Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[SH:9].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:17]([CH2:21][CH3:22])[C:18](Br)=[O:19]>CN(C=O)C>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:18](=[O:19])[CH:17]([CH2:21][CH3:22])[S:9][C:3]=2[CH:4]=1
Reactant: CCC(Br)C(=O)Br
Reactant: Nc1ccc(Br)cc1S
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCC1Sc2cc(Br)ccc2NC1=O
Temperature: 25 °C
Yield: 13.6 %

Procedure:
To a mixture of 2-amino-5-bromo-benzenethiol (20 g, 0.1 mol) and cesium carbonate (33 g, 0.1 mol) in DMF (500 ml) at −35° C. was added dropwise 2-bromobutyrylbromide (23 g, 0.1 mol). The mixture was allowed to warm to room temperature, poured into ice/water, and extracted with CH2Cl2 (2×50 mL). The combined organic extracts were washed with water, then brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography (SiO2, ethyl acetate:hexane/1:6) to afford 7-bromo-2-ethyl-4H-benzo[1,4]thiazin-3-one (3.7 g, 14%): mp 100° C.; MS (EI) m/z 271/273 (M+).
Reaction SMILES: C([O:3][C:4]([C:6]1([S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C.CO.[OH-].[Na+]>C1COCC1>[CH2:30]([O:29][C:26]1[CH:25]=[CH:24][C:23]([S:20]([C:6]2([C:4]([OH:5])=[O:3])[CH2:11][CH2:10][N:9]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=3)[CH2:8][CH2:7]2)(=[O:21])=[O:22])=[CH:28][CH:27]=1)[CH2:31][CH2:32][CH3:33]
Reactant: CCCCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(Cc3ccc(C)cc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3ccc(C)cc3)CC2)cc1

Procedure:
4-(4-Butoxy-benzenesulfonyl)-1-(4-methylbenzyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-Butoxy-benzenesulfonyl)-1-(4-methylbenzyl)-piperidine-4-carboxylic ethyl ester (10.0 g, 22 mmol) dissolved in THF:Methanol (50:50 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 7.2 g (72%); off white solid, mp 244° C.; MS: 446.3 (M+H)+
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH:11]=[O:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH2:13]([Mg]Br)[CH:14]=[CH2:15]>>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH:11]([OH:12])[CH2:15][CH:14]=[CH2:13])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: C=CC[Mg]Br
Reactant: O=CC1CCC2(CC1)OCCO2
Product: C=CCC(O)C1CCC2(CC1)OCCO2
Temperature: -78 °C
Reaction time: 8 h

Procedure:
To a solution of 1,4-dioxaspiro[4.5]decane-8-carbaldehyde (627 mg, 3.68 mmol, prepared as described in Pearson, et al. in J. Org. Chem. 1997, 62(16), 5284-5292) cooled to −78° C. under argon was added a allylmagnesium bromide (5 mL, 5 mmol, 1 M in THF) dropwise. After the complete addition, the reaction mixture was allowed to reach room temperature overnight. It was then re-cooled to −78° C. and quenched with saturated NaHCO3 solution and warmed to room temperature. After extraction with ether, the organic layer was concentrated in vacuo and the residue purified by flash chromatography (silica gel, 0-100% ether/hexanes) to afford the product.
Reaction SMILES: [OH-].[Na+].BrBr.Br[O-].[C:7]([C:10]12[CH2:17][CH:16]3[CH2:18][C:12]([N:19]4[CH2:23][CH2:22][CH2:21][C:20]4=[O:24])([CH2:13][CH:14]1[CH2:15]3)[CH2:11]2)(=[O:9])C.C(O)(=[O:27])C>O1CCOCC1.O>[O:24]=[C:20]1[CH2:21][CH2:22][CH2:23][N:19]1[C:12]12[CH2:18][CH:16]3[CH2:15][CH:14]([CH2:13]1)[C:10]([C:7]([OH:9])=[O:27])([CH2:17]3)[CH2:11]2
Reactant: CC(=O)O
Reactant: CC(=O)C12CC3CC1CC(N1CCCC1=O)(C3)C2
Agent: BrBr
Agent: [Na+]
Agent: [O-]Br
Solvent: O
Solvent: C1COCCO1
Product: O=C1CCCN1C12CC3CC(C1)C(C(=O)O)(C3)C2
Reaction time: 0.08 h
Yield: 129.1 %

