Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[C:9](=O)[CH2:8][CH2:7][CH2:6][C:5]2=1.[CH3:16][O:17][C:18]1[C:19]([NH2:24])=[CH:20][CH:21]=[CH:22][CH:23]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:24][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[O:17][CH3:16])[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: COc1ccccc1N
Reactant: O=C1CCCc2c1[nH]c1ccc(Br)cc21
Product: COc1ccccc1NC1CCCc2c1[nH]c1ccc(Br)cc21

Procedure:
6-Bromo-N-(2-methoxyphenyl)-2,3,4,9-tetrahydro-1H-carbazol-1-amine was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-one (200 mg, 0.76 mmol) and o-anisidine (187 mg, 1.52 mmol) in a similar manner as described above and recrystallized from acetonitrile to give 30 mg (11%) as yellow crystals; 1H-NMR (DMSO-d6): δ 11.07 (s, 1H), 7.56 (d, 1H), 7.22 (d, 1H), 7.13 (dd, 1H), 6.84-6.73 (m, 3H), 6.60-6.56 (m, 1H), 4.85-4.80 (m, 1H), 4.72 (d, 1H), 3.73 (s, 3H), 2.70-2.53 (m, 2H), 2.00-1.75 (m, 4H); MS m/z (M−1) 369, 371.
Reaction SMILES: C(OC([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17](OCCCl)[CH:18]=2)[NH:13][C:12]=1C)=O)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].CC12CC([NH:37]C1)CC(C)(C)C2>C(#N)C>[NH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=[C:12]1[NH2:37]
Reactant: Cc1[nH]c2ccc(OCCCl)cc2c1C(=O)OCc1ccccc1
Reactant: CC1(C)CC2CC(C)(CN2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Nc1cc2ccccc2[nH]1
Yield: 52.2 %

Procedure:
5-(2-Chloro-ethoxy)-2-methyl-1H-indole-3-carboxylic acid benzyl ester (0.500 g, 1.450 mmol, 1 eq, Example 1, Step A) was suspended in dry acetonitrile (30 mL) under Ar. K2CO3 (0.400 g, 2.900 mmol, 2 eq) and KI (0.025 g, 0.145 mmol, 0.1 eq) were added followed by the addition of 1,3,3-trimethyl-6-azabicyclo-[3,2,1]octane (0.334 g, 2.180 mmol, 1.5 eq). The reaction mixture was stirred and heated to reflux for 24 hours. Then the reaction was quenched with saturated sodium bicarbonate and extracted with ethyl acetate (3×). The combined organic phases were washed with brine and dried over Na2SO4. After removing the solvent, the residue was loaded on silica gel and chromatographed, eluting with ethyl acetate/methanol/triethyl amine (100/10/1). 0.100 g (15%) of the indole-amine was obtained as a white solid. This was converted to the .HCl salt. LC/MS (ESI+) 461 (M+1); Anal. Calcd for C29H36N2O3.1 HCl.0.75H2O: C, 68.22; H, 7.60; N, 5.49; Found: C, 68.25; H, 7.41; N, 5.56.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:3]=1[C:4]#[N:5].C(=O)(O)O.[NH2:23][C:24]([NH2:26])=[NH:25]>CC(N(C)C)=O>[CH3:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][O:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:2]3[C:3]=2[C:4]([NH2:5])=[N:25][C:24]([NH2:26])=[N:23]3)=[CH:17][CH:16]=1
Reactant: N=C(N)N
Reactant: Cc1ccc(COc2cccc(F)c2C#N)cc1
Agent: O=C(O)O
Solvent: CC(=O)N(C)C
Product: Cc1ccc(COc2cccc3nc(N)nc(N)c23)cc1
Yield: 37.8 %

