Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.C[O:7][CH:8]=[CH:9][C:10]([CH3:15])([CH3:14])[CH2:11][CH:12]=[CH2:13].C(=O)(O)[O-].[Na+]>O1CCCC1>[CH3:14][C:10]([CH3:15])([CH2:11][CH:12]=[CH2:13])[CH2:9][CH:8]=[O:7]
Reactant: C=CCC(C)(C)C=COC
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCC(C)(C)CC=O
Reaction time: 1 h

Procedure:
In a 500-mL round-bottom flask, sulfuric acid (48 mL; 30%) was added to a stirred tetrahydrofuran (150 mL) solution of 1-methoxy-3,3-dimethylhexa-1,5-diene (15.89 g, 0.113 mol). After the mixture had been stirred for 1 hour, it was gradually poured into saturated sodium bicarbonate (ca. 500 mL), and then extracted with diethyl ether (4×200 mL). The combined extracts were washed with brine, dried over sodium sulfate, and filtered. Evaporation of the solvent gave the title compound as a pale yellow liquid.
Reaction SMILES: [CH3:1][C@@H:2]([O:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)=[C:9]([NH2:22])[N:8]=1)[CH2:3][CH2:4][CH3:5].[Br:23]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.ClCCl>[Br:23][C:12]1[N:13]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[C:14]2[C:10]([N:11]=1)=[C:9]([NH2:22])[N:8]=[C:7]([O:6][C@H:2]([CH3:1])[CH2:3][CH2:4][CH3:5])[N:15]=2
Reactant: CCC[C@@H](C)Oc1nc(N)c2ncn(C3CCCCO3)c2n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCC[C@@H](C)Oc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82.3 %

Procedure:
2-{[(1R)-1-methylbutyl]oxy}-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (5.05 g, 16.54 mmol) was dissolved in chloroform (30 ml) and cooled to 0° C. To this solution N-bromosuccinimide (3.24 g, 18.19 mmol) was added portionwise keeping the temperature below 2° C. This gave a dark green solution which was stirred at 0° C. for 30 minutes before allowing to warm to room temperature and stirring for 6 hours. The reaction mixture was washed with water (2×50 ml) and the layers separated using hydrophobic frit. The organic layer was concentrated to give a dark brown gum which was dissolved in dichloromethane and purified by chromatography silica (100 g) using a 0-50% gradient of ethyl acetate-cyclohexane over 60 mins on a Flashmaster II. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a yellow foam (5.23 g).
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.CCCCCC.C([Li])CCC.[C:21](#[N:23])[CH3:22].[CH3:24][O:25][C:26]1[CH:35]=[C:34]2[C:29]([CH2:30][CH2:31][C:32]([CH3:38])([CH3:37])[C:33]2=[O:36])=[CH:28][CH:27]=1>C1COCC1.O>[C:21]([CH2:22][C:33]1([OH:36])[C:34]2[C:29](=[CH:28][CH:27]=[C:26]([O:25][CH3:24])[CH:35]=2)[CH2:30][CH2:31][C:32]1([CH3:37])[CH3:38])#[N:23]
Reactant: CC#N
Reactant: COc1ccc2c(c1)C(=O)C(C)(C)CC2
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(c1)C(O)(CC#N)C(C)(C)CC2
Reaction time: 0.17 h
Yield: 88.2 %