Procedure:
To a stirred mixture of NaOH (2.4 g, 60.6 mmol), H2O (16 mL) and 1,4 dioxane (4 mL) at ice bath temperature was added Br2 (1.13 mL, 22.6 mmol) and stirred for 5 minutes. The resulting hypobromite solution was added dropwise to a stirred solution of the compound obtained in step I (1.0 g, 4.04 mmol) in 1,4-dioxane (18 mL) at 10° C. The temperature of the reaction was brought to room temperature and the reaction mixture was stirred for 1 h. Then it was cooled to ice bath temperature and quenched by adding acetic acid (3.9 mL, 65.7 mmol). The reaction mixture was diluted with water, extracted with EtOAc, and the combined organic layers were washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure to obtain 1-(2-oxopyrrolidin-1-yl)tricyclo[3.3.1.03,7]nonane-3-carboxylic acid as a viscous liquid (1.3 g) in 100% yield. m/z (M+1) 250; 1H NMR (CDCl3) 300 MHz δ 3.42 (t, J=7.0 Hz, 2H), 2.78-2.71 (m, 1H), 2.47-2.23 (m, 6H), 2.08-1.90 (m, 6H), 1.85-1.72 (m, 2H), 1.62 (dd, J=2.4, 11.0 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:20])[N:4]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:13](O)=[O:14])[C:5]([CH3:9])=[CH:6][C:7]=1[OH:8].[C:21](N1C=CN=C1)([N:23]1C=CN=C1)=O.CN.O1CCCC1.Cl>CN(C)C=O>[Br:1][C:2]1[C:3](=[O:20])[N:4]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:13]([NH:23][CH3:21])=[O:14])[C:5]([CH3:9])=[CH:6][C:7]=1[OH:8]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1ccc(C(=O)O)cc1-n1c(C)cc(O)c(Br)c1=O
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(C)c(-n2c(C)cc(O)c(Br)c2=O)c1
Yield: 100 %

Procedure:
(−)3-(3-bromo-4-hydroxy-6-methyl-2-oxopyridin-1(2H)-yl)-4-methylbenzoic acid (10) (1.50 kg, 4.44 moles), 1,1′-carbonyldiimidazole (1.08 kg, 6.66 moles) and N,N-dimethylformamide (3 mL) were mixed together at ambient temperature. Once the activation reaction was deemed complete, 2 M methylamine solution in tetrahydrofuran (5.5 L, 11.1 moles) was added at a rate that maintained the temperature below 30° C. The mixture became homogeneous as the reaction reached completion. A solution of 1 N hydrochloric acid solution (15.4 kg) was added to reach pH 3 or less. The acidification precipitated the product. The product was filtered, washed with water and vacuum dried at 60° C. overnight to give (−)3-(3-bromo-4-hydroxy-6-methyl-2-oxopyridin-1(2H)-yl)-N,4-dimethylbenzamide (9) (1.56 kg, 4.44 moles, 97% purity).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[Cl:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[C:11](Cl)[C:10]([N+:17]([O-:19])=[O:18])=[CH:9][C:8]=1[C:20]([F:23])([F:22])[F:21]>C1CCCCC1>[CH3:1][O:2][CH2:3][CH2:4][NH:5][C:11]1[C:10]([N+:17]([O-:19])=[O:18])=[CH:9][C:8]([C:20]([F:21])([F:22])[F:23])=[C:7]([Cl:6])[C:12]=1[N+:13]([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c([N+](=O)[O-])c1Cl
Reactant: COCCN
Solvent: C1CCCCC1
Product: COCCNc1c([N+](=O)[O-])cc(C(F)(F)F)c(Cl)c1[N+](=O)[O-]

Procedure:
The compound was prepared by reacting 2-methoxyethylamine was 2,4-dichloro-3,5-dinitrobenzotrifluoride in cyclohexane to give the product melting at 106.5° - 107.5°C.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[NH2:10][CH2:11][P:12](=[O:19])([O:16]CC)[O:13]CC.C[Si](Br)(C)C>>[P:12]([CH2:11][NH:10][C:7]([C:5]1[O:6][C:2]([Br:1])=[CH:3][CH:4]=1)=[O:9])([OH:19])([OH:16])=[O:13]
Reactant: CCOP(=O)(CN)OCC
Reactant: O=C(O)c1ccc(Br)o1
Agent: C[Si](C)(C)Br
Product: O=C(NCP(=O)(O)O)c1ccc(Br)o1

