Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:6]=[C:5]([C:7](=[N:13][O:14][CH3:15])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[NH:4][CH2:3][CH2:2]1.[C:16](OC(=O)C)(=[O:18])C.C(O)=O>O>[CH:16]([N:4]1[C:5]([C:7](=[N:13][O:14][CH3:15])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][S:1][CH2:2][CH2:3]1)=[O:18]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)C(=NOC)C1=CSCCN1
Solvent: O
Solvent: O=CO
Product: CCOC(=O)C(=NOC)C1=CSCCN1C=O
Temperature: 50 °C
Reaction time: 8 h
Yield: 76.9 %

Procedure:
Ethyl 2-(2,3-dihydro-4H-1,4-thiazin-5-yl)-2-methoxyiminoacetate (syn isomer, 5.8 g.) was added to a mixture of acetic anhydride (7.7 g.) and formic acid (3.48 g.), which was warmed at 50° C. for 2 hours previously, under ice-cooling, and stirred at room temperature overnight. After adding chilled water (100 ml.) to the resultant solution, the solution was extracted with ethyl acetate three times. The extract was washed with a saturated aqueous solution of sodium chloride once, an aqueous solution of sodium bicarbonate four times and a saturated aqueous solution of sodium chloride once in turn, and dried over magnesium sulfate. The solution was concentrated in vacuo, and the residue was triturated with diisopropyl ether (15 ml.). The crystals were collected by filtration and washed with diisopropyl ether to give ethyl 2-(4-formyl-2,3-dihydro-4H-1,4-thiazin-5-yl)-2-methoxyiminoacetate (syn isomer, 5.0 g.), mp. 94° to 96° C.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[C:9]1([S:15]([N:18]2[C:26]3[C:21](=[C:22]4[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29][CH2:28][O:27][C:23]4=[CH:24][CH:25]=3)[CH:20]=[CH:19]2)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)(Cl)Cl>[Cl:1][C:20]1[C:21]2[C:26](=[CH:25][CH:24]=[C:23]3[O:27][CH2:28][CH2:29][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:31][C:22]3=2)[N:18]([S:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)(=[O:17])=[O:16])[CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc3c(ccn3S(=O)(=O)c3ccccc3)c2C1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCOc2ccc3c(c(Cl)cn3S(=O)(=O)c3ccccc3)c2C1
Temperature: 130 °C
Yield: 66.8 %

Procedure:
N-chlorosuccinimide (0.23 g, 0.54 mmol) was added to a solution of tert-butyl 8-(phenylsulfonyl)-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 17, 0.23 g, 0.54 mmol) in chloroform (4 mL) and heated at 130° C. for 40 minutes in a microwave heater. The mixture was evaporated and purified by flash chromatography on silica gel using MeOH and DCM (1:99) as the eluent to give 167 mg of tert-butyl 10-chloro-8-(phenylsulfonyl)-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate. This intermediate (167 mg, 0.360 mmol) was dissolved in EtOH (20 mL) and a solution of 10 M KOH (0.2 mL, 2 mmol) was added. The mixture was heated at 65° C. for 20 minutes and the reaction mixture was evaporated and purified by preparative HPLC (ACE C8, 0.1% TFA-CH3CN) to give an off-white solid (40 mg) in the form of the trifluoroacetate salt. MS m/z 223 [M+H−Boc]+.
Reaction SMILES: [O:1]=[C:2]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=1)[CH2:3][C:4]([O:6]CC)=[O:5].C[O-].[Na+].CO[CH:25]=[CH:26][C:27](=O)[CH3:28].[OH-].[Na+]>CCO.O>[CH3:25][C:26]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:18])[F:19])[CH:11]=2)[C:2](=[O:1])[C:3]([C:4]([OH:6])=[O:5])=[CH:28][CH:27]=1
Reactant: COC=CC(C)=O
Reactant: CCOC(=O)CC(=O)Nc1cccc(C(F)(F)F)c1
Agent: C[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccc(C(=O)O)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.7 %

