Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([NH2:17])=[N:14][CH:13]=[N:12][C:11]=3[N:10]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH:9]=2)=[CH:4][C:3]=1[O:24][CH3:25].N1C=CC=CC=1.[C:32](=O)([O:43][CH2:44][C:45]1[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=1)[O:33]C1C=CC([N+]([O-])=O)=CC=1>ClCCl>[NH2:17][C:15]1[C:16]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:32](=[O:33])[O:43][CH2:44][C:45]4[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=4)=[C:3]([O:24][CH3:25])[CH:4]=3)=[CH:9][N:10]([CH:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: COc1cc(-c2cn(C3CCOCC3)c3ncnc(N)c23)ccc1N
Reactant: O=C(OCc1cccnc1)Oc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(-c2cn(C3CCOCC3)c3ncnc(N)c23)ccc1NC(=O)OCc1cccnc1
Temperature: 100 °C
Yield: 33.8 %

Procedure:
5-(4-Amino-3-methoxyphenyl)-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (25 mg, 0.074 mmol) was dissolved in dichloromethane (0.7 mL). Pyridine (0.7 mL) was added followed by 4-nitrophenyl (3-pyridylmethyl) carbonate (30 mg, 0.110 mmol). After heating at 100° C. overnight, the solvent was removed and the residue was purified by preparative LC/MS to give 3-pyridylmethyl N-[4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate (12 mg, 0.025 mmol). 1H NMR (CDCl3-d) δ 2.08 (m, 4H), 3.65 (m, 2H), 3.92 (s, 3H), 4.15 (m, 2H), 4.96 (m, 1H), 5.26 (s, 2H), 5.54 (bs, 2H), 6.97 (s, 1H), 7.04 (s, 1H), 7.08 (d, J=8.2 Hz, 1H), 7.35 (m, 2H), 7.79 (d, J=7.8 Hz, 1H), 8.15 (m, 1H), 8.29 (s, 1H), 8.61 (s, 1H), 8.71 (s, 1H). LC/MS MH+=475.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]2[CH2:13][CH2:14][N:15](C(OC(C)(C)C)=O)[CH2:16][CH:4]2[CH2:3]1.[H-].[Na+].[CH3:26]I.Cl>CN(C)C=O>[CH3:26][N:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]2[CH2:13][CH2:14][NH:15][CH2:16][CH:4]2[CH2:3][C:2]1=[O:1]
Reactant: CC(C)(C)OC(=O)N1CCN2c3ccccc3NC(=O)CC2C1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)CC2CNCCN2c2ccccc21
Reaction time: 8 h

Procedure:
To a solution of Example 1C (50 mg, 0.16 mmol) in N,N-dimethylformamide (1 mL) was added sodium hydride (65%, 6.98 mg, 0.19 mmol). The solution was allowed to stir at room temperature for 1 hour before addition of methyl iodide (11.77 μL, 0.19 mmol). The reaction mixture was stirred overnight. The solution was concentrated, and dichloromethane (1 mL) was added followed by HCl (4M in dioxane, 394 μL, 1.6 mmol). After reaction completion as indicated by LC/MS analysis, the solution was concentrated and purified by preparative HPLC to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.35 (d, J=7.80 Hz, 1H), 7.13-7.30 (m, 3H), 3.32-3.47 (m, 3H), 3.17-3.32 (m, 5H) 2.89-3.15 (m, 2H), 2.62 (dd, J=13.22, 7.12 Hz, 1H), 2.12 (d, J=13.56 Hz, 1H); MS (ESI) m/z 231.9 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8](Br)[CH:7]=[CH:6][C:5]=1[NH2:11].[C:13]1(C)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(B(O)O)C=CC=CC=1>CO.O.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>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=[CH:6][C:5]=1[NH2:11])=[O:12]
Reactant: Cc1ccccc1
Reactant: COC(=O)c1cc(Br)ccc1N
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: OB(O)c1ccccc1
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(-c2ccccc2)ccc1N

