Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][C:11]([C:14]([F:17])([F:16])[F:15])(O)[O:10][N:9]=2)=[CH:4][CH:3]=1.C1(C2CC(O)(C(F)(F)F)ON=2)C=CC=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[C:11]([C:14]([F:16])([F:15])[F:17])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: OC1(C(F)(F)F)CC(c2ccc(Cl)cc2)=NO1
Agent: OC1(C(F)(F)F)CC(c2ccccc2)=NO1
Product: FC(F)(F)c1cc(-c2ccc(Cl)cc2)no1
Yield: 97.6 %

Procedure:
As described for Example 1b, 3-(4-chloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-5-ol (39.6 g, 149 mmol), instead of 3-phenyl-5-hydroxy-5-(trifluoromethyl)isoxazoline, was converted to the title compound (36.0 g, 98%) which was obtained as a light brown oil. MS: m/e=247.3 [M−H]−.
Reaction SMILES: C[O:2][C:3](=[O:27])[C@@H:4]([N:9]1[CH2:13][C:12]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][C:22]([OH:25])([CH3:24])[CH3:23])[CH:16]=2)=[CH:11][C:10]1=[O:26])[CH2:5][CH:6]([CH3:8])[CH3:7].O.[OH-].[Li+]>O1CCCC1.O>[OH:25][C:22]([CH3:24])([CH3:23])[CH2:21][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[O:14][C:12]1[CH2:13][N:9]([C@@H:4]([CH2:5][CH:6]([CH3:8])[CH3:7])[C:3]([OH:27])=[O:2])[C:10](=[O:26])[CH:11]=1
Reactant: COC(=O)[C@H](CC(C)C)N1CC(Oc2cccc(CC(C)(C)O)c2)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C[C@@H](C(=O)O)N1CC(Oc2cccc(CC(C)(C)O)c2)=CC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.6 %

Procedure:
To a solution of (S)-2-{4-[3-(2-hydroxy-2-methyl-propyl)-phenoxy]-2-oxo-2,5-dihydro-pyrrol-1-yl}-4-methyl-pentanoic acid methyl ester (0.480 g, 1.28 mmol) in tetrahydrofuran (10 mL) and water (2 mL) was added lithium hydroxide monohydrate (0.058 g 1.35 mmol). The mixture was stirred at room temperature for 2 h. The reaction mixture was poured into water and washed with diethyl ether. The aqueous phase was acidified with 1N aqueous hydrochloric acid solution (pH<2), and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was precipitated from dichloromethane with an excess of hexanes to afford (S)-2-{4-[3-(2-hydroxy-2-methyl-propyl)-phenoxy]-2-oxo-2,5-dihydro-pyrrol-1-yl}-4-methyl-pentanoic acid (0.410 g, 89%), as an off-white solid.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[CH2:9]([O:11][C:12](=O)[CH:13]=[C:14](OCC)[O:15]CC)[CH3:10]>C(O)(=O)C>[CH2:9]([O:11][C:12]1[CH2:13][C:14](=[O:15])[NH:8][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=2[N:7]=1)[CH3:10]
Reactant: CCOC(=O)C=C(OCC)OCC
Reactant: Nc1ccccc1N
Solvent: CC(=O)O
Product: CCOC1=Nc2ccccc2NC(=O)C1
Temperature: 140 °C
Reaction time: 24 h
Yield: 56.5 %

Procedure:
To a solution phenylenediamine (17.2 g, 159.2 mmol) and acetic acid (0.4 mL) in xylenes (225 mL) at 140° C. was added 3,3-diethoxyacrylic acid ethyl ester (30.0 g, 159.2 mmol) in xylenes (80 mL) dropwise over 50 minutes. The reaction was heated at 140° C. for 2 hours, was cooled to room temperature, and was stirred for 24 h. The resulting white precipitate was filtered, was washed with ether (100 mL), and was dried under vacuum to provide 18.37 g of 4-ethoxy-1,3-dihydro-benzo[b][1,4]diazepin-2-one as a white fluffy solid. MS 205 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11](Cl)(=[O:13])=[O:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH:15]([NH:18][CH2:19][CH2:20][NH:21][CH:22]([CH3:24])[CH3:23])([CH3:17])[CH3:16]>>[CH3:16][CH:15]([NH:18][CH2:19][CH2:20][N:21]([CH:22]([CH3:24])[CH3:23])[S:11]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:13])=[O:12])[CH3:17]
Reactant: CC(C)NCCNC(C)C
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Product: COc1ccc(S(=O)(=O)N(CCNC(C)C)C(C)C)cc1OC

