Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][N:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[CH:17](O)=[O:18].C(OC(=O)C)(=O)C>COCCOC>[CH:17]([N:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[N:9]=[CH:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:18]
Reactant: Clc1ccc(NN=Cc2ccccc2)cc1
Reactant: O=CO
Solvent: CC(=O)OC(C)=O
Solvent: COCCOC
Product: O=CN(N=Cc1ccccc1)c1ccc(Cl)cc1
Reaction time: 4 h

Procedure:
6.91 g of 1A was dissolved in 37.5 ml of dry 1,2-dimethoxyethane and treated with 4.5 g of distilled mixed anhydride of formic acid and acetic acid prepared by mixing the appropriate amount of formic acid and acetic anhydride. The resulting mixture was left for 4 hours at room temperature and then heated up to boiling point and excess solvent removed in vacuo. The residue was triturated with 5% sodium bicarbonate solution, dried and crystallized from methanol to give 1, mp 122°-123° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH:10]([NH2:13])([CH3:12])[CH3:11]>>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:13][CH:10]([CH3:12])[CH3:11]
Reactant: O=Cc1ccccc1Cl
Reactant: CC(C)N
Product: CC(C)NCc1ccccc1Cl

Procedure:
Synthesized according to typical procedure J from 2-chlorobenzaldehyde and isopropylamine.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][CH:6]=1.[O:7]1[C:11]2[CH:12]=[CH:13][C:14]([CH2:16][C:17](N(OC)C)=[O:18])=[CH:15][C:10]=2[O:9][CH2:8]1.[Cl-].[NH4+]>CCCCCC.O1CCCC1>[O:7]1[C:11]2[CH:12]=[CH:13][C:14]([CH2:16][C:17]([C:4]3[S:5][CH:6]=[C:2]([CH3:1])[N:3]=3)=[O:18])=[CH:15][C:10]=2[O:9][CH2:8]1
Reactant: CON(C)C(=O)Cc1ccc2c(c1)OCO2
Reactant: Cc1cscn1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1csc(C(=O)Cc2ccc3c(c2)OCO3)n1
Reaction time: 0.5 h
Yield: 91.5 %

Procedure:
A 2.6M solution of n-butylithium in hexane (34 ml) was dropped into a solution of 4-methylthiazole (8.0 g) of tetrahydrofuran (150 ml) at −70° C. and the mixture was stirred for 30 minutes. Further, a solution of 2-benzo(1,3)dioxol-5-yl-N-methoxy-N-methylacetamide (20.0 g) in tetrahydrofuran (20 ml) was dropped therein and the mixture was stirred for 1 hour. This solution, to which a saturated aqueous solution of ammonium chloride was added, was extracted with ethyl acetate, and after the organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated. The resultant residue was purified by silica gel flash column chromatography using a mixed solvent of ethyl acetate and hexane to yield 2-benzo(1,3)dioxol-5-yl-1-(4-methylthiazol-2-yl)ethanone (19.3 g).
Reaction SMILES: CN1CCOCC1.[CH3:8][N:9]([CH3:27])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([N:19]2[CH2:26][CH2:25][CH2:24][C@@H:20]2[C:21]([OH:23])=O)=[O:18])=[CH:12][CH:11]=1.ClC(OCC)=O.Cl.[Br:35][C:36]1[CH:50]=[C:49]([Cl:51])[CH:48]=[CH:47][C:37]=1[CH2:38][O:39][C:40]1[CH:46]=[CH:45][CH:44]=[CH:43][C:41]=1[NH2:42]>O.C1(C)C=CC=CC=1>[Br:35][C:36]1[CH:50]=[C:49]([Cl:51])[CH:48]=[CH:47][C:37]=1[CH2:38][O:39][C:40]1[CH:46]=[CH:45][CH:44]=[CH:43][C:41]=1[NH:42][C:21]([C@H:20]1[CH2:24][CH2:25][CH2:26][N:19]1[C:17](=[O:18])[CH2:16][C:13]1[CH:12]=[CH:11][C:10]([N:9]([CH3:8])[CH3:27])=[CH:15][CH:14]=1)=[O:23]
Reactant: CN(C)c1ccc(CC(=O)N2CCC[C@@H]2C(=O)O)cc1
Reactant: Nc1ccccc1OCc1ccc(Cl)cc1Br
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: O
Solvent: CN1CCOCC1
Solvent: Cc1ccccc1
Product: CN(C)c1ccc(CC(=O)N2CCC[C@@H]2C(=O)Nc2ccccc2OCc2ccc(Cl)cc2Br)cc1
Reaction time: 2 h

