Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH:5]1[CH:18]=[C:17]2[C:8](=[C:9]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=3[C:32]([OH:34])=[O:33])[C:10]3[C:15]([O:16]2)=[CH:14][C:13]([O:19]C(=O)C)=[CH:12][CH:11]=3)[CH:7]=[CH:6]1)(=O)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH2:49]([S:56][C:57](=[O:60])[CH2:58][NH2:59])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>C1COCC1.CN(C=O)C>[CH2:49]([S:56][C:57]([CH2:58][NH:59][C:27](=[O:29])[C:26]1[CH:25]=[C:24]([C:23]([C:9]2[C:10]3[C:15]([O:16][C:17]4[C:8]=2[CH:7]=[CH:6][CH:5]([OH:4])[CH:18]=4)=[CH:14][C:13]([OH:19])=[CH:12][CH:11]=3)=[CH:31][CH:30]=1)[C:32]([OH:34])=[O:33])=[O:60])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: CC(=O)Oc1ccc2c(c1)OC1=CC(OC(C)=O)C=CC1=C2c1ccc(C(=O)O)cc1C(=O)O
Reactant: NCC(=O)SCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: C1CCOC1
Product: O=C(CNC(=O)c1ccc(C2=C3C=CC(O)C=C3Oc3cc(O)ccc32)c(C(=O)O)c1)SCc1ccccc1
Reaction time: 0.5 h
Yield: 64.2 %

Procedure:
To a solution of 13 (0.424 g, 0.92 mmol) in dry THF was added EDC (0.176 g, 0.92 mmol) and HOBt (0.14 g, 0.92 mmol). The solution was stirred for 30 minutes under ice-cold conditions, followed by addition of 8 (0.2523 g, 1.16 mmol) dissolved in minimal amount of DMF. The resulting solution was stirred further for 6 hours at RT. Upon removal of the solvent in vacuo, the residue was taken into ethyl acetate and washed with 1 N HCl (2×30 ml), water (2×30 ml) and brine (2×30 ml). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford a crude mixture, which was further purified by flash chromatography (silica gel, dichloromethane/methanol=9:1) to afford 2 (0.32 g, 56%). 1H-NMR (300 MHz, CDCl3) δ 8.52 (s, 1H), 8.22 (d, J=8.04 Hz, 1H), 7.25-7.21 (m, 6H), 7.12-7.09 (m, 2H), 6.81-6.75 (m, 4H), 4.39 (d, J=5.61 Hz, 2H), 4.15 (s, 2H), 2.3 (s, 6H). 3C-NMR (60 MHz, DMSO) δ 196.52, 168.78, 168.37, 165.84, 155.31, 152.20, 151.42, 136.72, 134.08, 129.58, 127.74, 127.50, 127.33, 126.45,125.61, 124.50, 123.91, 115.53, 110.46, 82.09, 49.48, 32.90, 20.98. MS (ESI): m/z 623.9 [(M+1)]+.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[N:19]=[C:18]2[C:14](=[N:15][CH:16]=[N:17]2)[C:13](=[O:20])[N:12]=1)[CH2:2][CH3:3].Cl[S:22]([OH:25])(=O)=[O:23].[CH3:26][NH2:27]>>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([S:22](=[O:25])(=[O:23])[NH:27][CH3:26])=[CH:7][C:6]=1[C:11]1[N:19]=[C:18]2[C:14](=[N:15][CH:16]=[N:17]2)[C:13](=[O:20])[N:12]=1)[CH2:2][CH3:3]
Reactant: O=S(=O)(O)Cl
Reactant: CCCOc1ccccc1C1=NC(=O)C2=NC=NC2=N1
Reactant: CN
Product: CCCOc1ccc(S(=O)(=O)NC)cc1C1=NC(=O)C2=NC=NC2=N1

