) and acetone (10 mL) in toluene (20 mL) was heated to reflux overnight. After removal of the solvent, the residue was purified by column chromatography on silica gel (MeOH: dichloromethane=1:9) to afford the title compound (130 mg, yield 74%) as an orange solid:
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][CH:6]([CH:10]([CH3:12])[CH3:11])[C:7]([OH:9])=O)=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:37]([O:39][C:40]([CH:42]1[CH2:49][C:45]2([CH2:48][CH2:47][CH2:46]2)[O:44][NH:43]1)=[O:41])[CH3:38].C(N(C(C)C)CC)(C)C>CN(C)C=O.C(OCC)(=O)C>[CH2:37]([O:39][C:40]([CH:42]1[CH2:49][C:45]2([CH2:46][CH2:47][CH2:48]2)[O:44][N:43]1[C:7](=[O:9])[CH:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])[CH:10]([CH3:12])[CH3:11])=[O:41])[CH3:38]
Reactant: CCOC(=O)C1CC2(CCC2)ON1
Reactant: COC(=O)NC(C(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CC2(CCC2)ON1C(=O)C(NC(=O)OC)C(C)C
Temperature: 60 °C
Yield: 72.2 %

Procedure:
To a solution of 2-methoxycarbonylamino-3-methyl-butyric acid (1.11 g, 6.33 mmol) and HATU (2.41 g, 6.34 mmol) in dimethylformamide (13 mL) was added a solution of 5-oxa-6-aza-spiro[3.4]octane-7-carboxylic acid ethyl ester (980 mg, 5.3 mmol) in dimethylformamide (13 mL). To the resulting reaction mixture was added diisopropylethylamine (1.85 mL, 10.6 mmol) and the reaction was heated to 60° C. for 16 hours. The reaction was diluted with ethyl acetate, washed with water and brine, dried (MgSO4) and concentrated. The resulting residue was purified by flash chromatography to give 6-(2-methoxycarbonylamino-3-methyl-butyryl)-5-oxa-6-aza-spiro[3.4]octane-7-carboxylic acid ethyl ester (1.31 g, 72%). LCMS-ESI+: calculated for C16H26N2O6: 342.18; observed [M+1]+: 342.90.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([Cl:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:13])[C:3]=1[CH3:14].[Br:15][C:16]1[CH:17]=[CH:18][C:19]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[C:20]([NH2:22])[CH:21]=1.Cl.O1CCOCC1>CO>[Br:15][C:16]1[CH:17]=[CH:18][C:19]([N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)=[C:20]([NH:22][C:2]2[C:11]3[C:6](=[C:7]([Cl:12])[CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([CH3:13])[C:3]=2[CH3:14])[CH:21]=1
Reactant: Cc1nc2c(Cl)cccc2c(Cl)c1C
Reactant: Nc1cc(Br)ccc1N1CCOCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1nc2c(Cl)cccc2c(Nc2cc(Br)ccc2N2CCOCC2)c1C