Procedure:
To a solution of ethyl 3-oxo-3-{[3-(trifluoromethyl)phenyl]amino}propanoate (19.2 g, 70 mmol) and sodium methoxide (7.6 g, 140 mmol) in EtOH (250 ml) was added 4-methoxybut-3-en-2-one (90%) (7.72 g, 77 mmol). After the addition, the reaction mixture was refluxed for 2 h and then cooled. Water (50 ml) and 2M NaOH were added and the mixture was stirred at room temperature overnight. The organic solvents were removed and the reaction mixture was extracted (washed) with EtOAc. The water phases were acidified with hydrochloric acid to pH 3-4, an orange coloured precipitate appeared and was filtered off, washed with water and dried. Recrystallisation twice from heptane/EtOAc (4:1) afforded the title compound (12 g, 58%) as a white powder.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[N:4]=[C:3]1[CH2:8]O.Cl.[NH2:11][CH2:12][CH2:13][SH:14].C(O)(C)C.CO.[BrH:21]>>[BrH:21].[BrH:21].[CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[N:4]=[C:3]1[CH2:8][S:14][CH2:13][CH2:12][NH2:11]
Reactant: NCCS
Reactant: Cc1cn(C)c(CO)n1
Agent: Br
Agent: Cl
Solvent: CC(C)O
Solvent: CO
Product: Cc1cn(C)c(CSCCN)n1

Procedure:
The reaction of 1,4-dimethyl-2-hydroxymethylimidazole (2.5 g.) with cysteamine hydrochloride (2.5 g.) in aqueous hydrobromic acid by the method described in Example 1 (i) (a) gave 1,4-dimethyl-2-[(2-aminoethyl)thiomethyl]imidazole dihydrobromide (6.2 g.), m.p. 161°-163° (from isopropyl alcohol-methanol).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH3:13])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].C(N(CC)CC)C.CS(Cl)(=O)=O.[CH2:26]([N:28]([CH2:33][CH3:34])[CH2:29][CH2:30][NH:31][CH3:32])[CH3:27]>C(Cl)Cl>[CH2:26]([N:28]([CH2:33][CH3:34])[CH2:29][CH2:30][N:31]([CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH3:13])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])[CH3:32])[CH3:27]
Reactant: COC(=O)c1cc(C)cc(CO)c1
Reactant: CCN(CC)CCNC
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(CC)CCN(C)Cc1cc(C)cc(C(=O)OC)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To an ice-cold, stirred solution of methyl 3-(hydroxymethyl)-5-methylbenzoate (200 mg, 1.19 mmol) and triethylamine (241 mg, 2.38 mmol) in methylene chloride (5 mL) is added methanesulfonyl chloride (191 mg, 1.67 mmol). The reaction mixture is stirred for 15 min, the precipitate that formed is removed by filtration, and N,N-diethyl-N′-methylethylenediamine (465 mg, 3.57 mmol) was added. The reaction mixture is stirred at room temperature for 2 h and then concentrated under reduced pressure. Purification by flash column chromatography (silica, 9:1 chloroform/methanol) gives the title compound. 1H NMR (300 MHz, CDCl3) δ 8.02 (s, 2H), 7.33 (s, 1H), 3.56 (s, 3H), 3.48 (s, 2H), 2.95 (m, 4H), 2.75 (m, 4H), 2.41 (s, 3H), 2.31 (s, 3H), 1.21 (m, 6H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][CH2:13][CH3:14])=[N:7]2.[NH2:15][C:16]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:17]=1[O:18][C:19]1[CH:20]=[C:21]([CH:27]=[CH:28][CH:29]=1)[C:22]([N:24]([CH3:26])[CH3:25])=[O:23]>C(O)C>[Cl:34][C:32]1[CH:31]=[CH:30][C:17]([O:18][C:19]2[CH:20]=[C:21]([CH:27]=[CH:28][CH:29]=2)[C:22]([N:24]([CH3:26])[CH3:25])=[O:23])=[C:16]([NH:15][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH2:12][CH2:13][CH3:14])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:33]=1
Reactant: CCCc1ccc2c(Cl)ccnc2n1
Reactant: CN(C)C(=O)c1cccc(Oc2ccc(Cl)cc2N)c1
Solvent: CCO
Product: CCCc1ccc2c(Nc3cc(Cl)ccc3Oc3cccc(C(=O)N(C)C)c3)ccnc2n1