Procedure:
In a similar manner to Example 18 reaction of 2-(2-propoxyphenyl)purin-6-one (0.81 g) with chlorosulphonic acid (4.5 ml), followed by reaction with methylamine in industrial methylated spirit (33%, 50 ml) yielded the title compound, 0.49 g, m.p. 245°-246° C. (recrystallised twice from aqueous ethanol).
Reaction SMILES: [OH:1][CH:2]1[CH:19]([CH2:20][CH2:21][CH:22]([O:28]C2CCCCO2)[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:5]2[CH2:6][C:7]3[C:12]([CH2:13][CH:4]2[CH2:3]1)=[C:11]([O:14][CH2:15][C:16]([OH:18])=O)[CH:10]=[CH:9][CH:8]=3.[F:35][C:36]([F:40])([F:39])[CH2:37][NH2:38].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CC(OC)(C)C>[OH:1][CH:2]1[CH:19]([CH2:20][CH2:21][CH:22]([OH:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:5]2[CH2:6][C:7]3[C:12]([CH2:13][CH:4]2[CH2:3]1)=[C:11]([O:14][CH2:15][C:16]([NH:38][CH2:37][C:36]([F:40])([F:39])[F:35])=[O:18])[CH:10]=[CH:9][CH:8]=3
Reactant: CCCCCC(CCC1C(O)CC2Cc3c(cccc3OCC(=O)O)CC21)OC1CCCCO1
Reactant: NCC(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: COC(C)(C)C
Product: CCCCCC(O)CCC1C(O)CC2Cc3c(cccc3OCC(=O)NCC(F)(F)F)CC21
Temperature: 25 °C
Reaction time: 24 h
Yield: 48.8 %

Procedure:
A solution of {2-Hydroxy-1-[3-(tetrahydro-pyran-2-yloxy)-octyl]-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy}-acetic acid (94 mg, 0.2 mmol), trifluoroethylamine (54 mg, 0.6 mmol) and DIPEA (104 μl, 0.6 mmol) in DMF (2 ml) was treated with HATU and stirred 24 hr at RT. The reaction mixture was diluted with MTBE and washed with saturated sodium bicarbonate solution and brine, dried over sodium sulfate and concentrated under vacuum. The residue was purified by silica gel chromatography. This resulting material was dissolved in MeOH (4 ml), treated with Amberlite IR120H and stirred 24 hr. The reaction mixture was filtered and concentrated to yield 2-[2-hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-N-(2,2,2-trifluoro-ethyl)-acetamide (46 mg) as an oil. 1HNMR (400 MHz, CDCl3) δ 7.06 (d, 1H, J=7.6); 6.80 (d, 1H, J=7.2); 6.63 (d, 1H, J=8.0); 4.86 (quint., 1H, J=6.4); 4.60 (s, 2H); 3.7-3.8 (m, 1H); 3.55-3.65 (m, 1H); 2.85-2.95 (ddd, 1H); 2.70-2.80 (dd, 1H); 2.50-2.60 (ddd, 1H); 2.40-2.50 (dd, 1H); 2.15-2.3 (m, 2H); 1.75-1.95 (m, 2H); 1.24-1.70 (m, 17H); 1.20 (d, 3H, J=6.4); 0.85-0.95 (m, 8H); MS: m/z 494 [M+Na]+
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[C:7](Cl)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(Cl)Cl.O>CCOCC>[C:7]([C:4]1[S:3][C:2]([Br:1])=[CH:6][CH:5]=1)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Brc1cccs1
Solvent: ClCCl
Solvent: O
Solvent: CCOCC
Product: O=C(c1ccccc1)c1ccc(Br)s1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
2-Bromothiophene (9.7 ml., 0.1 mole), benzoyl chloride (11.6 ml., 0.1 mole) and stannic chloride (11.5 ml., 0.1 mole) were combined in 100 ml. of methylene chloride and stirred at room temperature for 4 hours. The reaction mixture was cooled to room temperature, water (65 ml.) was added and the two phase system stirred for 20 minutes. Ether (165 ml.) was added, the organic phase was separated, back-washed with 20 ml. of 1 N sodium hydroxide and twice with 20 ml. of water, and concentrated to an oil (20.8 g.) which crystallized on standing. The crude was melted by warming with 25 ml. of hexane (two phases formed) and cooled to yield purified crystalline 5-benzoyl-2-bromothiophene (16.5 g., m/e 266/268).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]#[N:23])[CH:17]=1)[CH2:10][C:9]2([CH3:25])[CH3:24])=[O:5])C.[OH-:26].[Na+].O.Cl>C(#N)C>[C:22]([C:18]1[CH:17]=[C:16]([CH:11]2[CH2:10][C:9]([CH3:24])([CH3:25])[C:8]3[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:3])=[O:5])[CH:7]=3)[NH:12]2)[CH:21]=[CH:20][CH:19]=1)(=[O:26])[NH2:23]
Reactant: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1cccc(C#N)c1)N2
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC1(C)CC(c2cccc(C(N)=O)c2)Nc2ccc(C(=O)O)cc21
Temperature: 60 °C
Reaction time: 4 h
Yield: 22.5 %