Procedure:
Toluene (111 ml) and N-methylmorpholine (3.85 ml, 35.0 mmol) were added to N-[(4-dimethylaminophenyl)acetyl]-D-proline (8.56 g, 31.0 mmol). Ethyl chloroformate (3.26 ml, 34.1 mmol) was added to the obtained mixture, and they were stirred for 2 hours. 2-(2-Bromo-4-chlorobenzyloxy)aniline hydrochloride (10.8 g, 31.0 mmol) and N-methylmorpholine (4.09 ml, 37.2 mmol) were added thereto and they were stirred at room temperature overnight. Water (40 ml) was added to the reaction mixture. The organic layer was washed with water (40 ml) and then dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to the silica gel column chromatography. After the elution with methylene chloride and methanol (30:1), suitable fractions were collected and the solvent was evaporated under reduced pressure to obtain the title compound in the form of a yellow solid (16.3 g, 92%).
Reaction SMILES: [Br:1]Br.C([O:6][CH2:7][CH2:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)(=[O:11])=[O:10])(=O)C.[O-]S([O-])=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>C(O)(=O)C.CC(=O)OCC>[Br:1][C:14]1[CH:13]=[C:12]([S:9]([CH2:8][CH2:7][OH:6])(=[O:11])=[O:10])[CH:17]=[CH:16][C:15]=1[O:18][CH3:19]
Reactant: BrBr
Reactant: COc1ccc(S(=O)(=O)CCOC(C)=O)cc1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1ccc(S(=O)(=O)CCO)cc1Br
Temperature: 50 °C
Yield: 29.5 %

Procedure:
Br2 (25 g, 155.0 mmol) was added dropwise over 30 min to the title compound of step 2 (8.0 g, 31.0 mmol) in acetic acid (100 mL) at 0° C. The mixture was heated at 50° C. for 12 h. Aqueous Na2SO3 (200 mL) was added and the pH was adjusted to 8 with sat. aq. NaHCO3. The mixture was subjected to EA extractive work up and silica gel chromatography (PE: EA=1:0-1:1) to give the title compound (2.7 g, 27.3%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 8.11 (d, J=2.4 Hz, 1H), 7.87 (dd, J1=8.8 Hz, J2=2.4 Hz, 1H), 7.04 (d, J=2.4 Hz, 1H), 4.05-4.00 (m, 5H), 3.34-3.67 (m, 3H). LCMS: 316.9, 318.9 (M+Na)+
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[C:3]=1[Cl:10].C(=O)([O-])[O-].[K+].[K+].[CH3:17][C:18]([CH3:20])=[O:19]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:17][CH:18]2[CH2:20][O:19]2)=[C:4]([Cl:9])[C:3]=1[Cl:10]
Reactant: Oc1ccc(Br)c(Cl)c1Cl
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Clc1c(Br)ccc(OCC2CO2)c1Cl
Yield: 71 %