Procedure:
The product from Example 2g (177 mg, 0.86 mmol) was reacted with the product from Example 168d (249 mg, 0.86 mmol) in ethanol (5 mL) at 85° C. in a sealed tube for 18 h giving the crude title compound which was purified by HPLC with TFA providing the product as the trifluoroacetic acid (100 mg, 20.2%). 1H NMR (500 MHz, DMSO-D6) δ ppm: 8.86 (d, J=8.79 Hz, 1H) 8.52 (d, J=6.84 Hz, 1 H) 7.74 (d, 1 H) 7.72 (d, 1H) 7.60 (dd, J=8.79, 2.93 Hz, 1 H) 7.28-7.33 (m, 1 H) 7.27 (d, 2H) 7.06 (d, J=7.81 Hz, 1 H) 6.99 (dd, J=8.06, 2.69 Hz, 1 H) 6.71 (d, J=6.84 Hz, 1 H) 2.96 (t, 2 H) 2.91 (s, 3 H) 2.70 (s, 3 H) 1.79-1.86 (m, 2 H) 0.96 (t, J=7.49 Hz, 3 H); MS (ESI+) m/z 461 (M+H)+.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([CH:15]([CH2:20][CH2:21][CH2:22][CH3:23])[C:16]([O:18][CH3:19])=[O:17])[CH3:14].[CH2:24]=[O:25]>CC(OC)(C)C>[CH3:19][O:18][C:16](=[O:17])[C:15]([CH2:13][CH3:14])([CH2:24][OH:25])[CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: C=O
Reactant: CCCCC(CC)C(=O)OC
Agent: [Li]CCCC
Solvent: COC(C)(C)C
Solvent: CC(C)NC(C)C
Product: CCCCC(CC)(CO)C(=O)OC
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
9.8 ml (0.070 mol) of diisopropylamine are added dropwise at 20° C. to a solution of 24.4 ml (0.065 mol) of n-butyllithium (2.7 M in heptane) in 25 ml of MTBE, and the mixture is stirred at −20° C. for 30 min. Within approx. 10 min, 10 g (0.063 mol) of methyl 2-ethylhexanoate are added dropwise at −20° C., and the mixture is stirred at 20° C. for a further 30 min and subsequently admixed with 5.7 g (0.19 mol) of paraformaldehyde. After 30 min at −20° C., the mixture is stirred at 0° C. for 2 h. After the removal of the solvent at 20° C. and 20 mbar, 20 ml of MTBE and 40 ml of saturated aqueous solution of ammonium chloride are added to the oily residue (approx. 20 g) and the mixture is stirred at RT for 2 h. The organic phase is removed, the aqueous phase is re-extracted 1× with 20 ml of MTBE and the combined organic phases are concentrated on a rotary evaporator. The yield of pure product is 86% (GC).
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([C:19]1[N:23]3[CH:24]=[C:25]([CH:28]4[CH2:30][CH2:29]4)[CH:26]=[CH:27][C:22]3=[N:21][N:20]=1)[CH:15]=[CH:14]2)(C(C)(C)C)(C)C>C1COCC1.[NH4+].[Cl-].O>[CH:28]1([C:25]2[CH:26]=[CH:27][C:22]3[N:23]([C:19]([C:16]4[CH:15]=[CH:14][C:13]5[C:18](=[C:9]([OH:8])[CH:10]=[CH:11][CH:12]=5)[N:17]=4)=[N:20][N:21]=3)[CH:24]=2)[CH2:30][CH2:29]1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc2ccc(-c3nnc4ccc(C5CC5)cn34)nc12
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: Oc1cccc2ccc(-c3nnc4ccc(C5CC5)cn34)nc12
Temperature: 25 °C
Reaction time: 17 h
Yield: 62.3 %

