Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1C(N)=NC(N)=NC=1.[OH:10][C:11]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:12]=1[C:13]([OH:15])=[O:14].C(=O)([O-])[O-].[K+].[K+].IC>>[OH:10][C:11]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:12]=1[C:13]([O:15][CH3:2])=[O:14]
Reactant: Nc1ncc(F)c(N)n1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: COC(=O)c1cc([N+](=O)[O-])ccc1O
Yield: 77 %

Procedure:
In a manner analogous to the preparation of N2,N4-bis(3-methoxy-4-methoxycarbonyl)phenyl)-5-fluoro-2,4-pyrimidinediamine, 2-hydroxy-5-nitrobenzoic acid (1 g, 5.5 mmol), potassium carbonate (3 g, 22 mmol) and iodomethane (1 mL, 16 mmol) gave methyl 2-hydroxy-5-nitrobenzoate (880 mg, 77%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH2:15][CH3:16])=[CH:12][C:11]([CH2:17][C:18]3[C:19]([NH2:25])=[N:20][C:21]([NH2:24])=[N:22][CH:23]=3)=[CH:10][C:9]=2[O:26][CH2:27][CH3:28])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>CN(C)C=O>[NH2:24][C:21]1[N:20]=[C:19]([NH2:25])[C:18]([CH2:17][C:11]2[CH:12]=[C:13]([O:14][CH2:15][CH3:16])[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][S:37]([CH3:36])(=[O:39])=[O:38])[CH:3]=3)=[C:9]([O:26][CH2:27][CH3:28])[CH:10]=2)=[CH:23][N:22]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCOc1cc(Cc2cnc(N)nc2N)cc(OCC)c1-c1cccc(N)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOc1cc(Cc2cnc(N)nc2N)cc(OCC)c1-c1cccc(NS(C)(=O)=O)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
5-(3′-Amino-2,6-diethoxy-biphenyl-4-ylmethyl)-pyrimidine-2,4-diamine (228 mg; 0.6 mmol) is dissolved in dimethylformamide (6 ml; dried over a molecular sieve), triethylamine (0.090 ml; 0.66 mmol) is added at room temperature, and the mixture is cooled to 0° C. and a solution of methanesulphonyl chloride (0.051 ml; 0.66 mmol) in dimethylformamide (1.0 ml) is added in the course of 5 minutes. After 1 hour at 0-5° C. the reaction mixture is concentrated and the residue is taken up in water, after which the pH is adjusted to 10 by addition of NH4OH conc. After stirring for 15 minutes the mixture is filtered with suction and the residue is dried under a high vacuum and chromatographed over silica gel (60 g) with methylene chloride/methanol/NH4OH conc. (19/1/0.05).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:12][C:13]2[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][C:14]=2[F:20])=[CH:7][CH:6]=1)[CH3:2].O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH:48](=[O:52])[CH:49]([CH3:51])[CH3:50].O>O1CCCC1>[CH2:1]([O:3][C:4]([C:5]1[CH:10]=[C:9]2[C:8](=[CH:7][CH:6]=1)[NH:11][CH:12]([C:13]1[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][C:14]=1[F:20])[C:49]([CH3:51])([CH3:50])[CH:48]2[OH:52])=[O:21])[CH3:2]
Reactant: CCOC(=O)c1ccc(N=Cc2cc(Br)ccc2F)cc1
Reactant: CC(C)C=O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1cc(Br)ccc1F)N2
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.8 %