Procedure:
A solution of the crude 4-bromo-2,3-dichlorophenol (7.96 g) and (2R)-glycidyl 3-nitrobenzenesulfonate (8.52 g) in dry acetone (250 mL) was treated with potassium carbonate (13.61 g) and refluxed under nitrogen for 12 h. The reaction was cooled, filtered and filtrate was concentrated in vacuo and the residue was flash chromatographed (20% ethyl acetate/hexanes) to yield the desired product (6.94 g) in 71% yield. 1H-NMR (400 MHz, CDCl3) δ: 7.48 and 6.82 (d, 2H), 4.37 and 4.34 (dd, 1H), 4.06 and 4.03 (dd, 1H), 3.42-3.39 (m, 1H), 2.96-2.94 (m, 1H), 2.85-2.83 (m, 1H).
Reaction SMILES: [CH:1]([C:4]1[C:5]([O:16][CH2:17][O:18][CH3:19])=[C:6](B(O)O)[CH:7]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:9]=1)([CH3:3])[CH3:2].[C:20]([C:23]1[CH:39]=[CH:38][C:26]2[S:27][CH:28]=[C:29](OS(C(F)(F)F)(=O)=O)[C:25]=2[CH:24]=1)(=[O:22])[CH3:21].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.[Cl-].[Na+].O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]([C:4]1[C:5]([O:16][CH2:17][O:18][CH3:19])=[C:6]([C:29]2[C:25]3[CH:24]=[C:23]([C:20](=[O:22])[CH3:21])[CH:39]=[CH:38][C:26]=3[S:27][CH:28]=2)[CH:7]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:9]=1)([CH3:3])[CH3:2]
Reactant: COCOc1c(B(O)O)cc(C(C)C)cc1C(C)C
Reactant: CC(=O)c1ccc2scc(OS(=O)(=O)C(F)(F)F)c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: COCOc1c(-c2csc3ccc(C(C)=O)cc23)cc(C(C)C)cc1C(C)C
Yield: 58.1 %

Procedure:
3,5-Diisopropyl-2-methoxymethoxy-phenyl-boronic acid (470 mg, 1.8 mmol) was dissolved in toluene (15 ml) and ethanol (15 ml). Trifluoro-methanesulfonic acid 5-acetyl-benzo[b]thiophen-3-yl ester (320 mg, 0.99 mmol), tetrakis(triphenylphosphine)palladium(0) (114 mg, 0.1 mmol) followed by some 2M sodium carbonate solution (1.98 mmol) was added to this solution. The reaction was then heated overnight, then poured into brine (20 ml) and extracted with ethyl acetate (2×20 ml). The organic layers were then dried over MgSO4 and concentrated in vacuo. The residue was purified by chromatography (chromatotron, 4μ plate, 0-10% ethyl acetate in hexanes) to give 1-[3-(3,5-diisopropyl-2-methoxymethoxy-phenyl)-benzo[b]thiophen-5-yl]-ethanone as a yellow oil (228 mg, 58%). An analytical sample was obtained by preparatory thin layer chromatography (5% ethyl acetate in hexanes). 1HNMR (250 MHz, CDCl3): δ 8.23 (s, 1H), 7.85-7.97 (m, 2H), 7.48 (s, 1H), 7.14 (d, 1H, J=1.2),7.04 (d, 1H, J=1.2),4.41 (s, 2H), 3.40 (m, 1H), 2.95 (s, 3H), 2.86 (m, 1H), 2.55 (s, 3H), 1.26 (s, 3H), 1.23 (s, 3H), 1.21, (s, 3H), 1.18 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:8]/[CH:9]=[CH:10]/[Sn:11]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH2:14][CH3:15]>CN(C=O)C>[CH2:20]([Sn:11]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:12][CH2:13][CH2:14][CH3:15])/[CH:10]=[CH:9]/[CH2:8][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCC[Sn](/C=C/CBr)(CCCC)CCCC
Reactant: C1COCCN1
Solvent: CN(C)C=O
Product: CCCC[Sn](/C=C/CN1CCOCC1)(CCCC)CCCC

Procedure:
A solution of morpholine (637 mg) and [(1E)-3-bromoprop-1-enyl](tributyl)stannane (1.00 g) in dry DMF (8.0 mL) was stirred for 24 h at 20° C. The reaction mixture was quenched with saturated Na2SO4(aq.). Extraction with Et2O and drying (MgSO4) of the organic phase gave, after concentration in vacuo, the crude product. Purification was done by chromatography eluting with petroleum ether/EtOAc 10:1 to afford the title compound as a liquid.
Reaction SMILES: C(O[C:4]([C:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[NH:13][N:12]=2)[NH:8][CH:7]=1)=[O:5])C.S(Cl)(Cl)=O.Cl.[NH2:25][CH2:26][C:27]([NH2:29])=[O:28]>O>[C:27]([CH2:26][NH:25][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[NH:13][N:12]=2)[NH:8][CH:7]=1)=[O:5])(=[O:28])[NH2:29]
Reactant: NCC(N)=O
Reactant: CCOC(=O)c1c[nH]c(-c2n[nH]c3ncccc23)c1
Agent: Cl
Solvent: O
Solvent: O=S(Cl)Cl
Product: NC(=O)CNC(=O)c1c[nH]c(-c2n[nH]c3ncccc23)c1
Temperature: 25 °C