Procedure:
To a solution of 1,1,1,3,3,3-hexamethyldisilazane (4.74 g, 29.4 mmol) in THF (30 ml) was gradually added dropwise, at −78° C., a butyllithium hexane solution (1.56 M hexane solution, 18.8 ml, 29.4 mmol). The mixture was stirred for 10 minutes, to which was then added acetonitrile (1.41 ml, 26.9 mmol). The reaction mixture was stirred for further 20 minutes, to which was then added dropwise a solution of 7-methoxy-2,2-dimethyl-1-tetralone (5.0 g, 24.5 mmol) in THF (10 ml), followed by stirring for 2 hours. The reaction mixture was poured into water, and the organic layer was subjected to extraction with chloroform. The extract solution was washed with brine and water, which was dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was purified by means of a silica gel column chromatography (ethyl acetate:hexane=2:8) to give the above-titled compound (5.3 g, yield 88%).
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[C:6]2[CH:13]=[CH:12][NH:11][C:7]=2[N:8]=[CH:9][N:10]=1.C([O-])=O.[NH4+]>C(O)C>[F:1][C:2]1[CH:17]=[C:16]([NH2:18])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[C:6]2[CH:13]=[CH:12][NH:11][C:7]=2[N:8]=[CH:9][N:10]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ncnc3[nH]ccc23)c(F)c1
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: Nc1ccc(Oc2ncnc3[nH]ccc23)c(F)c1
Reaction time: 0.5 h

Procedure:
To a round bottom flask equipped with a magnetic stir bar was added 4-(2-fluoro-4-nitro-phenoxy)-7H-pyrrolo[2,3-d]pyrimidine (0.5 g, 2.0 mmol, 1.0 eq.), 5% PtS (20% by weight, 120 mg) ammonium formate (451 mg, 6 eq), and ethanol (20 ml). The reaction mixture was heated at reflux with stirring for 30 min upon which the reaction was filtered hot through celite. Removal of the ethanol was followed by the addition of 1N HCl, which was further washed twice with DCM (50 ml). The aqueous layer was basified and extracted with DCM. The organic layer was then washed twice with brine (50 ml) and dried over sodium sulfate. After removal of solvent in vacuo, 3-fluoro-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)-phenylamine as a brownish solid was obtained (0.281 g, 63%). MS (ESI) for C12H9FN4O: 244 (MH+).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:4]=[C:3]1[CH2:15][C:16]([O-:18])=O.[Na+].Cl.[CH3:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][CH2:25][NH:26]2.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[N:4]=[C:3]1[CH2:15][C:16]([N:26]1[C:27]2[C:23](=[C:22]([CH3:21])[CH:30]=[CH:29][CH:28]=2)[CH2:24][CH2:25]1)=[O:18]
Reactant: Cc1cccc2c1CCN2
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cc1cccc2c1CCN2C(=O)Cc1nc(N2CCOCC2)cc(=O)n1C
Yield: 25.3 %

Procedure:
The product is prepared according to the procedure described in example 68, using 275 mg of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 339 mg of 4-methylindoline hydrochloride and 254 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 240 μl of pyridine and 4.0 ml of N,N-dimethylformamide. 93 mg of 3-methyl-2-[2-(4-methyl-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a pink powder, the characteristics of which are the following:
Reaction SMILES: [CH:1]1[C:2]([CH2:10][C@@H:11]([NH2:28])[CH2:12][C:13]([N:15]2[CH2:27][C:19]3=[N:20][N:21]=[C:22]([C:23]([F:26])([F:25])[F:24])[N:18]3[CH2:17][CH2:16]2)=[O:14])=[C:3]([F:9])[CH:4]=[C:5]([F:8])[C:6]=1[F:7].[C:29]([OH:36])(=[O:35])[CH2:30][CH2:31][C:32]([OH:34])=[O:33]>C(O)(C)C>[CH:1]1[C:2]([CH2:10][C@@H:11]([NH2:28])[CH2:12][C:13]([N:15]2[CH2:27][C:19]3=[N:20][N:21]=[C:22]([C:23]([F:26])([F:25])[F:24])[N:18]3[CH2:17][CH2:16]2)=[O:14])=[C:3]([F:9])[CH:4]=[C:5]([F:8])[C:6]=1[F:7].[C:29]([O-:36])(=[O:35])[CH2:30][CH2:31][C:32]([O-:34])=[O:33]
Reactant: O=C(O)CCC(=O)O
Agent: N[C@@H](CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Solvent: CC(C)O
Product: O=C([O-])CCC(=O)[O-]
Temperature: 80 °C
Reaction time: 23 h

