Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:28][C:29]3[CH:38]=[C:37]([CH3:39])[C:32]4[NH:33][C:34](=[O:36])[O:35][C:31]=4[CH:30]=3)[C:19](=[O:27])[N:20]3[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:40]=[CH:41][CH:42]=[CH:43][C:4]=2[NH:3]1.[NH:44]1[CH2:49][CH2:48][S:47](=[O:50])[CH2:46][CH2:45]1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C@H:18]([CH2:28][C:29]3[CH:38]=[C:37]([CH3:39])[C:32]4[NH:33][C:34](=[O:36])[O:35][C:31]=4[CH:30]=3)[C:19](=[O:27])[N:20]3[CH2:21][CH2:22][CH:23]([N:44]4[CH2:49][CH2:48][S:47](=[O:50])[CH2:46][CH2:45]4)[CH2:24][CH2:25]3)=[O:16])[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:5]2[CH:40]=[CH:41][CH:42]=[CH:43][C:4]=2[NH:3]1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(=O)CC2)cc2oc(=O)[nH]c12
Reactant: O=S1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCS(=O)CC3)CC2)cc2oc(=O)[nH]c12
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A solution of 80 mg (0.14 mmol) (R)-1-(4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-2-(4-oxo-piperidin-1-yl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 32 mg (0.27 mmol) thiomorpholin-1-oxide in 5 mL DCM was stirred overnight at RT. After the solution had been cooled to 0° C., 15 μL (0.27 mmol) of AcOH and 50 mg (0.33 mmol) of sodium triacetoxyborohydride were added and the reaction mixture was stirred for 4 h at this temperature. It was evaporated down i.vac., the residue was taken up in 1 mL MeOH, filtered to remove any insoluble constituents and the crude product was purified by HPLC. The fractions containing the product were combined and lyophilised.
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:7]=1.[N:12]([C:15]1[N:20]=[C:19]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])[CH:18]=[C:17]([O:27][CH2:28][C:29]([F:32])([F:31])[F:30])[N:16]=1)=[C:13]=[O:14].CCOC(C)=O>C(Cl)Cl>[F:26][C:23]([F:24])([F:25])[CH2:22][O:21][C:19]1[CH:18]=[C:17]([O:27][CH2:28][C:29]([F:32])([F:31])[F:30])[N:16]=[C:15]([NH:12][C:13](=[O:14])[N:2]([CH3:1])[C:3]2[S:4][C:5]([C:8]([F:10])([F:9])[F:11])=[CH:6][CH:7]=2)[N:20]=1
Reactant: CNc1ccc(C(F)(F)F)s1
Reactant: O=C=Nc1nc(OCC(F)(F)F)cc(OCC(F)(F)F)n1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN(C(=O)Nc1nc(OCC(F)(F)F)cc(OCC(F)(F)F)n1)c1ccc(C(F)(F)F)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-methyl-5-(trifluoromethyl)thiophen-2-amine in CH2Cl2 (2 mL) was added 2-isocyanato-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine (1.6 mL, 1.0 M in THF) (prepared as described in U.S. Pat. No. 8,013,154, the contents of which were incorporated herein above by reference in their entirety). This reaction was stirred at ambient temperature overnight. TLC indicated the reaction was complete. The solvent was removed under reduced pressure and the residue was purified using normal phase chromatography which afforded product (471 mg, 56% over three steps) as an off-white solid, mp 99-101° C.: Rf=0.26 (30% EtOAc, hex); 1H NMR (DMSO-d6) 10.34 (s, 1H), 7.48 (d, 1H, J=3.3 Hz), 6.78 (d, 1H, J=4.3 Hz), 6.28 (s, 1H), 5.02 (q, 4H, J=17.8, 8.9 Hz), 3.49 (s, 3H); ESIMS m/z 497 [(M−1)+].
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH:10]12[C:19](=O)[O:18][C:16](=[O:17])[CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15]2>C(O)(=O)C>[F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[N:4]1[C:16](=[O:17])[CH:11]2[CH:10]([CH2:15][CH2:14][CH2:13][CH2:12]2)[C:19]1=[O:18]
Reactant: O=C1OC(=O)C2CCCCC12
Reactant: Nc1ccc(F)cc1F
Solvent: CC(=O)O
Product: O=C1C2CCCCC2C(=O)N1c1ccc(F)cc1F
Reaction time: 2 h

