Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([CH2:16][C:17]([OH:19])=[O:18])=[CH:10][C:11](=[O:15])[O:12]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[Cl:20][C:21]([Cl:25])([Cl:24])[CH2:22]O.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[Cl:20][C:21]([Cl:25])([Cl:24])[CH2:22][O:18][C:17](=[O:19])[CH2:16][C:9]1[C:8]2[C:13](=[CH:14][C:5]([O:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=2)[O:12][C:11](=[O:15])[CH:10]=1
Reactant: OCC(Cl)(Cl)Cl
Reactant: CC(=O)Oc1ccc2c(CC(=O)O)cc(=O)oc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(=O)Oc1ccc2c(CC(=O)OCC(Cl)(Cl)Cl)cc(=O)oc2c1
Reaction time: 0.25 h
Yield: 96.7 %

Procedure:
To a suspension of 7-acetoxycoumarin-4-acetic acid 5 (945 mg, 3.6 mmol, 1 eq) in 47 mL of anhydrous dichloromethane at room temperature under nitrogen was added 2,2,2-trichloroethanol (431 μL, 4.5 mmol, 1.25 eq). A solution of N,N′-dicyclohexylcarbodiimide (818 mg, 4 mmol, 1.1 eq) in 10 mL of anhydrous dichloromethane was added. The reaction mixture was stirred for 15 min, after which it was diluted with dichloromethane and filtered. The filtrate was concentrated under vacuum. Column chromatography on silica gel (CH2Cl2 then CH2Cl2:EtOAc, 10:1) afforded product 6a (1.37 g, 96%): Rƒ 0.78 (CH2Cl2:EtOAc, 5:1); 1H NMR (300 MHz, CDCl3): δ 7.61 (d, 1 H, J5,6 8.7 Hz, H-5), 7.15 (d, 1 H, J6,8 2.1 Hz, H-8), 7.07 (dd, 1 H, J6,8 2.3, J5,6 8.7 Hz, H-6), 6.42 (s, 1 H, H-3), 4.77 (s, 2 H, CH2CCl3), 3.91 (2 s, 2 H, CH2CO2), 2.33 (s, 3 H, OAc); 13C NMR (75 MHz, CDCl3): δ 168.6, 167.0, 154.5, 153.5, 146.5, 125.5, 118.5, 117.0, 116.5, 110.9, 74.6, 37.7, 21.2; ESI-MS: m/z 393 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]([NH:5][C@H:6]([CH3:10])[C:7](O)=[O:8])=[O:4].N1C=CC=CC=1.C(Cl)(=O)C([Cl:22])=O>ClCCl>[F:1][C:2]([F:12])([F:11])[C:3]([NH:5][C@H:6]([CH3:10])[C:7]([Cl:22])=[O:8])=[O:4]
Reactant: C[C@@H](NC(=O)C(F)(F)F)C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[C@@H](NC(=O)C(F)(F)F)C(=O)Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The compound obtained in step 1) (17.2 g, 0.0845 mol) was dissolved in 300 ml of dichloromethane, and 1 ml of pyridine was added. The reaction mixture was cooled in ice-water bath to 0˜3, and oxalyl chloride (25.8 g, 0.203 mol) was added dropwise. After the completion of the addition, the temperature was slowly raised to room temperature, and a reaction was allowed to proceed for 3 hours. Evaporation was carried out under reduced pressure to remove the solvent, and 50 ml×2 benzene was added to remove residual solvent by azeotropism. The obtained (R)—N-trifluoroacetyl-2-amino propionyl chloride can be directly used for the subsequent reaction.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][N:9]2[CH2:14][CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=3)[NH:18][C:17]=2[CH3:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[Na].[C:31]([C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=[O:40])=[CH:37][CH:36]=1)([CH3:34])([CH3:33])[CH3:32]>CN(C=O)C>[C:31]([C:35]1[CH:36]=[CH:37][C:38]([C:39]([N:18]2[C:19]3[C:24](=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[C:16]([CH2:15][CH2:14][N:9]3[CH2:10][CH2:11][CH2:12][CH2:13][CH:8]3[CH2:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[C:17]2[CH3:27])=[O:40])=[CH:42][CH:43]=1)([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: COc1ccc2[nH]c(C)c(CCN3CCCCC3CC3CCCCC3)c2c1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(CCN1CCCCC1CC1CCCCC1)c(C)n2C(=O)c1ccc(C(C)(C)C)cc1