Procedure:
Sitagliptin (5 g) and isopropanol (50 mL) are charged into a round-bottom flask and the mixture is heated to about 80° C. for about 30 minutes to obtain a clear dissolution. Succinic acid (1.44 g) is added and the reaction mixture is refluxed for about 1.5 hours. The reaction mixture is cooled to about 30° C. and stirred for about 23 hours. The separated solid is filtered, washed with isopropanol (5 mL), and dried under reduced pressure at about 50° C. for about 3 hours to afford the title compound. (Yield: 4.0 g; MC: 1.79% w/w; HPLC purity: 99.72%)
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[CH3:13][O:14][C:15]1[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[C:21]2[C:16]=1[CH2:17][CH2:18][NH:19][CH2:20]2.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:13][O:14][C:15]1[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[C:21]2[C:16]=1[CH2:17][CH2:18][N:19]([CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1)[CH2:20]2
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Reactant: COc1ccc2c(c1OC)CCNC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1OC)CCN(CCc1ccc([N+](=O)[O-])cc1)C2
Yield: 67.7 %

Procedure:
A mixture of 1-(2-bromoethyl)-4-nitrobenzene (0.3 g), 1,2,3,4-tetrahydro-5,6-dimethoxyisoquinoline [0.25 g; R. D. Haworth, J. Chem. Soc., 2281 (1987); Robin D. Clark, J. Med. Chem., 596-600, 33, (1990)] and potassium carbonate (0.5 g) in DMF (25 ml) was heated at 60° for 3 h. The mixture was then filtered and the filtrate evaporated. The residue was taken up in water, extracted with dichloromethane, dried, evaporated and purified by column chromatography eluting with dichloromethane/methanol (99:1) to give the title compound (0.3 g) as an orange solid, MP:97°. NMR includes signals at d 3.6 (2H,s,N--CH2Ar), 3.75 (6H,s,OCH3).
Reaction SMILES: O[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=O.CC1C(=O)CCCC=1C.[CH3:18][CH2:19][C:20](=[O:23])[CH:21]=[CH2:22].[OH-].[K+].[Li+].CC([N-]C(C)C)C>CO.C1COCC1>[CH3:22][CH:21]1[CH2:6][C:7]2[C:18]([CH2:5][CH2:4][CH2:3][CH:2]=2)=[CH:19][C:20]1=[O:23]
Reactant: O=C1CCCCC1O
Reactant: C=CC(=O)CC
Agent: CC(C)[N-]C(C)C
Agent: CC1=C(C)C(=O)CCC1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: CC1CC2=CCCCC2=CC1=O

Procedure:
This material is prepared according to the procedure for Preparation 5 wherein 2-hydroxycyclohexanone is substituted for 2,3-dimethylcyclohexenone, methylbutenone is substituted for MVK, and 2N KOH in MeOH is substituted fro LDA in THF.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:14](O)=[O:15])[C:11]3[CH:23]=[C:24]([F:28])[C:25]([F:27])=[CH:26][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[NH2:29][C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][C:31]=1[F:38]>CCCCCCC.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH:13]([CH:17]3[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]3)[C:14]([NH:29][C:30]3[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][C:31]=3[F:38])=[O:15])[C:11]3[CH:23]=[C:24]([F:28])[C:25]([F:27])=[CH:26][C:10]=3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Reactant: N#Cc1ccc(N)c(F)c1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: N#Cc1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)c(F)c1

Procedure:
The title compound was prepared in analogy to example 22, int. d) from [2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-cyclohexyl-acetic acid and 4-amino-3-fluorobenzonitrile and using a gradient of heptane:ethyl acetate (1:1 to 4:1) as eluant. The title product was crystallized from tert-butyl methyl ether to give 0.79 g (61%) of a white solid (29%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:14])=[C:6]([NH:8][C:9](=[O:13])/[CH:10]=N\O)[CH:7]=1.[OH:15]S(O)(=O)=O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:14])=[C:6]2[C:7]=1[C:10](=[O:15])[C:9](=[O:13])[NH:8]2
Reactant: O=S(=O)(O)O
Reactant: Cc1ccc(F)cc1NC(=O)/C=N\O
Product: Cc1ccc(F)c2c1NC(=O)C2=O
Temperature: 60 °C