Procedure:
To a 0° C. solution of 8-(tert-butyldimethylsilyloxy)-2-(6-cyclopropyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinoline (0.159 g, 0.382 mmol) in 4 mL THF was added solid TBAF hydrate (0.150 g, 0.573 mmol), causing the reaction mixture to turn cloudy. The reaction mixture was warmed to ambient temperature after 5 minutes and then stirred 17 hours, after which it was diluted with saturated NH4Cl and water, causing solids to form. The solids were isolated by vacuum filtration through a Buchner funnel, rinsed with water, and air dried in vacuo to give the title compound (0.072 g, 0.238 mmol, 62.4% yield) as a light pink powder.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Br:28][C:29]1[CH:30]=[C:31]([CH:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([OH:42])=O)[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].[NH2:49][C:50]1[CH:55]=[CH:54][C:53]([Br:56])=[CH:52][N:51]=1>C(Cl)Cl>[Br:28][C:29]1[CH:30]=[C:31]([CH:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([NH:49][C:50]2[CH:55]=[CH:54][C:53]([Br:56])=[CH:52][N:51]=2)=[O:42])[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:36])=[O:37]
Reactant: Nc1ccc(Br)cn1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1Br
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2ccc(Br)cn2)cc1Br
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 58.4 %

Procedure:
A solution of triphenylphosphine (154 mg, 0.59 mmol) in methylene chloride (3 mL) was cooled to 0° C. and then slowly treated with N-bromosuccinimide (104 mg, 0.59 mmol). The reaction mixture was stirred at 0° C. for 10 min and then treated with 2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (200 mg, 0.53 mmol). The resulting reaction mixture was stirred at 0° C. for 5 min and then allowed to warm to 25° C. where it was stirred for 30 min. The reaction mixture was then treated with 2-amino-5-bromopyridine (203 mg, 1.17 mmol). The resulting reaction mixture was stirred at 25° C. for 15 h. The crude reaction mixture was then directly purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 3/1 hexanes/ethyl acetate) to afford the 2-(3-bromo-4-methanesulfonyl-phenyl)-N-(5-bromo-pyridin-2-yl)-3-cyclopentyl-propionamide (164 mg, 58%) as a white foam: mp 83-86° C. (foam to gel); FAB-HRMS m/e calcd for C20H22Br2N2O3S (M+H)+ 528.9796, found 528.9783.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[S:3]([O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[OH:16])[CH2:12][CH:11]([N:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])[CH2:10]2)(=[O:5])=[O:4].[CH2:26](Br)[CH2:27][CH3:28]>>[F:25][C:2]([F:24])([F:1])[S:3]([O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[O:16][CH2:26][CH2:27][CH3:28])[CH2:12][CH:11]([N:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])[CH2:10]2)(=[O:4])=[O:5]
Reactant: CCCN(CCC)C1Cc2cc(O)c(OS(=O)(=O)C(F)(F)F)cc2C1
Reactant: CCCBr
Product: CCCOc1cc2c(cc1OS(=O)(=O)C(F)(F)F)CC(N(CCC)CCC)C2