Procedure:
1-(4-t-Butylbenzoyl)-3-[2-(2-cyclohexylmethylpiperidino)ethyl]-5-methoxy-2-methylindole is prepared by reaction of 3-[2-(2-cyclohexylmethylpiperidino)ethyl]-5-methoxy-2-methylindole with sodium hydride in DMF and reaction of the resulting sodium salt with 4-t-butylbenzoyl chloride following the procedure described above in Example 1.
Reaction SMILES: [CH3:1][S:2]Cl.[CH2:4]([N:7]([CH2:25][CH2:26][CH3:27])[C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:11]([S:17]([NH:20][CH3:21])(=[O:19])=[O:18])=[CH:10][C:9]=1[N+:22]([O-:24])=[O:23])[CH2:5][CH3:6].N1C=CC=CC=1>ClCCl>[CH2:25]([N:7]([CH2:4][CH2:5][CH3:6])[C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:11]([S:17]([N:20]([S:2][CH3:1])[CH3:21])(=[O:19])=[O:18])=[CH:10][C:9]=1[N+:22]([O-:24])=[O:23])[CH2:26][CH3:27]
Reactant: CCCN(CCC)c1c([N+](=O)[O-])cc(S(=O)(=O)NC)cc1[N+](=O)[O-]
Reactant: CSCl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCN(CCC)c1c([N+](=O)[O-])cc(S(=O)(=O)N(C)SC)cc1[N+](=O)[O-]

Procedure:
A 1.1 g (0.012 mol) sample of methylsulfenyl chloride was added dropwise to a cooled (-5° to -10° C.) solution of 3.6 g (0.01 mol) 4-dipropylamino-N-methyl-3,5-dinitrobenzenesulfonamide and 1.1 g (0.014 mol) pyridine in 25 ml dichloromethane. The reaction mixture was then stirred at about 0° C. until the sulfonamide reactant could not be detected by thin layer chromatography on silica gel (benzene/acetone eluant). The reaction mixture was then washed with water, dried over magnesium sulfate and evaporated under reduced pressure to give a yellow semi-solid residue. The residue was recrystallized from ethanol to give 2.3 g of the product, as a yellow solid, m.p. 119°-121° C. Elemental analysis for C14H22N4O6S2 showed: % S, calc. 15.8, found 15.9.
Reaction SMILES: [CH3:1][C:2]1([CH2:15][N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:6][C:5]2[C:7]([CH3:14])=[C:8]([NH2:13])[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1.[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=1>>[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([N:19]2[CH2:20][CH2:21][N:16]([CH2:15][C:2]3([CH3:1])[CH2:6][C:5]4[C:7]([CH3:14])=[C:8]([NH2:13])[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=4[O:3]3)[CH2:17][CH2:18]2)=[O:28])=[CH:25][CH:24]=1
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCNCC1)O2
Product: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCN(C(=O)c3ccc(Cl)cc3)CC1)O2
Yield: 64 %

Procedure:
Using 2,3-dihydro-2,4,6,7-tetramethyl-2-[(1-piperazinyl)methyl]-5-benzofuranamine and 4-chlorobenzoic acid, the procedure of Example 10, presented hereinafter, was otherwise followed to provide the title compound. Yield 64%.
Reaction SMILES: [CH2:1]([S:3][C:4]1[C:9]([C:10](O)=[O:11])=[C:8]([C:13]([F:16])([F:15])[F:14])[CH:7]=[C:6]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:5]=1)[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[F:54][C:55]1[CH:56]=[C:57]([CH:60]=[CH:61][CH:62]=1)[CH2:58][NH2:59]>C1COCC1>[CH2:1]([S:3][C:4]1[C:9]([C:10]([NH:59][CH2:58][C:57]2[CH:60]=[CH:61][CH:62]=[C:55]([F:54])[CH:56]=2)=[O:11])=[C:8]([C:13]([F:15])([F:14])[F:16])[CH:7]=[C:6]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:5]=1)[CH3:2]
Reactant: CCSc1nc(N2CCOCC2)cc(C(F)(F)F)c1C(=O)O
Reactant: NCc1cccc(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCSc1nc(N2CCOCC2)cc(C(F)(F)F)c1C(=O)NCc1cccc(F)c1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 26 %