Procedure:
(Z)—N-(5-Fluoro-2-methylphenyl)-2-(hydroxyimino)acetamide (7.22, 37 mmol) was dissolved in neat H2SO4 (50 ml) and heated at 60° C. for 1 h. The resulting solid was collected by filtration and washed with water to yield the title compound. 1H NMR (CDCl3, 400 MHz) δ 8.35 (bs, 1H), 7.45 (m, 1H), 6.73 (m, 1H), 2.25 (s, 3H).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH:10]1([C:13]2[N:18]=[C:17]([Cl:19])[C:16]([CH3:20])=[C:15](Cl)[N:14]=2)[CH2:12][CH2:11]1.N1CCC([C:28]2[CH:37]=[CH:36][C:35]3[C:30](=[N:31][CH:32]=[CH:33][CH:34]=3)[N:29]=2)CC1.N1C2C(=CC=CN=2)C=CC=1.C(=O)(O)[O-].[Na+]>O.C(OCC)(=O)C.CC(N(C)C)=O>[CH:10]1([C:13]2[N:14]=[C:15]([C:28]3[CH:37]=[CH:36][C:35]4[C:30](=[N:31][CH:32]=[CH:33][CH:34]=4)[N:29]=3)[C:16]([CH3:20])=[C:17]([Cl:19])[N:18]=2)[CH2:11][CH2:12]1
Reactant: c1cnc2nc(C3CCNCC3)ccc2c1
Reactant: Cc1c(Cl)nc(C2CC2)nc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1cnc2ncccc2c1
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(Cl)nc(C2CC2)nc1-c1ccc2cccnc2n1
Temperature: 100 °C
Yield: 66.1 %

Procedure:
20 ml of dimethylacetamide and 3.36 ml (19.2 mmoles) of diisopropylethylamine are added into a single-necked flask containing 1.5 g (7.39 mmoles) of 2-cyclopropyl-4,6-dichloro-5-methyl-pyrimidine and 1.58 g (7.39 mmoles) of 2-piperidin-4-yl-[1,8]naphthyridine. This mixture is heated at 100° C. overnight. The next day 0.2 equivalent of naphthyridine is added and the reaction mixture is heated for another 6 hours, followed by returning to ambient temperature before concentration to dryness. The residue obtained is taken up in a mixture of water, ethyl acetate and a saturated solution of sodium bicarbonate. The organic phase is separated and the aqueous phase reextracted with ethyl acetate. The collected organic phases are dried over magnesium sulphate then the solvent is evaporated off under reduced pressure (2 kPa). The residue is chromatographed on silica gel eluting with a gradient of heptane-ethyl acetate (50-50) to 100% ethyl acetate, 1.45 g of expected product is obtained.
Reaction SMILES: [CH:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([CH3:3])[CH3:2].Cl[C:10]1[CH:19]=[C:18]([O:20]CC2C=CC(OC)=CC=2)[C:17]2[C:12](=[C:13]([CH3:32])[C:14]([O:30][CH3:31])=[CH:15][CH:16]=2)[N:11]=1.O>CN1CCCC1=O>[OH:20][C:18]1[C:17]2[C:12](=[C:13]([CH3:32])[C:14]([O:30][CH3:31])=[CH:15][CH:16]=2)[N:11]=[C:10]([N:6]2[CH:7]=[CH:8][C:4]([CH:1]([CH3:3])[CH3:2])=[N:5]2)[CH:19]=1
Reactant: COc1ccc(COc2cc(Cl)nc3c(C)c(OC)ccc23)cc1
Reactant: CC(C)c1cc[nH]n1
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1ccc2c(O)cc(-n3ccc(C(C)C)n3)nc2c1C
Temperature: 25 °C
Yield: 49 %