Procedure:
Using procedure 38, 2-(dipropylamino)-2,3-dihydro-6-hydroxy-1H-inden-5-yl trifluoromethanesulfonate (69, 1.9 g, 5 mmol) was treated with propylbromide (2.5 g, 20 mmol). Chromatographic purification yielded pure product 72 as a oil which was converted into the HCl salt and crystallized from EtOAc/hexane to give a white solid (mp 169-170° C.)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][CH3:34])=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)[CH:7]=1.[S:35]1[CH:39]=[N:38][N:37]=[C:36]1[NH2:40].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>CCOC(C)=O.Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][CH3:34])=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([NH:40][C:36]4[S:35][CH:39]=[N:38][N:37]=4)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)[CH:7]=1
Reactant: Nc1nncs1
Reactant: COc1ccc(Cl)cc1-c1nccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(Cl)cc1-c1nccc2cc(S(=O)(=O)Nc3nncs3)ccc12
Reaction time: 8 h
Yield: 96.9 %

Procedure:
A round-bottom flask was charged with perfluorophenyl 1-(5-chloro-2-methoxyphenyl)isoquinoline-6-sulfonate (INTERMEDIATE XXXX, 464.57 mg, 0.901 mmol), 1,3,4-thiadiazol-2-amine (182 mg, 1.801 mmol), and cesium carbonate (880 mg, 2.70 mmol). DMF (4503 μl) was added, and the mixture was stirred overnight. The mixture was diluted with EtOAc and 0.5 N aq. HCl. The layers were separated, and the organic extract was washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (25-g SNAP Ultra column, 0-7% MeOH/DCM) to give 1-(5-chloro-2-methoxyphenyl)-N-(1,3,4-thiadiazol-2-yl)isoquinoline-6-sulfonamide (378 mg, 0.873 mmol, 97% yield) as a light-yellow foam. m/z (ESI) 433.2 (M+H)+.
Reaction SMILES: CON(C)[C:4]([CH:6]1[CH:14]2[CH:7]1[CH2:8][C:9]1([CH2:13]2)[CH2:12][O:11][CH2:10]1)=[O:5].[CH3:16][Mg]Br>O1CCCC1.[Cl-].N>[O:11]1[CH2:10][C:9]2([CH2:8][CH:7]3[CH:14]([CH:6]3[C:4](=[O:5])[CH3:16])[CH2:13]2)[CH2:12]1
Reactant: CON(C)C(=O)C1C2CC3(COC3)CC21
Reactant: C[Mg]Br
Agent: N
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC(=O)C1C2CC3(COC3)CC21
Temperature: 0 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
To an ice-cooled solution of N-methoxy-N-methylspiro[bicyclo[3.1.0]hexane-3,3′-oxetane]-6-carboxamide (0.30 g, 1.4 mmol) in tetrahydrofuran (15 mL) was added methylmagnesium bromide (1 mL, 3M in tetrahydrofuran) dropwise. After 1 h, the reaction mixture was diluted with saturated aqueous ammonia chloride solution (10 mL), and the resulting solution was extracted with ethyl acetate (3×20 mL). The collected organic was concentrated to provide product as a brown oil (220 mg, 93% yield).
Reaction SMILES: C1COCC1.Cl[Si](C)(C)C.Br[CH2:12]/[CH:13]=[CH:14]/[C:15]([O:17][CH2:18][CH3:19])=[O:16].[CH:20]1([NH:26][C:27]2[CH:36]=[C:35]3[C:30]([C:31](=[O:44])[C:32]([CH:42]=[O:43])=[CH:33][N:34]3[CH:37]([CH2:40][CH3:41])[CH2:38][CH3:39])=[CH:29][C:28]=2[F:45])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>[Zn].O>[CH:20]1([NH:26][C:27]2[CH:36]=[C:35]3[C:30]([C:31](=[O:44])[C:32]([CH:42]([OH:43])[CH2:12]/[CH:13]=[CH:14]/[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:33][N:34]3[CH:37]([CH2:38][CH3:39])[CH2:40][CH3:41])=[CH:29][C:28]=2[F:45])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CCOC(=O)/C=C/CBr
Reactant: CCC(CC)n1cc(C=O)c(=O)c2cc(F)c(NC3CCCCC3)cc21
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)/C=C/CC(O)c1cn(C(CC)CC)c2cc(NC3CCCCC3)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2.0 ml of THF and 0.071 ml of chlorotrimethylsilane were added to 73 mg of zinc, followed by stirring at room temperature for 15 minutes. Then, 200 mg of ethyl (2E)-4-bromobut-2-enoate was added thereto, followed by stirring at room temperature for 30 minutes. To the reaction mixture was added 7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydro quinoline-3-carbaldehyde, followed by overnight stirring at room temperature. Water was added to the reaction mixture, followed by extraction with chloroform. The organic layer was washed with aqueous saturated sodium chloride, dried over anhydrous sodium sulfate and then evaporated under a reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 30 mg of ethyl (2E)-5-[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]-5-hydroxypent-2-enoate.
Reaction SMILES: [Cl-].[Mg+2].[Cl-].[O:4]=[C:5]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].N1C=CC=CC=1.[F:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1>O1CCCC1>[F:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([CH:6]([C:5](=[O:4])[CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:31])=[CH:28][CH:27]=1
Reactant: CCOC(=O)CC(=O)Cc1ccccc1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: [Cl-]
Agent: [Mg+2]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)Cc1ccccc1)C(=O)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67.5 %