Procedure:
8.38 Parts of 2,4-difluoroaniline were added to a solution of 10 parts of cyclohexane-1,2-dicarboxylic anhydride in 100 parts of glacial acetic acid. The mixture was stirred for two hours. The mixture was refluxed for 20 hours and the resulting product was poured into 200 parts of ice. The resulting crystals were filtered and recrystallized twice from 70 parts of methanol at -40° C to yield 10.2 parts of white crystals of 2-(2,4-difluorophenyl)-3a,4,5,6,7,7a-hexahydro-1H-isoindole-1,3(2H)-dione melting at 117°-123° C.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([Cl:16])[C:7]=1[N:17]1[CH:21]=[C:20]2[CH:22](O)[CH2:23][CH2:24][C:19]2=[N:18]1.CCOC(C)=O.C([O-])(O)=O.[Na+]>C1COCC1>[Cl:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([Cl:16])[C:7]=1[N:17]1[CH:21]=[C:20]2[CH:22]([Cl:3])[CH2:23][CH2:24][C:19]2=[N:18]1
Reactant: O=S(Cl)Cl
Reactant: OC1CCc2nn(-c3c(Cl)cc(C(F)(F)F)cc3Cl)cc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: FC(F)(F)c1cc(Cl)c(-n2cc3c(n2)CCC3Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Thionyl chloride (0.1 mL, 1.37 mmol) was added to a solution of (62) (100.0 mg, 0.29 mmol) in THF (2 mL). After stirring for 2 hours at ambient temperature, EtOAc (10 mL) was added and the resulting mixture was poured into 5% aq. NaHCO3 (20 mL) at 4° C. The resulting mixture was extracted with EtOAc (10 mL). The organic layer was washed with 5% NaHCO3 (20 mL) at 4° C., dried (Na2SO4) and concentrated in vacuo to give the title compound as a pale solid in quantitative yield. 1H NMR (CDCl3); δ 7.72 (s, 2H), 7.42 (s, 1H), 5.43 (d, 1H, J=5.6), 3.22-2.94 (m, 2H), 2.85-2.70 (m, 2H); MS (M++1) 355.4.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[C:10]=1[C:16](=[O:18])[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].[C:21]1([CH3:29])[CH:26]=[CH:25][C:24]([CH:27]=O)=[CH:23][CH:22]=1.Cl>C(O)C.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[C:10]=1[C:16](=[O:18])[CH:17]=[CH:29][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1c(O)cccc1OCc1ccccc1
Reactant: Cc1ccc(C=O)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccc(C=CC(=O)c2c(O)cccc2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 2′-benzyloxy-6′-hydroxyacetophenone (0.5 g) in ethanol (10 mL)-water (3 mL) was added potassium hydroxide (1.39 g), and the mixture was stirred at room temperature for 10 minutes. To the reaction mixture was added p-tolualdehyde (0.37 mL), and the mixture was stirred at room temperature for 45 minutes. The reaction mixture was acidified by addition of 2 mol/L hydrochloric acid (12.5 mL), and the precipitated crystals were collected by filtration. The crystals were washed with water and dried under reduced pressure to give the title compound (0.69 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:19][CH2:18][N:17]3[C:10](=[CH:11][C:12]4[CH2:13][C:14]([CH3:21])([CH3:20])[CH2:15][C:16]=43)[C:9]2=[O:22])[C:3]=1[CH2:23][OH:24].C(N(CC)CC)C.[C:32](Cl)(=[O:34])[CH3:33]>C1COCC1>[C:32]([O:24][CH2:23][C:3]1[C:4]([N:8]2[CH2:19][CH2:18][N:17]3[C:10](=[CH:11][C:12]4[CH2:13][C:14]([CH3:21])([CH3:20])[CH2:15][C:16]=43)[C:9]2=[O:22])=[N:5][CH:6]=[CH:7][C:2]=1[Cl:1])(=[O:34])[CH3:33]
Reactant: CC(=O)Cl
Reactant: CC1(C)Cc2cc3n(c2C1)CCN(c1nccc(Cl)c1CO)C3=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)OCc1c(Cl)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.3 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with 199c (7.0 g, 20.2 mmol, 1.0 eq.), triethylamine (4.08 g, 40.4 mmol, 2.0 eq.), and THF (50 mL). To the mixture was added the solution of acetyl chloride (2.36 g, 30.3 mmol, 1.5 eq.) in THF (20 mL) dropwise. The reaction mixture was stirred at room temperature for one hour. After the reaction was completed, it was quenched with ice water and evaporated under reduced pressure. The residue was extracted with dichloromethane. The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was washed with 1:8 ethyl acetate/petroleum to afford 199d as a white solid (5.9 g, 76%). MS-ESI: [M+H]+ 388.3.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([NH:8][CH3:9])=[O:7])=O.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:20][C:21]([O:23][CH3:24])=[O:22])C=CC=CC=1>ClCCl>[CH3:9][NH:8][C:6]([C:5]1[CH:4]=[C:3](/[CH:1]=[CH:20]/[C:21]([O:23][CH3:24])=[O:22])[CH:12]=[CH:11][CH:10]=1)=[O:7]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CNC(=O)c1cccc(C=O)c1
Solvent: ClCCl
Product: CNC(=O)c1cccc(/C=C/C(=O)OC)c1
Yield: 96.8 %