Procedure:
5-Bromofuroic acid was reacted with diethyl aminomethylphosphonate in a manner similar to that described in Step D, Example 5. The product was treated with TMSBr as described in Step D, Example 1 to provide the title compound (no. 8.01) as a solid. HPLC Rt=3.72 min; negative ion electrospray MS M−1 found: 282/284.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]4([O:24][CH3:25])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)[N:14]3[CH3:17])=[C:10]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[N:9]=2)[C:6]2[CH:32]=[CH:33][CH:34]=[CH:35][C:5]=2[N:4]=1)[CH3:2].[OH:36][CH2:37][C:38](O)=[O:39].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C>C1COCC1.C(Cl)Cl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]4([O:24][CH3:25])[CH2:23][CH2:22][N:21]([C:37](=[O:36])[CH2:38][OH:39])[CH2:20][CH2:19]4)[N:14]3[CH3:17])=[C:10]([N:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)[N:9]=2)[C:6]2[CH:32]=[CH:33][CH:34]=[CH:35][C:5]=2[N:4]=1)[CH3:2]
Reactant: O=C(O)CO
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(OC)CCNCC3)n(C)c2n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(OC)CCN(C(=O)CO)CC3)n(C)c2n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-8-(4-methoxypiperidin-4-yl)-9-methyl-6-morpholin-4-yl-9H-purine (150 mg, 0.32 mmol), hydroxyacetic acid (36 mg, 0.47 mmol), HOBt (47 mg, 0.35 mmol), NMM (77 μL, 0.69 mmol) and EDCI (91 mg, 0.47 mmol) in THF (3 mL) was allowed to stir at r.t. for 4 h. The resulting mixture was diluted with DCM and washed with sat. aq. NaHCO3, dried (phase separator) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, THF:EtOAc, 0-50%) then loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH affording 823 (88 mg, 52%). LCMS (method I): RT 3.25 min, [M+H]+ 535.3. 1H NMR (DMSO, 400 MHz): δ 8.05-8.04 (1 H, m), 7.64-7.63 (1 H, m), 7.26-7.25 (2 H, m), 4.54 (1 H, t, J=5.40 Hz), 4.17-4.06 (6 H, m), 3.92 (3 H, s), 3.78 (4 H, t, J=4.51 Hz), 3.65-3.55 (1 H, m), 3.40-3.25 (3 H, m), 3.18 (1 H, m), 3.09 (3 H, s), 2.17-2.14 (4 H, m), 1.35 (3 H, t, J=7.43 Hz)
Reaction SMILES: [Br-].C[O:3][C:4]1[CH:29]=[CH:28][C:7]([CH2:8][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:6][CH:5]=1.C([Li])CCC.C[O:36][C:37]1[CH:38]=[C:39]([CH:42]=[C:43]([O:45]C)[CH:44]=1)[CH:40]=O.O>O1CCCC1>[OH:3][C:4]1[CH:5]=[CH:6][C:7](/[CH:8]=[CH:40]/[C:39]2[CH:42]=[C:43]([OH:45])[CH:44]=[C:37]([OH:36])[CH:38]=2)=[CH:28][CH:29]=1
Reactant: COc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: COc1cc(C=O)cc(OC)c1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Oc1ccc(/C=C/c2cc(O)cc(O)c2)cc1
Reaction time: 3 h
Yield: 36.7 %