Procedure:
To a mixture of 4-{[1-(5-bromo-2-fluoro-phenyl)-methylidene]-amino}-benzoic acid ethyl ester (2.76 g, 7.9 mmol) and ytterbium(III) triflate hydrate (0.49 g, 0.79 mmol) in dry tetrahydrofuran (10 mL) at 25° C. was added isobutyraldehyde (0.72 mL, 7.9 mmol) and water (0.14 mL, 7.9 mmol) dropwise. The reaction mixture was stirred at 25° C. for 5 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×100 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-(5-bromo-2-fluoro-phenyl)-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (3.33 g, 100%) as a light yellow oil: LC/MS m/e calcd for C20H21BrFNO3 M+: 422.3, observed: 404.2, 406.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[F:17])[O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1.[CH3:18][CH:19]([CH3:36])[C:20]([NH:22][C:23]1[CH:28]=[C:27]([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:26]=[CH:25][C:24]=1[CH3:35])=[O:21]>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[F:17])[O:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][N:32]2[CH2:33][CH2:34][CH:29]([C:27]3[CH:26]=[CH:25][C:24]([CH3:35])=[C:23]([NH:22][C:20](=[O:21])[CH:19]([CH3:18])[CH3:36])[CH:28]=3)[CH2:30][CH2:31]2)=[CH:8][CH:7]=1
Reactant: Cc1ccc(C2CCNCC2)cc1NC(=O)C(C)C
Reactant: O=Cc1ccc(Oc2ccc(F)c(F)c2)cc1
Product: Cc1ccc(C2CCN(Cc3ccc(Oc4ccc(F)c(F)c4)cc3)CC2)cc1NC(=O)C(C)C

Procedure:
Prepared by Procedure AA and Scheme AJ using 4-(3,4-difluorophenoxy)benzaldehyde and 2-methyl-N-[2-methyl-5-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 479.2 (M+H)+.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.CC([N:24]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]2[CH2:39][CH2:38][NH:37][CH2:36]2)=[CH:31][CH:30]=1)C(=O)[O-])(C)C>>[NH2:24][CH2:28][C:29]1[CH:30]=[CH:31][C:32]([CH:35]2[CH2:39][CH2:38][N:37]([C:11]3[CH:12]=[C:13]4[C:8]([C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5][N:4]4[CH:1]4[CH2:3][CH2:2]4)=[CH:9][C:10]=3[F:15])[CH2:36]2)=[CH:33][CH:34]=1
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Reactant: CC(C)(C)N(Cc1ccc(C2CCNC2)cc1)C(=O)[O-]
Product: NCc1ccc(C2CCN(c3cc4c(cc3F)c(=O)c(C(=O)O)cn4C3CC3)C2)cc1

Procedure:
Starting from 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.88 g, 3.3 mmol) and 1,1-dimethylethyl[[4-(3-pyrrolidinyl)phenyl]methyl]carbamate, a procedure analogous to that given in Example 6 provided the title compound (1.02 g) as a bright yellow solid, mp 268°-272° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[N:7]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([CH:19]=O)[CH:13]=1)[CH2:8][CH3:9])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH:29]1([NH2:32])[CH2:31][CH2:30]1.[BH4-].[Na+].C([O-])(O)=O.[Na+]>CO>[C:1]([O:5][C:6](=[O:21])[N:7]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([CH2:19][NH:32][CH:29]2[CH2:31][CH2:30]2)[CH:13]=1)[CH2:8][CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: NC1CC1
Reactant: CCN(CCc1ccc(Cl)c(C=O)c1)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: CCN(CCc1ccc(Cl)c(CNC2CC2)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.1 %

Procedure:
A mixture of [2-(4-chloro-3-formyl-phenyl)-ethyl]-ethyl-carbamic acid tert-butyl ester (80.1 mg, 0.257 mmol), Et3N (0.054 mL, 0.386 mmol) and cyclopropylamine (0.027 mL, 0.386 mmol) in MeOH (0.86 mL) was heated to reflux for 4 h. The mixture was allowed to cool to rt, and NaBH4 (24.2 mg, 0.642 mmol) was added in portions. The mixture was stirred for 1 h, and aq. sat. NaHCO3 was added. The mixture was extracted with EtOAc several times, and the combined org. extracts were washed with brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (CH2Cl2/MeOH 95:5) yielded the title compound (40 mg, 44%). LC-MS: tR=0.81 min; ES+: 353.22.
Reaction SMILES: O=[C:2]1[CH:6]([C:7]([O:9][CH3:10])=[O:8])[CH2:5][S:4][CH2:3]1.[C:11]1([NH:17][C:18]([NH2:20])=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1(C)C(S(O)(=O)=O)=CC=CC=1.C1CCCCC1>O>[C:11]1([NH:17][C:18]([NH:20][C:2]2[CH2:3][S:4][CH2:5][C:6]=2[C:7]([O:9][CH3:10])=[O:8])=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)C1CSCC1=O
Reactant: NC(=O)Nc1ccccc1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: C1CCCCC1
Solvent: O
Product: COC(=O)C1=C(NC(=O)Nc2ccccc2)CSC1