Procedure:
To a suspension of 5-bromo-2-amino-benzoic acid methyl ester (3.0 g, 13,04 mmol), tetrakis(triphenylphosphine)palladium(0) (0.5 g, 0.44 mmol), toluene (40 ml) and 2 N aqueous sodium carbonate (14.8 ml) was added a solution of phenylboronic acid (2.2 g, 17.73 mmol) in methanol (10 ml) at room temperature. The resulting reaction mixture was heated at reflux temperature for 4 h. cooled and diluted with water (50 ml). The insoluble matter was filtered off and the phases were separated. The aqueous phase was extracted with ethyl acetate (100 ml) and the combined organic phases were washed with water (2×80 ml), diluted aqueous ammoniac (80 ml) and saturated aqueous sodium chloride (80 ml). The organic phase was dried (MgSO4), filtered and evaporated in vacuo affording 3.4 g of crude 4-amino-biphenyl-3-carboxylic acid methyl ester which was purified on silicagel (1 l) using a mixture of ethyl acetate and heptane (1:3) as eluent. Pure fractions were collected and evaporated in vacuo affording 2.7 g (91%) of 4-amino-biphenyl-3-carboxylic acid methyl ester.
Reaction SMILES: [CH2:1]([C:3]1[C:21]([F:22])=[C:20]([F:23])[C:19]([F:24])=[C:18](F)[C:4]=1[C:5]([C:7](=[CH:13][NH:14][CH:15]1[CH2:17][CH2:16]1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:6])[CH3:2].[H-].[Na+]>>[CH:15]1([N:14]2[C:18]3[C:4](=[C:3]([CH2:1][CH3:2])[C:21]([F:22])=[C:20]([F:23])[C:19]=3[F:24])[C:5](=[O:6])[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13]2)[CH2:17][CH2:16]1
Reactant: CCOC(=O)C(=CNC1CC1)C(=O)c1c(F)c(F)c(F)c(F)c1CC
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)c(CC)c2c1=O
Yield: 60.8 %

Procedure:
Employing ethyl 2-(2-ethyl-3,4,5,6-tetrafluorobenzoyl)-3-cyclopropylaminoacrylate (8.71 g) and 60% sodium hydride (1.09 g), the procedure of Reference Example 22 is repeated to give ethyl 1-cyclopropyl-6,7,8-trifluoro-5-ethyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (5 g), as white powder, m.p. 139°14 140° C.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:11]1([CH3:18])[CH:16]=[CH:15][CH:14]=[C:13]([NH2:17])[CH:12]=1.CCN(CC)CC>CN(C=O)C>[N+:8]([C:7]1[C:2]([NH:17][C:13]2[CH:12]=[C:11]([CH3:18])[CH:16]=[CH:15][CH:14]=2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: Cc1cccc(N)c1
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cccc(Nc2ncccc2[N+](=O)[O-])c1
Temperature: 90 °C
Reaction time: 16 h
Yield: 70 %

Procedure:
A mixture of 2-chloro-3-nitropyridine (2.28 g, 14.4 mmol), m-tolylamine (2.78 g, 25.9 mmol) and Et3N (3.6 mL, 25.9 mmol) in DMF (10 mL) was stirred at 90° C. for 16 h under a nitrogen atmosphere. The reaction mixture was partitioned between DCM and water. The aqueous phase was extracted with DCM (×3) and the combined organic layers were dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 30-100% DCM in cyclohexane) to afford the title compound as an orange solid (2.31 g, 70%). LCMS (Method C): RT 3.81 min [M+H]+ 230.1.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.Br[CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[O:25]([CH2:24][CH2:23][N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: BrCCOc1ccccc1
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(CCOc3ccccc3)CC1)O2