Procedure:
A mixture of 2-(3-cyano-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (3.0 g, 7.96 mmol), sodium hydroxide (1.8 g, 44.9 mmol), water (15 mL) in acetonitrile (30 mL) was stirred at 60° C. for 4 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-(3-carbamoyl-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (0.58 g, 20%) as a white solid which was used for next step without further purification: MS (ESI) M+1=325.2.
Reaction SMILES: [CH2:1]([C:3]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:4]=1[OH:5])[CH3:2].O1CCOCC1.[CH:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>P(Cl)(Cl)(Cl)=O.O>[CH2:1]([C:3]1([C:19]2[C:18]([CH:17]=[O:24])=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][CH:4]1[OH:5])[CH3:2]
Reactant: O=Cc1ccccc1
Reactant: CCc1c(O)cccc1O
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1COCCO1
Solvent: O
Product: CCC1(c2ccccc2C=O)C(O)=CC=CC1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 629 g. of 2-ethylresorcinol in 1 l. of dioxane were added 530 g. of benzaldehyde and 30 g. of phosphorus oxychloride as a catalyst. The resulting mixture was stirred at room temperature for 24 hours and thereafter poured into 5 l. of a cold water with stirring to give a pale brown powdery resin.
Reaction SMILES: [CH3:1][N:2]1[C:14]2([CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)[C:6]2=[CH:7][CH:8]=[C:9]([C:10]([F:13])([F:12])[F:11])[N:5]2[CH2:4][CH2:3]1.O1CCOCC1.CO.[ClH:35]>>[ClH:35].[ClH:35].[CH3:1][N:2]1[CH2:3][CH2:4][N:5]2[C:9]([C:10]([F:11])([F:12])[F:13])=[CH:8][CH:7]=[C:6]2[C:14]21[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2
Reactant: CN1CCn2c(C(F)(F)F)ccc2C12CCN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CN1CCn2c(C(F)(F)F)ccc2C12CCNCC2

Procedure:
tert-Butyl 2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carboxylate (7.8 g, 20.89 mmol) was stirred in 4M HCl in dioxane (26.10 mL of 4 M, 104.4 mmol) and methanol (22 mL) at room temperature for 1 h. The reaction mixture was evaporated to dryness and the residue was co-evaporated with 100 mL of MTBE to afford 2′-methyl-6′-(trifluoromethyl)-3′,4′-dihydro-2′H-spiro[piperidine-4,1′-pyrrolo[1,2-a]pyrazine]dihydrochloride as a yellow foam/solid (7.23 g, quantitative). ESI-MS m/z calc. 273.2, found 274.5 (M+1)+; Retention time: 0.44 minutes (3 min run).
Reaction SMILES: [N:1](C(N(C)C)=O)=NC(N(C)C)=O.[OH:13][C:14]1[CH:22]=[CH:21][C:20]2[N:19]([S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH:18]=[CH:17][C:16]=2[C:15]=1[CH:32]=O.[C:34]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:39]=CC=C[CH:35]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:35][C@@H:34]1[NH:1][CH2:32][C:15]2=[C:16]3[C:20](=[CH:21][CH:22]=[C:14]2[O:13][CH2:39]1)[N:19]([S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:25])=[O:24])[CH:18]=[CH:17]3
Reactant: CN(C)C(=O)N=NC(=O)N(C)C
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=Cc1c(O)ccc2c1ccn2S(=O)(=O)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@H]1COc2ccc3c(ccn3S(=O)(=O)c3ccccc3)c2CN1
Temperature: 45 °C
Reaction time: 48 h
Yield: 27.4 %