Procedure:
Reaction of 3,4-dimethoxybenzene sulfonyl chloride with N,N'-diisopropylethylene diamine following the procedure of Example 1 gave a crude crystalline product which on recrystallization from diethyl ether provided the pure title compound, m.r. 53°-55° C.
Reaction SMILES: [S-2:1].[Na+:2].[Na+].[SH-].[Na+].[C:6]([Cl:15])(=[O:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].S>O.[Cl-].C[N+](CCCCCCCC)(CCCCCCCC)CCCCCCCC>[S-2:1].[Na+:2].[Na+:2].[C:6]([O-:14])(=[S:1])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[Na+:2].[Cl-:15].[Na+:2]
Reactant: CCCCCCCC(=O)Cl
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: S
Agent: [Cl-]
Solvent: O
Product: CCCCCCCC([O-])=S
Temperature: 25 °C
Reaction time: 0.05 h

Procedure:
A 16 weight percent aqueous solution of sodium sulfide was prepared by dissolving sodium sulfide (101 grams, 1.29 moles) in the form of hydrated flakes (168 grams, 60%) into 463 grams of water in a 5-liter round-bottomed flask. This solution was then converted to an aqueous solution of sodium hydrosulfide (NaSH) by saturating it with an excess of hydrogen sulfide by adding hydrogen sulfide with stirring until no more was absorbed. A dropping funnel was charged with octanoyl chloride (210.5 grams, 1.294 moles). The temperature of the sodium hydrosulfide solution in the 5-liter flask measured 23° C. The addition of the octanoyl chloride to the 5-liter flask was begun with stirring of the contents of the 5-liter flask with a mechanical stirrer, immediately after the addition of 0.21 grams of a concentrated aqueous solution of methyltrioctylammonium chloride to the 5-liter flask. Hydrogen sulfide was liberated during the addition of the octanoyl chloride. The addition of the octanoyl chloride was completed in 3 minutes with external cooling of the 5-liter flask using an ice-water bath. The contents of the 5-liter flask reached a maximum temperature of 59° C. The contents of the 5-liter flask were then cooled to ambient temperature and stirring was stopped, yielding a clear, slightly viscous, one-phase aqueous solution of sodium thiooctanoate and sodium chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=[O:27])[CH:12]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=2)C(OC)=O)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.B(O)(O)O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=[O:27])[CH2:12][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: COC(=O)C(C(=O)c1cc(OC)cc(OC)c1)c1ccc(OC)c(OC)c1
Agent: OB(O)O
Product: COc1cc(OC)cc(C(=O)Cc2ccc(OC)c(OC)c2)c1
Temperature: 140 °C
Reaction time: 1 h

Procedure:
90.9 g of crude methyl 3-(3,5-dimethoxyphenyl)-2-(3,4-dimethoxyphenyl)-3-oxopropionate prepared according to Example 3 and 30 g of boric acid are introduced into a 250 ml three-necked round-bottomed flask. The mixture is heated with stirring at 100° C. for 1 h, 120° C. for 1 140° C. for 1 h and then 160° C. for 4 h while distilling off light products. The mixture is cooled to approximately 60° C., 226 g of a 15% sodium hydroxide solution are added dropwise and the mixture is maintained at reflux for 2 h with stirring. The reaction medium is extracted at ambient temperature with 350 ml of toluene, which is washed with 100 ml of water. The organic phase is concentrated to recover 51.70 g of 1-(3,5-dimethoxyphenyl)-2-(3,4-dimethoxyphenyl)ethanone in the form of an oil with a dark brown colour.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH:7]=O)([O-:3])=[O:2].[CH3:18][CH:19]([CH3:35])[C:20]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:24]=1)=[O:21]>>[CH3:18][CH:19]([CH3:35])[C:20]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]2[CH2:34][CH2:33][N:32]([CH2:7][C:6]3[CH:9]=[CH:10][C:11]([N:12]4[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]4)=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[CH2:31][CH2:30]2)[CH:24]=1)=[O:21]
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=Cc1ccc(N2CCCCC2)c([N+](=O)[O-])c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc(N4CCCCC4)c([N+](=O)[O-])c3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 3-nitro-4-(1-piperidinyl)benzaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 465.2 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.C(O[CH:11]=[C:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])C>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][CH:11]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:2]=1
Reactant: Nc1cccnc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)C(=CNc1cccnc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 15 h
Yield: 95.3 %