Procedure:
A mixture of 5-(1H-pyrazolo[3,4-b]pyridin-3-yl)-1H-pyrrole-3-carboxylic acid (100 mg, 0.43 mmol) (from Example 11) and thionyl chloride (0.2M in DCM, 10 mL) was heated to reflux for 2 hours. The reaction was concentrated, the residue was dissolved in DCM, to it was added glycinamide hydrochloride (242 mg, 2.19 mmol), followed by TEA. The mixture was then stirred at room temperature until the reaction was completed by TLC. The reaction was diluted with water and extracted with DCM. The combined DCM was concentrated and purified on a silica gel column to give the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[S:17][CH3:18])[NH:6][C:5]=2[CH:4]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[S:17][CH3:18])[N:6]([C:19](=[O:21])[CH3:20])[C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)Nc1cccc(SC)c1S2
Reactant: CC(=O)OC(C)=O
Product: COc1ccc2c(c1)N(C(C)=O)c1cccc(SC)c1S2

Procedure:
2-Methoxy-6-methylthio-10-acetylphenothiazine (m.p. 106°-108°C.; 29.6 g.) is prepared by acetylation of 2-methoxy-6-methylthiophenothiazine (m.p. 152°-154°C.; 26.2 g.) by means of acetic anhydride.
Reaction SMILES: Cl[CH2:2][C:3]1[C:8]([O:9][CH2:10][CH3:11])=[CH:7][C:6]([O:12][CH2:13][CH3:14])=[CH:5][N:4]=1.[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]2[NH:23][CH:24]=[CH:25][N:26]=2)[N:17]=1>CN(C=O)C.O>[F:15][C:16]1[N:17]=[C:18]([C:22]2[N:26]([CH2:2][C:3]3[C:8]([O:9][CH2:10][CH3:11])=[CH:7][C:6]([O:12][CH2:13][CH3:14])=[CH:5][N:4]=3)[CH:25]=[CH:24][N:23]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: Fc1cccc(-c2ncc[nH]2)n1
Reactant: CCOc1cnc(CCl)c(OCC)c1
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cnc(Cn2ccnc2-c2cccc(F)n2)c(OCC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
To a solution of 2-chloromethyl-3,5-diethoxy-pyridine (174 mg, 0.69 mmol) in DMF (5 mL) is added 2-fluoro-6-(1H-imidazol-2-yl)-pyridine (112 mg, 0.69 mmol), and the reaction is stirred at room temperature overnight. The reaction mixture is diluted with water, extracted with EtOAc, washed with brine, dried over Na2SO4, and concentrated. The residue is purified by column chromatography eluting with 8% MeOH—CH2Cl2 containing few drops of NH4OH to afford 2-[2-(6-fluoro-pyridin-2-yl)-imidazol-1-yl methyl]-3,5-diethoxy-pyridine (118 mg, 49%); 1H NMR (300 MHz, CDCl3): 8.06 (dd, J=5.1, 2.4 Hz, 1H), 7.81 (t, J=7.9 Hz, 1H), 7.75 (d, J=2.4 Hz, 1H), 7.09 (s, 1H), 7.04 (s, 1H), 6.80 (dd, J=5.1, 2.7 Hz, 1H), 6.65 (d, J=2.4 Hz, 1H), 5.95 (s, 2H), 4.02 (q, J=6.9 Hz, 2H), 3.90 (q, J=6.9 Hz, 2H), 1.39 (t, J=6.9 Hz, 2H), 1.16 (t, J=6.9 Hz, 2H), m/z 343 [M+1].
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][C@H:12]([CH2:16][O:17][C:18]([CH3:27])([CH3:26])[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:11]1)(C(C)(C)C)(C)C.O.CC(OC)(C)C>C1COCC1>[OH:8][CH2:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][C@H:12]([CH2:16][O:17][C:18]([CH3:27])([CH3:26])[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:11]1
Reactant: CC(C)(C)OC(=O)C(C)(C)OC[C@H]1CCC[C@@H](CO[Si](C)(C)C(C)(C)C)C1
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Solvent: O
Product: CC(C)(C)OC(=O)C(C)(C)OC[C@H]1CCC[C@@H](CO)C1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 45.1 %

