Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.S(Cl)([Cl:17])(=O)=O>C(NCC(C)C)C(C)C.C1(C)C=CC=CC=1>[Cl:17][C:7]1[CH:6]=[C:5]([O:4][CH2:3][C:2]([F:12])([F:13])[F:1])[CH:10]=[CH:9][C:8]=1[OH:11]
Reactant: Oc1ccc(OCC(F)(F)F)cc1
Reactant: O=S(=O)(Cl)Cl
Agent: CC(C)CNCC(C)C
Solvent: Cc1ccccc1
Product: Oc1ccc(OCC(F)(F)F)cc1Cl
Temperature: 70 °C
Yield: 106.1 %

Procedure:
To a 30 ml toluene solution of 4-(2,2,2-trifluoroethoxy)phenol (1.02 g, 5.31 mmol) and diisobutylamine (0.074 ml, 0.42 mmol) was added sulfuryl chloride (0.38 ml, 4.7 mmol). This solution was heated to 70° C. for 2 hr. The solvent was removed under reduced pressure. The residue was diluted with AcOEt and sat. bicarb. solution. The organic layer was separated, and the aqueous layer was extracted twice with AcOEt. The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated, and chromatographed on silica gel eluting with 10% AcOEt/hexanes to give the title compound as a pale yellow oil 1.13 g (94%).
Reaction SMILES: C(OC[S:6]([C:9]1[C:14]([F:15])=[CH:13][C:12]([C:16]2[C:17]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:18][O:19][C:20]=2[CH3:21])=[CH:11][C:10]=1[F:28])(=[O:8])=[O:7])(=O)C.[OH-].[Li+].[NH:31](S(O)(=O)=O)O>C1COCC1.CO.O>[F:28][C:10]1[CH:11]=[C:12]([C:16]2[C:17]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:18][O:19][C:20]=2[CH3:21])[CH:13]=[C:14]([F:15])[C:9]=1[S:6]([NH2:31])(=[O:8])=[O:7]
Reactant: O=S(=O)(O)NO
Reactant: CC(=O)OCS(=O)(=O)c1c(F)cc(-c2c(-c3ccccc3)noc2C)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1onc(-c2ccccc2)c1-c1cc(F)c(S(N)(=O)=O)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of {[2,6-difluoro-4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl}methyl acetate (1.5 g, 3.9 mmol) in THF (25 mL) and methanol (25 mL) was added a solution of lithium hydroxide (0.50 g, 12 mmol) in water (4 mL). The resulting solution was stirred at room temperature for 1 hour. Additional solution of lithium hydroxide (0.60 g, 14 mmol) in water (8 mL) was added, followed by solid hydroxylamine sulfonic acid (1.6 g, 14.1 mmol) and methanol (5 mL). The reaction mixture was stirred overnight and poured into water (250 mL). The 2,6-difluoro-4-(5-methyl-3-phenyl-isoxazol-4-yl)benzenesulfonamide was isolated as a white solid (1.08 g, 85%). MP 226.1-226.2° C. 1H NMR (CD3OD/400 MHz) 7.36-7.46 (m, 5H), 6.95 (d, 2H, J=9.4), 2.51 (s, 3H). ESHRMS m/z 351.0621 (M+H+, Calcd 351.0615). Anal. Calcd for C,16H12F2N2O3S: C, 54.85; H, 3.45; N, 8.00; Found: C, 54.95; H, 3.51, N 7.81.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][CH2:10][CH2:11][CH2:12][N:13]([C@H:29]1[CH2:34][CH2:33][C@H:32]([CH3:35])[CH2:31][CH2:30]1)[C:14](=[O:28])[NH:15][C:16]1[S:17][C:18]([S:21]C(C)(C)C(O)=O)=[CH:19][N:20]=1.C1(S)C=CC=CC=1.C([O:45][C:46](=[O:58])[C:47]([CH3:57])([CH3:56])[CH2:48]SC1SC(N)=NC=1)C>>[CH3:48][C:47]([CH3:57])([CH2:56][S:21][C:18]1[S:17][C:16]([NH:15][C:14]([N:13]([C@H:29]2[CH2:30][CH2:31][C@H:32]([CH3:35])[CH2:33][CH2:34]2)[CH2:12][CH2:11][CH2:10][S:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:3]=2)=[O:28])=[N:20][CH:19]=1)[C:46]([OH:58])=[O:45]
Reactant: CCOC(=O)C(C)(C)CSc1cnc(N)s1
Reactant: COc1ccccc1SCCCN(C(=O)Nc1ncc(SC(C)(C)C(=O)O)s1)[C@H]1CC[C@H](C)CC1
Agent: Sc1ccccc1
Product: CC(C)(CSc1cnc(NC(=O)N(CCCSc2ccccc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis 2-{2-[3-[3-(2-methoxy-phenylsulfanyl)-propyl]-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2-methyl-propionic acid using thiophenol and 3-(2-amino-thiazol-5-ylsulfanyl)-2,2-dimethyl-propionic acid ethyl ester.
Reaction SMILES: [C:1]([C:3]1([OH:11])[CH:8]2[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]2)[CH2:4]1)#[CH:2].[H][H]>[Pd].C(O)C>[CH:1]([C:3]1([OH:11])[CH:8]2[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]2)[CH2:4]1)=[CH2:2]
Reactant: C#CC1(O)CN2CCC1CC2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: C=CC1(O)CN2CCC1CC2
Yield: 98.7 %