Procedure:
To a solution of 4-methoxy-benzyltriphenylphosphonium bromide (12.5 g) in anhydrous tetrahydrofuran (200 mL) at −78° C. was added n-butyllithium (2.44 M, 1.0 equiv), and the resulting red solution was stirred under argon for 2-4 h. A solution of 3,5-dimethoxybenzaldehyde (4.5 g) in tetrahydrofuran was added dropwise over 30 min and the mixture stirred for 6-15 h. The resulting cream suspension was poured into water and extracted with dichloromethane. The organic phase was washed with water, and removal of the solvent in vacuo afforded an oil. The oil was separated by flash column chromatography (49:1 hexane/ethyl acetate). The cis-stilbene eluted first as a clear oil followed by the trans isomer as a colorless solid or oil. Overall yield: 91%. To a solution of the trans isomer (3.1.g) in anhydrous dichloromethane (150 mL) at −78° C. was added (dropwise) boron tribromide (1.0 M, 34.5 mL), and the resulting red solution was stirred under argon for 30 min. The solution was poured into water and extracted with dichloromethane. The organic phase was washed with water, and removal of the solvent in vacuo afforded an oil, which was separated by flash column chromatography (1:1 hexane/ethyl acetate) to afford a colorless solid (2.26 g, 86%): mp 260° C.
Reaction SMILES: [CH3:1][N:2]1[N:6]=[N:5][C:4]([C:7]2[CH:8]=[C:9]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=2)[CH2:10][O:11][CH2:12][C:13]2([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)=[N:3]1.Cl>C(OCC)(=O)C>[CH3:1][N:2]1[N:6]=[N:5][C:4]([C:7]2[CH:8]=[C:9]([CH:32]=[C:33]([C:35]([F:37])([F:38])[F:36])[CH:34]=2)[CH2:10][O:11][CH2:12][C:13]2([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]2)=[N:3]1
Reactant: Cn1nnc(-c2cc(COCC3(c4ccccc4)CCN(C(=O)OC(C)(C)C)CC3)cc(C(F)(F)F)c2)n1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cn1nnc(-c2cc(COCC3(c4ccccc4)CCNCC3)cc(C(F)(F)F)c2)n1
Reaction time: 1 h

Procedure:
tert-Butyl 4-((3-(2-methyl-2H-tetrazol-5-yl)-5-(trifluoromethyl)benzyloxy)methyl)-4-phenylpiperidine-1-carboxylate (48.0 mg, 0.09 mmol) was dissolved in a minimum amount of ethyl acetate, followed by addition of 4 N hydrochloric acid (1 mL). The mixture was stirred under nitrogen for 1 h. After removing the solvents, the crude mixture was precipitated in diethyl ether and filtered to afford 26.0 mg (67%) as a white powder. 1H-NMR (CDCl3, 300 MHz) δ 8.23 (s, 1H), 8.10 (s, 1H), 7.40 (s, 1H), 7.28-7.36 (m, 4H), 7.20 (m, 1H), 4.41 (s, 2H), 4.38 (s, 3H), 3.44 (s, 2H), 2.86-2.93 (m, 2H), 2.69-2.77 (m, 2H), 2.16-2.20 (m, 2H), 1.83-1.96 (m, 2H). 13C-NMR (CDCl3, 76 MHz) δ 164.0, 143.4, 141.0, 131.4 (q, J=32.8 Hz), 128.3, 128.0, 127.0, 126.1, 135.5, 124.0 (q, J=213.8 Hz), 122.6, 121.9, 79.9, 72.0, 42.3, 41.7, 39.5, 32.9. Mass spec.: 432.20 (MH)+. Accurate mass spec.: m/z 432.1994 [MH]+, Δ=4.0 ppm.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][N:4]=1>C(Cl)Cl.O=[Mn]=O>[CH3:9][C:8]1[C:3]([CH:2]=[O:1])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnc1CO
Agent: O=[Mn]=O
Solvent: ClCCl
Product: Cc1cccnc1C=O
Reaction time: 21 h
Yield: 64 %

Procedure:
To a stirred solution of 2-(hydroxymethyl)-3-methylpyridine (1.08 g, 8.77 mmol) in dry CH2Cl2 (45 mL) at room temperature was added MnO2 (8.09 g, 79.1 mmol). The mixture was stirred for 21 hrs then filtered through celite. The filtrate was concentrated to give 0.68 g (64%) of 3-methylpyridine-2-carboxaldehyde. 1H NMR (CDCl3) □ 2.66 (s, 3H), 7.39 (dd, 1H, J=8.3, 4.3 Hz), 7.63 (d, 1H, J=7.9 Hz), 8.66 (d, 1H, J=3.3 Hz), 10.19 (s, 1H). This was used without further purification.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])(C)(C)C.C(O[C:26](=[O:48])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[C:40]([CH3:42])[N:39]=[C:38]([NH:43][CH2:44][CH2:45][O:46][CH3:47])[N:37]=2)[CH:31]=1)=O)(C)(C)C>>[CH3:47][O:46][CH2:45][CH2:44][NH:43][C:38]1[N:37]=[C:36]([C:32]2[CH:31]=[C:30]([C:28]3[CH2:27][C:26](=[O:48])[NH:19][C:9]4[CH:10]=[C:11]([C:15]([F:16])([F:17])[F:18])[C:12]([CH3:14])=[CH:13][C:8]=4[N:7]=3)[CH:35]=[CH:34][CH:33]=2)[CH:41]=[C:40]([CH3:42])[N:39]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: COCCNc1nc(C)cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)n1
Product: COCCNc1nc(C)cc(-c2cccc(C3=Nc4cc(C)c(C(F)(F)F)cc4NC(=O)C3)c2)n1

