Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[OH:26][CH2:27][CH2:28][N:29]([CH2:40][CH2:41][OH:42])[S:30]([C:33]1[S:37][C:36]([NH2:38])=[N:35][C:34]=1[CH3:39])(=[O:32])=[O:31]>>[OH:26][CH2:27][CH2:28][N:29]([CH2:40][CH2:41][OH:42])[S:30]([C:33]1[S:37][C:36]([NH:38][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:13])=[N:35][C:34]=1[CH3:39])(=[O:31])=[O:32]
Reactant: Cc1nc(N)sc1S(=O)(=O)N(CCO)CCO
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: Cc1nc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)sc1S(=O)(=O)N(CCO)CCO

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C. 1) and 2-amino-4-methyl-thiazole-5-sulfonic acid bis-(2-hydroxy-ethyl)-amide (example B.8) according to general procedure II. Light yellow solid. MS (ISP) 621.1 [(M+H)+]; mp 191° C.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([O:31][CH:32]([F:34])[F:33])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26](=O)[CH:27]([CH3:29])[CH3:28])=[CH:22][CH:21]=1)[C:10]([CH2:17][CH3:18])=[N:11]2.[OH-].[Li+]>O1CCCC1.O>[Cl:16][C:13]1[CH:14]=[CH:15][C:6]([O:5][CH2:4][C:3]([OH:35])=[O:2])=[C:7]2[C:12]=1[N:11]=[C:10]([CH2:17][CH3:18])[C:9]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][CH:27]([CH3:28])[CH3:29])=[CH:24][CH:25]=1)=[C:8]2[O:31][CH:32]([F:34])[F:33]
Reactant: CCc1nc2c(Cl)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(C(=O)C(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCc1nc2c(Cl)ccc(OCC(=O)O)c2c(OC(F)F)c1Cc1ccc(CC(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.6 %

Procedure:
A solution of [8-chloro-4-difluoromethoxy-2-ethyl-3-(4-isobutyrylbenzyl)quinolin-5-yloxy]acetic acid methyl ester (0.22 g) in tetrahydrofuran (5.0 mL) and water (1.0 mL) was treated with 1.0M aqueous lithium hydroxide solution (0.86 mL), and the resulting mixture was stirred at room temperature for 2 hours. The mixture was concentrated to low bulk under reduced pressure, and the pH adjusted to 4-5 by the addition of 1.0M aqueous hydrochloric acid solution. The mixture was extracted with ethyl acetate, and the combined extracts were dried over magnesium sulfate and then concentrated under reduced pressure. Purification of the residue by preparative reverse-phase HPLC gave title compound (0.18 g).
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]2[N:13]([S:14]([C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)(=[O:16])=[O:15])[CH:12]=[C:11]([CH2:22][N:23](C)[C:24](=O)OC(C)(C)C)[CH:10]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].C(OCC)(=O)C.[ClH:38]>C(OCC)(=O)C.CC(O)C>[ClH:38].[O:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[S:14]([N:13]1[CH:12]=[C:11]([CH2:22][NH:23][CH3:24])[CH:10]=[C:9]1[C:8]1[C:3]([C:1]#[N:2])=[N:4][CH:5]=[CH:6][CH:7]=1)(=[O:16])=[O:15]
Reactant: CN(Cc1cc(-c2cccnc2C#N)n(S(=O)(=O)c2ccco2)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CNCc1cc(-c2cccnc2C#N)n(S(=O)(=O)c2ccco2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
To a solution of tert-butyl {[5-(2-cyanopyridin-3-yl)-1-(2-furylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (193 mg) in ethyl acetate (2 mL) and 2-propanol (1 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (3 mL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound as a white solid (yield 127 mg, 77%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[C:7]2[N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1.[Cl:18][C:19]1[C:26]([N:27]([CH3:46])[C:28](=[O:45])[CH2:29][NH:30][C:31](=[O:44])[CH:32]=[CH:33][C:34]2[CH:39]=[CH:38][C:37]([C:40](=[O:43])[NH:41][CH3:42])=[CH:36][CH:35]=2)=[CH:25][CH:24]=[C:23]([Cl:47])[C:20]=1[CH2:21]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:18][C:19]1[C:26]([N:27]([CH3:46])[C:28](=[O:45])[CH2:29][NH:30][C:31](=[O:44])[CH:32]=[CH:33][C:34]2[CH:35]=[CH:36][C:37]([C:40](=[O:43])[NH:41][CH3:42])=[CH:38][CH:39]=2)=[CH:25][CH:24]=[C:23]([Cl:47])[C:20]=1[CH2:21][O:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[C:7]2[N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: CNC(=O)c1ccc(C=CC(=O)NCC(=O)N(C)c2ccc(Cl)c(CBr)c2Cl)cc1
Reactant: Cc1cc(-n2ccnc2)c2cccc(O)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(C=CC(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4c(-n5ccnc5)cc(C)nc34)c2Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.4 %