Procedure:
To a solution of 170 mg (0.5 mmol) 2-(ethylsulfanyl)-6-morpholin-4-yl-4-(trifluoromethyl)-pyridine-3-carboxylic acid in THF (3 ml) were added 192 mg (0.5 mmol) HATU and 210 μl (1.5 mmol) NEt3 and the RM was stirred at 50° C. for 90 min. Then 69 μl (0.6 mmol) 3-fluorobenzylamine were added and stirring was continued at 50° C. for 5 d. After cooling to RT the mixture was partitioned between water and EtOAc. The organic layer was separated, washed with a 4N aq. NH4Cl sol. and brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 3:1) provided 57 mg (0.13 mmol, 26%) 2-ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-6-morpholin-4-yl-4-(trifluoromethyl)-pyridine-3-carboxylic acid amide (example 11). [M+H]+ 444.1.
Reaction SMILES: N(OCCC(C)C)=O.[CH3:9][O:10][C:11]([C:13]1[C:18](N)=[N:17][CH:16]=[CH:15][N:14]=1)=[O:12].[I:20]CI>>[CH3:9][O:10][C:11]([C:13]1[C:18]([I:20])=[N:17][CH:16]=[CH:15][N:14]=1)=[O:12]
Reactant: ICI
Reactant: COC(=O)c1nccnc1N
Agent: CC(C)CCON=O
Product: COC(=O)c1nccnc1I
Temperature: 100 °C
Reaction time: 15 h
Yield: 44 %

Procedure:
Isoamyl nitrite (5.2 mL, 39 mmol) was added to a suspension of 3-aminopyrazine-2-carboxylic acid methyl ester (1.9 g, 12 mmol) in diiodomethane (20 mL) at 85° C., then the mixture was stirred at 100° C. for 15 hours. The reaction mixture was allowed to stand and purified by silica gel column chromatography to give 1.4 g of the title reference compound as a pale yellow solid. (Yield 44%)
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH2:8]2)=[CH:4][C:3]=1[CH2:11]O.C(Br)(Br)(Br)[Br:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:14][CH2:11][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:2]=1[I:1])[CH2:8][CH2:7][CH2:6]2
Reactant: BrC(Br)(Br)Br
Reactant: OCc1cc2c(cc1I)CCC2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCc1cc2c(cc1I)CCC2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (6-iodo-2,3-dihydro-1H-inden-5-yl)methanol (36 mg, 0.131 mmol) and carbon tetrabromide (52 mg, 0.158 mmol) in CH2Cl2 (1 mL) at 0° C. under N2, was added triphenylphosphine (41 mg, 0.158 mmol). The resulting solution was allowed to warm to room temperature and was stirred for 4 h. Another portion of carbon tetrabromide (52 mg, 0.158 mmol) and triphenylphosphine (41 mg, 0.158 mmol) was added to the mixture at 0° C. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo. The residue was purified by flash chromatography (Si, 1% EtOAc in hexanes) to afford 5-(bromomethyl)-6-iodoindane. 1H NMR (500 MHz, CDCl3) δ 7.72 (s, 1H), 7.36 (s, 1H), 4.62 (s, 2H), 2.89 (m, 4H), 2.11-2.07 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][C:14]2=[O:26])[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[CH3:27][N:28](C=O)C.C(OCC)(=O)C.N>[C-]#N.[Zn+2].[C-]#N.O>[C:22]([O:21][C:19]([N:16]1[CH2:17][CH2:18][N:13]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:27]#[N:28])=[CH:3][CH:4]=2)[C:9]([O:11][CH3:12])=[O:10])[C:14](=[O:26])[CH2:15]1)=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: COC(=O)C(c1ccc(Br)cc1)N1CCN(C(=O)OC(C)(C)C)CC1=O
Reactant: CN(C)C=O
Agent: N
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)C(c1ccc(C#N)cc1)N1CCN(C(=O)OC(C)(C)C)CC1=O
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A mixture of methyl 2-(4-bromophenyl)-2-[4-(tert-butoxycarbonyl)-2-oxo-1-piperazinyl]acetate (1.28 g), zinc cyanide (211 mg), tetrakis (triphenylphosphine)palladium (139 mg) and DMF (10 ml) was stirred at 80° C. for 6 hours and cooled. To the reaction solution were added ethyl acetate, water and a little amount of ammonia solution. The organic layer was separated, washed with saturated brine, dried and concentrated, and the residue was purified with silica gel column chromatography (hexane:ethyl acetate=1:1) to give yellow syrup of methyl 2-[4-(tert-butoxycarbonyl)-2-oxo-1-piperazinyl]-2-(4-cyanophenyl)acetate (1.01 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[C@@H:4]([CH3:6])[NH2:5].C([O-])(=O)C.[Na+].[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([BH3-])#N.[Na+]>CO>[CH3:1][O:2][C:3](=[O:7])[C@@H:4]([CH3:6])[NH:5][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccccc1
Reactant: COC(=O)[C@@H](C)N
Agent: CC(=O)[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@@H](C)NCc1ccccc1
Reaction time: 0.25 h
Yield: 59.6 %