Procedure:
A solution of compound 233b (350 mg, 1 eq.) and compound 221b (480 mg, 6 eq.) in N-methylpyrrolidone (5 mL) was heated at 200° C. for 30 min. After the reaction mixture was cooled to room temperature, water was added. The mixture was extracted with EtOAc, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by chromatography on silica gel (EtOAc/DCM). Recrystallisation in diethylether gave compound 236b as a white solid in 49% yield. 1H NMR (CDCl3, 376 MHz) δ (ppm) 1.35 (s, 3H), 1.36 (s, 3H), 2.85 (s, 3H), 3.97 (s, 3H), 6.40 (d, J=2.65 Hz, 2H), 7.01 (d, J=9.00 Hz, 1H), 8.00 (brs, 1H), 8.23 (d, J=9.00 Hz, 1H), 9.81 (brs, 1H); MS (ESI, EI+) m/z=298 (MH+).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[O:8][N:7]=1)=O)C.[BH4-].[Na+]>C1COCC1.CO>[F:20][C:17]([F:18])([F:19])[C:14]1[CH:13]=[CH:12][C:11]([C:9]2[O:8][N:7]=[C:6]([CH2:4][OH:3])[CH:10]=2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)on1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: OCc1cc(-c2ccc(C(F)(F)F)cc2)on1
Yield: 98.2 %

Procedure:
A solution of 13A (14.1 g, 49.4 mmol) in 3:1 THF/MeOH, was treated with NaBH4 (5.6 g, 148 mmol) at ambient temperature. The reaction was then stired for 3H, followed by concentrating in vacuo to about 50 mL, quenching with 2 M HCl, extract 1×150 mL EtOAC, dry (Na2SO4) and concentrate in vacuo to give 11.8 g of the title compound pure enough for subsequent use. MS m/z 244 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH:13]=[CH:14][C:15]([O:17]CC)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[Li].O>C1COCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH:13]=[CH:14][C:15]([OH:17])=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C=CC1CCCN1C(=O)OC(C)(C)C
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC1C=CC(=O)O
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a stirred suspension of the crude 2-(2-ethoxycarbonyl-vinyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (136 mg) in THF (1 ml) and H2O (1 ml) was added LiOH.H2O (48 mg, 1.14 mmol) at room temperature. The mixture was stirred at room temperature for 17 hr. The mixture was extracted with 1N NaOH and AcOEt. The aqueous layer was acidified with 1N HCl, extracted with AcOEt, washed with saturated aqueous NaCl, dried (MgSO4), and concentrated in vacuo to give 2-(2-carboxy-vinyl)-pyrrolidine-1-carboxylic acid tert-butyl ester as a crude oil (109 mg). To a stirred solution of the crude oil (105 mg) in CH3CN (2 ml) were added BOP reagent (306 mg, 0.692 mmol), phenethylamine (87 μl, 0.693 mmol), and diisopropylethylamine (121 μl, 0.695 mmol) at 0° C. The mixture was allowed to warm to room temperature and stirred for 12 hr. After being evaporated in vacuo, the mixture was dissolved in CH2Cl2. The solution was washed with 10% aqueous citric acid, saturated aqueous NaHCO3, and saturated aqueous NaCl, dried (MgSO4, and concentrated in vacuo. The residual oil was purified by preparative TLC (hexane:AcOEt=1:1) to give 3-(N-tert-butoxycarbonyl-2′-pyrrolidinyl)-3-ethylsulfanyl-N-phenylethylpropanamide (104 mg, 67% ) as an oil which was the 5:1 (R:S) mixture of the two diastereomers at the newly formed chiral center determined by 1H-NMR.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[Br:15][CH2:16][C:17](Br)=[O:18].O>ClCCl>[Br:15][CH2:16][C:17]([N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:18]
Reactant: CNc1ccccc1
Reactant: O=C(Br)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CN(C(=O)CBr)c1ccccc1