Procedure:
A suspension of 8-hydroxy-4-(imidazol-1-yl)-2-methylquinoline (23 mg), 2,6-dichloro-3-[N-methyl-N-[4-(methylcarbamoyl)cinnamoylglycyl]amino]benzyl bromide (52.4 mg) and potassium carbonate (42.3 mg) in N,N-dimethylformamide (0.5 ml) was stirred for 3 hours at ambient temperature. Water was added thereto, and the resulting precipitate was collected by filtration. The residue was purified by preparative thin layer chromatography (chloroform:methanol, 10:1, v/v) to give 8-[2,6-dichloro-3-[N-methyl-N-[4-(methylcarbamoyl)cinnamoylglycyl]amino]benzyloxy]-4-(imidazol-1-yl)-2-methylquinoline (60 mg) as colorless amorphous.
Reaction SMILES: [I:1]I.[Si:3]([N:10]1[C@@H:13]([CH2:14]O)[CH2:12][C:11]1=[O:16])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C=CN=C1>CC#N>[Si:3]([N:10]1[C@@H:13]([CH2:14][I:1])[CH2:12][C:11]1=[O:16])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)C[C@@H]1CO
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)N1C(=O)C[C@@H]1CI
Temperature: 25 °C
Reaction time: 96 h
Yield: 80.2 %

Procedure:
Iodine (4.25 g, 16.7 mmol) was added to a solution of 1-(tert-butyldimethylsilyl)-4(R)-(hydroxymethyl)azetidin-2-one (2.25 g, 10.47 mmol), Ph3P (5.48 g, 20.93 mmol) and imidazole (1.64 g, 24.07 mmol) in MeCN (100 mL) at 0°. After stirring at room temperature for four days, the mixture was concentrated and suspended in EtOAc-hexane (1:1). The suspension was filtered through a silica gel pad and washed with EtOAc-hexane (1:1). Concentration of the filtrate and purification by flash chromatography (SiO2, 10% EtOAc-hexane) afforded pure 1-(tert-butyldimethylsilyl)-4(R)-(iodomethyl)azetidin-2-one as a white solid (2.73 g, 80% yield). 1H NMR (400 MHz, CDCl3) δ 3.72-3.66 (m, 1H), 3.50 (ddd, J=9.8, 3.2, 0.6 Hz, 1H), 3.21 (ddd, J=15.6, 5.4, 0.6 Hz, 1H), 3.11 (dd, J=9.8, 9.8 Hz, 1H), 2.76 (dd, J=15.6, 2.5 Hz, 1H), 0.96 (s, 9H), 0.27 (s, 3H), 0.22 (s, 3H).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=2[F:26])=[C:4]([C:9]([N:11]2[CH2:14][CH:13]([C:15]([OH:17])=O)[CH2:12]2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:51][CH2:52][CH2:53][OH:54].CN1CCOCC1>CN(C)C=O.C(Cl)(Cl)Cl>[F:1][C:2]1[C:3]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=2[F:26])=[C:4]([C:9]([N:11]2[CH2:12][CH:13]([C:15]([NH:51][CH2:52][CH2:53][OH:54])=[O:17])[CH2:14]2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: NCCO
Reactant: O=C(O)C1CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(NCCO)C1CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59.1 %