Procedure:
Pyridin-3-amine (9.41 g, 100 mmol) and diethyl 2-(ethoxymethylene)malonate (21.6 g, 100 mmol) were combined in a 250 mL screw capped vessel and this mixture was placed into a preheated oil bath at 80° C. and the resulting light brown solution was stirred for 15 h at which time LCMS analysis indicated the presence of a new spot. Then, the light brown solution was cooled to room temperature and as a result some solids started to form. The mixture was left at room temperature for 2 h. The solids were hard to break, but the big chunks were collected by filtration and washed with hexanes. After air drying, 25.18 g of diethyl 2-((pyridin-3-ylamino)methylene)malonate (24) (95.3% yield) was isolated as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([NH:11][C:12]([C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][CH2:19][N:20]3[S:23]([C:26]3[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=3[O:33][CH3:34])(=[O:25])=[O:24])=[C:16]([O:35][CH3:36])[CH:15]=2)=[O:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:38]1C=CC(OC)=C(S(Cl)(=O)=O)C=1>>[CH3:38][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([NH:11][C:12]([C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][CH2:19][N:20]3[S:23]([C:26]3[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=3[O:33][CH3:34])(=[O:24])=[O:25])=[C:16]([O:35][CH3:36])[CH:15]=2)=[O:13])=[CH:10][C:2]=1[Cl:1]
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Cl
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1CCc2c(OC)cc(C(=O)Nc3ccc(C(=O)O)c(Cl)c3)cc21
Product: COC(=O)c1ccc(NC(=O)c2cc(OC)c3c(c2)N(S(=O)(=O)c2cc(Cl)ccc2OC)CC3)cc1Cl

Procedure:
2-Chloro-4-{[1-(5-chloro-2-methoxy-benzenesulfonyl)-4-methoxy-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid, m/z (ES+): 551.28 (M+H+.), was prepared in analogy to example 21, steps 1 to 6. Step 5 was performed using 5-chloro-2-methoxy-benzenesulfonyl chloride, yielding 2-chloro-4-{[1-(5-chloro-2-methoxy-benzenesulfonyl)-4-methoxy-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid methyl ester, which was hydrolyzed in step 6.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[Cl:27][C:28]1[CH:43]=[CH:42][C:31]2[N:32]([CH3:41])[C:33]([N:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)=[N:34][C:30]=2[CH:29]=1>>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:38]2[CH2:39][CH2:40][N:35]([C:33]3[N:32]([CH3:41])[C:31]4[CH:42]=[CH:43][C:28]([Cl:27])=[CH:29][C:30]=4[N:34]=3)[CH2:36][CH2:37]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: Cn1c(N2CCNCC2)nc2cc(Cl)ccc21
Product: Cn1c(N2CCN(CCCCC3(C(=O)NCC(F)(F)F)c4ccccc4-c4ccccc43)CC2)nc2cc(Cl)ccc21

Procedure:
Prepared analogously to Example 18 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 5-chloro-1-methyl-2-piperazin-1-yl-1H-benzimidazole
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH2:12])([CH3:11])[CH3:10])=[CH:5][CH:4]=1.[F:13]C1C=CC(C(OC)=O)=CC=1>>[F:13][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH2:12])([CH3:11])[CH3:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(C)(C)N)cc1
Reactant: COC(=O)c1ccc(F)cc1
Product: CC(C)(N)c1ccc(F)cc1
Yield: 20 %

Procedure:
Following a procedure similar to that described in Preparation 10a, but using methyl 4-fluorobenzoate as a starting material, in a relative amount similar to that used in that Preparation, the title compound was obtained in a yield of 20%.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:13][CH2:12]3)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1.C1C(=O)N([I:34])C(=O)C1>CN(C)C=O.CCOC(C)=O>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[O:18])[CH2:13][CH2:12]3)=[N:9][C:10]=2[I:34])[CH:5]=[CH:6][N:7]=1
Reactant: O=C(OCc1ccccc1)N1CCC(c2ncc3c(Cl)nccn23)CC1
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)N1CCC(c2nc(I)c3c(Cl)nccn23)CC1
Temperature: 55 °C
Reaction time: 20 h