Procedure:
14.4 parts by weight of methyl 3-keto-3,4-dihydrothiophene-4-carboxylate, 16.1 parts by weight of phenylurea and 0.5 part by weight of toluenesulfonic acid in 90 parts by weight of cyclohexane were refluxed for 3 hours, while stirring, in an apparatus equipped with a water separator. The mixture was cooled, and the residue was then filtered off under suction and recrystallized from ethanol. 16.1 parts by weight of N-phenyl-N'-(3-methoxycarbonyl-2,5-dihydrothien-4-yl)-urea of melting point 182°-184° C. were obtained.
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[CH2:17]([O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=O)[CH2:18][CH3:19].Cl>C1COCC1.O>[CH2:17]([O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:18][CH3:19]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CCCOc1cccc(C=O)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCOc1cccc(C=CC(=O)OCC)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 104.5 %

Procedure:
To ethyl diethylphosphonoacetate (24.7 g) was added THF (200 ml), and sodium hydride (60%, 4.4 g) was added at 0° C. to the resulting mixture, to which was then added dropwise a solution of 3-propoxybenzaldehyde (16.1 g) in THF (100 ml). The resulting mixture was stirred at room temperature for 1.5 hours. The reaction mixture was poured into water, was neutralized with hydrochloric acid and was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with anhydrous magnesium sulfate. After concentration under reduced pressure to remove the solvent, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=6:1) to obtain ethyl 3-propoxycinnamate (24.0 g) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.[CH:17]1([CH2:20][NH2:21])[CH2:19][CH2:18]1.C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:21][CH2:20][CH:17]1[CH2:19][CH2:18]1)=[O:9]
Reactant: O=C(O)c1cncc(Br)c1
Reactant: NCC1CC1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(NCC1CC1)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.1 %

Procedure:
To a solution of 5-bromonicotinic acid (XVI) (1.01 g, 5 mmol) in dry DCM (10 mL) under nitrogen was added oxalyl chloride (0.654 mL, 7.5 mmol) followed by dry DMF (0.1 mL) The solution was stirred at r.t. for 30 min. The solvent was evaporated under vacuum before adding dry pyridine (10 mL) followed by cyclopropylmethanamine (0.39 mL, 4.5 mmol). The solution was stirred at r.t. under nitrogen for 2 h. The solution was poured into ice water, basified with sat. aq. NaHCO3 and extracted with DCM. The combined organic phases were dried over MgSO4, concentrated and dried under vacuum to yield 5-bromo-N-(cyclopropylmethyl)nicotinamide (XVII) as an off-white solid (0.82 g, 3.2 mmol, 71% yield). 1H NMR (DMSO-d6) δ ppm −0.07-0.07 (m, 2H), 0.15-0.29 (m, 2H), 0.68-0.88 (m, 1H), 2.93 (t, J=6.22 Hz, 2H), 8.20 (t, J=1.88 Hz, 1H), 8.62 (d, J=1.70 Hz, 2H), 8.75 (s, 1H); ESIMS found C10H11BrN2O m/z 254, 256 (M+, M+2).
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:5])[CH3:4].[H-].[Na+].CO[C:10]([C:12]1[N:13]([CH:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][C:18]2([CH3:27])[CH3:26])[CH:14]=[N:15][CH:16]=1)=O>C1COCC1>[CH3:26][C:18]1([CH3:27])[CH2:19][C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:17]1[N:13]1[C:12]([C:10]2[O:1][N:2]=[C:3]([CH3:4])[N:5]=2)=[CH:16][N:15]=[CH:14]1
Reactant: COC(=O)c1cncn1C1c2ccccc2CC1(C)C
Reactant: CC(=N)NO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1noc(-c2cncn2C2c3ccccc3CC2(C)C)n1
Temperature: 0 °C