Procedure:
A solution of 3-formyl-N-methylbenzamide (2.9 g, 17.77 mmol) and methyl 2-triphenylphosphoranylideneacetate (8.91 g, 26.66 mmol) in dichloromethane (85 mL), was stirred at room temperature for 18 h. The reaction mixture was evaporated to dryness. The crude product was purified by silica column chromatography, eluting with a gradient of 0 to 10% MeOH in DCM. Pure fractions were evaporated to dryness to afford impure product. Re-purified by silica column chromatography, eluting with a gradient of 50 to 100% EtOAc in hexanes. Pure fractions were evaporated to dryness to afford (E)-methyl 3-[3-(methylcarbamoyl)phenyl]prop-2-enoate (3.77 g, 97%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([C:22](=[O:26])[N:23]([CH3:25])[CH3:24])[N:11]([C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)[C:10]=1[C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:39][S:40][CH2:41][CH2:42][CH2:43]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH2:1]([O:8][C:9]1[C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([C:22](=[O:26])[N:23]([CH3:25])[CH3:24])[N:11]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:43][CH2:42][CH2:41][S:40][CH3:39])=[CH:29][CH:28]=2)[C:10]=1[C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(OCc2ccccc2)c(OCc2ccccc2)c(C(=O)N(C)C)n1-c1ccc(O)cc1
Reactant: CSCCCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1c(OCc2ccccc2)c(OCc2ccccc2)c(C(=O)N(C)C)n1-c1ccc(OCCCSC)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 94.9 %