Procedure:
D-Alanine methyl ester (4 g, 28.66 mmol) is taken up in methanol (100 mL). To this is added sodium acetate (5.88 g, 71.65 mmol) and benzaldehyde (2.9 mL, 28.66 mmol). The mixture is stirred for 15 minutes and then a solution of sodium cyanoborohydride (1.08 g, 17.2 mmol) in methanol (5 mL) is added dropwise to the mixture. After stirring for 2 hours methanol is evaporated under reduced pressure and the product is extracted into ether and washed with water (2×). The crude product is purified by silica gel flash chromatography (8:2 hexane:ethyl acetate) to give 3.3 g of N-benzyl D-alanine methyl ester as an oil.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([S:20][CH2:21][CH2:22][CH3:23])[N:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:21]([S:20][C:16]1[N:15]=[C:14]([C:12]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:13]=2)[CH:19]=[CH:18][CH:17]=1)[CH2:22][CH3:23]
Reactant: CCCSc1cccc(C#N)n1
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCSc1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 36.6 %

Procedure:
A mixture of methyl thiosalicylate (0.67 g, 4.0 mmol), 2-cyano-6-propylthiopyridine (0.72 g, 4.0 mmol), triethylamine (0.84 ml, 6.0 mmol) and toluene (50 ml) was refluxed for 48 hrs as described in Example 1. The reaction mixture was concentrated under reduced pressure and the residue was recrystallized from ethanol to give the titled compound (0.46 g, 37%) as crystals.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl.C(N(CC)CC)C.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:24]([CH:25]([CH:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)[CH2:26][O:27][C:28]3[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][C:29]=3[F:36])=[C:23]3[CH2:43][CH2:44][CH2:45][C:22]3=[N:21]2)=[CH:16][CH:15]=1>CN(C=O)C>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:24]([CH:25]([CH:37]3[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]3)[CH2:26][O:27][C:28]3[CH:35]=[CH:34][C:31]([C:32]4[N:1]=[N:2][NH:3][N:33]=4)=[CH:30][C:29]=3[F:36])=[C:23]3[CH2:43][CH2:44][CH2:45][C:22]3=[N:21]2)=[CH:16][CH:15]=1
Reactant: N#Cc1ccc(OCC(c2c3c(nn2-c2ccc(Cl)cc2)CCC3)C2CCCCC2)c(F)c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Fc1cc(-c2nn[nH]n2)ccc1OCC(c1c2c(nn1-c1ccc(Cl)cc1)CCC2)C1CCCCC1
Temperature: 120 °C
Reaction time: 14 h
Yield: 60.5 %

Procedure:
Sodium azide (14 mg, 215 umol) and triethylamine hydrochloride (29 mg, 215 umol) were added to a solution of 4-{2-[2-(4-chloro-phenyl)-2,4,5,6-tetrahydro-cyclopentapyrazol-3-yl]-2-cyclohexyl-ethoxy}-3-fluoro-benzonitrile (20 mg, 43 umol; example 3) in DMF (0.5 ml). The solution was stirred at 120° C. for 14 h, poured onto ice water/1 N aqueous HCl solution 1/1 and extracted two times with iPrOAc. The combined extracts were washed with ice water/brine 1/1 and dried over Na2SO4. The solvent was removed under reduced pressure to give a solid which was crystallized from heptane/dichloromethane to obtain the title compound (13 mg, 26 umol; 59%) as off-white solid. MS: m/e=507.2 [M+H+].
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CS(C)=O>[F:1][C:2]1[C:3]([N:25]2[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]2)=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23
Reactant: CN1CCNCC1
Reactant: CC1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Solvent: CS(C)=O
Product: CC1COc2c(N3CCN(C)CC3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reaction time: 12 h
Yield: 42.8 %