Procedure:
To a solution N-hydroxy-acetamidine (137 mg, 1.85 mmol) in THF (5 mL) is added 4 angstrom molecular sieves (500 mg) followed by a 60% oil dispersion of NaH (80 mg, 2.0 mmol). The heterogeneous mixture is heated at 60° C. for 1 hour at which time a solution of 3-(2,2-dimethyl-indan-1-yl)-3H-imidazole-4-carboxylic acid methyl ester, which can be prepared as described in Example 10, (200 mg, 0.74 mmol) in THF (5 mL) is added. The reaction is heated at reflux for 1.5 hours, at which time the reaction is cooled to 0° C. and quenched with water. The reaction is diluted with dichloromethane and filtered. The layers are separated and the aqueous layer is extracted three times with dichloromethane. The organic layers are combined, dried with Na2SO4, filtered, and concentrated. The resulting residue is purified by silica gel flash chromatography (ethyl acetate-dichloromethane, 0:1 to 1:9) to afford 5-[3-(2,2-Dimethyl-indan-1-yl)-3H-imidazol-4-yl]-3-methyl-[1,2,4]oxadiazole; HRMS: (ESI) m/z 259.1566 [(M+H)+: Calcd for C17H19N4O: 295.1559]; 1H NMR (400 MHz, CDCl3) δ ppm 0.75 (s, 3 H), 1.27 (s, 3 H), 2.50 (s, 3 H), 2.71-3.10 (m, 2 H), 6.37 (s, 1 H), 7.17 (s, 1 H), 7.23-7.43 (m, 4 H), 7.98 (s, 1 H).
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].[F:15][C:16]([F:34])([F:33])[C:17]1[C:27]2[S:26][C:25]3[CH:28]=[CH:29][CH2:30][CH2:31][C:24]=3[NH:23][C:22](=O)[C:21]=2[CH:20]=[CH:19][CH:18]=1.O>N1C=CC=CC=1>[F:15][C:16]([F:34])([F:33])[C:17]1[C:27]2[S:26][C:25]3[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=3[NH:23][C:22](=[S:2])[C:21]=2[CH:20]=[CH:19][CH:18]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C1NC2=C(C=CCC2)Sc2c1cccc2C(F)(F)F
Solvent: c1ccncc1
Solvent: O
Product: FC(F)(F)c1cccc2c1Sc1ccccc1NC2=S
Yield: 80.8 %

Procedure:
Phosphorus pentasulphide (0.6 g, 2.5 mmol) was added to a stirred solution of 4-trifluoromethyl-9,10-dihydrodibenzo[b,f][1,4]thiazepin-11-one (0.59 g, 2 mmol) in pyridine (20 ml). The mixture was heated under reflux for 6.5 hr and then at room temperature overnight before hot water (40 ml) added. Filtration and recrystallisation from ethanol gave the title compound as fine yellow needles (0.503 g, m.p. 265°-267° C., Rf 0.65, petrol/EtOAc 1:1).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[CH:9][N:10]=[C:4]2[CH:3]=1.[CH3:11][S:12]([C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1)(=[O:14])=[O:13].C(=O)([O-])[O-].[Cs+].[Cs+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCO>[CH3:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([C:2]2[CH:7]=[CH:6][N:5]3[CH:8]=[CH:9][N:10]=[C:4]3[CH:3]=2)=[CH:17][CH:16]=1)(=[O:14])=[O:13]
Reactant: Clc1ccn2ccnc2c1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: CCO
Product: CS(=O)(=O)c1ccc(-c2ccn3ccnc3c2)cc1
Temperature: 25 °C
Yield: 361.2 %