Procedure:
2-Fluoro-6-(4-methylbenzyloxy)benzonitrile (241.3 mg; 1 mmol) and guanidine carbonate (180.2 mg; 1 mmol) were heated at 145° C. in dimethyl acetamide for 7 hours. The solvent was removed. Purification by recrystallization in hot ethanol/water yielded 106 milligrams of 5-(4-methylbenzyloxy)quinazoline-2,4-diamine.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]([CH3:12])([CH3:11])[CH2:6][S:7]([NH2:10])(=[O:9])=[O:8].Cl[C:14]1[C:23]2[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=2[C:17]2=[N:24][CH:25]=[CH:26][N:16]2[N:15]=1>CN(C)C=O>[CH3:11][C:5]([CH3:12])([CH2:6][S:7](=[O:9])(=[O:8])[NH2:10])[CH2:4][O:3][C:14]1[C:23]2[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=2[C:17]2=[N:24][CH:25]=[CH:26][N:16]2[N:15]=1
Reactant: CC(C)(CO)CS(N)(=O)=O
Reactant: Clc1nn2ccnc2c2c1CCCC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(COc1nn2ccnc2c2c1CCCC2)CS(N)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30 %

Procedure:
0.59 g of 60% oily sodium hydride was suspended in 20 ml of dimethylformamide. To this suspension, 1.18 g of 3-hydroxy-2,2-dimethyl-1-propanesulfonamide was added, followed by stirring at room temperature (15° to 20° C.) under reduced pressure for 30 minutes. To this mixture was added 1.35 g of 6-chloro-7,8,9,10-tetrahydroimidazo[2,1-a]phthalazine, followed by stirring at 60° C. for 1.5 hours. After dimethylformamide was distilled off under reduced pressure, ice water was added to the residue, which was subsequently adjusted to pH 6 by the addition of 5 N hydrochloric acid and then extracted with ethyl acetate-tetrahydrofuran (2:1). The extract was washed with 20 ml of saturated saline and then dried over magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with dichloromethane-ethyl acetate-methanol (20:20:1). The fraction containing the desired product was concentrated, and ethyl ether was added to separate a crystal, which was collected by filtration, to yield 0.66 g of the title compound.
Reaction SMILES: N([C@H]([C:6]1[C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[F:16])C)=[N+]=[N-].N([C@H](C1C(Cl)=NC2C(C=1)=CC=CC=2F)C)=[N+]=[N-].C(=O)([O-])[O-].[Na+].[Na+].FC1C=C(B(O)O)C=CC=1>>[F:16][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[N:8]=[C:7]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=1)[CH:6]=[CH:15]2
Reactant: C[C@H](N=[N+]=[N-])c1cc2cccc(F)c2nc1-c1cccc(F)c1
Agent: C[C@H](N=[N+]=[N-])c1cc2cccc(F)c2nc1Cl
Agent: O=C([O-])[O-]
Agent: OB(O)c1cccc(F)c1
Product: Fc1cccc(-c2ccc3cccc(F)c3n2)c1