Procedure:
To a solution of 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidine-3-carboxylic acid (15 mg, 0.03 mmol), prepared using procedures similar to those in Example 1, in N,N-dimethylformamide (2.00 mL) was added HBTU (38 mg, 0.10 mmol). The mixture was stirred for 15 minutes at room temperature followed by the addition of 2-aminoethanol (3.6 μL, 0.06 mmol) and N-methylmorpholine (110 μL, 1.00 mmol). The mixture was allowed to stir at room temperature for 3 d, then diluted the mixture with chloroform (20 mL), and washed with water (30 mL). The aqueous phase was back extracted with chloroform (10 mL). The combined organic phases were dried over sodium sulfate, filtered and the filtrate concentrated in vacuo. The residue was purified by high pressure liquid chromatography to afford the title compound (9.20 mg, 58%) as the trifluoroacetic acid salt: 1H NMR (400 MHz, CDCl3): 8.54 (s, 1H), 7.41-7.37 (m, 1H), 7.34-7.31 (m, 1H), 7.18-7.14 (m, 1H), 6.85-6.77 (m, 1H), 6.64-6.58 (m, 1H), 4.66 (br, 1H), 4.40-4.24 (br, 3H), 3.83-3.23 (br m, 7H), 1.18 (t, 3H); MS (EI) for C19H17F3IN3O3: 542 (MNa+).
Reaction SMILES: [N:1]1([C:6]2[C:7]3[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][C:8]=3[N:9]=[CH:10][N:11]=2)[CH:5]=[N:4][CH:3]=[N:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH3:1].[N:1]1([C:6]2[C:7]3[CH2:15][CH2:14][NH:13][CH2:12][C:8]=3[N:9]=[CH:10][N:11]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: CC(C)(C)OC(=O)N1CCc2c(ncnc2-n2cncn2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N
Product: c1nc2c(c(-n3cncn3)n1)CCNC2
Reaction time: 2 h
Yield: 33 %

Procedure:
To the product of Example 110, step a (850 mg, 2.8 mmol) in DCM (14 mL) was added TFA (5 mL). After stirring 2 h, the reaction was concentrated in vacuo. Chromatography on SiO2 eluting with 2 M NH3 in MeOH/DCM afforded the desired product as a pale yellow solid (190 mg, 33%). This material was used without further purification. MS (ESI) mass calcd. C9H10N6, 202.2. m/z found 203.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 8.92 (s, 1H), 8.63 (d, J=1.2 Hz, 1H), 7.85 (d, J=1.2 Hz, 1H), 4.23 (s, 2H), 3.36 (t, J=5.7 Hz, 2H), 3.23 (t, J=5.9 Hz, 2H).
Reaction SMILES: [CH2:1]([CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2][CH:3]([CH3:5])[CH3:4].[H-].[Na+].[H][H].I[CH3:22]>CN(C)C=O.C(OCC)C>[CH2:10]([O:9][C:7](=[O:8])[C:6]([CH3:22])([CH2:1][CH2:2][CH:3]([CH3:5])[CH3:4])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH3:11]
Reactant: CCOC(=O)C(CCC(C)C)C(=O)OCC
Reactant: [H][H]
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)C(C)(CCC(C)C)C(=O)OCC
Temperature: 25 °C
Yield: 85.6 %