Procedure:
Compound 140 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (2-bromoethoxy)benzene and conditions outlined in procedure V. LCMS: 422 [M+H]; Rt=1.01 min.
Reaction SMILES: C12BC(CCC1)CCC2.[CH3:10][C:11]([CH2:13][CH3:14])=[CH2:12].Br[C:16]1[N:17]=[C:18]([CH2:34][CH3:35])[C:19]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=2[O:32][CH3:33])=[N:20][C:21]=1[CH2:22][CH3:23].[OH-].[Na+].OO>C1COCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:34]([C:18]1[C:19]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=2[O:32][CH3:33])=[N:20][C:21]([CH2:22][CH3:23])=[C:16]([CH2:10][CH:11]([CH3:12])[CH2:13][CH3:14])[N:17]=1)[CH3:35]
Reactant: CCc1nc(-c2ccc(OC)cc2OC)c(CC)nc1Br
Reactant: C=C(C)CC
Agent: [Pd]
Agent: B1C2CCCC1CCC2
Agent: OO
Solvent: C1CCOC1
Product: CCc1nc(-c2ccc(OC)cc2OC)c(CC)nc1CC(C)CC
Reaction time: 1 h
Yield: 57.4 %

Procedure:
A solution of 9-BBN (9-borabicyclo[3.3.1]nonane) in THF (0.5 M, 6.0 mL, 3.0 mmol) is added to a solution of 2-methyl-1-butene (210 mg, 3.0 mmol) in THF. The mixture is heated at reflux, under a nitrogen atmosphere for 12 hours and cooled. 1-(5-Bromo-3,6-diethylpyrazin-2-yl)-2,4-dimethoxybenzene (664 mg, 2.0 mmol), tetrakis(triphenylphosphine) palladium(0) (50 mg), and sodium hydroxide (3.0 M, 3.0 mL, 3.0 mmol) are added to the solution. The mixture is heated at 50 C for 12 hours and cooled. 30% Hydrogen peroxide (1 mL) is added, the solution stirred for 1 hour and the reaction mixture extracted with ether. The combined extracts are dried (sodium sulfate), filtered and concentrated. The residue is purified by flash chromatography, eluting with 40% ether in hexanes to give 1-[3,6-diethyl-5-(2-methylbutyl)pyrazin-2-yl]-2,4-dimethoxybenzene (393 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[C:11](Br)[CH:10]=1)[C:5]([O:7][CH3:8])=[O:6].[C:20]1(B(O)O)[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CCOC(C)=O>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][O:2][C:3](=[O:19])[CH:4]([C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[C:11]([C:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]=2)[CH:10]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: OB(O)C1=CCCCC1
Reactant: COC(=O)C(C(=O)OC)c1ccc([N+](=O)[O-])c(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C(C(=O)OC)c1ccc([N+](=O)[O-])c(C2=CCCCC2)c1
Temperature: 60 °C
Reaction time: 9 h
Yield: 70 %

Procedure:
To a mixture of 2-(3-bromo-4-nitro-phenyl)-malonic acid dimethyl ester (as prepared in the previous step, 300 mg, 0.903 mmol), cyclohexane-1-enyl boronic acid (125 mg, 0.994 mmol) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (Pd(dppf)Cl2-CH2Cl2) (66.0 mg, 0.0903 mmol) in 5 mL of DMF was added K3PO4 (765 mg, 3.61 mmol). The resulting mixture was stirred at 60° C. for 9 h under Ar. After cooling to RT, the mixture was treated with 50 mL of EtOAc, washed with H2O (3×10 mL) and brine (10 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel with 10% EtOAc-hexane to afford 210 mg (70%) of the title compound as a yellow oil: Mass spectrum (ESI, m/z): Calcd. for C17H19NO6, 334.1 (M+H). found 334.0.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1.[CH2:16]([O:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)[CH3:17]>>[CH2:16]([O:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[N:6]([CH3:7])[CH:5]=[N:4][C:3]=2[C:8]2[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=2)=[CH:21][CH:20]=1)[CH3:17]
Reactant: CCOc1ccc(B(O)O)cc1
Reactant: Cn1cnc(-c2cc(C#N)ccn2)c1Br
Product: CCOc1ccc(-c2c(-c3cc(C#N)ccn3)ncn2C)cc1

Procedure:
The title compound was prepared from 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile and 4-ethoxyphenylboronic acid according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C18H16N4O, 305. Found, 305.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH2:11][OH:12])[CH:7]=1.C(N(CC)CC)C.[Cl-].[NH4+].C(OC)(C)(C)C>ClCCl.CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=[O:12])[CH:7]=1
Reactant: COc1ccc(Br)cc1C(C)(C)CC(O)(CO)C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: COC(C)(C)C
Product: COc1ccc(Br)cc1C(C)(C)CC(O)(C=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.9 %