Procedure:
3-((S)-1-Azidoethyl)-8-fluoro-2-(3-fluorophenyl)quinoline was made according to Procedure BSL-1 using (S)-3-(1-azidoethyl)-2-chloro-8-fluoroquinoline (50 mg, 0.199 mmol), tetrakis triphenylphosphine palladium (0) (9 mg, 0.008 μmol, 0.04 eq), sodium carbonate (106 mg, 0.997 mmol, 5 eq), and 3-fluoro-phenylboronic acid (42 mg, 0.299 mmol, 1.5 eq). 34(S)-1-azidoethyl)-8-fluoro-2-(3-fluorophenyl)quinoline was obtained after purification. 1H NMR (400 MHz, CDCl3) δ ppm 8.39 (d, J=1.6 Hz, 1H), 7.71 (br d, J=8.2 Hz, 1H), 7.54 (td, J=7.8, 4.7 Hz, 1H), 7.52-7.42 (series of m, 2H), 7.35 (dt, J=7.8, 1.2 Hz), 7.31 (ddd, J=9.0, 2.4, 1.6 Hz, 1H), 7.20 (tdd, J=8.6, 2.7, 1.2 Hz, 1H), 4.94 (q, J=6.7 Hz, 1H), 1.56 (d, J=6.7 Hz, 3H). Mass Spectrum (ESI) m/e=310.9 (M+1).
Reaction SMILES: [CH3:1][C:2]([CH3:46])([O:4][C:5]([NH:7][CH:8]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH:9]([OH:38])[CH2:10][N:11](CC1C=CC=CC=1)[CH2:12][CH:13]([OH:30])[CH:14]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:6])[CH3:3].CO>CN(C=O)C>[CH3:28][C:25]([O:24][C:23](=[O:29])[NH:22][CH:14]([CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH:13]([OH:30])[CH2:12][NH:11][CH2:10][CH:9]([OH:38])[CH:8]([NH:7][C:5]([O:4][C:2]([CH3:1])([CH3:3])[CH3:46])=[O:6])[CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(O)CN(Cc1ccccc1)CC(O)C(Cc1ccccc1)NC(=O)OC(C)(C)C
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(O)CNCC(O)C(Cc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
A mixture of Compounds 26a(i) and 26a(ii) were reacted with Compound 27a by a procedure analogous to that used for the preparation of Compound 4b (except that MeOH at 55° was used in place of DMF) to give the title Compound 27b as a mixture of diastereomers. m.p. 156°-159° C.; MS: (CI/NH3): 544 (M+H). Anal. Calc. for C30H45N3O6 ·0.16 H2O
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH:6]([CH3:8])[CH2:5][C:4](=[O:9])[CH:3]=1>CC(O)C.[Pd].CCCCCC>[CH3:1][C@H:2]1[CH2:7][C@@H:6]([CH3:8])[CH2:5][C:4](=[O:9])[CH2:3]1
Reactant: CC1=CC(=O)CC(C)C1
Agent: [Pd]
Solvent: CCCCCC
Solvent: CC(C)O
Product: C[C@@H]1CC(=O)C[C@H](C)C1
Reaction time: 4 h
Yield: 76.8 %

Procedure:
A solution of 3,5-dimethyl-2-cyclohexenone (2.0 g, 16.1 mmol) in 2-propanol (32 ml) was hydrogenated over 5% palladium on charcoal (200 mg) at room temperature and 103 kPa (14.7 psi) for 4 hours, then diluted with 1:1 hexane:ether (150 ml) and filtered using a filter aid. The filtrate was evaporated under reduced pressure to provided the substantially stereochemically pure title compound (1.56 g) as a yellow oil. 13C NMR spectroscopy revealed a cis:trans ratio of 150:3.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:19]=[C:18]([C:20]([N:22]3[CH2:31][CH2:30][C:29]4[C:24](=[CH:25][CH:26]=[C:27]([O:33][CH3:34])[C:28]=4[OH:32])[CH2:23]3)=[O:21])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[CH:6][CH:5]=1)([O-])=O.O.[NH4+].[Cl-]>[Fe].C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:19]=[C:18]([C:20]([N:22]3[CH2:31][CH2:30][C:29]4[C:24](=[CH:25][CH:26]=[C:27]([O:33][CH3:34])[C:28]=4[OH:32])[CH2:23]3)=[O:21])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[CH:8][CH:9]=1
Reactant: COc1ccc2c(c1O)CCN(C(=O)c1nc(-c3ccc([N+](=O)[O-])cc3)nc3ccccc13)C2
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COc1ccc2c(c1O)CCN(C(=O)c1nc(-c3ccc(N)cc3)nc3ccccc13)C2
Temperature: 90 °C
Reaction time: 8 h