Procedure:
To a stirred solution of ethyl 3,4-bis(benzyloxy)-5-(dimethylcarbamoyl)-1-(4-hydroxyphenyl)-1H-pyrrole-2-carboxylate (36) (350 mg, 0.68 mmol) in THF (2 mL) at 0° C. was added 3-(methylthio)propan-1-ol (84 μL, 0.82 mmol), triphenylphosphine (214 mg, 0.82 mmol), and DIAD (159 μL, 0.82 mmol). After 2 h further portions of 3-(methylthio)propan-1-ol (84 μL, 0.82 mmol), triphenylphosphine (214 mg, 0.82 mmol) and DIAD (159 μL, 0.82 mmol) were added, and the reaction mixture was allowed to stir at RT for 4 days. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (2×20 mL), the combined organics were washed with brine (30 mL), dried (MgSO4) filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (12 g, 0-100% EtOAc in isohexane) to afford ethyl 3,4-bis(benzyloxy)-5-(dimethylcarbamoyl)-1-(4-(3-(methylthio)propoxy)phenyl)-1H-pyrrole-2-carboxylate (43) (389 mg, 85%) as a clear yellow oil: m/z 603 (M+H)+ (ES+).
Reaction SMILES: [S:1]1(=[O:13])(=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=O)[CH2:3][CH2:2]1.[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.C1C=CC=CC=1>O>[N:14]1([C:4]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=3[S:1](=[O:13])(=[O:12])[CH2:2][CH:3]=2)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: C1CCNC1
Reactant: O=C1CCS(=O)(=O)c2ccccc21
Solvent: O
Solvent: c1ccccc1
Product: O=S1(=O)CC=C(N2CCCC2)c2ccccc21

Procedure:
A mixture of 9.8 g. (0.05 mole) of thiochroman-4-one 1,1-dioxide, 5.3 g. (0.075 mole) of pyrrolidine, and 150 ml. of benzene was placed in a flask equipped with a Dean-Stark water separator and was refluxed for 4 hr. The precipitate (4.9 g.) which separated on standing at room temperature was collected. Concentration to one-fourth the original volume gave an additional 5.0 g. These crops were combined and recrystallized from benzene to give 8.0 g. of product, m.p. 154°-157° dec.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[NH:10][C:9]=2[C:18]([OH:20])=O)=[CH:4][CH:3]=1.Cl.[NH2:22][CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]([O:32][CH3:33])=[O:31])=[N:28][CH:29]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[C:11]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[NH:10][C:9]=2[C:18]([NH:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([C:30]([O:32][CH3:33])=[O:31])=[N:28][CH:29]=2)=[O:20])=[CH:6][CH:7]=1
Reactant: O=C(O)c1[nH]c(-c2cccs2)cc1-c1ccc(F)cc1
Reactant: COC(=O)c1ccc(CN)cn1
Agent: Cl
Product: COC(=O)c1ccc(CNC(=O)c2[nH]c(-c3cccs3)cc2-c2ccc(F)cc2)cn1
Yield: 66 %

Procedure:
This material was prepared using a method substantially similar to that of Example 5 from 3-(4-fluorophenyl)-5-(2-thienyl)-1H-pyrrole-2-carboxylic acid and methyl 5-(aminomethyl)pyridine-2-carboxylate hydrochloride, yielding the title compound. Methyl 5-[({[3-(4-fluorophenyl)-5-(2-thienyl)-1H-pyrrol-2-yl]carbonyl}amino)methyl]pyridine-2-carboxylate: Yield 66%; m.p. 174-175° C.; IR 3398, 3255, 1733, 1643, 1541, 1432, 1258, 1121 cm−1; 1H-NMR (500 MHz, δ ppm, CDCl3) 9.59 (sb, 1H), 8.56 (s, 1H), 8.07 (d, J=8.0 Hz, 1H), 7.66 (dd, J=8.0 Hz, J′=2.1 Hz, 1H), 7.41 (dd, J=5.3 Hz, J′=2.1 Hz, 2H), 7.25 (dd, J=5.1 Hz, J′=1.0 Hz, 1H), 7.22 (dd, J=3.6 Hz, J′=1.0 Hz, 1H), 7.10 (t, J=8.6 Hz, 2H), 7.05 (dd, J=5.0 Hz, J′=3.6 Hz, 1H), 6.38 (d, J=3.0 Hz, 1H), 6.01 (tb, J=5.9 Hz, 1H), 4.53 (d, J=6.1 Hz, 2H), 4.01 (s, 3H); 13C-NMR (126 MHz, δ ppm, CDCl3) 165.6, 163.8, 161.8, 161.4, 149.1, 147.3, 137.9, 136.2, 134.3, 131.4, 131.3, 131.2, 129.7, 128.1, 127.6, 125.2, 124.8, 123.5, 121.6, 116.5, 116.3, 110.4, 53.1, 40.8.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:20][C:21]2[C:22]3[N:29]([CH2:30][CH2:31][NH:32]C(=O)OC(C)(C)C)[CH:28]=[CH:27][C:23]=3[N:24]=[CH:25][N:26]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]([F:19])([F:18])[F:17])[CH:10]=1.[ClH:40].O1CCCC1>C(O)C>[ClH:1].[ClH:40].[NH2:32][CH2:31][CH2:30][N:29]1[C:22]2[C:21]([NH:20][C:4]3[CH:5]=[CH:6][C:7]([O:8][C:9]4[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]([F:19])([F:18])[F:17])[CH:10]=4)=[C:2]([Cl:1])[CH:3]=3)=[N:26][CH:25]=[N:24][C:23]=2[CH:27]=[CH:28]1
Reactant: CC(C)(C)OC(=O)NCCn1ccc2ncnc(Nc3ccc(Oc4cccc(OC(F)(F)F)c4)c(Cl)c3)c21
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Product: NCCn1ccc2ncnc(Nc3ccc(Oc4cccc(OC(F)(F)F)c4)c(Cl)c3)c21
Temperature: 60 °C
Reaction time: 6 h