Procedure:
A solution of diethyl isopentylmalonate (2.31 g, 10 mmol) in a 6:2 mixture of anhydrous N,N-dimethylformamide/diethyl ether (8 mL) was stirred under a nitrogen atmosphere at 25° C. and treated with a 60% oil dispersion of sodium hydride (480 mg, 12 mmol). The reaction mixture was stirred until the evolution of hydrogen gas ceased. The reaction was then treated dropwise via syringe with iodomethane (1.87 mL, 30 mmol) and stirred for 3 h at 25° C. The reaction was quenched with a 1.0 M aqueous hydrochloric acid solution (30 mL) and extracted with diethyl ether (2×50 mL). The combined organic layers were washed with a saturated aqueous sodium bicarbonate solution (50 mL) and saturated aqueous brine solution (50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to afford the desired product, 2-methyl-2-(3-methyl-butyl)-malonic acid diethyl ester (2.09 g, 8.56 mmol, 85%), as a clear oil. 1H NMR (400 MHz, CDCl3) δ: 0.88 (d, 6H, J=6.9 Hz), 1.06-1.12 (m, 2H), 1.24 (t, 6H, J=7.0 Hz), 1.38 (s, 3H), 1.51 (septet, 1H, J=6.6 Hz), 1.82-1.87 (m, 2H), 4.12-4.20 (m, 4H). LC-MS (ESI) calculated for C13H24O4 244.17. found 245.3 [M+H+].
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[OH:32][C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[N:36]([CH3:43])[C:35](=[O:44])[CH:34]=1.[N:45]1[CH:50]=[CH:49][CH:48]=[C:47]([CH2:51][CH2:52][N:53]([CH2:58][C:59]2[CH:64]=[CH:63][N:62]=[CH:61][CH:60]=2)[CH2:54][CH2:55][CH2:56]O)[CH:46]=1.C(OC(=O)C)C.[ClH:71]>C(OCC)(=O)C.O1CCCC1>[ClH:71].[ClH:71].[ClH:71].[CH3:43][N:36]1[C:37]2[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:33]([O:32][CH2:56][CH2:55][CH2:54][N:53]([CH2:52][CH2:51][C:47]2[CH:46]=[N:45][CH:50]=[CH:49][CH:48]=2)[CH2:58][C:59]2[CH:64]=[CH:63][N:62]=[CH:61][CH:60]=2)=[CH:34][C:35]1=[O:44]
Reactant: OCCCN(CCc1cccnc1)Cc1ccncc1
Reactant: Cn1c(=O)cc(O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1c(=O)cc(OCCCN(CCc2cccnc2)Cc2ccncc2)c2ccccc21
Reaction time: 8 h

Procedure:
Triphenyl phosphine (102 mg) and diethyl azodicarboxylate (68 mg) were added to a tetrahydrofuran (THF) solution (5 ml) of 4-hydroxy-1-methyl-1H-quinolin-2-one (63 mg), and 3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propane-1-ol (81.4 mg). The mixture was stirred overnight. After the reaction mixture was condensed under reduced pressure, the residue was purified by silica gel column chromatography (dichloromethane:methanol=20:1→10:1). The purified product was condensed under reduced pressure. A 4N-hydrogen chloride ethyl acetate solution (0.29 ml) was added to an ethyl acetate solution of the residue, which was stirred at room temperature for 30 minutes. The generated insoluble matter was separated by filtration, and dried to give the title compound (126.8 mg) as a white powder.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:3]=1[CH:4]=O.[ClH:13].[C:14]([CH2:17][O:18][NH2:19])([OH:16])=[O:15].C(CON)(O)=O.C([O-])(=O)C.[Na+]>O>[Cl:13][CH:17]([O:18][N:19]=[CH:4][C:3]1[C:6]([N+:10]([O-:12])=[O:11])=[CH:7][CH:8]=[CH:9][CH:2]=1)[C:14]([OH:16])=[O:15]
Reactant: Cl
Reactant: NOCC(=O)O
Reactant: O=Cc1c(Cl)cccc1[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)C(Cl)ON=Cc1ccccc1[N+](=O)[O-]