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J20) (145 mg, 0.5 mmol) and 3-{3-[2-(2-methoxy-ethylamino)-6-methyl-pyrimidin-4-yl]-phenyl}-3-oxo-propionic acid tert-butyl ester (Example K51) (212 mg, 0.55 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (169 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15](CC#N)[C:14]=3[CH:13]=[CH:12][N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:23]([OH:26])(=[O:25])[CH3:24]>S(=O)(=O)(O)O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([CH2:24][C:23]([OH:26])=[O:25])[C:14]=3[CH:13]=[CH:12][N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(=O)O
Reactant: N#CCc1cccc2c(-c3ccc([N+](=O)[O-])cc3)nccc12
Agent: O=S(=O)(O)O
Product: O=C(O)Cc1cccc2c(-c3ccc([N+](=O)[O-])cc3)nccc12
Temperature: 0 °C

Procedure:
1-(4-Nitrophenyl)isoquinoline-5-acetonitrile (2.1 g) was dissolved in 12 ml of 75% sulfuric acid and 2 ml of acetic acid, and refluxed for 3 hours. The reaction mixture was poured into ice water, and washed with ether. The aqueous layer was neutralized with an aqueous solution of sodium hydroxide. The crystals that precipitated were collected by filtration, and recrystallized from tetrahydrofuran to afford 2.1 g of 1-(4-nitrophenyl)isoquinoline-5-acetic acid having a melting point of 252.2° to 253.8° C.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([N:16]3[CH:20]=[C:19]([CH2:21][CH3:22])[CH:18]=[N:17]3)[C@@H:13]([OH:23])[C@H:12]2[OH:24])=[C:4]([NH:25][CH2:26][CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:3]=1.[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].C1(C(C2C=CC=CC=2)CNC2N=C(NCCN3CCCCC3)N=C3C=2N=CN3[C@@H]2C[C@H](N3C=C(CO)C=N3)[C@@H](O)[C@H]2O)C=CC=CC=1.[CH:94]1([NH2:101])[CH2:99][CH2:98][CH:97]([NH2:100])[CH2:96][CH2:95]1>>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[NH2:100][CH:97]1[CH2:98][CH2:99][CH:94]([NH:101][C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[C@@H:11]3[CH2:15][C@H:14]([N:16]4[CH:20]=[C:19]([CH2:21][CH3:22])[CH:18]=[N:17]4)[C@@H:13]([OH:23])[C@H:12]3[OH:24])=[C:4]([NH:25][CH2:26][CH:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:3]=2)[CH2:95][CH2:96]1
Reactant: NC1CCC(N)CC1
Reactant: CCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(Cl)nc43)[C@H](O)[C@@H]2O)c1
Agent: OCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(NCCN5CCCCC5)nc43)[C@H](O)[C@@H]2O)c1
Solvent: O=C(O)C(F)(F)F
Product: CCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(NC5CCC(N)CC5)nc43)[C@H](O)[C@@H]2O)c1