Procedure:
A mixture of 3-ethynyl-3-hydroxyquinuclidine (5.0 g), palladium on calcium carbonate (5 % w/w, 0.5 g) and ethanol (200 ml) was stirred under an atmosphere of hydrogen until 900 ml of hydrogen has been consumed. The mixture was filtered and evaporated to give 3-ethenyl-3-hydroxyquinuclidine (5.0 g) as an oil which gave a solid on standing and was used without further purification, m.p. 76°-80° C.; NMR(DMSO-d6): 1.2(1H, m), 1.4-1.6(3H, m), 2.0(1H, m), 2.45-2.85(6H, m), 4.55(1H, s), 5.0(1H, d of d), 5.25(1H, d of d), 6.1(1H, d of d); m/z 154 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][C:31]=1[NH:32][C:33](=[O:37])[C@@H:34]([OH:36])[CH3:35])[NH:28][C:27](=[O:38])[CH2:26]2>>[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][C:31]=1[NH:32][C:33](=[O:37])[C@@H:34]([OH:36])[CH3:35])[NH:28][C:27](=[O:38])[C:26]2=[CH:20][C:3]1[NH:4][C:5]2[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[C:7](=[O:19])[C:6]=2[C:2]=1[CH3:1]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Reactant: C[C@H](O)C(=O)Nc1cc2c(cc1F)CC(=O)N2
Product: Cc1c(C=C2C(=O)Nc3cc(NC(=O)[C@H](C)O)c(F)cc32)[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Yield: 61.3 %

Procedure:
The title compound was prepared under the same conditions as described in Example 15 with 3-methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and (S)—N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-hydroxy-propionamide as starting materials to give (S)—N-{5-fluoro-3-[3-methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-hydroxy-propionamide (44 mg, 61.3%) as a yellow solid.
Reaction SMILES: [NH:1]1C=CN=N1.[C@@H:6]1([N:15]2C3N=C[N:21]=[C:19]([OH:20])[C:18]=3[N:17]=[CH:16]2)[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[C@H:7]1[OH:8].P([O-])(O)(O)=O.[K+]>>[CH:16]1[N:15]([C@@H:6]2[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[C@H:7]2[OH:8])[N:1]=[C:18]([C:19]([NH2:21])=[O:20])[N:17]=1
Reactant: c1c[nH]nn1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(O)ncnc32)[C@H](O)[C@@H]1O
Agent: O=P([O-])(O)O
Agent: [K+]
Product: NC(=O)c1ncn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)n1
Reaction time: 24 h

Procedure:
By using a substrate solution (pH 6.0) containing 40 mM triazole as the base donor, 60 mM inosine as the saccharide residue donor and 40 mM potassium dihydrogenphosphate, reactions were carried out in the same manner as in Example 1 at respective reaction temperature (40° to 70° C.) for 24 hours to produce ribavirin. The results are shown in Table 8.
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:17][C:18]([N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([C:30]3[N:35]=[C:34]([C:36]([O:38]C(C)(C)C)=[O:37])[CH:33]=[CH:32][CH:31]=3)[CH:28]=2)[N:23]([CH3:43])[CH2:22][CH2:21]1)=[O:19]>C(Cl)Cl>[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:17][C:18]([N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([C:30]3[N:35]=[C:34]([C:36]([OH:38])=[O:37])[CH:33]=[CH:32][CH:31]=3)[CH:28]=2)[N:23]([CH3:43])[CH2:22][CH2:21]1)=[O:19]
Reactant: CN1CCN(C(=O)Nc2nc3ccccc3s2)c2cc(-c3cccc(C(=O)OC(C)(C)C)n3)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(C(=O)Nc2nc3ccccc3s2)c2cc(-c3cccc(C(=O)O)n3)ccc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 87 %