Procedure:
1,1′-Azobis(N,N-dimethylformamide) (57 mg, 0.33 mmol) was added to a solution of 5-hydroxy-1-(phenylsulfonyl)-1H-indole-4-carbaldehyde (Intermediate 10, 0.050 g, 0.16 mmol), S-(−)-2-(tert-butoxycarbonylamino)-1-propanol (58 mg, 0.33 mmol) and triphenylphosphine (87 mg, 0.33 mmol) in DCM (5 mL). The mixture was stirred at 45° C. for 2 days and the mixture was evaporated. The crude material was purified by flash chromatography using 1% to 2.5% MeOH in DCM. This boc-protected intermediate was dissolved in DCM (3 mL) and TFA (1 mL) was added. The mixture was stirred for 1 hour and evaporated. The residue was dissolved in THF (3 mL) and sodium triacetoxyborohydride (30.0 mg, 0.141 mmol) was added all in one portion. The reaction mixture was stirred for 20 minutes and evaporated. The crude product was purified by flash chromatography on silica gel using MeOH:DCM:NEt3 (5:94:1) as the eluent to give a light yellow solid (15 mg) of the title compound. MS m/z 343 [M+H]+.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C@H:7]([NH:12][C:13](=[O:22])[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6]2.S(Cl)(Cl)=O.C(=O)([O-])[O-].[K+].[K+].[F:33][C:34]([F:46])([F:45])[C:35]1[C:39]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:38][NH:37][N:36]=1>C(Cl)Cl.CN(C=O)C>[CH2:15]([O:14][C:13]([NH:12][C@@H:7]1[CH2:6][C:5]2[C:9](=[CH:10][CH:11]=[C:3]([CH2:2][N:36]3[C:35]([C:34]([F:46])([F:33])[F:45])=[C:39]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH:38]=[N:37]3)[CH:4]=2)[CH2:8]1)=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(N[C@H]1Cc2ccc(CO)cc2C1)OCc1ccccc1
Reactant: CCOC(=O)c1c[nH]nc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(Cc2ccc3c(c2)C[C@@H](NC(=O)OCc2ccccc2)C3)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 3.1 %

Procedure:
(S)-Benzyl 5-(hydroxymethyl)-2,3-dihydro-1H-inden-2-ylcarbamate (2.96 mmol, 880 mg) was dissolved in DCM (10 mL) and thionyl chloride (5.92 mmol, 0.432 ml, 704 mg) added. The mixture was stirred at room temperature for 30 min TLC before the solvent was removed under reduced pressure and residual thionylchloride azeotroped with DCM (×3). To the residue was added potassium carbonate (8.88 mmol, 1227 mg) followed by DMF (8 ml) then ethyl 3-(trifluoromethyl)-1H-pyrazole-4-carboxylate (2.96 mmol, 616 mg) and the mixture heated to 60° C. After 1 h the mixture was concentrated and partitioned between EtOAc/H2O and the organic layer was washed with water (×3). The organic layer was dried, filtered and concentrated to give a yellow oil which was purified by flash chromatography eluting with 15% EtOAc/Heptane to give the desired isomer as a colourless oil (45 mg, 0.092 mmol, 3.1%). 1H NMR (400 MHz, CDCl3) δ 1.34 (t, 3H) 2.75 (m, 2H) 3.25 (m, 2H) 4.33 (q, 2H), 4.50 (m, 1H) 4.95 (m, 1H), 5.08 (s, 2H) 5.48 (s, 2H) 7.00 (m, 2H) 7.15 (d, 1H) 7.34 (m, 5H) 7.99 (s, 1H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-].[CH3:12][S+](C)(C)=O.[H-].[Na+].O>CS(C)=O>[O:10]1[CH:9]([CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12]1
Reactant: O=CCCc1ccccc1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: c1ccc(CCC2CO2)cc1
Reaction time: 1 h