Procedure:
A warm solution of 2.5 gm. (0.014 mole) of 2-chloro-6-nitrobenzaldehyde in 40 ml. of alcohol 3A was added, with stirring, to a warm solution of 1.5 gm. (0.014 equivs.) of carboxymethoxylamine hemihydrochloride and 1.7 gm. (0.021 equiv.) of anhyd. sodium acetate in 40 ml. of water. The reaction mixture was heated a half-hour on the steam bath, and was then evaporated to a volume of about 20 ml. A solid separated upon cooling; it was filtered from the mixture, washed with cold water and dried in air to give 2.7 gm. (77.3%) of tan-yellow colored material melting at 136°-141° C. Recrystallization from n-hexane/isopropyl alcohol yield 2.5 gm. of pale tan-yellow crystalline product melting at 144°-146° C.
Reaction SMILES: Cl.Cl.[C:3]1([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][C:17](=[NH:20])OC)[CH2:12][CH2:11]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[O:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[CH2:26][NH:27][C:28]1[C:29](N)=[CH:30][CH:31]=[CH:32][CH:33]=1>C(O)(=O)C>[O:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[CH2:26][N:27]1[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N:20]=[C:17]1[CH2:16][CH:13]1[CH2:12][CH2:11][N:10]([CH2:9][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:15][CH2:14]1
Reactant: Nc1ccccc1NCc1ccco1
Reactant: COC(=N)CC1CCN(Cc2ccccc2)CC1
Agent: Cl
Solvent: CC(=O)O
Product: c1ccc(CN2CCC(Cc3nc4ccccc4n3Cc3ccco3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
A mixture of 27.3 parts of O-methyl 1-(phenylmethyl)-4-piperidineethanimidate dihydrochloride, 14 parts of N-(2-furanylmethyl)-1,2-benzenediamine and 250 parts of acetic acid was stirred overnight at room temperature. The reaction mixture was evaporated and water was added to the residue. The whole was alkalized with sodium carbonate and extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was crystallized from 1,1'-oxybisethane. The product was filtered off and dried, yielding 15.5 parts (57%) of 1-(2-furanylmethyl)-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-benzimidazole; mp. 124.8° C. (3).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](C(O)=O)=[CH:7]2)([O-])=O.[H-].[Na+].CI.O>CN(C=O)C>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2
Reactant: O=C(O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: Nc1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 69.8 %

Procedure:
The ethyl ester of 5-nitroindole-2-carboxylic acid (0.300 g, 1.28 mmol) was dissolved in anhydrous DMF (6 mL) and NaH (0.078 g, 60%, 1.92 mmol) was added. The reaction was stirred at RT for 20 min, then MeI (160 μL, 2.56 mmol) was added and stirring was continued for 3 h. The reaction was quenched with the addition of aqueous NaHCO3 (˜1%) while stirring vigorously. The brown solid formed (0.096 g) was filtered and dried in air overnight. The N-methyl nitro derivative (196 mg, 0.79 mmol) was then dissolved in DMF (4 mL), H2O (400 μL) and SnCl22H2O (888 mg, 3.95 mmol) were added, and the mixture was stirred at 60° C. for 3 h. The mixture was then partitioned between 10% aqueous NaHCO3 and EtOAc and stirred vigorously. The aqueous layer was re-extracted with EtOAc and the combined EtOAc layers were washed with brine, dried over anhydrous MgSO4 and concentrated to dryness. The residue was purified by flash column chromatography, using 1:1 ration EtOAc/hexane as the eluent, to obtain the pure 5-aminoindole derivative (118 mg) of example 27.
Reaction SMILES: [CH2:1]([O:8][C:9]1C=[CH:13][N:12]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][Br:25])=[CH:20][CH:19]=2)=[O:17])[C:11](=[O:26])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1N=C[N:38](CC(C2C=CC(CO)=CC=2)=O)C(=O)C=1)C1C=CC=CC=1.P(Br)(Br)Br>>[CH2:1]([O:8][C:9]1[N:38]=[CH:13][N:12]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][Br:25])=[CH:20][CH:19]=2)=[O:17])[C:11](=[O:26])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cn1ccc(OCc2ccccc2)cc1=O)c1ccc(CBr)cc1
Reactant: O=C(Cn1cnc(OCc2ccccc2)cc1=O)c1ccc(CO)cc1
Agent: BrP(Br)Br
Product: O=C(Cn1cnc(OCc2ccccc2)cc1=O)c1ccc(CBr)cc1