Procedure:
This compound is prepared from (1R,2S,3R,5S)-3-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(4-ethyl-pyrazol-1-yl)-cyclopentane-1,2-diol (Intermediate BA8) using a procedure analogous to that of (1R,2S,3R,5S)-3-[6-(2,2-diphenyl-ethylamino)-2-(2-piperidin-1-yl-ethylamino)-purin-9-yl]-5-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentane-1,2-diol trifluoroacetate (Example 461 by replacing 1-(2-amino-ethyl)piperidine with cyclohexane-1,4-diamine. MS (ES+) m/e 622.42 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:27]=[C:26]([C:28]2[C:37]3[C:38]4[CH:44]=[CH:43][CH:42]=[CH:41][C:39]=4[S:40][C:36]=3[C:35]([Br:45])=[C:34]3[C:29]=2[CH:30]=[CH:31][CH:32]=[CH:33]3)[CH:25]=[C:24]([Br:46])[C:3]=1[O:4][CH:5]([CH2:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=1)[C:6]([O:8]C(C)(C)C)=[O:7].O.CCOCC>FC(F)(F)C(O)=O>[Br:46][C:24]1[CH:25]=[C:26]([C:28]2[C:37]3[C:38]4[CH:44]=[CH:43][CH:42]=[CH:41][C:39]=4[S:40][C:36]=3[C:35]([Br:45])=[C:34]3[C:29]=2[CH:30]=[CH:31][CH:32]=[CH:33]3)[CH:27]=[C:2]([Br:1])[C:3]=1[O:4][CH:5]([CH2:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=1)[C:6]([OH:8])=[O:7]
Reactant: CC(C)(C)OC(=O)C(Cc1ccc2ccccc2c1)Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CCOCC
Product: O=C(O)C(Cc1ccc2ccccc2c1)Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Temperature: 25 °C

Procedure:
A solution of 2-[2,6-dibromo-4-(6-bromo-benzo[b]naphtho[2,3-d]thiophen-11-yl)-phenoxy ]-3-naphthalen-2yl--propionic acid, tert butyl ester (0.221 g, 0.270 mmol) in trifluoroacetic acid (10 mL) was heated to 50° C. for 15 hours. The mixture was cooled to room temperature and combined with water. Ether was added and the resulting organic suspension was separated from the water layer and concentrated. The residue was dried in vacuo at 46 C. to provide the title compound as an off white solid (0.186 g, 90%) mp 270-271° C.; NMR (DMSO-d6); δ13.25 (broad singlet, 1 H), 8.28 (d, J=8 Hz, 1 H,), 8.06 (d, J=8 Hz, 1 H), 7.91(m, 4 H), 7.81(d, J=2 Hz, 1 H), 7.79(d, J =2 Hz, 1 H) 7.82-7.77(m, 1 H), 7.63-7.47(m, 6 H), 7.25 (dd, J=7, 1 Hz,, 1 H), 6.64 (d, J=8 Hz, 1 H) 5.42 (t, J=7 Hz, 1 H), 3.59 (d, J=7 Hz, 2 H); MS (FAB+): [M+], 3 bromine pattern, 757.8 (21%) 759.8 (100%) 761.8 (100%) 763.8 (50%); Anal. Calcd. for C31H19Br3O3S: C, 55.07; H,3.04, N, 0.00. Found: C, 55.36; H, 2.89, N, 0.06.
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]([CH3:13])=O)[C:6]([O:8]CC)=[O:7])C.Cl.Cl.[F:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][NH2:24])=[CH:19][CH:18]=1>C(O)C>[F:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:11]([CH3:13])=[C:5]([C:6]([OH:8])=[O:7])[CH:4]=[N:24]2)=[CH:19][CH:18]=1
Reactant: CCOC=C(C(C)=O)C(=O)OCC
Reactant: NNc1ccc(F)cc1
Agent: Cl
Solvent: CCO
Product: Cc1c(C(=O)O)cnn1-c1ccc(F)cc1
Yield: 47.5 %