Procedure:
1.13 g (3.06 mmol) of 4-(5-bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentan-1-ol is added in 20 ml of dichloromethane and 5.4 ml of DMSO. After mixing with 1.55 g (15.32 mmol) of triethylamine and 975.28 mg (6.13 mmol) of SO3/pyridine complex, the batch is stirred overnight at room temperature. After TLC, another spatula tip full of SO3/pyridine complex is added, and it is further stirred for several hours. The reaction mixture is mixed with saturated ammonium chloride solution and shaken out three times with methyl tert-butyl ether. The combined organic extracts are washed with water and brine. After the solvent is dried and spun off, the residue is chromatographed on a Flashmaster. 902.7 mg (79.81%) of the desired aldehyde (together with the Desbrom compound) is isolated.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>ClCCl>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][S:35]([CH3:34])(=[O:37])=[O:36])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred mixture of trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) in dichloromethane (1.5 ml) was added at room temperature triethylamine (88.7 mg, 122 μl, 0.876 mmol) and methanesulfonyl chloride (43 mg, 29.2 μl, 376 μmol). The mixture was allowed to stir at room temperature for 18 h, and was afterwards evaporated. The crude material was further purified by flash chromatography on silica gel (dichloromethane/MeOH/NH4OH 150:10:1) and trituration with dichloromethane (1 ml) and heptane (5 mL) for 30 min to yield the title compound as a white solid (62 mg, 61%), MS (ISP) m/z=405.4 [(M+H)+], mp 142° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[C:11]([OH:15])(=[O:14])[CH:12]=[CH2:13].C(OC(=O)C)(=O)C>C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:13][CH2:12][C:11]([OH:15])=[O:14]
Reactant: C=CC(=O)O
Reactant: Fc1ccc2[nH]ccc2c1
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C(O)CCc1c[nH]c2ccc(F)cc12
Temperature: 90 °C
Yield: 57.5 %

Procedure:
Thus, a solution of 5-fluoroindole (1.35 g, 0.010 mol) in 10 mL of acetic acid containing acrylic acid (1.5 mL, 0.022 mol) and acetic anhydride (1.9 mL, 0.02 mol) was heated (oil bath) at 90° C. under Ar for 5 days. The volatiles were then removed in vacuo and the residue was taken up in 3N NaOH. Insoluble material was removed by filtration and the filtrate was acidified with conc. HCl and then extracted with CH2Cl2. The organic extract was dried (Na2SO4) and evaporated to give the product (1.191 g, 57%) as a solid which was used without further purification: IR (neat) 3420, 1710 cm-1 ; 1Hnmr (200 MHz, CDCl3) δ7.94 (br s, 1H), 7.28-7.18 (m, 3H), 7.05 (d, J=2.5 Hz, 1H), 6.93 (dt, J=9.0, 2.6 Hz, 1H), 3.05 (t, J=7.5 Hz, 2H), 2.73 (t, J=7.6 Hz, 2H).
Reaction SMILES: [BH4-].[Na+].[OH:3][CH:4]([CH2:14][CH2:15][C:16]1[C:17]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][N:19]2[C:28]=1[CH:29]([CH3:31])[CH3:30])[CH2:5][C:6](=[O:13])[CH2:7][C:8]([O:10]CC)=[O:9].[OH-].[Na+].C(O)(=O)C>CO.O>[OH:13][CH:6]([CH2:5][CH:4]([OH:3])[CH2:14][CH2:15][C:16]1[C:17]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][N:19]2[C:28]=1[CH:29]([CH3:30])[CH3:31])[CH2:7][C:8]([OH:10])=[O:9]
Reactant: CCOC(=O)CC(=O)CC(O)CCc1c(-c2ccccc2)c2c3ccccc3ccn2c1C(C)C
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CC(C)c1c(CCC(O)CC(O)CC(=O)O)c(-c2ccccc2)c2c3ccccc3ccn12
Reaction time: 0.5 h
Yield: 101.7 %