Procedure:
To a solution of benzyl 4-(8-chloroimidazo[1,5-a]pyrazin-3-yl)piperidine-1-carboxylate (1.31 g, 0.00354 mol) in DMF (0.6 mL) was added NIS (1.6 g, 0.0071 mol). The reaction mixture was left to stir at 55° C. for 20 h. then the mixture was diluted with EtOAc (20 mL), washed with water (2×40 mL) and brine, then dried over Na2SO4 and concentrated in vacuo. The crude reaction mixture was chromatographed over silica gel eluting with hexane→hexane:EtOAc 1:1 yielding 1.63 g of desired product. 1H NMR (400 MHz, CDCl3): δ 1.95-2.04 (m, 4H), 3.02-3.15 (m, 3H), 4.29-4.32 (m, 2H), 5.15 (s, 2H), 7.32 (d, J=5.2 Hz, 1H), 7.34-7.37 (m, 5H), 7.66 (d, J=5.2 Hz, 1H). MS (ES+): m/z 497.03 [MH+].
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([C:8](O)=[O:9])=[N:6][CH:7]=1.ClC(OCC(C)C)=O.[BH4-].[Na+].[Cl-].[NH4+]>O1CCCC1.CO.C(N(CC)CC)C>[CH3:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][OH:9])=[N:6][CH:7]=1
Reactant: Cc1cnc(C(=O)O)cn1
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cnc(CO)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65.9 %

Procedure:
To a solution of 5-methyl-2-pyrazinecarboxylic acid (1.0 g) in tetrahydrofuran (10 mL) was added triethylamine (1.1 mL) and isobutyl chloroformate (1.0 mL), and the mixture was stirred at 0° C. for 30 minutes. To the reaction mixture was added sodium borohydride (603 mg) and methanol (5 mL) at −78° C. After stirring, to the mixture was added aqueous ammonium chloride and the mixture was extracted with ethyl acetate. The organic layer was separated and concentrated in vacuo. The resultant crude product was purified by a column chromatography on silica gel (solvent; chloroform/methanol=90:10) to give 5-methylpyrazin-2-ylmethyl alcohol (592 mg, yield: 66%).
Reaction SMILES: [C:1]([C:3]1[CH:23]=[CH:22][C:6]([O:7][CH2:8][CH:9]2[CH2:11][N:10]2[C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])=[CH:5][CH:4]=1)#[N:2].[CH:24]12[CH2:32][CH:28]([CH2:29][NH:30][CH2:31]1)[CH2:27][N:26]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:25]2>C(O)(C)C>[CH2:15]([O:14][C:12]([NH:10][CH:9]([CH2:8][O:7][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:23][CH:22]=1)[CH2:11][N:30]1[CH2:31][CH:24]2[CH2:32][CH:28]([CH2:27][N:26]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:25]2)[CH2:29]1)=[O:13])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: N#Cc1ccc(OCC2CN2C(=O)OCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC(C2)C1
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CC2CC(CN(CC(COc3ccc(C#N)cc3)NC(=O)OCc3ccccc3)C2)C1
Temperature: 60 °C
Reaction time: 5 h
Yield: 76 %

Procedure:
Benzyl 2-[(4-cyanophenoxy)methyl]-1-aziridinecarboxylate (1.0 g; 3.2 mmol; from step (iii) above) was mixed with tert-butyl 3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (from step (v) above; 0.73 g; 3.2 mmol) and 30 mL of iso-propanol, and stirred at 60° C. for 5 h, and then at rt overnight. The solvent was evaporated and the crude material was purified on silica (DCM:5% MeOH) yielding 1.3 g (76%) of sub-title compound.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[NH:7][C:6]=1[C:16]([NH:18][CH3:19])=[O:17].O1CCCC1.C(N(CC)CC)C.[CH2:32]([N:34]=[C:35]=[O:36])[CH3:33]>CO>[CH2:32]([NH:34][C:35]([NH:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[NH:7][C:6]=1[C:16]([NH:18][CH3:19])=[O:17])=[O:36])[CH3:33]
Reactant: CNC(=O)c1[nH]c2ccc(OC)cc2c1CCN
Reactant: CCN=C=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CO
Product: CCNC(=O)NCCc1c(C(=O)NC)[nH]c2ccc(OC)cc12
Reaction time: 1 h