Procedure:
A mixture of tert-butyl {2-[4-({3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}carbamate (173 mg), 2N hydrochloric acid (2.5 mL) and tetrahydrofuran (5.0 mL) was stirred at 60° C. for 6 hrs. Ethanol was added to the reaction system. The solvent was evaporated under reduced pressure. Ethanol was added to the concentrate, and the mixture was further concentrated under reduced pressure. The residual crystals were collected by filtration and the crystals were washed with ethyl acetate to give the title compound (155 mg) as pale-yellow crystals.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:14]2[O:15][C:16]([CH3:19])([CH3:18])[O:17][C@:13]32[C@H:8]([C@H:9]([C:21]([OH:25])(C)[CH2:22]O)[CH2:10][CH2:11][C@@H:12]3[CH3:20])[CH:7]=[C:6]1[CH3:26])(=[O:3])[CH3:2].I([O-])(=O)(=O)=O.[Na+]>CO.O>[C:1]([O:4][C@H:5]1[C@@H:14]2[O:15][C:16]([CH3:18])([CH3:19])[O:17][C@:13]32[C@H:8]([C@H:9]([C:21](=[O:25])[CH3:22])[CH2:10][CH2:11][C@@H:12]3[CH3:20])[CH:7]=[C:6]1[CH3:26])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1C(C)=C[C@H]2[C@H](C(C)(O)CO)CC[C@H](C)[C@]23OC(C)(C)O[C@@H]13
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CO
Solvent: O
Product: CC(=O)O[C@@H]1C(C)=C[C@H]2[C@H](C(C)=O)CC[C@H](C)[C@]23OC(C)(C)O[C@@H]13
Reaction time: 0.25 h
Yield: 80.1 %

Procedure:
A solution of the product of (3aS,4R,6aS,7R,10S,10aS)-7-(1,2-dihydroxy-1-methylethyl)-2,2,5,10-tetramethyl-4,6a,7,8,9,10-hexahydro-3aH-naphtho[1,8a-d][1,3]dioxol-4-yl acetate (Preparation 147, 930 mg) in methanol (50 ml) was treated with sodium periodate (540 mg) and sonicated in an ultrasonic bath for 15 minutes. As the sodium periodate dissolved, a cloudy suspension formed. A further amount of sodium periodate (540 mg) was added and sonication was resumed for 15 min. After standing for 1 hour, the reaction mixture was diluted with water and solvent was evaporated. The residue was partitioned between water and dichloromethane and the organic phase was separated, washed with water and brine, dried (Na2SO4) and, concentrated in vacuo. The residual oil was purified by flash column chromatography on silica gel eluting with ethyl acetate:hexane (1:4) to give the product as a colourless oil (680 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[N+:23]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH2:23])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1C(F)(F)F
Agent: [Pd]
Product: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F