Procedure:
To a mixture of N-methyl aniline (5 mL) and potassium carbonate (9.6 g) in 100 mL dichloromethane was added bromoacetyl bromide (8.1 mL) (exotherm). The mixture was stirred for 4.5h then water was added. The phases were separated and the organic layer was concentrated. The crude product was purified by silica gel chromatography eluting with 0-100% EtOAc/cyclohexane. The relevant fractions were combined and evaporated and the residue was taken up in dichloromethane and washed with water. The organic layer was stirred with another portion of water for a few minutes and then the layers were separated. Evaporation of the organic layer gave the sub-titled compound (10.2 g) as a straw coloured solid.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][Br:23].[OH-].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[C:5]([CH2:10][CH2:11][CH2:12][CH2:4][CH2:3][CH2:2][Br:1])([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][Br:23])[C:4]=2[CH:3]=1
Reactant: Brc1ccc2c(c1)Cc1cc(Br)ccc1-2
Reactant: BrCCCCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Product: BrCCCCCCC1(CCCCCCBr)c2cc(Br)ccc2-c2ccc(Br)cc21
Temperature: 70 °C
Reaction time: 24 h
Yield: 56.5 %

Procedure:
A mixture of 1 (5.0 g, 15.43 mmol), 1,6-dibromohexane (30 mL), tetrabutylammonium bromide (TBAB) (0.5 g), and potassium hydroxide aqueous solution (30 mL, 50% w/w) was stirred at 70° C. for 24 h under nitrogen. After diluting the reaction mixture with dichloromethane, the organic layer was washed with water and brine. The separated organic layer was dried over magnesium sulfate, and dichloromethane was evaporated. The residual 1,6-dibromohexane was distilled in a vacuum, and compound 2 (5.67 g, 56.5%) was obtained as a white crystal by chromatography with hexane/CH2Cl2 (95:5) as the eluent; m.p. 68° C. 1H NMR (500 MHz, CDCl3). δ (ppm): 7.51 (d, 2H, J=8.0 Hz), 7.45 (d, 2H, J=8.0 Hz), 7.42 (s, 2H), 3.27 (t, 4H, J=7 Hz), 1.91 (t, 4H, J=8.5 Hz), 1.65 (p, 4H, J=8 Hz), 1.18 (p, 4H, J=8 Hz), 1.06 (p, 4H, J=7.5 Hz), 0.57 (m, 4H).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([C:26](=[O:28])[CH3:27])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:25])[C:15]2[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=2F)[CH2:10][CH2:9]1.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.O>C1COCC1>[CH3:29][N:30]1[CH2:35][CH2:34][N:33]([C:16]2[CH:17]=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:15]=2[C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:7]3[CH:6]=[CH:5][C:4]([C:26](=[O:28])[CH3:27])=[CH:3][CH:2]=3)[CH2:9][CH2:10]2)=[O:25])[CH2:32][CH2:31]1
Reactant: CN1CCNCC1
Reactant: CC(=O)c1ccc(N2CCN(C(=O)c3cc([N+](=O)[O-])ccc3F)CC2)c(F)c1
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1ccc(N2CCN(C(=O)c3cc([N+](=O)[O-])ccc3N3CCN(C)CC3)CC2)cc1
Temperature: 80 °C

Procedure:
A stirred mixture of 150 mg (0.39 mmol) 1-{3-fluoro-4-[4-(2-fluoro-5-nitro-benzoyl)-piperazin-1-yl]-phenyl}-ethanone, 200 mg (2.0 mmol) 1-methylpiperazine in 4 ml THF was heated to 80° C. for 1 h. Water was added to the reaction mixture, the precipitate isolated, dried and purified by flash-chromatography on silica gel with heptane/AcOEt as eluent. The title compound was obtained as a light yellow powder, MS (m/e): 471.2 (MH+, 100%).
Reaction SMILES: N1C2C3C(CN[C:6](=[O:13])C=3C=CC=2)=C1.C1NC=CC2C=1C1=CC=NC1=CC=2.[CH3:27][O:28][C:29]([C:31]1[C:32]2[CH:33]=[CH:34][NH:35][C:36]=2[CH:37]=[CH:38][CH:39]=1)=[O:30].CN(C=O)C1C=CC=CC=1.P(Cl)(Cl)(Cl)=O>>[CH3:27][O:28][C:29]([C:31]1[C:32]2[C:33]([CH:6]=[O:13])=[CH:34][NH:35][C:36]=2[CH:37]=[CH:38][CH:39]=1)=[O:30]
Reactant: COC(=O)c1cccc2[nH]ccc12
Reactant: O=C1NCc2c[nH]c3cccc1c23
Agent: CN(C=O)c1ccccc1
Agent: c1cc2c(ccc3cc[nH]cc32)n1
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cccc2[nH]cc(C=O)c12