Procedure:
To an ethanol (75 ml) solution of ethyl 2-(ethoxymethylene)acetoacetate (28.63 g) prepared according to a method described in J. Chem. Soc. Perkin trans. I, 1875 (1988), was added 1N hydrochloric acid aqueous solution (75 ml) of 4-fluorophenylhydrazine hydrochloride (25 g) and the mixture was stirred at reflux temperature for three hours. After evaporation of ethanol, sodium hydroxide (12 g) was added to the residue and stirred at reflux temperature for three hours. After completion of the reaction, the solvent was evaporated, diluted hydrochloric acid was added to the residue, and the precipitated solid was washed with ethyl acetate to give the titled compound (16.08 g).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[C:13](=[O:31])[NH:14][C:15](=[O:30])[C:16]=3[C:17]3[C:25]4[C:20](=[CH:21][C:22]([N+:26]([O-])=O)=[CH:23][CH:24]=4)[N:19]([CH3:29])[CH:18]=3)=[CH:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.Cl.O.NN>C(O)C.O1CCCC1.[Pd]>[NH2:26][C:22]1[CH:21]=[C:20]2[C:25]([C:17]([C:16]3[C:15](=[O:30])[NH:14][C:13](=[O:31])[C:12]=3[C:6]3[C:5]4[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=4)[N:8]([CH3:11])[CH:7]=3)=[CH:18][N:19]2[CH3:29])=[CH:24][CH:23]=1
Reactant: Cn1cc(C2=C(c3cn(C)c4cc([N+](=O)[O-])ccc34)C(=O)NC2=O)c2ccc(F)cc21
Agent: [Pd]
Agent: Cl
Agent: NN
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: Cn1cc(C2=C(c3cn(C)c4cc(F)ccc34)C(=O)NC2=O)c2ccc(N)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 1.0 g (2.39 mmole) of 3-(6-fluoro-1-methyl-1H-indol-3-yl)-4-(1-methyl-6-nitro-1H-indol-3-yl)-pyrrole-2,5-dione in 20 ml of ethanol and 10 mL of tetrahydrofuran was added 0.55 g of 10% Pd/C and 0.54 mL of 5% hydrochloric acid. The mixture was cooled in an ice bath, and 0.54 mL (14.34 mmole) of hydrazine hydrate (85%) was added dropwise over 5 min. The reaction mixture was allowed to warm to room temp as it was stirred for two hours. The catalyst was removed by filtration over Celite. The filtrate was evaporated and the residue was crystallized from ethyl acetate/tetrahydrofuran/hexane to give 708 mg (76%) of )3-(6-amino-1-methyl-1H-indol-3-yl)-4-(6-fluoro-1-methyl-1H-indol-3-yl)-pyrrole-2,5-dione.
Reaction SMILES: N[C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH3:17])=[CH:11][C:10]=2[OH:18])=[CH:4][CH:3]=1.N([O-])=[O:20].[Na+].C([O-])(O)=O.[Na+]>OS(O)(=O)=O.O.[O-]S([O-])(=O)=O.[Cu+2]>[OH:18][C:10]1[CH:11]=[C:12]([CH2:15][CH2:16][CH3:17])[CH:13]=[CH:14][C:9]=1[O:8][C:5]1[CH:4]=[CH:3][C:2]([OH:20])=[N:7][CH:6]=1
Reactant: CCCc1ccc(Oc2ccc(N)nc2)c(O)c1
Reactant: O=N[O-]
Agent: [Cu+2]
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCc1ccc(Oc2ccc(O)nc2)c(O)c1
Reaction time: 0.5 h
Yield: 10 %

Procedure:
To a solution of 2-[(6-aminopyridin-3-yl)oxy]-5-propylphenol (0.20 mmol; 50 mg) under argon, in H2SO4 (35%; 0.2 mL), cooled to 0° C., was slowly added NaNO2 (0.26 mmol; 18 mg) in water (0.2 mL). After 30 min, CuSO4 (3 mmol; 477 mg) in water (1 mL), then Cu2O (0.18 mmol; 26 mg) were added. After 30 min, the mixture was neutralised with NaHCO3 sat. (1 mL), extracted with ethyl acetate (3*3 mL). Combined organic phases were washed with water (3 mL), dried over MgSO4, concentrated in vacuo. An analytical sample was obtained by preparative TLC to yield the title compound as a white solid (5 mg; 0.02 mmol; ca 20%).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:14])[CH2:11][O:12][CH3:13])=[CH:6][CH:5]=1>CO>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]([OH:14])[CH2:11][O:12][CH3:13])=[CH:8][CH:9]=1
Reactant: COCC(=O)c1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COCC(O)c1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
Sodium borohydride (111 mg, 2.9 mmol) was added in portions to a solution of 1-(4-chlorophenyl)-2-methoxy-ethanone (1 g, 6.4 mmol) in methanol at room temperature. After 1 hour, reaction was quenched with 3 mls (aq) sat. NH4Cl. Water was added to dissolve the inorganic and mixture was extracted with ethyl acetate 3×5 ml. Combined organics were washed with brine (2×3 ml) and dried over MgSO4. Crude material was obtained upon filtration and concentration to an amber oil which was purified by flash silica gel and eluted with 10-17% EA/Hex gradient. 1-(4-chlorophenyl)-2-methoxy-ethan-1-ol was obtained as an amber oil (370 mg, 68% yield).