Procedure:
Prepared according to Procedure K, Method 1 using 4,8-dichloro-2,3-dimethylquinoline (104 mg, 460 μmol), 5-bromo-2-morpholinobenzenamine (118 mg, 460 μmol) and 4N hydrochloric acid solution in dioxane (0.050 mL, 200 μmol) in MeOH (1.00 mL) to afford a colorless solid upon purification by chromatography on silica gel, eluting with a Et2O gradient in toluene. 1H NMR (400 MHz, chloroform-d) δ ppm 7.69 (1H, dd, J=7.4, 1.2 Hz), 7.55-7.63 (1H, m), 7.23-7.30 (1H, m), 6.92-6.98 (1H, m), 6.85-6.92 (1H, m), 6.83 (1H, s), 6.18 (1H, d, J=2.3 Hz), 3.80-3.91 (4H, m), 2.92-3.08 (4H, m), 2.71-2.78 (3H, m), 2.23 (3H, s).
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5](=[O:31])[C@@H:6]([O:11][C@H:12]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:13]1[CH:18]=[CH:17][C:16]([C:19]#[C:20][Si](C)(C)C)=[CH:15][CH:14]=1)[CH2:7][CH:8]([CH3:10])[CH3:9])#[N:2].CO>C1COCC1.CC(O)=O.[Na]>[C:1]([CH2:3][NH:4][C:5](=[O:31])[C@@H:6]([O:11][C@@H:12]([C:13]1[CH:18]=[CH:17][C:16]([C:19]#[CH:20])=[CH:15][CH:14]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:7][CH:8]([CH3:10])[CH3:9])#[N:2]
Reactant: CC(C)C[C@H](O[C@H](c1ccccc1)c1ccc(C#C[Si](C)(C)C)cc1)C(=O)NCC#N
Agent: [Na]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: C#Cc1ccc([C@H](O[C@@H](CC(C)C)C(=O)NCC#N)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of (2S)-N-(cyanomethyl)-4-methyl-2-[((R)-phenyl{4-[(trimethylsilyl)ethynyl]phenyl}methyl)oxy]pentanamide from example 70 (0.12 mmol, 50 mg) in THF:MeOH (1.3 mL: 50 uL) at 0° C., AcOH (3 drops) was added followed by tetrabutylammonium triphenyldifluorosilicate (0.01 mmol, 7 mg). The mixture was stirred 20 minutes at 0° C. The mixture was diluted with 1% sodium hydroxyde (3 mL) and diethlyl ether (5 mL). The phases were separated. The organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure. Purification: 30:70 (AcOEt:Hex.) gave the title amide.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([C@H:15]3[CH2:17][C@H:16]3[CH2:18][O:19][CH2:20][C:21]3[CH:29]=[CH:28][C:24]([C:25]([NH2:27])=[O:26])=[CH:23][CH:22]=3)[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2].NO.CC(O)=O.CO[CH:38](OC)[N:39](C)C>O1CCOCC1>[CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([C@H:15]3[CH2:17][C@H:16]3[CH2:18][O:19][CH2:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]4[O:26][N:39]=[CH:38][N:27]=4)=[CH:28][CH:29]=3)[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2]
Reactant: COC(OC)N(C)C
Reactant: CCc1cnc(N2CCC([C@H]3C[C@H]3COCc3ccc(C(N)=O)cc3)CC2)nc1
Agent: NO
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CCc1cnc(N2CCC([C@H]3C[C@H]3COCc3ccc(-c4ncno4)cc3)CC2)nc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of the product of step B (80 mg, 0.203 mmol) in N,N-dimethylformamide dimethyl acetal (2 mL) was stirred at 120° C. for 4 h. Upon cooling to RT, the solvent was removed under vacuum to leave a residue. The resulting residue was dissolved in 1,4-dioxane (1 mL) followed by the addition of NH2OH (0.016 mL of 50% solution in H2O, 0.243 mmol) and HOAc (0.5 mL). The reaction was stirred at 90° C. for 4 h before being cooled to RT. The reaction was quenched with a saturated aqueous solution of NaHCO3 and the layer was extracted with EtOAc (×3). The combined organic layers were washed with brine (1×), dried over MgSO4, filtered, and concentrated under vacuum to leave a residue which was purified by silica gel column chromatography (elution with 5:1 hexane:ethyl acetate) to give the title compound. MS (ESI) m/z 420 [M+H]+. GPR119 Human EC50: 5.5 nM
Reaction SMILES: I[CH2:2][Cl:3].C[O:5][C:6](=O)[C@@H:7]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([F:16])[CH:10]=1.[Li+].CC([N-]C(C)C)C.C([Li])CCC>C1COCC1>[Cl:3][CH2:2][C:6](=[O:5])[C@@H:7]([NH:17][C:18](=[O:19])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])[CH2:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([F:16])[CH:10]=1
Reactant: ClCI
Reactant: COC(=O)[C@H](Cc1cc(F)cc(F)c1)NC(=O)OC(C)(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)C(=O)CCl
Reaction time: 0.5 h