Procedure:
To a suspension of magnesium chloride (1.46 g) in tetrahydrofuran (10 ml) was added a solution of ethyl 3-oxo-4-phenylbutanoate (2.0 g) in tetrahydrofuran (10 ml) and the mixture was cooled to 0° C., then pyridine (25 ml) was added. The mixture was stirred at 20° C. for 30 minutes, then a solution of 4-fluorobenzoyl chloride (2.44 g) in tetrahydrofuran (10 ml) was added at 0° C. After stirring at 20° C. for 2 hours, the mixture was partitioned between 0.5N hydrochloric acid and ethyl acetate. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated. The residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexane (1:5) to give ethyl 2-(4-fluorobenzoyl)-3-oxo-4-phenylbutanoate (2.15 g) as an oil.
Reaction SMILES: O[CH2:2]/[CH:3]=[CH:4]/[C:5]1[CH:6]=[C:7]([CH:14]=[C:15]([O:17][CH3:18])[CH:16]=1)[O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11].C(Br)(Br)(Br)[Br:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOCC>ClCCl>[Br:20][CH2:2]/[CH:3]=[CH:4]/[C:5]1[CH:6]=[C:7]([CH:14]=[C:15]([O:17][CH3:18])[CH:16]=1)[O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: BrC(Br)(Br)Br
Reactant: COC(=O)COc1cc(/C=C/CO)cc(OC)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)COc1cc(/C=C/CBr)cc(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.3 %

Procedure:
To a solution of the compound (150 mg, 0.594 mmol) of Example 16-4 in dicloromethane (2 ml) were added carbon tetrabromide (207 mg, 0.623 mmol) and triphenylphosphine (163 mg, 0.623 mmol), and the mixture was stirred for 30 minutes at room temperature. By adding ether to the reaction mixture, the resulting precipitate was filtered off. The filtrate was concentrated and the residue was purified with silica gel chromatography (hexane:ethyl acetate=2:1) to give the subject compound (141 mg, 75.3%).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2C)(=[O:5])[CH2:2][CH2:3][CH3:4].[CH3:18][O:19][C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH2:22]>O1CCOCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:22][C:21]1[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=1[O:19][CH3:18])=[CH:13][CH:12]=[CH:11][CH:10]=2)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: COc1ccccc1N
Reactant: CCCC(=O)c1cnc2c(C)cccc2c1Cl
Solvent: C1COCCO1
Product: CCCC(=O)c1cnc2ccccc2c1Nc1ccccc1OC
Yield: 86.8 %