Procedure:
Into a 1-L round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2-[[2-(4-nitrophenyl)quinazolin-4-yl]carbonyl]-5-hydroxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline (9 g, 19.72 mmol, 1.00 equiv), water (300 mL), ethanol (300 mL), Fe (2.5 g, 2.30 equiv) and NH4Cl (2.4 g, 44.87 mmol, 2.30 equiv). The resulting solution was stirred overnight at 90° C. The solids were collected by filtration. The residue was dissolved in 200 mL of DMSO. The solids were filtered out. The resulting solution was diluted with 3 L of H2O. The solids were collected by filtration. The filter cake was washed with 1×1 L of water. This resulted in 2.5 g (30%) of 2-[[2-(4-aminophenyl)quinazolin-4-yl]carbonyl]-6-methoxy-1,2,3,4-tetrahydroisoquinolin-5-ol as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 2.62 and 2.88 (2t, 2H), 3.45 and 4.01 (2t, 2H), 3.74-3.80 (2s, 3H), 4.36 and 4.89 (2s, 2H), 5.80 (s, 2H), 6.31-6.92 (m, 4H), 7.53-7.63 (m, 1H), 7.73-7.84 (2d, 1H), 7.94-7.99 (m, 2H), 8.18-8.25 (m, 2H), 8.68-8.74 (2s, 1H); MS (ESI) m/z 427 ([M+H]+).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[C:23](=[O:28])N(OC)C)=[O:16])([CH3:13])([CH3:12])[CH3:11].[Cl-].[NH4+]>C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:23]([CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22][N:17]1[C:15]([O:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:16])=[O:28]
Reactant: CON(C)C(=O)C1CCCCN1C(=O)OC(C)(C)C
Reactant: c1ccc2occc2c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCCC1C(=O)c1cc2ccccc2o1
Yield: 28.9 %

Procedure:
To a solution of benzofuran (0.37 ml, 3.36 mmol) in THF (40 ml) at −35° C. was added nbutyllithium (1M in THF) (3.34 ml, 3.34 mmol) over 3 min. The resultant mixture was stirred for 10 min. at −35° C. then (RS)-1-(tert-butyloxycarbonyl)-2-(N-methoxy-N-methylcarbamoyl)-piperidine (1.0 g, 3.68 mmol) in THF (5 ml) was added over 1 min. and the resultant solution stirred for 15 min. at −35° C. The mixture was poured into saturated ammonium chloride (20 ml) and extracted with ethyl acetate (3×20 ml). The combined organics were washed with saturated aqueous sodium hydrogen carbonate (15 ml), then evaporated in vacuo. The resultant residue was chromatographed on silica gel eluting with 10% ethyl acetate in hexane to give the title compound (0.32 g, 26%) as a yellow solid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH:10]=[O:11])=[CH:2]1.[Mg+2].[Cl-].[Cl-].[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18](I)[CH:17]=1>C1COCC1.[NH4+].[Cl-].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>[F:15][C:16]1[CH:17]=[C:18]([C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[C:3]=2[CH:10]=[O:11])[CH:19]=[CH:20][CH:21]=1
Reactant: Fc1cccc(I)c1
Reactant: O=Cc1csc2ccccc12
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: O=Cc1c(-c2cccc(F)c2)sc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.1 %