Procedure:
4.5 g of tert-butyl 2-[cis-3-(tert-butyidimethylsilanyloxymethyl)cyclohexyl-methoxy]-2-methylpropionate (synthesis analogously to tert-butyl 2-[cis-3-(tert-butyldimethylsilanyloxymethyl)cyclohexylmethoxy]-2-methylpropionate in Example 55) are dissolved in 85 ml of THF, 2.24 g of TBAF trihydrate are added and the mixture is stirred at 60° C. for 90 min. Water and MTBE are added, the phases are separated and the organic phase is dried over MgSO4 and concentrated. The residue is chromatographed on silica gel (heptane/ethyl acetate 1:1), which gives 1.45 g of tert-butyl 2-[cis-3-hydroxymethylcyclohexylmethoxy]-2-methylpropionate. C16H30O4 (286.42), MS (ESI): 287 (MH+).
Reaction SMILES: NC1C=NC=CC=1.C[N:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)C.[ClH:17].[CH3:18][C:19]1[N:23]2[CH2:24][CH2:25][CH2:26][N:27]=[C:22]2[S:21][C:20]=1[C:28]([Cl:30])=[O:29]>N1C=CC=CC=1>[ClH:30].[ClH:17].[CH3:18][C:19]1[N:23]2[CH2:24][CH2:25][CH2:26][N:27]=[C:22]2[S:21][C:20]=1[C:28]([NH:9][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=[O:29]
Reactant: CC1=C(C(=O)Cl)SC2=NCCCN21
Reactant: CN(C)c1ccccn1
Agent: Cl
Agent: Nc1cccnc1
Solvent: c1ccncc1
Product: CC1=C(C(=O)Nc2ccccn2)SC2=NCCCN21
Temperature: 25 °C
Reaction time: 20 h
Yield: 211.1 %

Procedure:
In 20 ml of pyridine was dissolved 200 mg of 3-aminopyridine. To this solution were added 50 mg of dimethylaminopyridine and 600 mg of 3-methyl-6,7-dihydro-5H-thiazolo[3,2-a]pyrimidine-2-carbonylchloride hydrochloride obtained in Example 28, followed by stirring at room temperature for 20 hours. The reaction mixture was concentrated and to the mixture was added saturated sodium hydrogencarbonate aqueous solution. The mixture was extracted with chloroform. The extact was washed with water and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was dissolved in ethanol. To the solution was added saturated hydrogenchloride diethylether solution. The formed crystals were collected by filtration. This crystals were recrystallized from a mixed solvent of ethanol and diethylether to obtain 300 mg of the titled compound.
Reaction SMILES: [CH:1]1([CH2:7][Mg]Cl)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CON(C)[C:13]([C:15]1[N:16]=[C:17]([CH:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]2)[S:18][CH:19]=1)=[O:14].[Cl-].[NH4+]>C(OCC)C.O1CCCC1>[CH:1]1([CH2:7][C:13]([C:15]2[N:16]=[C:17]([CH:20]3[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:24][CH2:25]3)[S:18][CH:19]=2)=[O:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cl[Mg]CC1CCCCC1
Reactant: CON(C)C(=O)c1csc(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2nc(C(=O)CC3CCCCC3)cs2)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Under argon and at −78° C., cyclohexylmethylmagnesium chloride 0.5M in diethyl ether (2.7 ml) was added dropwise to a solution of tert-butyl 4-{4-[methoxy(methyl)carbamoyl]-1,3-thiazol-2-yl}piperidine-1-carboxylate (480 mg) in tetrahydrofuran (5 ml). The reaction mixture was stirred at −78° C. for one hour. The reaction mixture was then stirred at room temperature for one hour. Saturated ammonium chloride solution was then added to the reaction mixture, and the aqueous phase was separated off. After extraction of the aqueous phase with ethyl acetate, the combined organic phases were dried over sodium sulphate and the solvent was removed under reduced pressure. This gave tert-butyl 4-[4-(cyclohexylacetyl)-1,3-thiazol-2-yl]piperidine-1-carboxylate (335 mg).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:3]1[CH:14]=[CH:15][C:16](=[O:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C(N(CC)CC)C.[BH4-].[Na+].C(O)(=O)C(O)=O>CCO.O.O>[OH:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:3]1[CH:14]=[CH:15][CH:16]([OH:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCC(=O)C=CC1=C(CCC(=O)OC)C(=O)CC1O
Agent: O=C(O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCCCCCCC(O)C=CC1=C(CCC(=O)OC)C(=O)CC1O