Procedure:
The title compound 6-(4-(benzo[d]thiazol-2-ylcarbamoyl)-1-methyl-1,2,3,4-tetrahydroquinoxalin-6-yl)picolinic acid (25) was prepared by the following procedure: Trifluoroacetic acid (2.0 mL) was added dropwise to tert-butyl 6-(4-(benzo[d]thiazol-2-ylcarbamoyl)-1-methyl-1,2,3,4-tetrahydroquinoxalin-6-yl)picolinate (25H) (79 mg, 0.16 mmol) in DCM (2.0 mL) at 0° C. The mixture was allowed to warm up to rt and stirred for 72 hours. The mixture was concentrated, triturated with diethylether, filtered, and dried in vacuo to provide 62 mg (70%) of the desired product 6-(4-(benzo[d]thiazol-2-ylcarbamoyl)-1-methyl-1,2,3,4-tetrahydroquinoxalin-6-yl)picolinic acid (25): 1H NMR (300 MHz, DMSO-d6) δ 8.28 (1H, s), 8.01-7.72 (5H, m), 7.45-7.30 (2H, m), 7.21 (1H, t), 6.82 (1H, d), 4.03 (2H, t), 3.45 (2H, t), 3.00 (3H, s). MS (ESI(+)): m/z 446.0 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:8]=[CH:9][N:10]([C@H:12]([CH3:31])[CH2:13][CH2:14][N:15](C(OC(C)(C)C)=O)[NH:16]C(OC(C)(C)C)=O)[CH:11]=2)[CH:2]=1.Cl>CO>[NH:15]([CH2:14][CH2:13][C@H:12]([N:10]1[CH:11]=[C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[N:8]=[CH:9]1)[CH3:31])[NH2:16]
Reactant: C[C@H](CCN(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n1cnc(-c2cccnc2)c1
Agent: Cl
Solvent: CO
Product: C[C@H](CCNN)n1cnc(-c2cccnc2)c1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
To a solution of bis(1,1-dimethylethyl) 1-[(3R)-3-[4-(3-pyridinyl)-1H-imidazol-1-yl]butyl]-1,2-hydrazinedicarboxylate (32) in methanol was added 6N hydrochloric acid. The reaction was heated to 50° C. and stirred 18 h.
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@@H:2]([C:10]([OH:12])=O)[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].Cl.[NH2:21][C@@H:22]([C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])[CH2:23][C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][CH:25]=1.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.ClCCl>[NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@@H:2]([C:10]([NH:21][C@@H:22]([C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])[CH2:23][C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][CH:25]=1)=[O:12])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8]
Reactant: N[C@H](Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H](CCCNC(=N)N)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H](CCCNC(=N)N)C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
To a stirred solution of Boc-D-Arg-OH hydrochloride (855 mg, 2.75 mmoles), H-D-Trp-OBzl hydrochloride (832 mg, 2.5 mmoles), HOBt (1378 mg, 9 mmoles) and DIPEA (2.05 ml, 12 mmoles) in DMF (5 ml) and dichloromethane (1 ml) cooled on ice was added HBTU (1138 mg, 3 mmoles) in small portions over 10 minutes. The mixture was stirred on ice for 1 hour, 40 ml dichloromethane was added and the organic phase washed successively with 3×40 ml saturated NaHCO3, 2×30 ml 5% citric acid, 50 ml water and 2×30 ml brine. Evaporation afforded a white solid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[N:11]([C:17]1[CH:22]=[CH:21][C:20]([N:23]3[CH2:27][CH2:26][C@@H:25]([NH:28][CH3:29])[CH2:24]3)=[C:19]([F:30])[CH:18]=1)[CH2:10][CH2:9]2)[CH2:2][CH2:3][CH3:4].[CH3:31][C:32]([CH3:34])=O>>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[N:11]([C:17]1[CH:22]=[CH:21][C:20]([N:23]3[CH2:27][CH2:26][C@@H:25]([N:28]([CH:32]([CH3:34])[CH3:31])[CH3:29])[CH2:24]3)=[C:19]([F:30])[CH:18]=1)[CH2:10][CH2:9]2)[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)=O
Reactant: CCCCOc1ccc2c(c1)CCN(c1ccc(N3CC[C@@H](NC)C3)c(F)c1)C2=O
Product: CCCCOc1ccc2c(c1)CCN(c1ccc(N3CC[C@@H](N(C)C(C)C)C3)c(F)c1)C2=O

Procedure:
6-Butoxy-2-[3-fluoro-4-((R)-3-methylaminopyrrolidin-1-yl)phenyl]-3,4-dihydro-2H-isoquinolin-1-one (hydrochloride) was reductively alkylated with acetone by method J. The product with the molecular weight of 453.61 (C27H36FN3O2) was obtained in this way; MS (ESI): 454 (M+H+).
Reaction SMILES: [S:1]1[C:5]2[C:6](B(O)O)=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([N:26]2[CH:30]=[C:29]([C:31]3[CH:36]=[N:35][C:34]([NH2:37])=[C:33]4[O:38][C:39](Cl)=[CH:40][C:32]=34)[CH:28]=[N:27]2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:37][C:34]1[N:35]=[CH:36][C:31]([C:29]2[CH:28]=[N:27][N:26]([CH:23]3[CH2:24][CH2:25][N:20]([C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:19])[CH2:21][CH2:22]3)[CH:30]=2)=[C:32]2[CH:40]=[C:39]([C:6]3[C:5]4[S:1][CH:2]=[CH:3][C:4]=4[CH:9]=[CH:8][CH:7]=3)[O:38][C:33]=12
Reactant: OB(O)c1cccc2ccsc12
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c4oc(Cl)cc34)cn2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c4oc(-c5cccc6ccsc56)cc34)cn2)CC1
Temperature: 100 °C
Yield: 64 %