Procedure:
Heat a mixture of 7-chloro-imidazo[1,2-a]pyridine (100 g, 152.5 mmol, 1 eq), 4-methylsulfonylphenyl boronic acid (157.3 g, 786.8 mmol, 1.2 eq), Pd(PPh3)4 (19 g, 16.3 mmol, 0.025 eq) and cesium carbonate (472.4 g, 1.44 mol, 2.2 eq) in a mixture of anhydrous DME (2000 mL) and EtOH (1000 mL) at 80° C. under N2 atmosphere for 24 hours. Cool the mixture to room temperature and filter through Celite® to remove Pd catalyst. Add water (5000 mL) and extract this solution with CH2Cl2 (3×2000 mL). Dry the organic phase over MgSO4 and evaporate. Add to the crude 2000 mL of CH2Cl2 and heat to reflux. Remove insoluble materials by filtration and evaporate the solvent to afford a yellow solid. Wash the solid with ethyl ether to give 150 g of the desired compound as a light yellow solid. (Yield: 85%). MS (ES), m/z 273 (M+1).
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([C:11](=[O:25])[CH2:12][CH2:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]3[CH2:22][CH2:23][CH2:24][C@H:18]3[CH2:17]2)=[O:15])[CH:6]=[CH:7][C:8]=1OC.[Cl:26]C1C=CC(C(CCC(O)=O)=O)=CC=1>>[Cl:26][C:8]1[CH:7]=[CH:6][C:5]([C:11](=[O:25])[CH2:12][CH2:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]3[CH2:22][CH2:23][CH2:24][C@H:18]3[CH2:17]2)=[O:15])=[CH:4][CH:3]=1
Reactant: O=C(O)CCC(=O)c1ccc(Cl)cc1
Reactant: COc1ccc(C(=O)CCC(=O)N2CCN3CCC[C@H]3C2)cc1OC
Product: O=C(CCC(=O)N1CCN2CCC[C@H]2C1)c1ccc(Cl)cc1

Procedure:
279 mg of the title compound were prepared as described for 1-(3,4-dimethoxy-phenyl)-4-((S)-hexahydropyrrolo[1,2-a]pyrazin-2-yl)butane-1,4-dione, using 3-(4-chlorobenzoyl) propionic acid instead of 3-(3,4-dimethoxybenzoyl)propionic acid.
Reaction SMILES: [CH3:1][C:2]([CH3:12])([CH2:9][CH2:10][CH3:11])[CH2:3][CH:4]([OH:8])/[CH:5]=[CH:6]/[I:7].[C:13]1([C:19](Br)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:1][C:2]([CH3:12])([CH2:9][CH2:10][CH3:11])[CH2:3][CH:4]([O:8][C:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)/[CH:5]=[CH:6]/[I:7]
Reactant: CCCC(C)(C)CC(O)/C=C/I
Reactant: BrC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCCC(C)(C)CC(/C=C/I)OC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
Treatment of 6.0 g. of 5,5-dimethyl-1-iodo-trans-1-octen-3-ol (Example 1000) with 6.9 g. of triphenylmethyl bromide in 30 ml. of pyridine and purification on Florisil, all as described in Example 728 gives the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:21]([CH3:23])[CH3:22])[CH:15]=3)[C:9]2=[O:12])=[CH:4][C:3]=1[N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH3:36])[CH2:26][CH2:25]1.ClCCl.C(N(CC)C(C)C)(C)C.[O:49]1[CH:53]=[CH:52][CH:51]=[C:50]1[C:54](Cl)=[O:55]>>[CH3:22][N:21]([CH2:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[CH2:13][N:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][C:2]([NH:1][C:54]([C:50]3[O:49][CH:53]=[CH:52][CH:51]=3)=[O:55])=[C:3]([N:24]3[CH2:25][CH2:26][N:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[CH3:36])[CH2:28][CH2:29]3)[CH:4]=2)[C:9]1=[O:12])[CH3:23]
Reactant: O=C(Cl)c1ccco1
Reactant: Cc1ccccc1N1CCN(c2cc3c(cc2N)C(=O)N(Cc2cccc(CN(C)C)c2)CC3)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccccc1N1CCN(c2cc3c(cc2NC(=O)c2ccco2)C(=O)N(Cc2cccc(CN(C)C)c2)CC3)CC1
Reaction time: 8 h
Yield: 13.3 %