Procedure:
3-Butyryl-4-chloro-8-methylquinoline (2.33 g, 10 mmol), 2-methoxyaniline (1.69 ml, 15 mmol) and dioxan (10 ml) were heated at reflux for 30 minutes, then allowed to cool. The hydrochloride salt was filtered off, converted to free base and recrystallised from ethanol to give 3-butyryl-4-(2-methoxy-phenylamino)quinoline (2.78 g), m.p. 167°-168°.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].FC1C=CC([I:26])=C(C=1)C(O)=O>>[I:26][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cc(F)ccc1-n1nccn1
Reactant: O=C(O)c1cc(F)ccc1I
Product: O=C(O)c1cc(I)ccc1-n1nccn1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 13, substituting 2-bromo-5-iodobenzoic acid for 5-fluoro-2-iodo-benzoic acid in Step A. 1H NMR (400 MHz, CD3OD): 8.09 (d, J=2.0, 1H), 8.03-7.97 (m, 1H), 7.95-7.86 (m, 3H), 7.53 (d, J=8.4, 1H).
Reaction SMILES: Br.[N:2]1([C:8]2[CH:9]=[CH:10][C:11]3[C:12]4[N:13]([CH2:19][CH2:20][N:21]=4)[C:14]([NH2:18])=[N:15][C:16]=3[CH:17]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[C:22]([NH:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][N:27]=1)(=[O:24])[CH3:23].C(N(CC)C(C)C)(C)C.C([O-])(O)=O.[Na+]>CN(C)C=O>[C:22]([NH:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:18][C:14]2[N:13]3[CH2:19][CH2:20][N:21]=[C:12]3[C:11]3[CH:10]=[CH:9][C:8]([N:2]4[CH2:7][CH2:6][O:5][CH2:4][CH2:3]4)=[CH:17][C:16]=3[N:15]=2)=[O:31])=[CH:28][N:27]=1)(=[O:24])[CH3:23]
Reactant: NC1=Nc2cc(N3CCOCC3)ccc2C2=NCCN12
Reactant: CC(=O)Nc1ccc(C(=O)O)cn1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(C(=O)NC2=Nc3cc(N4CCOCC4)ccc3C3=NCCN23)cn1
Temperature: 90 °C
Reaction time: 16 h
Yield: 31.6 %

Procedure:
To a mixture of 8-(morpholin-4-yl)-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine hydrobromide 105.7 mg (0.30 mmol), 6-(acetamido)nicotinic acid 81.1 mg (0.45 mmol) and N,N-diisopropylethylamine 0.26 mL (1.50 mmol) in N,N-dimethylformamide 2 mL was added PyBOP((1H-1,2,3-benzotriazol-1-yloxy)(tripyrrolidin-1-yl)-phosphonium hexafluorophosphate) 234.2 mg (0.45 mmol) and stirred at 90° C. for 16 hours. After cooling to room temperature, saturated NaHCO3 solution was added. The precipitate was collected and washed with water, methanol, and diethyl ether to give the title compound 41.1 mg as yellow solid. Yield 31.6%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.C(O)(=O)C(O)=O.[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]2[CH2:33][CH2:32][NH:31][CH2:30]2)=[CH:25][CH:24]=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:31]2[CH2:32][CH2:33][CH:29]([C:26]3[CH:27]=[CH:28][C:23]([CH3:22])=[CH:24][CH:25]=3)[CH2:30]2)=[O:15])=[CH:6][CH:7]=1
Reactant: Cc1ccc(C2CCNC2)cc1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Agent: O=C(O)C(=O)O
Product: Cc1ccc(-c2oncc2C(=O)N2CCC(c3ccc(C)cc3)C2)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and 3-(4-methylphenyl)pyrrolidine oxalate (15.1 mg, 0.060 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (2.7 mg). Calcd for C22H22N2O2: 346.1681, found 346.1692.