Procedure:
Sodium borohydride (38 mg) was added to a stirred solution of ethyl 5-hydroxy-7-(3-isopropyl-1-phenylpyrrolo[2,1-a]isoquinolin-2-yl)-3-oxoheptanoate (760 mg; prepared as described in Reference Example 3) in methanol (20 ml) at 0° C. under an argon atmosphere. The mixture was stirred at 30 minutes and then a solution of sodium hydroxide (320 mg) in water (8 ml) was added and the mixture was stirred for 1 hour. The mixture was then diluted with water (20 ml) and acidified with glacial acetic acid. The resulting milky solution was extracted with diethyl ether (3×50 ml) and the combined extracts were dried over magnesium sulphate and evaporated, to give 3,5-dihydroxy-7-(3-isopropyl-1-phenylpyrrolo[2,1-a]-isoquinolin-2-yl)heptanoic acid (730 mg), in the form of a yellow gum.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH:4]([NH2:8])[CH2:5][CH2:6][CH3:7].C(N(CC)CC)C.[O:16]1[C:20]2[CH:21]=[CH:22][C:23]([C:25](Cl)=[O:26])=[CH:24][C:19]=2[O:18][CH2:17]1>ClCCl>[CH3:1][CH2:2][CH2:3][CH:4]([NH:8][C:25]([C:23]1[CH:22]=[CH:21][C:20]2[O:16][CH2:17][O:18][C:19]=2[CH:24]=1)=[O:26])[CH2:5][CH2:6][CH3:7]
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Reactant: CCCC(N)CCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(CCC)NC(=O)c1ccc2c(c1)OCO2
Reaction time: 1 h
Yield: 48.5 %

Procedure:
To a solution of heptan-4-amine (8.06 mL, 54 mmol) in triethylamine (15.3 mL, 108 mmol) and dichloromethane (135 mL), was added, dropwise at 0° C., a solution of benzo[1,3]dioxole-5-carbonyl chloride (10 g, 54 mmol) dissolved in dichloromethane (135 mL). The reaction mixture was stirred for 1 h. Solvent was removed under reduced pressure and the residue was dissolved in EtOAc. The organic layer was washed successively with 1 N aq. HCl, 1 N aq. NaOH, water, brine, dried (MgSO4) and concentrated. The residue was recrystallized in EtOAc and Hexanes to afford 6.9 g of N-(heptan-4-yl)benzo[d][1,3]dioxole-5-carboxamide (48.3%) as a white solid. 1H NMR (500 MHz, CDCl3): δ 0.92 (t, 6H), 1.38 (m, 6H), 1.53 (m, 2H), 4.11 (m, 1H), 5.63 (m, 1H), 6.01 (s, 2H), 7.98 (d, 1H), 7.27 (s, d, 2H). MS (M+H, 264).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[O:28]1[CH2:32][CH2:31][CH2:30][C@@H:29]1[CH2:33][C:34](O)=[O:35]>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:34](=[O:35])[CH2:33][C@H:29]5[CH2:30][CH2:31][CH2:32][O:28]5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: O=C(O)C[C@H]1CCCO1
Agent: Cl
Product: O=C(C[C@H]1CCCO1)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (87 mg, 79%), MS (ISP) m/z=443.5 [(M+H)+], mp 183° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and (R)-(tetrahydro-furan-2-yl)-acetic acid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10]([C:12]1[C:21]([Cl:22])=[C:15]2[C:16](=[O:20])[NH:17][CH2:18][CH2:19][N:14]2[N:13]=1)=O)C>C1COCC1.CCOC(C)=O>[Cl:22][C:21]1[C:12]([CH2:10][OH:9])=[N:13][N:14]2[CH2:19][CH2:18][NH:17][C:16](=[O:20])[C:15]=12
Reactant: CCOC(=O)c1nn2c(c1Cl)C(=O)NCC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1NCCn2nc(CO)c(Cl)c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.8 %