Procedure:
ICH2Cl (3.54 g, 1.46 mL, 19.82 mmol, 1.25 equivalent) and THF (5 mL) are added to (2S)-2-[(tert-butoxycarbonyl)amino]-3-(3,5-difluorophenyl)propanoic acid methyl ester (II, EXAMPLE 1, 5 g, 15.86 mmol, 1 equivalent). The mixture is cooled to −78° and LDA (22.3 mL, 44.60 mmol, 2.25 equivalents, 2.0M) is added dropwise maintaining an internal temperature below −60°. Once the addition is complete, the contents are stirred for 30 min at −78° at which time n-butyllithium (15.3 mL, 19.82 mmol, 1.25 equivalents; 1.3M in hexanes) is added dropwise maintaining an internal temperature below about −60°. The reaction is stirred for 30 min then quenched into 0° hydrochloric acid (IN). Ethyl acetate is added and the phases are separated and the aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with saturated sodium bicarbonate, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound, NMR (DMSO-d6) δ 7.47, 7.06-7.14, 4.78, 4.49, 3.20, 2.82 and 1.40; CMR (DMSO-d6) δ 200.87, 163.74, 161.20, 142.74, 112.80, 102.13, 79.04, 58.97, 47.72, 34.95 and 28.30.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[O:6]1[C:10]2[CH2:11][N:12]([C:15](=[O:27])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:13][CH2:14][C:9]=2[CH:8]=[CH:7]1.O.CN(C)[CH:31]=[O:32]>>[CH:31]([C:7]1[O:6][C:10]2[CH2:11][N:12]([C:15](=[O:27])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:13][CH2:14][C:9]=2[CH:8]=1)=[O:32]
Reactant: CN(C)C=O
Reactant: O=C(CCCCCc1ccccc1)N1CCc2ccoc2C1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: O=Cc1cc2c(o1)CN(C(=O)CCCCCc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 30 ml of N,N-dimethylformamide, 0.33 ml (3.6 mmol) of phosphorus oxychloride was added under ice-cooling, followed by stirring at room temperature for 0.5 hours. To this mixture, a solution of 1.064 g (3.578 mmol) of 1-(5,7-dihydro-4H-furo[2,3-c]pyridin-6-yl)-6-phenylhexan-1-one in 20 ml of N,N-dimethylformamide was added, followed by overnight stirring at room temperature. After water was added, the reaction mixture was extracted with ethyl acetate 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel flush column chromatography (hexane/ethyl acetate=2/1 to 1/1) to yield the desired product.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]([CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:18][CH:17]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5])[CH3:2].[H-].[Na+].[Br:29][C:30]1[C:35]([CH2:36]Br)=[C:34]([O:38][CH3:39])[C:33]([O:40][CH3:41])=[C:32]([O:42][CH3:43])[C:31]=1[O:44][CH3:45]>CN(C=O)C.O>[Br:29][C:30]1[C:31]([O:44][CH3:45])=[C:32]([O:42][CH3:43])[C:33]([O:40][CH3:41])=[C:34]([O:38][CH3:39])[C:35]=1[CH2:36][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:21]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOC(=O)c1ccc(OCCCC(C(=O)OCC)C(=O)OCC)cc1
Reactant: COc1c(Br)c(CBr)c(OC)c(OC)c1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(OCCCC(Cc2c(Br)c(OC)c(OC)c(OC)c2OC)(C(=O)OCC)C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.9 %

Procedure:
To a solution of ethyl 2-ethoxycarbonyl-5-(4-ethoxycarbonylphenoxy)pentanoate (25.9 g) in DMF (200 ml) was portionwise added sodium hydride (60% oil dispersion, 3.11 g) with cooling with ice. The reaction mixture was allowed to warm to room temperature and stirred for 30 min. To the reaction mixture was dropwise added a solution of 1-bromo-6-bromomethyl-2,3,4,5-tetramethoxybenzene (28.8 g) in DMF (50 ml) with cooling with ice. The reaction mixture was allowed to warm to room temperature and stirred for 6 hr. The reaction mixture was diluted with water and extracted with diethyl ether. The organic layer was washed with water and saturated aqueous sodium chloride and dried. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography (hexane to hexane:ethyl acetate=7:1) to yield the entitled compound (42.6 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[CH2:10][C:11](=[O:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][C:11](=[O:13])[CH3:12])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)COc1ccc(Cl)cc1

Procedure:
A suspension of 4-chlorophenol (2.6 g, 20 mmol), chloroacetone (2.8 g, 30 mmol) and potassium carbonate (3.45 g, 25 mmol) in acetone (100 ml) is heated at reflux for 3 hours. The precipitating inorganic salts are filtered off and the filtrate is evaporated to dryness to give the 1-(4-chlorophenoxy)-propan-2-one.
Reaction SMILES: [CH2:1]([N:4]([CH2:8][C:9]1[S:13][C:12]([S:14](Cl)(=[O:16])=[O:15])=[CH:11][CH:10]=1)[CH2:5][CH:6]=[CH2:7])[CH:2]=[CH2:3].CCN(C(C)C)C(C)C.[CH3:27][O:28][C:29](=[O:36])[CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>C(Cl)(Cl)Cl.C(Cl)Cl>[CH2:1]([N:4]([CH2:8][C:9]1[S:13][C:12]([S:14]([N:33]2[CH2:34][CH2:35][CH:30]([C:29]([O:28][CH3:27])=[O:36])[CH2:31][CH2:32]2)(=[O:16])=[O:15])=[CH:11][CH:10]=1)[CH2:5][CH:6]=[CH2:7])[CH:2]=[CH2:3]
Reactant: COC(=O)C1CCNCC1
Reactant: C=CCN(CC=C)Cc1ccc(S(=O)(=O)Cl)s1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: C=CCN(CC=C)Cc1ccc(S(=O)(=O)N2CCC(C(=O)OC)CC2)s1
Reaction time: 3 h
Yield: 58.7 %