Procedure:
3-Phenylpropionaldehyde (26.8 g.) is added under nitrogen to the ylide prepared from trimethylsulfoxonium iodide (48.4 g.) and sodium hydride (55% dispersion in oil; 9.6 g.) in dry dimethylsulfoxide (200 ml.), according to the procedure in Journal of the American Chemical Society, Vol. 84, page 867 (1962) and Vol. 87, page 1353 (1965). After one hour, the solution was poured into 1 liter of water and the product extracted with ether (3 × 300 ml.). The extract was washed with water (2 × 150 ml.) dried (MgSO4) and evaporated to give an oil, 1,2-epoxy-4-phenylbutane, used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:28][CH2:29][CH:30]4[CH2:32][O:31]4)=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][CH:17]=2)[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:7]=1[CH3:8].FC(F)(F)C(O)=[O:36].[OH-].[Na+].O>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:28][CH2:29][CH:30]([OH:31])[CH2:32][OH:36])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][CH:17]=2)[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:7]=1[CH3:8]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1cc2c(Oc3cc(C)c(C)nc3-c3ccccc3)ccnc2cc1OCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3ccccc3)ccnc2cc1OCC(O)CO
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
4-(5,6-Dimethyl-2-phenyl-pyridin-3-yloxy)-6-methoxy-7-oxiranylmethoxy-quinoline (compound 334) (130 mg) was dissolved in methylene chloride (2 ml) to prepare a solution which was then brought to 0° C. Trifluoroacetic acid (1 ml) was added to the solution, and the mixture was stirred at 0° C. for 30 min and was then stirred at room temperature for 3 hr. The reaction solution was brought to 0° C., was stirred, and was made alkaline by the addition of a 10% aqueous sodium hydroxide solution. Water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (89 mg, yield 66%).
Reaction SMILES: [CH3:1][C:2]1[CH:39]=[C:38]([CH3:40])[CH:37]=[CH:36][C:3]=1[O:4][CH2:5][C@H:6]([OH:35])[CH2:7][NH:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[C:10]=1[C:16]1[NH:27][C:26]2[C:18](=[CH:19][C:20]3[CH2:21][N:22]([CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)[C:23](=[O:28])[C:24]=3[CH:25]=2)[N:17]=1.Br[CH:42]1[CH2:44][CH2:43]1.CCN(C(C)C)C(C)C>CC#N>[CH:42]1([N:32]2[CH2:31][CH2:30][CH:29]([N:22]3[CH2:21][C:20]4[CH:19]=[C:18]5[C:26]([NH:27][C:16]([C:10]6[C:11](=[O:15])[NH:12][CH:13]=[CH:14][C:9]=6[NH:8][CH2:7][CH:6]([OH:35])[CH2:5][O:4][C:3]6[CH:36]=[CH:37][C:38]([CH3:40])=[CH:39][C:2]=6[CH3:1])=[N:17]5)=[CH:25][C:24]=4[C:23]3=[O:28])[CH2:34][CH2:33]2)[CH2:44][CH2:43]1
Reactant: BrC1CC1
Reactant: Cc1ccc(OC[C@H](O)CNc2cc[nH]c(=O)c2-c2nc3cc4c(cc3[nH]2)C(=O)N(C2CCNCC2)C4)c(C)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1ccc(OCC(O)CNc2cc[nH]c(=O)c2-c2nc3cc4c(cc3[nH]2)C(=O)N(C2CCN(C3CC3)CC2)C4)c(C)c1
Temperature: 25 °C
Reaction time: 112 h
Yield: 5.6 %