Procedure:
1.0 g of 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid and 2.85 g of N-methylpiperazine were added to 15 ml of dimethylsulfoxide. The mixture was stirred at a temperature of from about 100° to 110° C. (bath temperature) for 12 hours and the reaction mixture was concentrated to dryness in vacuo and 40 ml of water was added to the residue. Then the product was extracted with chloroform. The extract was dried and concentrated to dryness in vacuo. The residue was recrystallized from ethanol to provide 550 mg of 9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid as colorless needles with m.p. 250°-257° C. (with decomposition).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:8][C:9]([CH3:14])([CH2:12][NH2:13])[CH2:10][NH2:11]>N1C=CC=CC=1>[NH2:11][CH2:10][C:9]([CH3:14])([CH3:8])[CH2:12][NH:13][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Fc1ccccn1
Reactant: CC(C)(CN)CN
Solvent: c1ccncc1
Product: CC(C)(CN)CNc1ccccn1

Procedure:
A mixture of 2-fluoropyridine and 2,2-dimethyl-1,3-propanediamine (2 eq) in pyridine (0.3M) was refluxed for 18 hrs. and then concentrated by rotary evaporation. The solution was then concentrated in vacuo and the residue was partitioned between ethyl acetate and 10% sodium carbonate. The phases were separated, and the organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The product was purified by flash chromatography using 10:1:1 EtOH/NH4OH/H2O as eluent. EI-MS m/z 180 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:19]([O:20][CH3:21])=[CH:18][C:6]2[CH2:7][C:8](=[O:17])[N:9]([CH2:12][CH2:13][CH2:14][NH:15][CH3:16])[CH2:10][CH2:11][C:5]=2[CH:4]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([O:32][CH2:33][CH2:34]Cl)[CH:27]=[CH:28][C:29]=1[O:30][CH3:31]>>[CH3:1][O:2][C:3]1[C:19]([O:20][CH3:21])=[CH:18][C:6]2[CH2:7][C:8](=[O:17])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:16])[CH2:34][CH2:33][O:32][C:26]3[CH:27]=[CH:28][C:29]([O:30][CH3:31])=[C:24]([O:23][CH3:22])[CH:25]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1ccc(OCCCl)cc1OC
Reactant: CNCCCN1CCc2cc(OC)c(OC)cc2CC1=O
Product: COc1ccc(OCCN(C)CCCN2CCc3cc(OC)c(OC)cc3CC2=O)cc1OC

Procedure:
The title compound is prepared from N-[3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-propyl]-methylamine and 2-(3,4-dimethoxyphenyloxy)-ethyl chloride analogously to Example 3.
Reaction SMILES: C(NC(C)C)(C)C.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([F:17])[CH:10]=1.CN(C)[CH:20]=[O:21]>O1CCCC1>[Br:8][C:9]1[C:10]([CH:20]=[O:21])=[C:11]([F:17])[C:12]([O:15][CH3:16])=[CH:13][CH:14]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(Br)cc1F
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1ccc(Br)c(C=O)c1F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 58 %

Procedure:
A solution of anhydrous tetrahydrofuran (50 mL) and diisopropylamine (11 mL) was cooled to 0° C. and had 1.6 M n-butyl lithium/hexanes (47 mL) added drop wise under nitrogen balloon. The mixture was stirred for 10 minutes at 0° C. and was then cooled to −78° C. with an acetone dry ice bath. A mixture of 4-bromo-2-fluoro-1-methoxybenzene (7.9 mL, 61 mmol) in anhydrous tetrahydrofuran (50 mL) was added drop wise, under nitrogen balloon, to the reaction. The mixture was then allowed to stir for 30 minutes at −78° C. N,N-dimethylformamide (7.5 mL) was added drop wise at −78° C. under a nitrogen balloon. The reaction was stirred for 1 hour at room temperature under a nitrogen balloon. Half of the solvent from the solution was removed under reduced pressure and the solution was extracted using ethyl acetate, water (300 mL), and 1 M HCl (65 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The solvent was removed under reduced pressure. The residue was crystallized by washing with hexanes. The solid was collected via filtration and dried under reduced pressure to give 6-bromo-2-fluoro-3-methoxybenzaldehyde (8.21 g, 58% yield).
Reaction SMILES: [NH:1]([C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])N.[C:13]1(=O)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>CC(O)=O>[C:4]1([C:5]([O:7][CH3:8])=[O:6])[C:3]2[NH:1][C:14]3[CH2:15][CH2:16][CH2:17][CH2:18][C:13]=3[C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: O=C1CCCCC1
Reactant: COC(=O)c1ccccc1NN
Solvent: CC(=O)O
Product: COC(=O)c1cccc2c3c([nH]c12)CCCC3
Temperature: 80 °C
Yield: 57 %