Procedure:
To 3-(2-aminoethyl)-5-methoxy-N-methyl-1H-indole-2-carboxamide hydrochloride (100 mg) were added tetrahydrofuran (1.20 mL), triethylamine (0.147 mL), and ethylisocyanate (0.0415 mL), followed by stirring for 1 hour. To the mixture were added silica gel and methanol, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=100:0 to 94:6) to obtain a colorless solid. The obtained solid was washed with hexane/ethyl acetate to obtain 3-{2-[(ethylcarbamoyl)amino]ethyl}-5-methoxy-N-methyl-1H-indole-2-carboxamide (86.0 mg) as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][C:23]([N+:29]([O-:31])=[O:30])=[CH:24][CH:25]=4)[NH:20][C:19]3=S)[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[OH-:35].[K+].O.OO>C(O)C.C(O)(=O)C>[F:1][C:2]1[CH:34]=[CH:33][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][C:23]([N+:29]([O-:31])=[O:30])=[CH:24][CH:25]=4)[NH:20][C:19]3=[O:35])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: O=C(c1ccc(F)cc1)C1CCN(CCCCn2c(=S)[nH]c3cc([N+](=O)[O-])ccc3c2=O)CC1
Agent: OO
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: O=C(c1ccc(F)cc1)C1CCN(CCCCn2c(=O)[nH]c3cc([N+](=O)[O-])ccc3c2=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a stirred mixture of 36 parts of 3-[4-[4-(4-fluorobenzoyl)-1-piperidinyl]butyl]-2,3-dihydro-7-nitro-2-thioxo-4(1H)-quinazolinone, 700 parts of a potassium hydroxide solution in ethanol 5% and 150 parts of water were added 500 parts of a hydrogen peroxide solution 3% at room temperature. The whole was stirred overnight at room temperature. The mixture was neutralized with acetic acid. The product was filtered off, washed with water and 2-propanol and stirred in 2,2'-oxybispropane and thrichloromethane. The product was filtered off and dried, yielding 31 parts (88%) of 3-[4-[4-(4-fluorobenzoyl)-1-piperidinyl]butyl]-7-nitro-2,4(1H,3H)-quinazolinedione; mp. 188° C. (24).
Reaction SMILES: [CH2:1]([N:3]([CH2:27][CH3:28])[C:4](=[O:26])[NH:5][C@H:6]1[CH2:20][C@H:19]2[C@@H:9]([CH2:10][C:11]3[C:21]4[C:14](=[CH:15][CH:16]=[C:17]([C:22]([NH2:24])=O)[C:18]2=4)[NH:13][CH:12]=3)[N:8]([CH3:25])[CH2:7]1)[CH3:2].P(Cl)(Cl)(Cl)=O.[OH-].[K+]>C(Cl)(Cl)Cl>[C:22]([C:17]1[C:18]2=[C:21]3[C:14]([NH:13][CH:12]=[C:11]3[CH2:10][C@@H:9]3[C@@H:19]2[CH2:20][C@H:6]([NH:5][C:4](=[O:26])[N:3]([CH2:27][CH3:28])[CH2:1][CH3:2])[CH2:7][N:8]3[CH3:25])=[CH:15][CH:16]=1)#[N:24]
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3c(C(N)=O)ccc4[nH]cc(c34)C[C@H]2N(C)C1
Agent: [K+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3c(C#N)ccc4[nH]cc(c34)C[C@H]2N(C)C1
Temperature: 55 °C
Reaction time: 16 h
Yield: 43 %

Procedure:
383 mg of [8α-(3,3-diethylureido)-6-methylergolin-12-yl]carboxylic acid amide (1 mmol) is dissolved in 25 ml of chloroform, 3 ml of phosphorus oxychloride is added thereto, and the mixture is agitated for 16 hours at 55° C. The mixture is poured on ice, allowed to stand for 30 minutes, then made alkaline with 1N potassium hydroxide solution, and extracted with methylene chloride. The organic phase is dried with sodium sulfate and evaporated. The residue is crystallized from ethyl acetate in a 43% yield. [α]D =+16° (0.5% in chloroform).
Reaction SMILES: [CH:1]1([S:4][C:5]2[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=2[C:7]#[N:8])[CH2:3][CH2:2]1.S(C)C.[ClH:16]>C1COCC1>[ClH:16].[CH:1]1([S:4][C:5]2[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=2[CH2:7][NH2:8])[CH2:3][CH2:2]1
Reactant: N#Cc1ccccc1SC1CC1
Agent: Cl
Solvent: CSC
Solvent: C1CCOC1
Product: NCc1ccccc1SC1CC1
Temperature: 25 °C
Yield: 79 %