Procedure:
A dry, argon-filled Schlenk tube with a magnetic stirrer bar and septum is initially charged with 1-benzothiophene-3-carbaldehyde (163 mg, 1 mmol) in anhydrous THF (1 ml). After adding (TMP)2Zn.MgCl2 (3.16 ml, 1.2 mmol) at 25° C., the mixture is stirred for 1 h, then a solution of 1-fluoro-3-iodobenzene (311 mg, 1.4 mmol), bis(dibenzylideneacetone)palladium(0) (17 mg, 3 mol %) and tri-2-furylphosphine (14 mg, 6 mol %) in anhydrous THF (2 ml) is added dropwise and the mixture is stirred at 25° C. overnight. For workup, the mixture is diluted with aqueous sat. NH4Cl solution (30 ml) and extracted with ethyl acetate (3×30 ml). After the combined organic phases have been dried over Na2SO4, the solvent has been distilled off and purification has been effected by column chromatography on silica gel (heptane:ethyl acetate), the desired compound (195 mg, 76% of theory) was obtained as a colourless crystalline product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].Cl[S:13]([C:16]1[CH:25]=[C:24]2[C:19]([CH:20]=[CH:21][C:22]([NH:26][C:27](=[O:29])[CH3:28])=[CH:23]2)=[CH:18][CH:17]=1)(=[O:15])=[O:14]>C1COCC1.N1C=CC=CC=1>[C:27]([NH:26][C:22]1[CH:23]=[C:24]2[C:19]([CH:18]=[CH:17][C:16]([S:13]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=3)[C:7]([OH:9])=[O:8])(=[O:15])=[O:14])=[CH:25]2)=[CH:20][CH:21]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)Nc1ccc2ccc(S(=O)(=O)Cl)cc2c1
Reactant: Nc1ccc(Cl)c(C(=O)O)c1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc2ccc(S(=O)(=O)Nc3ccc(Cl)c(C(=O)O)c3)cc2c1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
To 15 g (0.087 mol) of 5-amino-2-chlorobenzoic acid was dissolved in 450 mL of THF and 15 mL of pyridine. The solution was cooled to 5° C. in an ice-water bath. Then, a solution of 20.8 g (0.074 mol) of compound 131 dissolved in 200 mL of THF was added over a 10 min period. The reaction was kept at 5° C. for 30 min, and then allowed to warm to room temperature. The reaction was allowed to stir for an additional 4 hours. Then, the reaction was filtered to remove some insoluble material and the resulting clear filtrate was reduced to a solid by the removal of the volatiles by rotary evaporation. This solid was extracted with ethyl acetate and 1 N HCl. The ethyl acetate layer was further extracted with 0.5 M NaOH (once) and 0.33 M NaOH (three times). The aqueous layers were combined, acidified with HCl, and back extracted into ethyl acetate. After drying (MgSO4), filtration, and removal of the ethyl acetate by rotary evaporation, the solid residue was dissolved in 2.8 L of 50/50 methanol/water with heating. The solution was allowed to cool to room temperature and a small amount of solid was removed by vacuum filtration and discarded. The clear filtrate was allowed to sit for 48 hours and then was reduced in volume to about 500 mL by rotary evaporation. The solid was collected by vacuum filtration. After drying in vacuo, this provided 17.6 g of compound 132.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH2:8][CH3:9])=[CH:6][CH:5]=[C:4]([N+]([O-])=O)[C:3]=1[CH:13]=[CH:14][N:15]1CCCC1>CC(O)=O.O.C([O-])([O-])=O.[Na+].[Na+].[Fe]>[Br:1][C:2]1[C:7]([CH2:8][CH3:9])=[CH:6][CH:5]=[C:4]2[C:3]=1[CH:13]=[CH:14][NH:15]2
Reactant: CCc1ccc([N+](=O)[O-])c(C=CN2CCCC2)c1Br
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCc1ccc2[nH]ccc2c1Br
Yield: 12 %

Procedure:
A solution of crude 1-[2-(2-bromo-3-ethyl-6-nitro-phenyl)-vinyl]-pyrrolidine from Step 3 in 80 mL of AcOH was added in one portion to a refluxing suspension of iron (13 g) in 50 mL of AcOH. The resultant mixture was refluxed for 2 hrs. After cooling, the mixture was diluted with water and neutralized with Na2CO3, and extracted 3 times with EtOAc. The combined organic phases were concentrated and purified by silica gel column chromatography and preparative HPLC to yield the title compound (1.5 g, 12% from 6-ethyl-2-methyl-3-nitro-phenylamine).
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][CH2:5][C:6]1([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=3)[N:11]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=3)[C:10]=2[CH3:28])[CH2:8][CH2:7]1.[OH-].[Na+]>CO.CCOCC.CCCCCC>[Br:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:11]2[C:12]3[C:17](=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:9]([C:6]3([CH2:5][CH2:4][C:3]([OH:29])=[O:2])[CH2:8][CH2:7]3)=[C:10]2[CH3:28])=[CH:22][CH:23]=1
Reactant: COC(=O)CCC1(c2c(C)n(Cc3ccc(Br)cc3)c3ccc(OC)cc23)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Solvent: CCCCCC
Product: COc1ccc2c(c1)c(C1(CCC(=O)O)CC1)c(C)n2Cc1ccc(Br)cc1
Yield: 75.4 %