Procedure:
6-Benzyloxy-3-[2-(4-bromomethyl-phenyl)-2-oxo-ethyl]-3H-pyrimidin-4-one is prepared following preparation 15c from 2.50 g (7.14 mmol) 6-benzyloxy-3-[2-(4-hydroxymethyl-phenyl)-2-oxo-ethyl]-3H-pyrimidin-4-one (preparation 20a) and 0.67 mL (7.14 mmol) phosphorus tribromide.
Reaction SMILES: C[CH:2]([CH2:17][CH3:18])[CH2:3][CH2:4][C:5]1[CH:16]=[CH:15][C:8]2[O:9][CH2:10][C:11](=[O:14])[CH2:12][O:13][C:7]=2[CH:6]=1.[CH2:19](C1C=CC2OCC(=O)COC=2C=1)CCCC.CC(CC)CC1C=CC2OCC(=O)COC=2C=1.CC(C)CCC1C=CC2OCC(=O)COC=2C=1.CC1C2C=C3OCC(=O)COC3=CC=2CC1>>[CH3:19][CH:3]([CH2:2][CH2:17][CH3:18])[CH2:4][C:5]1[CH:16]=[CH:15][C:8]2[O:9][CH2:10][C:11](=[O:14])[CH2:12][O:13][C:7]=2[CH:6]=1
Reactant: CCC(C)CCc1ccc2c(c1)OCC(=O)CO2
Reactant: CCCCCc1ccc2c(c1)OCC(=O)CO2
Agent: CC(C)CCc1ccc2c(c1)OCC(=O)CO2
Agent: CC1CCc2cc3c(cc21)OCC(=O)CO3
Agent: CCC(C)Cc1ccc2c(c1)OCC(=O)CO2
Product: CCCC(C)Cc1ccc2c(c1)OCC(=O)CO2

Procedure:
Odor: Marine, floral-aldehyde odor. -IR (film): ν=1501/1434/1460/1580 cm−1 (ν C═C, Ar), 1265/1303/1201 cm−1 (ν ring), 1049 cm−(ν C—O—C), 1740 cm−1 (ν C═O), -1H-NMR (CDCl3): δ=0.83 (d, 3H, 2′-Me), 0.88 (t, J=7.0 Hz, 3H, 5′-H3), 1.11-1.40 (m, 4H, 3′-,4′-H2), 1.68 (mc1 1H, 2′-H), 2.26 (dd, J=13.6, 8.4 Hz, 1H, 1′-Hb), 2.54 (dd, J=13.6, 6.0 Hz, 1H, 1′-Ha), 4.69 (d, J=8.4 Hz, 4H, 2-,4-H2) 6.73 (dd, J=8.0, 2.0 Hz, 1H, 8-H), 6.78 (d, J=2.0 Hz, 1H, 6-H), 6.89 (d, J=8.0 Hz, 1H, 9-H). -13 C-NMR (CDCl3): δ=14.15 (q, C-5′), 19.17 (q, 2′-Me), 20.02 (t, C-4′), 34.50 (d, C-2′), 38.77 (t, C-3′), 42.61 (t, C-1′), 75.36.75.63 (2t, C-2, -4), 120.30/121.04 (2d, C-6,-9), 124.28 (d, C-8), 137.61 (s, C-7), 146.05/147.70 (2s, C-5a,-9a), 204.77 (s, C-3). -MS (EI): m/z (%)=77 (9) [C6H5+], 91 (6) [C7H7+], 135 (5) [M+-C5H11—C2H2O], 149 (3) [M+-C5H11—CO], 177 (100) [M+-C5H11], 205 (2) [M+-C3H7], 248 (21) [M+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:7]2[C:18]1[CH:19]=[C:20](N)[CH:21]=[CH:22][CH:23]=1.[Br:25][C:26]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:27]=1[CH:28]=[O:29]>>[Br:25][C:26]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:27]=1[CH2:28][O:29][C:20]1[CH:19]=[C:18]([C:7]2[C:6]3[C:11](=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=3)[N:10]=[N:9][C:8]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: Nc1cccc(-c2c(-c3ccccc3)nnc3c(Cl)cccc23)c1
Reactant: COc1ccc(Br)c(C=O)c1
Product: COc1ccc(Br)c(COc2cccc(-c3c(-c4ccccc4)nnc4c(Cl)cccc34)c2)c1