Procedure:
The starting material for the compounds of this invention is the amide, 3,4-dihydropyrrolo[4,3,2-de]isoquinolin5(lH)-one (2). The preparation of this starting material is described in detail in our copending patent application of Philipp et al., Ser. No. 413,417 now U.S. Pat. No. 3,950,343 and entitled "Pyrroloisoquinoline Derivatives". Briefly a preferred preparation of this starting material involves treating 4-indolecarboxylic acid methyl ester, F. C. Uhle, J. Amer. Chem. Soc., 71, 761 (1949), with N-methylformanilide in the presence of phosphorus oxychloride according to the conditions of the Vilsmeier reaction to obtain 3-formylindole-4-carboxylic acid methyl ester, converting the latter compound to its corresponding oxime, catalytically reducing the oxime in the presence of hydrochloric acid and palladium on charcoal to obtain 3-(aminomethyl)indole-4-carboxylic acid methyl ester hydrochloride and finally treating the latter compound with sodium methoxide to give the desired starting material of formula 2.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:14]([CH3:15])[C:6]2=[N:7][CH:8]=[C:9]([N+:11]([O-])=O)[CH:10]=[C:5]2[N:4]=1.[H][H]>[Pd]>[NH2:11][C:9]1[CH:10]=[C:5]2[N:4]=[C:3]([CH2:2][OH:1])[N:14]([CH3:15])[C:6]2=[N:7][CH:8]=1
Reactant: [H][H]
Reactant: Cn1c(CO)nc2cc([N+](=O)[O-])cnc21
Agent: [Pd]
Product: Cn1c(CO)nc2cc(N)cnc21
Yield: 0.1 %

Procedure:
A suspension of 0.5 g (2.4 mol) of 2-hydroxymethyl-6-nitro-3-methyl-3H-imidazo[4,5-b]pyridine, prepared in the preceding step, and 0.3 g of 10% palladium-on-charcoal is stirred for 3 hours under 2.5 atm. of hydrogen. After this time, the suspension is filtered through a pad of Celite and the filtrate is concentrated under reduced pressure. 0.4 g of the expected product is thus isolated, and is used without further purification in the rest of the synthesis.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:17]3[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=3)[C:11](=[O:19])[CH2:10]2)=[CH:5][CH:4]=1.[OH:22][C:23]1C=C2C(C(C3C=CC=CC=3)CC2=O)=C[CH:24]=1>>[C:23]([O:18][C:14]1[CH:13]=[C:12]2[C:17](=[CH:16][CH:15]=1)[CH:9]([C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:20])([F:21])[F:1])=[CH:8][CH:7]=1)[CH2:10][C:11]2=[O:19])(=[O:22])[CH3:24]
Reactant: O=C1CC(c2ccc(C(F)(F)F)cc2)c2ccc(O)cc21
Reactant: O=C1CC(c2ccccc2)c2ccc(O)cc21
Product: CC(=O)Oc1ccc2c(c1)C(=O)CC2c1ccc(C(F)(F)F)cc1
Reaction time: 3 h
Yield: 99 %

Procedure:
The procedure of Step 3 of Example 1 was repeated except for using 3-(4-(trifluoromethyl)phenyl)-2,3-dihydro-6-hydroxyinden-1-one obtained in Step 2 as a starting material instead of 2,3-dihydro-6-hydroxy-3-phenylinden-1-one and being stirred for 3 h to obtain the title compound (99%).