Procedure:
To a solution of ester from Step 11 (150 mg, 0.33 mmol) in 5 mL MeOH was added 2N NaOH (0.5 mL, 1 mmol). The reaction mixture was heated to reflux for 3 h then cooled and partitioned between 1N HCl and ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and evaporated. The residue was filtered through a plug of silicic acid and the solid obtained was swished in (1: 1 ) Et2O-hexane. Collection of the solid provided 110 mg of the title compound.
Reaction SMILES: [N:1]1[N:8]2[C:4]([O:5][C:6]3[CH2:12][O:11][CH2:10][CH2:9][C:7]=32)=[CH:3][C:2]=1[C:13]([O-])=[O:14].[BH4-].[Li+].CO>C1COCC1>[N:1]1[N:8]2[C:4]([O:5][C:6]3[CH2:12][O:11][CH2:10][CH2:9][C:7]=32)=[CH:3][C:2]=1[CH2:13][OH:14]
Reactant: O=C([O-])c1cc2oc3c(n2n1)CCOC3
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: OCc1cc2oc3c(n2n1)CCOC3
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.5 %

Procedure:
To the stirred solution of 7,8-dihydro-5H-pyrano[4,3-d]pyrazolo[5,1-b][1,3]oxazole-2-carboxylate (1.5 g, 6.3 mmol) of in 100 ml of THF was added 1.05 g of lithium borohydride and 1.54 g of methanol. The solution was heated at 40 C for 2.5 hour. The reaction was quenched by 1 N HCl, and adjusted to pH 1.3 and stirred at room temperature for 1 hour. The reaction mixture was adjusted pH to 8 with k2CO3. The reaction mixture was extracted with ethyl acetate. The organic layer was dried over MgSO4, and concentrated to an oil and column chromatographed to give 0.74 g of the desired product (60%). (M+H) 196.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[O:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[O:16][CH2:17][C:18]#[C:19][CH2:20]Br.O>C(O)C>[O:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[O:16][CH2:17][C:18]#[C:19][CH2:20][O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCC#CCOC1CCCCO1
Reactant: Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C(#CCOC1CCCCO1)COc1ccccc1

Procedure:
To a solution of 2.35 g (0.025 mol) of phenol in 20 ml of absolute ethanol, there was added 1.10 g (0.0275 mol) of sodium hydroxide. The mixture was refluxed until complete disolution and 2.92 g (0.0125 mol) of 1-bromobut-2-yn-4-ol tetrahydropyranyl ether were added, and the reflux resumed for 2 additional hours. It was then cooled, poured into water and extracted with ether. The organic extracts were washed with 20% aqueous sodium hydroxide solution and water, dried and evaporated in vacuo. The residue was purified by column chromatography on 50 g of silica gel, using hexane-ethyl acetate (98:2) as eluant, to yield 4-phenoxybut-2-yn-1-ol tetrahydropyranyl ether, as an oil.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[CH2:9][CH:10]([OH:48])[CH2:11][N:12]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20][CH2:19][N:18]([CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:17][CH2:16][N:15]([CH2:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:14][CH2:13]1)C1C=CC=CC=1.O>CO.[Pd]>[NH2:8][CH2:9][CH:10]([OH:48])[CH2:11][N:12]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20][CH2:19][N:18]([CH2:32][C:33]([O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:34])[CH2:17][CH2:16][N:15]([CH2:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)CN1CCN(CC(=O)OC(C)(C)C)CCN(CC(O)CN(Cc2ccccc2)Cc2ccccc2)CCN(CC(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)CN1CCN(CC(=O)OC(C)(C)C)CCN(CC(O)CN)CCN(CC(=O)OC(C)(C)C)CC1
Reaction time: 8 h