Procedure:
To a solution of 2-{4-[(R)-3-(2,4-dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-piperidin-4-yl-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one (54.3 mg, 0.1 mmol) and bromocyclopropane (121 mg, 1.0 mmol) in CH3CN (8 mL) was added DIEA (129.3 mg, 1.0 mmol) and the resulting reaction mixture was stirred at the room temperature for 112 h and then evaporated. Chromatography of the residue with CH2Cl2/MeOH/28% aqueous NH4OH (490:10:1) afforded the title compound (3.27 mg, 5.6%). 1H NMR (DMSO-d6) δ 1.70 (m, 2H), 1.80 (m, 2H), 2.04 (m, 2H), 2.19 (s, 3H, CH3), 2.22 (s, 3H, CH3), 2.90-3.00 (4H), 3.45 (m, 1H), 3.70 (m, 1H), 3.95-4.06 (3H), 4.11 (m, 1H), 4.42 (s, 1H), 4.47 (s, 1H), 5.10-5.22 (2H), 5.47 (d, J=3 Hz, 0.5H, NH), 5.52 (d, J=3 Hz, 0.5H, NH), 5.81 (m, 1H), 6.22 (m, 1H), 6.81 (m, 1H), 6.89-6.99 (2H), 7.32-7.38 (1.5H), 7.68 (s, 0.5H), 7.80 (s, 0.5H), 7.94 (s, 0.5H), 11.15 (d, J=6 Hz, 1H, NH), 11.21 (br d, J=6 Hz, 1H, NH); ESI-MS m/z 583.7 (MH+).
Reaction SMILES: [CH2:1]([P:5]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[Cl:14][CH2:15][C:16]([OH:18])=[O:17].P>CO>[Cl-:14].[CH2:10]([P+:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:15][C:16]([OH:18])=[O:17])[CH2:11][CH2:12][CH3:13]
Reactant: CCCCP(CCCC)CCCC
Reactant: O=C(O)CCl
Agent: P
Solvent: CO
Product: CCCC[P+](CCCC)(CCCC)CC(=O)O
Product: [Cl-]

Procedure:
Tri-n-butyl phosphine (4.04 g, 0.02 mole) was added dropwise to a rapidly stirred solution of monochloroacetic acid (1.85 g, 0.02 mole) and 3.2 ml of methanol. The addition of the phosphine was at a rate such that the reaction temperature did not exceed about 30° C. The methanol solvent was subsequently evaporated under reduced pressure leaving a colorless viscous liquid whose infrared spectrum and elemental analysis corresponded to a compound of the formula
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([CH2:9][CH3:10])=[CH:7][N:6]=[CH:5][C:4]=1[CH2:11][CH3:12].[CH3:13][C:14]1[N:19]=[C:18]([SH:20])[N:17]=[C:16]([OH:21])[CH:15]=1.C(N(CC)CC)C.CCOCC>C(O)C>[CH2:11]([C:4]1[CH:5]=[N:6][CH:7]=[C:8]([CH2:9][CH3:10])[C:3]=1[CH2:2][S:20][C:18]1[N:17]=[C:16]([OH:21])[CH:15]=[C:14]([CH3:13])[N:19]=1)[CH3:12]
Reactant: Cc1cc(O)nc(S)n1
Reactant: CCc1cncc(CC)c1CBr
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCc1cncc(CC)c1CSc1nc(C)cc(O)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of crude 4-(bromomethyl)-3,5-diethylpyridine (2.07 g, 9.07 mmol) and 6-methyl-2-sulfanylpyrimidin-4-ol (0.838 g, 5.89 mmol) in anhydrous ethanol (50 mL) at 0° C. was added triethylamine (3.21 g, 4.42 mL 31.75 mmol), and the reaction mixture was allowed to stir at room temperature overnight. The solvent was evaporated to provide a crude residue. Ether was added to precipitate the triethylamine hydrobromide salt. The solid was filtered and washed with ether several times. The combined ether layers were evaporated, and the crude residue was purified by Combiflash using 0-10% MeOH in dichloromethane to provide 2-{[(3,5-diethylpyridin-4-yl)methyl]sulfanyl}-6-methylpyrimidin-4-ol as a white solid; 1H NMR (400 MHz, DMSO-d6): δ 1.23 (t, 6H), 1.40 (t, 3H), 2.64 (q, 4H), 4.44 (q, 2H), 8.36 (s, 2H); M+1 290.4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[NH:8][C:5]2=[CH:6][N:7]=1.[N:14]1([CH2:20][CH2:21][NH2:22])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>>[N:14]1([CH2:20][CH2:21][NH:22][C:11]([C:9]2[NH:8][C:5]3=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]3[CH:10]=2)=[O:13])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: O=C(O)c1cc2cc(Cl)ncc2[nH]1
Reactant: NCCN1CCOCC1
Product: O=C(NCCN1CCOCC1)c1cc2cc(Cl)ncc2[nH]1