Procedure:
To 1A (1.50 g, 7.25 mmol) in refluxing THF (72 mL) was added a 2M THF solution of BH3.SMe2 (10.8 mL, 21.7 mmol). After heating at reflux for 2 h, the reaction was cooled to rt and 6M HCl (4.32 mL) was slowly added. The reaction was heated to reflux for 30 min, then cooled to rt, concentrated and azeotroped (3×) with THF/MeOH on a rotary evaporator. The resulting residue was taken up in THF and filtered to provide 1B (1.40 g, 79%) as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm 1.15 (m, 2H) 1.29 (m, 2H) 2.91 (m, 1H) 4.52 (s, 2H) 7.72 (m, J=7.69, 7.69 Hz, 2H) 7.80 (t, J=6.81 Hz, 1H) 8.04 (d, J=7.91 Hz, 1H).
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[N:10]=[C:9]([CH:14]([CH3:27])[CH2:15][C:16]3[CH:21]=[CH:20][C:19]([S:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:18][CH:17]=3)[NH:8][C:7]=2[N:6]([CH2:28][CH2:29][CH3:30])[C:5]1=[O:31])[CH2:2][CH3:3].S(=O)(=O)(O)O.[CH3:37]O>C(OCC)C>[CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[N:10]=[C:9]([CH:14]([CH3:27])[CH2:15][C:16]3[CH:21]=[CH:20][C:19]([S:22][CH2:23][C:24]([O:26][CH3:37])=[O:25])=[CH:18][CH:17]=3)[NH:8][C:7]=2[N:6]([CH2:28][CH2:29][CH3:30])[C:5]1=[O:31])[CH2:2][CH3:3]
Reactant: CCCn1c(=O)c2nc(C(C)Cc3ccc(SCC(=O)O)cc3)[nH]c2n(CCC)c1=O
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: CCCn1c(=O)c2nc(C(C)Cc3ccc(SCC(=O)OC)cc3)[nH]c2n(CCC)c1=O
Temperature: 60 °C

Procedure:
Dissolve 2-[4-[2-(2,3,6,9-tetrahydro-1,3-dipropyl-2,6-dioxo-1H-purin-8-yl)propyl]phenylthio]acetic acid (88.8 g, 0.2 mol) in methanol (500 mL) and treat with concentrated sulfuric acid (0.5 mL). Heat to 60° C. for 16 hours, cool and reduce the solvent by 50% in vacuo. Dilute with ethyl ether (500 mL), wash with saturated sodium hydrogen carbonate, then brine. Dry (MgSO4) and evaporate the solvent in vacuo to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:23])[C:5]([C:20]([OH:22])=[O:21])=[CH:6][N:7]2[CH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30][CH2:31][CH2:32][NH2:33].C(N(CC)CC)C>CS(C)=O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([NH:33][CH2:32][CH2:31][NH:30][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=2)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:23])[C:5]([C:20]([OH:22])=[O:21])=[CH:6][N:7]2[CH:14]1[CH2:15][CH2:16][O:17][CH2:18][CH2:19]1
Reactant: NCCNc1ccccn1
Reactant: Nc1c(F)c(F)cc2c1c(=O)c(C(=O)O)cn2C1CCOCC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Nc1c(F)c(NCCNc2ccccn2)cc2c1c(=O)c(C(=O)O)cn2C1CCOCC1
Temperature: 120 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
A mixture of 5-amino-6,7-difluoro-1,4-dihydro-4-oxo-1-(tetrahydropyran-4-yl)-3-quinolinecarboxylic acid (45.0 mg, 0.139 mmol), 2-(2-pyridylamino)ethylamine (29.0 mg, 0.211 mmol), and triethylamine (0.029 mL, 0.209 mmol) in DMSO (1.0 mL) was stirred at 120° C. for 3 h. After dilution of the reaction mixture with 10% MeOH in CHCl3, the whole mixture washed with water, and the washing was extracted with 10% MeOH in CHCl3 two times. The combined the organic layer and the extracts washed with water, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Flash chromatography of the residue (10% MeOH in CHCl3) gave 5-Amino-6-fluoro-1,4-dihydro-4-oxo-1-(tetrahydropyran-4-yl)-7-[2-(2-pyridylamino)ethylamino]-3-quinolinecarboxylic Acid (54.0 mg, 88%) as a white powder.