Procedure:
76.8 g (100 mmol) of 10-(3-dibenzylamino-2-hydroxypropyl)-1,4,7-tris-(tert-butoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane is dissolved in 500 ml of methanol, mixed with 40 ml of water, and 10 g of palladium catalyst (20% Pd/C) is added. It is hydrogenated for 8 hours at 50° C. under normal pressure. Catalyst is filtered out, and the filtrate is evaporated to the dry state in a vacuum.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[C:8]([C:10]([OH:12])=O)[CH:7]=[CH:6][C:5]=12.[CH2:13]1[C@H:22]2[C@H:17]([CH2:18][CH2:19][C:20]3[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=32)[NH:16][CH2:15][CH2:14]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[CH2:13]1[C@H:22]2[C@H:17]([CH2:18][CH2:19][C:20]3[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=32)[N:16]([C:10]([C:8]2[CH:7]=[CH:6][C:5]3[N:4]([CH:3]=[CH:2][N:1]=3)[CH:9]=2)=[O:12])[CH2:15][CH2:14]1
Reactant: O=C(O)c1ccc2nccn2c1
Reactant: c1ccc2c(c1)CC[C@@H]1NCCC[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(c1ccc2nccn2c1)N1CCC[C@@H]2c3ccccc3CC[C@@H]21
Yield: 72 %

Procedure:
The title compound is prepared from imidazo[1,2-a]pyridine-6-carboxylic acid and cis-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used]. Yield: 72% of theory; LC (method 3): tR=1.82 min; Mass spectrum (ESI+): m/z=335 [M+H]+.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[F:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]([CH3:18])=[CH:16][CH:15]=[C:14]2[CH3:19])=[C:9]([C:20]([F:23])([F:22])[F:21])[CH:8]=1.CN([CH:27]=[O:28])C>>[F:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]([CH3:18])=[CH:16][C:15]([CH:27]=[O:28])=[C:14]2[CH3:19])=[C:9]([C:20]([F:23])([F:21])[F:22])[CH:8]=1
Reactant: CN(C)C=O
Reactant: Cc1ccc(C)n1-c1ccc(F)cc1C(F)(F)F
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc(C=O)c(C)n1-c1ccc(F)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 37 %

Procedure:
To anhyd DMF (10 mL) cooled under nitrogen to 0° C. was added phosphorous oxychloride (1.2 mL, 13.1 mmol). The resulting mixture was stirred at 0° C. for 30 min and then a solution of 1-[4-fluoro-2-(trifluoromethyl)phenyl]-2,5-dimethyl-1H-pyrrole (3.19 g, 12.4 mmol) in anhyd DMF (15 mL) was added portionwise. The reaction mixture was maintained at 0-3° C. for 10 min and then the reaction flask was heated on an oil bath at 95-100° C. After heating 1.5 h, the reaction mixture was cooled and poured onto 200 mL of ice cold 1 M NaOH. The resulting suspension was extracted twice with DCM. The combined extracts were dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (SiO2), eluting with EtOAc/Hex (10:90 to 30:70) to afford the title compound as a light yellow solid (1.3 g, 37%); 1H-NMR (CDCl3): δ 9.90 (s, 1H), 7.58 (dd, J=8, 3 Hz, 1H), 7.43 (m, 1H), 7.29 (dd, J=5, 8 Hz, 1H), 6.39 (s, 1H), 2.20 (s, 3H), 1.91 (s, 3H); MS (ESI) m/z 286 [M+H]+.