Procedure:
The title compound was prepared from 3-(8-chloro-3-phenyl-cinnolin-4-yl)-phenylamine and 2-bromo-5-methoxylbenzaldehyde according to the procedure of Step 5 Example 6. MS (ES) m/z 531.1.
Reaction SMILES: B.CSC.[CH:5]1([C:11]2[C:12]3[CH:13]=[CH:14][C:15]([C:31]([O:33][CH3:34])=[O:32])=[CH:16][C:17]=3[N:18]3[C:25]=2[C:24]2[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=2[O:22][CH2:21][C:20](=[CH2:30])[CH2:19]3)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[OH-:35].[Na+].OO>C1COCC1.CCOC(C)=O>[CH:5]1([C:11]2[C:12]3[CH:13]=[CH:14][C:15]([C:31]([O:33][CH3:34])=[O:32])=[CH:16][C:17]=3[N:18]3[C:25]=2[C:24]2[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=2[O:22][CH2:21][CH:20]([CH2:30][OH:35])[CH2:19]3)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: [OH-]
Reactant: C=C1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)OC)cc3n2C1
Agent: B
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CSC
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(CO)COc1ccccc1-3
Temperature: 25 °C
Reaction time: 16 h
Yield: 50 %

Procedure:
Borane-dimethylsulfide complex (2M solution in THF, 1.6 eq) was added to a solution of methyl 14-cyclohexyl-7-methylene-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (from Step 1) in dry THF (0.12 M) at 0° C. The solution was stirred for 16 h at RT. The reaction mixture was cooled to 0° C. and treated dropwise with 3N NaOH (3 eq.) followed by 35% (v/v) H2O2 solution and the resulting mixture was stirred for 2 h at RT. The mixture was diluted with EtOAc, washed with aqueous saturated NaHCO3-solution and with brine, dried (Na2SO4). Evaporation afforded a crude residue which was purified by flash chromatography (4:1 PE/EtOAc). Methyl 14-cyclohexyl-7-(hydroxymethyl)-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (50%) was obtained as colorless solid; MS (ES+) m/z 402 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:4]=1[CH2:5][Cl:6].[Zn:13].NC1C=CC(I)=CC=1C#N>C1COCC1>[Cl-:6].[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:4]=1[CH2:5][Zn+:13]
Reactant: [Zn]
Reactant: COc1ccc(OC)c(CCl)c1
Agent: N#Cc1cc(I)ccc1N
Solvent: C1CCOC1
Product: COc1ccc(OC)c(C[Zn+])c1
Product: [Cl-]

Procedure:
2,5-Dimethoxybenzylzinc chloride was prepared from 2,5-dimethoxybenzyl chloride (746 mg, 4 mmol) and reactive metallic zinc suspension (0.76 M in THF, 6.3 mL, 4.8 mmol). The supernatant was transferred via a cannula into a solution of 9 (366 g, 1.5 mmol) in THF, followed by the usual workup; pale-yellow powder (280 mg, 69%): mp 90-92° C.; 1H NMR (CDCl3) δ 3.74 (s, 3H, OMe), 3.76 (s, 3H, OMe), 3.80 (s, 2H, CH2), 4.66 (br s, 2H, NH2), 6.63 (d, 1H, J=2.8 Hz, H-6′), 6.70 (d, J=8.4 Hz, 1H, H-3), 6.72 (dd, J=9.0 Hz, J=2.8 Hz, 1H, H4′), 6.80 (d, J=9.0 Hz, 1H, H-3;), 7.19 (d, J=8.4 Hz, 1H, H-4), 7.22 (s, 1H, H-6).