Procedure:
A 1M solution of lithium aluminum hydride was added to a stirred solution of 3-chloro-4-oxo-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine-2-carboxylic acid ethyl ester (0.37 g, 1.51 mmol) in THF (15 mL) at 0° C. The mixture was stirred at room temperature for 2 hours and then diluted with AcOEt. Na2SO4.10H2O was added at 0° C. and the mixture stirred for 15 minutes at 0° C., filtered through a pad of diatomaceous earth and then washed with additional THF. The solvents were evaporated in vacuo to yield 3-chloro-2-hydroxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (0.24 g, 79% yield) that was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[C:3]([C:7]([OH:9])=[O:8])=[CH:4][S:5][CH:6]=1.[C:10]([O:16][CH3:17])(=[O:15])[CH2:11]C(C)=O>>[C:7]([C:3]1[C:2]([CH2:11][C:10]([O:16][CH3:17])=[O:15])=[CH:6][S:5][CH:4]=1)([OH:9])=[O:8]
Reactant: O=C(O)c1cscc1Br
Reactant: COC(=O)CC(C)=O
Product: COC(=O)Cc1cscc1C(=O)O

Procedure:
Methyl (4-carboxy-3-thienyl)acetate was prepared from 4-bromothiophen-3-carboxylic acid and methyl acetoacetate by the method described by D. E. Ames and O. Ribeiro, J. Chem. Soc., Perkin I., 1975, 1390, for the preparation of the corresponding ethyl ester. It is a solid which, after crystallisation from aqueous methanol, had mp 121°-122° C., 1H nmr: delta 3.72 (3H, s), 3.95 (2H, s), 7.18 (1H, d J 3 Hz), 8.27 (1H, d J 3 Hz) ppm.
Reaction SMILES: O=[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)=[N:4][NH:3]1.P(Cl)(Cl)([Cl:20])=O>C(Cl)(Cl)Cl>[Cl:20][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)=[CH:6][N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1ccc(-c2cnc(=O)[nH]n2)cc1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(-c2cnc(Cl)nn2)cc1
Temperature: 100 °C
Yield: 17.3 %

Procedure:
A mixture of methyl 4-(3-oxo-2,3-dihydro-1,2,4-triazin-6-yl)benzoate (13.4 g, 0.0580 mol), phosphoryl chloride (30 mL, 0.3 mol) in chloroform (50 mL) was heated at reflux (oil-bath temperature about 100° C.) for 2 h. After cooling, the mixture was concentrated to remove excess phosphoryl chloride. The residue was dissolved in DCM. The solution was poured into ice-water, and carefully neutralized with K2CO3. The organic layer was separated. The aqueous solution was extracted with methylene chloride. The combined extracts were dried over Na2SO3. After filtration the filtrate was concentrated and further purified by flash column to afford the desired product (2.5 g, 17%). Analytical LCMS: (M+H)+=249.9. 1H NMR (300 MHz, CDCl3): δ(ppm) 3.98 (s, 3H), 8.18 (d, 2H), 8.24 (d, 2H), 8.96 (s, 1H).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([O:33][CH3:34])=[O:32])=[CH:21][CH:20]=2)[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:8]([S:10][CH2:11][CH3:12])[N:9]=1)[CH2:2][CH2:3][CH3:4].C(Cl)Cl.ClC1C=CC=C(C(OO)=[O:46])C=1>O>[CH2:1]([C:5]1[N:6]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([O:33][CH3:34])=[O:32])=[CH:23][CH:24]=2)[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:8]([S:10]([CH2:11][CH3:12])=[O:46])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCc1nc(SCC)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Solvent: ClCCl
Solvent: O
Product: CCCCc1nc(S(=O)CC)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Yield: 77.4 %

Procedure:
500 mg of product obtained in Example 5 with 5 cm3 of methylene chloride and 215 mg of meta chloroperbenzoic acid is agitated for 2 hours at ambient temperature. The mixture is poured into 50 cm3 of water, extracted 3 times with 50 cm3 of methylene chloride, the extracts are dried, filtered and brought to dryness under reduced pressure. The residue (675 mg) is chromatographed on silica (eluant: methylene chloride - acetone (6-4)). 400 mg of the desired product is obtained.