Procedure:
In a 40 ml scintillation vial equipped with a magnetic stir bar and fitted with a nitrogen inlet, the 7-amino-2-(3-dimethylaminomethyl-benzyl)-6-(4-o-tolyl-piperazin-1-yl)-3,4-dihydro-2H-isoquinolin-1-one 11b (73.70 mg, 0.15 mmol) was taken up in clean, dry, reagent-grade dichloromethane (3.00 ml, 46.52 mmol) and the mixture was stirred at room temperature under nitrogen atmosphere until the solids were all in solution. To this stirred solution was then added the N,N-diisopropylethylamine (0.08 ml, 0.46 mmol) followed by the furan-2-carbonyl chloride (0.02 ml, 0.20 mmol) and the reaction was allowed to stir overnight. The reaction was quenched with 3 ml of 2N HCl. The product solution was diluted with 10 ml of water and 10 ml of dichloromethane. The layers were separated and the product was extracted using dichloromethane (3×10 ml). The organic phases were combined and washed with brine (1×25 ml) and the product solution was then dried over MgSO4. The solution was then filtered under vacuum and the collected solution was concentrated under reduced pressure. The resultant yellow oil was then purified using silica gel column chromatography, eluting 100% dichloromethane to 7.5% MeOH in dichloromethane. The product needed further purification and was subjected to reverse-phase HPLC, eluting a gradient of 30% MeOH in water to 100% MeOH over a 5 min period. Furan-2-carboxylic acid [2-(3-dimethylaminomethyl-benzyl)-1-oxo-6-(4-o-tolyl-piperazin-1-yl)-1,2,3,4-tetrahydro-isoquinolin-7-yl]-amide 11c (11.30 mg, 0.02 mmol) was isolated as a white solid.
Reaction SMILES: [CH:1]([C:3]1[NH:4][CH:5]=[C:6]2[O:11][CH2:10][CH2:9][O:8][C:7]=12)=[O:2].[O:12](C(OC(C)(C)C)=O)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=O.C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[C:13]([N:4]1[CH:5]=[C:6]2[O:11][CH2:10][CH2:9][O:8][C:7]2=[C:3]1[CH:1]=[O:2])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:12]
Reactant: O=Cc1[nH]cc2c1OCCO2
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1cc2c(c1C=O)OCCO2
Reaction time: 3 h
Yield: 91.1 %

Procedure:
To a solution of aldehyde 19 (0.8 g, 5.2 mmol) in dichloromethane was added (BOC)2O (1.1 g, 5.2 mmol), triethylamine (1.1 g, 10.4 mmol), and 4-dimethylaminopyridine (DMAP) (61 mg, 0.5 mmol). The reaction mixture was stirred for 3 h and concentrated under reduced pressure. The residue was purified by chromatography on silica gel using hexane/ethyl acetate (3:1) as eluent to yield a colorless crystalline product (1.2 g, 90%): mp 94-95° C.; 1H NMR (300 MHz, CDCl3) δ10.24 (s, 1H), 6.88 (s, 1H), 4.38 (m, 2H), 4.22 (m, 2H), 1.60 (s, 9H); 13C NMR (75 MHz, CDCl3) δ180.9, 148.8, 143.2, 134.2, 116.6, 107.9, 85.1, 66.1, 64.9, 27.9; FT-IR (CDCl3) 2930, 2859, 1653, 1544, 1460, 1380, 1322 cm−1; Anal. Calcd for C12H15NO5: C, 56.91; H 5.97; N, 5.53. Found: C, 56.90; H, 5.80; N, 5.73.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[I-:11].[Na+]>CC(=O)CC>[NH2:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][C:5]([I:11])=[CH:6][CH:7]=1
Reactant: [I-]
Reactant: N#Cc1nc(Cl)ccc1N
Agent: [Na+]
Solvent: CCC(C)=O
Product: N#Cc1nc(I)ccc1N