Procedure:
A 150-mL round-bottom flask was placed a solution of methyl 2-hydrazinylbenzoate (7.81 g, 1.00 equiv, 1%) in AcOH (70 mL). To this solution was added cyclohexanone (4.5 g, 45.92 mmol, 1.00 equiv) dropwise with stirring at 80° C. The resulting solution was heated to reflux for 2 hr in an oil bath. Upon completion, the reaction was then quenched with water (50 mL). The solids were collected by filtration and washed with H2O (2×50 mL) affording methyl 6,7,8,9-tetrahydro-5H-carbazole-1-carboxylate as white solid (6 g, 55.8%).
Reaction SMILES: CI.N12CCCN=C1CCCC[CH2:4]2.[CH3:14][C:15]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:20][CH2:19][C:18](=[O:21])[CH:17]=[C:16]1[C:22]([OH:24])=[O:23]>CC(C)=O>[CH3:14][C:15]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:20][CH2:19][C:18](=[O:21])[CH:17]=[C:16]1[C:22]([O:24][CH3:4])=[O:23]
Reactant: CC1(c2ccccc2)CCC(=O)C=C1C(=O)O
Reactant: C1CCC2=NCCCN2CC1
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)C1=CC(=O)CCC1(C)c1ccccc1
Yield: 94.2 %

Procedure:
0.88 cm3 (14 mmol) of methyl iodide and 1.8 cm3 (12 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene, dropwise, were successively added to a solution of 2.3 g (10 mmol) of (RS)-2-methyl-5-oxo-2-phenylcyclohexene-1-carboxylic acid in 20 cm3 of acetone. The reaction mixture was subsequently heated at reflux for two hours. The acetone was subsequently concentrated, the residue was then stirred with 100 cm3 of water and then extracted with three times 30 cm3 of ethyl acetate. After drying over magnesium sulphate and concentrating under reduced pressure, 2.3 g (94%) of methyl (RS)-2-methyl-5-oxo-2-phenylcyclohexene-1-carboxylate were obtained in the form of an orange oil, the characteristic of which was as follows:
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].[CH3:15][NH:16][CH2:17][CH2:18][OH:19]>>[O:4]=[C:3]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][N:16]([CH3:15])[CH2:17][CH2:18][OH:19]
Reactant: O=C(CCl)N1CCc2ccccc2C1
Reactant: CNCCO
Product: CN(CCO)CC(=O)N1CCc2ccccc2C1

Procedure:
The procedure is similar to that described in Example 6a), reacting 4.78 g (23 mmol) of 2-(2-chloroacetyl)-1,2,3,4-tetrahydroisoquinoline and 3 g (40 mmol) of 2-(methylamino)ethanol.
Reaction SMILES: [CH:1]1([C:4](=O)[CH2:5][C:6]([O:8][CH3:9])=[O:7])[CH2:3][CH2:2]1.CS(O)(=O)=O.[NH2:16][C:17]1[CH:31]=[CH:30][CH:29]=[CH:28][C:18]=1[C:19]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)=O>CC(O)C>[CH:1]1([C:4]2[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[C:18]3[C:17](=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:16]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)CC(=O)C1CC1
Reactant: Nc1ccccc1C(=O)c1ccc(F)cc1
Agent: CS(=O)(=O)O
Solvent: CC(C)O
Product: COC(=O)c1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Temperature: 80 °C
Yield: 88.7 %

Procedure:
12 g of methyl 3-cyclopropyl-3-oxopropionate and 25 g of 2-amino-4′-fluorobenzophenone methanesulfonate were added to 146 g of 2-propanol, and 2-propanol was distilled off at 79 to 83° C. After distilling off 119 g of 2-propanol over 6 hours, 1.14 g of methyl 3-cyclopropyl-3-oxopropionate was added and the mixture was heated at 79 to 81° C. for 4 hours. An analysis of the mixture with high performance liquid chromatography (HPLC) showed that the residual amount of 2-amino-4′-fluorobenzophenone as a raw material was 0.9%. 146 g of toluene was added into the reaction solution, and the reaction solution was washed with 80 g of 4% aqueous solution of sodium hydroxide and then 35 g of 2% aqueous solution of sodium hydroxide. The reaction solution was further washed with 25 g of 5% brine solution, and then dried over 5 g of anhydrous magnesium sulfate. Toluene was removed under a reduced pressure, and crystallization was carried out in 180 g of cyclohexane to obtain 22.9 g of methyl 2-cyclopropyl-4-(4′-fluorophenyl)quinoline-3-carboxylate.