Procedure:
Methyl 3-[3-hydroxy-5-oxo-2-(3-oxodec-1-enyl)cyclopent-1-enyl]propanoate (2.1g.) was dissolved in EtOH/H2O 9:1 (30ml.) and chilled in an ice bath. Triethylamine (0.95ml.) was added followed by sodium borohydride (0.24g.) dissolved in water (2ml.). The reaction mixture was stirred for fifteen minutes and then water was added, followed by dilute oxalic acid solution to adjust the pH to 5. Ethyl acetate extraction, washing and drying of the extract followed by evaporation gave an oil. This was chromatographed on silicic acid, using as an eluent: MeOH/CHCl3. The appropriate fractions containing the major component were combined and evaporated to dryness (~800mg.oil). This was rechromatographed using a similar column. In this way, pure Methyl 3-[3-hydroxy-5-oxo-2-(3-hydroxydec-1-enyl)cyclopent-1-enyl]propanoate was obtained. Spectroscopic data was in full accord with the expected structure of the final product.
Reaction SMILES: [Cl:1][C:2]1[C:8]([I:9])=[CH:7][C:5]([NH2:6])=[C:4]([O:10][CH3:11])[CH:3]=1.[H-].[Na+].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28]Br)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>C1COCC1>[Cl:1][C:2]1[C:8]([I:9])=[CH:7][C:5]([NH:6][CH2:28][CH2:27][N:24]2[CH2:25][CH2:26][N:21]([C:19]([O:18][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:20])[CH2:22][CH2:23]2)=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CCBr)CC1
Reactant: COc1cc(Cl)c(I)cc1N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(Cl)c(I)cc1NCCN1CCN(C(=O)OC(C)(C)C)CC1
Yield: 21.2 %

Procedure:
To a stirred solution of 4-chloro-5-iodo-2-methoxyaniline (968 mg, 3.42 mmol) in anhydrous THF (20 mL) at 0° C., NaH (60% in mineral oil, 205.2 mg, 5.13 mmol) was added and the resulting mixture was stirred at reflux under nitrogen for 1 h. To this mixture, tert-butyl-4-(2-bromoethyl)piperazine-1-carboxylate (500 mg, 1.71 mmol) was added and the resulting mixture was stirred at room temperature for 15 h. The mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (10-30% ethyl acetate/petroleum ether) to afford the desired product (180 mg, 21% yield) as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C[Al](C)C.C1(C)C=CC=CC=1.[Cl:19][C:20]1[CH:21]=[CH:22][N:23]2[C:28]=1[C:27](=[O:29])[O:26][C:25]([CH2:30][N:31]1[CH:39]=[N:38][C:37]3[C:32]1=[N:33][CH:34]=[N:35][C:36]=3[N:40](C(OC(C)(C)C)=O)[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[N:24]2.O.O.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[Na+]>ClCCl.O>[Cl:19][C:20]1[CH:21]=[CH:22][N:23]([NH:24][C:25](=[O:26])[CH2:30][N:31]2[CH:39]=[N:38][C:37]3[C:32]2=[N:33][CH:34]=[N:35][C:36]=3[NH:40][C:41](=[O:42])[O:43][C:44]([CH3:47])([CH3:45])[CH3:46])[C:28]=1[C:27](=[O:29])[NH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncnc2c1ncn2Cc1nn2ccc(Cl)c2c(=O)o1
Reactant: Nc1ccncc1
Agent: C[Al](C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)Nc1ncnc2c1ncn2CC(=O)Nn1ccc(Cl)c1C(=O)Nc1ccncc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 93.6 %