Procedure:
A stirred suspension of 12.0 grams (0.08 mole) of 3-amino-6-chloro-2-cyanopyridine [prepared by the method of Colbry, Elslager, and Werbel; previously cited] and 26.9 grams (0.18 mole) of sodium iodide in 300 mL of n-butanone is heated at reflux for about 3 days. After this time, the reaction mixture is concentrated under reduced pressure to a residue. The residue is then stirred with about 50 mL of water. The resultant solid is collected by filtration and washed with water. The solid is dried, yielding 3-amino-2-cyano-6-iodopyridine.
Reaction SMILES: [C:1]1([C:7](=[O:22])[C:8]([S:20][CH3:21])=[CH:9][CH:10]=[C:11]([N:17]([CH3:19])[CH3:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[B-](F)(F)F.CN(C)C([C:36](OCC)=[O:37])=CC=[N+](C)C.CC[O-].[Na+]>C(O)C>[CH3:19][N:17]([CH3:18])[C:11](=[CH:10][CH:9]=[C:8]([S:20][CH3:21])[C:7]([C:1]1[CH:2]=[CH:3][C:4]([O:37][CH3:36])=[CH:5][CH:6]=1)=[O:22])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C(=CC=C(SC)C(=O)c1ccccc1)N(C)C
Reactant: CCOC(=O)C(=CC=[N+](C)C)N(C)C
Agent: CC[O-]
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=CC=C(SC)C(=O)c1ccc(OC)cc1)N(C)C

Procedure:
The procedure is as in Example 4 for the preparation of ethyl 6-phenyl-6-oxo-5-methylthio-2-dimethylamino-2,4-hexadienoate, starting with N-(3-dimethylamino-3-ethoxycarbonylpropenylidene)-N-methylmethanaminium tetrafluoroborate (13.9 g), a 2M ethanolic solution of sodium ethylate (24.2 cc) and α-methylthio-4-methoxyacetophenone (9.5 g) in ethanol (97 cc). After purification on a silica column with a mixture of cyclohexane and ethyl acetate (50:50 by volume) as eluent, ethyl 2-dimethylamino-6-(4-methoxyphenyl)-5-methylthio-6-oxo-2,4-hexadienoate (6.1 g) is obtained, and is used in the crude state in the subsequent syntheses.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:26][CH3:27])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:5]=1[O:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].[C:28]1([CH2:34]CO)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.S([O-])(O)(=O)=O.[K+].CO>C1(C)C=CC=CC=1>[C:4]1([CH2:3][CH2:27][O:26][CH:3]([O:2][CH2:1][CH2:34][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:5]=2[O:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCCc1ccccc1
Reactant: COC(OC)c1cccc(OC(=O)OC(C)(C)C)c1OC(=O)OC(C)(C)C
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(C)(C)OC(=O)Oc1cccc(C(OCCc2ccccc2)OCCc2ccccc2)c1OC(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
An amount of 1.43 g (3.73 mmol) of 2,3-bis-tert.-butoxycarbonyloxy-benzaldehyde dimethylacetal was dissolved in 40 ml of dried toluene. After the addition of 0.91 g (7.46 mmol) of 2-phenylethanol and 18 mg of potassium hydrogen sulfate, the resulting mixture was stirred for 1 hour under reflux. The methanol formed was then distilled off slowly, while more toluene was added to the mixture. After complete removal of the methanol, the mixture was cooled down and the potassium hydrogensulfate was filtered off. The filtrate was concentrated in a rotary evaporator. This gave a yellowish, viscous oil which was dried in an oil pump vacuum.