Procedure:
5-Diallylaminomethyl-thiophene-2-sulfonyl chloride 229b (270 mg, 1.88 mmol) and DIEA (0.88 mL, 5.13 mmol) were dissolved in 10 mL chloroform. This solution was added methylisonipecotate (269 mg, 1.88 mmol) in 1 mL chloroform. The reaction was stirred for 3 h, diluted with CH2Cl2 and extracted with HCl (0.1N), NaHCO3 sat. and brine. The organic layer was dried over MgSO4 and evaporated to dryness. The crude was purified by flash chromatography on silica gel using cyclohexane/EtOAc 1:1 as eluent to obtain 440 mg (65%) of 327a as colorless oil: H′ NMR (CDCl3) δ 7.30 (d, J=3.6 Hz, 1H), 6.83 (d, J=3.6 1H), 5.78 (m, 2H), 5.18 (m, 4H), 3.70 (s, 2H), 3.52 (m, 6H), 3.07 (m, 4H), 2.50 (m, 2H), 2.25 (m, 1H), 1.93 (m, 2H), 1.84 (m, 2H). M/Z APCI: 399.2 (M+1)
Reaction SMILES: F[B-](F)(F)F.[CH3:6][O+:7]([CH3:9])C.[CH3:10][C:11]1[NH:16]C(=O)[CH:14]=[CH:13][CH:12]=1.[OH-].[Na+]>ClCCl>[CH3:6][O:7][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:10])[N:16]=1
Reactant: Cc1cccc(=O)[nH]1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1cccc(C)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 27.3 %

Procedure:
Trimethyloxonium tetrafluoroborate (10.0 g, 67.6 mmol) was added portionwise to a suspension of 6-methylpyridin-2-one (7.3 g, 67.0 mmol) in dichloromethane (100 ml), and once addition was complete, the reaction was stirred at room temperature for 24 hours. Dichloromethane (50 ml) and aqueous sodium hydroxide solution (50 ml, 2N) were added and the layers separated. The aqueous phase was extracted with dichloromethane (2×50 ml), the combined organic solutions washed with brine (50 ml), dried (MgSO4) and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel, using an elution gradient of pentane: dichloromethane (66:34 to 0:100) to afford the title compound (2.25 g, 27%) as a colourless oil.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([O:19][C:20](=[O:24])[C@H:21]([CH3:23])[NH2:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.[N+:32]([C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][CH:43]=1)[C:38](Cl)=[O:39])([O-:34])=[O:33]>C(Cl)Cl>[CH2:12]([O:19][C:20](=[O:24])[C@H:21]([CH3:23])[NH:22][C:38](=[O:39])[C:37]1[CH:41]=[CH:42][CH:43]=[C:35]([N+:32]([O-:34])=[O:33])[CH:36]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: C[C@H](N)C(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)c1cccc([N+](=O)[O-])c1)C(=O)OCc1ccccc1
Yield: 99.6 %

Procedure:
To a solution of p-toluenesulfonic acid salt of L-alanine benzyl ester (7.03 g, 0.02 mol) and triethylamine (4.55 g, 0.045 mol) in methylene chloride (80 ml) was added dropwise a solution of 3-nitrobenzoyl chloride (3.71 g, 0.02 mol) in methylene chloride (20 ml) under ice-cooling and stirring. After the addition was completed, the mixture was stirred for 0.5 hour under the same condition and for 0.5 hour at ambient temperature. The mixture was washed with diluted hydrochloric acid and water twice successively. After drying over MgSO4, the solvent was removed in vacuo to give N-(3-nitrobenzoyl)-L-alanine benzyl ester (6.54 g, 99.6% yield) as a colorless crystal, which was used in a following reaction without further purification. 1H-NMR (CDCl3, δ): 1.56 (3H, d, J=7.2 Hz), 4.86 (1H, q, J=7.2 Hz), 5.24 (2H, dd, J=12.3 Hz, 13.6 Hz), 6.98 (1H, br, d, J=7.0 Hz), 7.37 (5H, s), 7.63 (1H, t, J=8.0 Hz), 8.14 (1H, dd, J=1.2Hz, 8.0 Hz), 8.35 (1H, d, t, J=8.0 Hz, 0.92 Hz), 8.62 (1H, t, J=0.92 Hz); APCI-MS: 329 (M+ +1)
Reaction SMILES: [Br:1][C:2]1[C:3]([F:22])=[C:4]([F:21])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([O:17]CC)=[O:16])[C:7]2=[O:20].C(O)(=O)C.S(=O)(=O)(O)O>O>[Br:1][C:2]1[C:3]([F:22])=[C:4]([F:21])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]2=[O:20]
Reactant: CCOC(=O)c1cn(C2CC2)c2c(Br)c(F)c(F)cc2c1=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cn(C2CC2)c2c(Br)c(F)c(F)cc2c1=O
Temperature: 0 °C
Yield: 88.7 %

Procedure:
A mixture of ethyl 8-bromo-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate (1.0 g), acetic acid (4 ml), water (3 ml) and concentrated sulfuric acid (0.5 ml) was heated on an oil bath (90°-100° C.) for an hour under stirring, then for an hour at room temperature and poured into ice water (20 ml). The resulting precipitate was collected by filtration and washed with water to give the title compound (0.82 g), mp 224°-225.5° C.