Procedure:
The title compound was prepared from [5-(methyl-propyl-amino)-2-nitro-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example C32) (3.78 g, 10.0 mmol) by hydrogenation with 10% Pd/C according to the general procedure J (method a). Obtained as a red oil (3.40 g, 98%).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][NH:3]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][N:31]=1>C(O)C>[NH2:29][C:30]1[N:31]=[CH:32][C:33]([C:34]([N:3]2[CH2:4][CH2:5][O:6][CH2:7][C@@H:2]2[CH3:1])=[O:35])=[CH:37][CH:38]=1
Reactant: C[C@H]1COCCN1
Reactant: Nc1ccc(C(=O)O)cn1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCO
Product: C[C@H]1COCCN1C(=O)c1ccc(N)nc1
Reaction time: 18 h
Yield: 30.1 %

Procedure:
To a solution of (S)-3-methylmorpholine (1.5 g, 15.0 mmol) in ethanol (20 mL) was added EDCI (3.33 g, 17.4 mmol), HOBt (2.35 g, 17.4 mmol), and 6-aminonicotinic acid (2.07 g, 15.0 mmol) at room temperature. After stirring for 18 h, the resulting suspension was filtered. The solid was purified by silica-gel column chromatography eluting with 2:1 petroleum ether/ethyl acetate to straight ethyl acetate to afford 136a (1.0 g, 30%) as a white solid. MS-ESI: 222.3 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([CH3:9])=[N:6][C:5]=1[C:10]([O:12]CC)=[O:11])(=[O:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([C:4]1[S:8][C:7]([CH3:9])=[N:6][C:5]=1[C:10]([OH:12])=[O:11])(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1nc(C)sc1C(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)c1sc(C)nc1C(=O)O
Temperature: 20 °C
Reaction time: 18 h
Yield: 33.8 %

Procedure:
To a solution of ethyl 5-acetyl-2-methyl-1,3-thiazole-4-carboxylate (75 mg) (available from Butt Park Ltd.) in methanol (5 ml) was added 2M sodium hydroxide (5 ml) and the mixture stirred at 20° C. for 18 h. The solvent was removed in vacuo and the mixture taken up in water (5 ml) and acidified to pH=2 using 2M hydrochloric acid then extracted with ethyl acetate (20 ml), dried over sodium sulphate and the mixture evaporated to give the title compound (22 mg) as a yellow solid.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:22])[C:8]=2[NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[N:3]=1.CC([Si](C)(C)[O:28][CH2:29][CH2:30][CH2:31][N:32]([CH2:40][CH:41]=[CH2:42])C(=O)OC(C)(C)C)(C)C>>[Cl:22][C:7]1[C:8]([NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([CH2:42][CH2:41][CH2:40][NH:32][CH2:31][CH2:30][CH2:29][OH:28])[CH:11]=[CH:10]2
Reactant: C=CCN(CCCO[Si](C)(C)C(C)(C)C)C(=O)OC(C)(C)C
Reactant: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(Cl)ccc12
Product: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(CCCNCCCO)ccc12
Yield: 13 %