Procedure:
The title compound was prepared as outlined in EXAMPLE 1 from 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 18) and 2-morpholin-4-ylethylamine. The product was purified by chromatography on silica gel eluting with methanol/dichloromethane (1:19) to give the title compound as a yellow solid. δH (CD3OD): 2.54-2.60 (4H, m), 2.64 (2H, t), 3.58 (2H, t), 3.69-3.73 (4H, m), 7.05 (1H, s), 7.66 (1H, s), 8.58 (1H, s); m/z (ES+)=309 [M+H]+.
Reaction SMILES: C1(=O)CCCCC1.NC1C=CC=CC=1.[N+](C1C=CC=CC=1)([O-])=O.[C:24]1([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1(N(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[CH:31]1([NH:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: c1ccc(Nc2ccccc2)cc1
Agent: c1ccc(N(c2ccccc2)c2ccccc2)cc1
Solvent: O=C1CCCCC1
Solvent: Nc1ccccc1
Solvent: O=[N+]([O-])c1ccccc1
Product: c1ccc(NC2CCCCC2)cc1
Yield: 2.9 %

Procedure:
Reaction was carried out by the same procedure as in Example I1 except that 32.39 g (0.39 mol) of cyclohexanone, 9.31 g (0.1 mol) of aniline and 24.62 g (0.2 mol) nitrobenzene were used. As a result, the yield of diphenylamine was 89.5%, and 1.8% of triphenylamine and 2.9% of N-cyclohexylaniline were produced.
Reaction SMILES: C1([Bi:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)C2C=CC=CC=2)C=CC=CC=1.C([C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30]([OH:32])=[O:31])(=O)C1C=CC=CC=1.[O:37]1CCOC[CH2:38]1>>[C:30]([O:32][C:38](=[O:37])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)(=[O:31])[C:29]1[CH:28]=[CH:36][CH:35]=[CH:34][CH:33]=1.[Bi+3:7]
Reactant: C1COCCO1
Reactant: O=C(O)c1ccccc1C(=O)c1ccccc1
Reactant: c1ccc([Bi](c2ccccc2)c2ccccc2)cc1
Product: O=C(OC(=O)c1ccccc1)c1ccccc1
Product: [Bi+3]
Temperature: 110 °C

Procedure:
In a dry three-neck-flask, 1.5 g (3.4 mmol) triphenylbismuth dissolved in 5 ml dioxane is added to a solution of 2.31 g (10.2 mmol) benzoylbenzoic acid in 3 ml dioxane under argon and the resulting solution is heated to 110° C. for 1.5 hours. The mixture is cooled to room temperature and concentrated yielding 1.5 g of the product. The structure is confirmed by 1H-NMR and 13C-NMR spectra.
Reaction SMILES: [C:1]([NH:4][C@@H:5]([C:13]([OH:15])=[O:14])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:3])[CH3:2].[CH3:16][O:17][C:18](=[O:28])[CH:19]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[NH2:20].CO.C(Cl)CCl>O>[C:1]([NH:4][C@@H:5]([C:13]([OH:15])=[O:14])[CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)(=[O:3])[CH3:2].[CH3:16][O:17][C:18](=[O:28])[C@H:19]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[NH2:20]
Reactant: COC(=O)C(N)Cc1ccccc1
Agent: CC(=O)N[C@H](Cc1ccccc1)C(=O)O
Solvent: O
Solvent: CO
Solvent: ClCCCl
Product: COC(=O)[C@@H](N)Cc1ccccc1

Procedure:
Typically, N-acetyl-D-phenylalanine is allowed to contact DL-phenylalanine methyl ester in a suitable solvent, e.g. methanol, ethylene chloride or water, to produce a crude crystalline salt of N-acetyl-D-phenylalanine and L-phenylalanine methyl ester. That salt is separated from the filtrate, purified and decomposed with aqueous hydrochloric acid to afford N-acetyl-D-phenylalanine as a precipitate and L-phenylalanine methyl ester hydrochloride in solution. After filtering, the solvent in the filtrate is removed to afford the hydrochloride salt of L-phenylalanine methyl ester. Alternatively, the salt of N-acetyl-D-phenylalanine and L-phenylalanine methyl ester is dissolved in aqueous potassium carbonate and extracted with ether. The D-amide remains in the aqueous phase and the L-ester is extracted into the organic phase. After phase separation, the ethereal solution is acidified with hydrochloric acid-isopropanol to precipitate the hydrochloride salt of L-phenylalanine methyl ester.