Procedure:
To a suspension of 4-aminopyridine (164 mg, 1.74 mmol) in 3.3 mL of dichloromethane under inert atmosphere was added a 2M solution of trimethyl aluminium in toluene (0.87 mL, 1.74 mmol) and the mixture was stirred during 20 minutes at room temperature. Next, this mixture was cooled in an ice-water bath and a solution of di-tert-butyl 9-((5-chloro-4-oxo-4H-pyrrolo[1,2-d][1,3,4]oxadiazin-2-yl)methyl)-9H-purin-6-ylimidodicarbonate (150 mg, 0.29 mmol) in 2.2 mL of dry dichloromethane was added stirring the mixture during 3 days at room temperature. At the end of this period, the reaction mixture was cooled-down with an ice-water bath and mL of water were added followed by a 5% aqueous solution disodium tartrate dihydrate. The resulting mixture was purified directly by reverse phase chromatography (C-18 silica from Waters, water/1:1 acetonitrile-methanol as eluents 0% to 100%). After purification were obtained 139 mg of tert-butyl 9-(2-(3-chloro-2-(pyridin-4-ylcarbamoyl)-1H-pyrrol-1-ylamino)-2-oxoethyl)-9H-purin-6-ylcarbamate (93% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[CH2:21][NH:22][CH2:23][CH3:24])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.Cl[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)=[O:28]>>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[CH2:21][N:22]([C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)=[O:28])[CH2:23][CH3:24])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: CCNCc1ccc(OC)cc1-c1cc(CC(=O)OC)ccc1OC
Reactant: O=C(Cl)OCc1ccc(Cl)cc1
Product: CCN(Cc1ccc(OC)cc1-c1cc(CC(=O)OC)ccc1OC)C(=O)OCc1ccc(Cl)cc1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-ethylaminomethyl-6,5′-dimethoxy-biphenyl-3-yl)-acetic acid methyl ester and 4-chlorobenzyl chloroformate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:29])[CH:11]=[C:12]([CH2:17][NH:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])(=[O:21])=[O:20])[O:13][C:14]=1[CH:15]=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(S(C(N)C2OC(C(O)=O)=C(OCC3C=CC=CC=3)C(=O)C=2)(=O)=[O:37])C=CC=CC=1>>[CH2:1]([O:8][C:9]1[C:10](=[O:29])[CH:11]=[C:12]([CH2:17][NH:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])(=[O:21])=[O:20])[O:13][C:14]=1[C:15]([OH:37])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1oc(CNS(=O)(=O)c2ccccc2Cl)cc(=O)c1OCc1ccccc1
Reactant: NC(c1cc(=O)c(OCc2ccccc2)c(C(=O)O)o1)S(=O)(=O)c1ccccc1
Product: O=C(O)c1oc(CNS(=O)(=O)c2ccccc2Cl)cc(=O)c1OCc1ccccc1

Procedure:
3-Benzyloxy-6-[(2-chloro-benzenesulfonylamino)-methyl]-4-oxo-4H-pyran-2-carboxylic acid (12-03) (2 g, crude) was synthesized as a white solid from N-(5-benzyloxy-6-formyl-4-oxo-4H-pyran-2-ylmethyl)-2-chloro-benzenesulfonamide (11-03) (2.8 g, 6.46 mmol) following the procedure described for 6-(benzenesulfonylamino-methyl)-3-benzyloxy-4-oxo-4H-pyran-2-carboxylic acid (12-01).