Procedure:
Prepared according to the method of example 1(b)/(c), using N-(2,6-dichloro-5-quinolinyl)-cyclohexaneacetamide (Example 1(a)) (130 mg) and [3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]propyl]-2-propenyl-carbamic acid, 1,1-dimethylethyl ester (example 22(a)) (152 mg). Purification (SiO2, methanol:dichloromethane 1:9 as eluant) gave the title compound as a colourless solid (21 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1F)[N:8]([CH:13]=[CH2:14])[CH:7]=[C:6]([C:15]([OH:17])=[O:16])[C:5]2=[O:18].[CH3:19][N:20]1[CH:26]2[CH2:27][CH2:28][CH:21]1[CH2:22][NH:23][CH2:24][CH2:25]2>>[CH:13]([N:8]1[C:9]2[C:4](=[CH:3][C:2]([F:1])=[C:11]([N:23]3[CH2:24][CH2:25][CH:26]4[N:20]([CH3:19])[CH:21]([CH2:28][CH2:27]4)[CH2:22]3)[CH:10]=2)[C:5](=[O:18])[C:6]([C:15]([OH:17])=[O:16])=[CH:7]1)=[CH2:14]
Reactant: CN1C2CCNCC1CC2
Reactant: C=Cn1cc(C(=O)O)c(=O)c2cc(F)c(F)cc21
Product: C=Cn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCC4CCC(C3)N4C)cc21
Yield: 44.7 %

Procedure:
The title comound was prepared in 44.7% yield according to example 8 by reacting 6,7-difluoro-1-vinyl-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid with 9-methyl-3,9-diazabicyclo[4.2.1]nonane, m.p. 214°-215° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:9]([O-:11])=[O:10])[CH:6]=[CH:7][CH:8]=1)#[N:2].[Na+].[Cl:13][C:14]1[C:19]2[O:20][C:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][C:22]=3[C:18]=2[CH:17]=[C:16](Br)[CH:15]=1>>[Cl:13][C:14]1[C:19]2[O:20][C:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][C:22]=3[C:18]=2[CH:17]=[C:16]([S:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=2)(=[O:11])=[O:10])[CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCc2oc3c(Cl)cc(Br)cc3c2C1
Reactant: N#Cc1cccc(S(=O)[O-])c1
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCc2oc3c(Cl)cc(S(=O)(=O)c4cccc(C#N)c4)cc3c2C1
Yield: 12 %

Procedure:
Sodium 3-cyanobenzenesulfinate was coupled with the product of Example 44, step B following the procedure of Example 29, step C. The crude product was purified by flash column chromatography (SiO2, 3:2 hexanes/ethyl acetate) to give tert-butyl 6-chloro-8-(3-cyanophenylsulfonyl)-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (30 mg, 12%) as an off-white solid: 1H NMR (CDCl3, 300 MHz) δ 8.22-8.17 (m, 2H), 7.98 (s, 1H), 7.86-7.83 (m, 2H), 7.70-7.64 (m, 1H), 4.59 (s, 2H), 3.85 (t, J=5.7 Hz, 2H), 2.92 (t, J=5.7 Hz, 2H), 1.48 (s, 9H).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.[Cl:11][C:12]1[CH:13]=[C:14](/[CH:18]=[CH:19]/[C@H:20]2[CH2:24][CH2:23][CH2:22][NH:21]2)[CH:15]=[CH:16][CH:17]=1.C(N(CC)CC)C>C(O)CCC>[Cl:11][C:12]1[CH:13]=[C:14](/[CH:18]=[CH:19]/[C@H:20]2[CH2:24][CH2:23][CH2:22][N:21]2[C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH:15]=[CH:16][CH:17]=1
Reactant: Clc1cccc(/C=C/[C@H]2CCCN2)c1
Reactant: Clc1ncnc2nc[nH]c12
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: Clc1cccc(/C=C/[C@H]2CCCN2c2ncnc3[nH]cnc23)c1
Yield: 16.5 %

Procedure:
695 mg of 6-chloropurine and 850 mg of (R)-2-[(E)-2-(3-chlorophenyl)vinyl]-pyrrolidine are dissolved in 20 ml of 1-butanol and warmed at 130° C. in the microwave for 6 h with 3.1 ml of triethylamine. For work-up, the batch is partitioned between ethyl acetate and water, the organic phase is dried over sodium sulfate, filtered off and evaporated in vacuo. The residue is purified by chromatography, giving 220 mg of 6-[(R)-2-((E)-2-(3-chlorophenyl)vinyl)pyrrolidin-1-yl]-9H-purine (“A11”); Rt: 1.778 min; [M+H]+326.2; m.p. 194-196°;