Procedure:
A solution of 7-benzothiophene boronic acid, 4-[4-(7-amino-2-chloro-furo[2,3-c]pyridin-4-yl)-pyrazol-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (150 mg, 359 μmol), Pd(dppf)Cl2 (2.63 mg, 3.59 μmol), K2CO3, (74.4 mg, 538 μmol) in 1,4-dioxane (1.96 mL), and H2O (647 μL) was degassed and refilled with argon (3×). The reaction was heated in a microwave reactor at 100° C. for 70 min. The reaction was diluted with water, extracted with EtOAc (3×) and the combined extracts were dried over Na2SO4, then concentrated in vacuo to give a solid. The solid was purified by flash chromatography (60-100% EtOAc:hexanes) to afford 96 mg (64%) of the title compound. 1H NMR (400 MHz, CDCl3): δ 8.03 (d, J=7.33 Hz, 1 H), 7.88-7.99 (m, 3 H), 7.75 (s, 1 H), 7.61 (d, J=5.31 Hz, 1 H), 7.56 (t, J=7.71 Hz, 1 H), 7.50 (d, J=5.56 Hz, 1 H), 7.44 (s, 1 H), 5.53 (br s, 2 H), 4.25-4.48 (m, 3 H), 2.90-3.01 (m, 2 H), 2.24 (d, J=15.16 Hz, 2 H), 1.97-2.11 (m, 2 H), 1.51 (s, 9 H); MS (ESI): 516.16 [M+H]+; HPLC tR=2.66 min.
Reaction SMILES: Br[C:2]1[C:3]([O:9][CH3:10])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.C([Li])CCC.CCCCCC.[Cl:22][C:23]1[CH:32]=[CH:31][C:26]([CH:27]=[CH:28][CH:29]=[O:30])=[CH:25][CH:24]=1.C(=O)(O)[O-].[Na+]>CCOCC>[Cl:8][C:6]1[CH:7]=[C:2]([CH:29](/[CH:28]=[CH:27]/[C:26]2[CH:25]=[CH:24][C:23]([Cl:22])=[CH:32][CH:31]=2)[OH:30])[C:3]([O:9][CH3:10])=[N:4][CH:5]=1
Reactant: COc1ncc(Cl)cc1Br
Reactant: O=CC=Cc1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Solvent: CCCCCC
Product: COc1ncc(Cl)cc1C(O)/C=C/c1ccc(Cl)cc1
Reaction time: 0.25 h

Procedure:
A solution of 4.0 g of 3-bromo-5-chloro-2-methoxypyridine in 75 ml of anhydrous ether was cooled to -70° C. under nitrogen. The resulting slurry was stirred rapidly and there was added 12.0 ml of 1.65M n-butyllithium/hexane dropwise over a period of about 5 minutes while keeping the temperature below -70° C. The reaction mixture became homogeneous and, after 15 minutes, a solution of 3.0 g of 4-chlorocinnamaldehyde in 35 ml of ether was added dropwise while keeping the temperature below -60° C. The cold mixture was then poured into aqueous saturated sodium bicarbonate solution and the resulting mixture was extracted with ether. The ether layer was washed with aqueous saturated sodium chloride solution, dried over potassium carbonate and concentrated under reduced pressure to give a white solid. This solid was recrystallized from a mixture of ethyl acetate/hexane to give (E)-5-chloro-α-[2-(4-chlorophenyl)ethenyl]-2-methoxy-3-pyridinemethanol as white needles melting at about 135°-139.5° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]([CH:19]=O)=[C:9]([CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])[C:10]=1[CH3:11])=[O:5])C.[Cl:21][C:22]1[CH:30]=[C:29]2[C:25]([CH2:26][C:27](=[O:31])[NH:28]2)=[CH:24][CH:23]=1.[OH-].[K+]>N1CCCCC1.C(O)C>[C:14]([CH2:13][CH2:12][C:9]1[C:10]([CH3:11])=[C:6]([C:4]([OH:3])=[O:5])[NH:7][C:8]=1[CH:19]=[C:26]1[C:25]2[C:29](=[CH:30][C:22]([Cl:21])=[CH:23][CH:24]=2)[NH:28][C:27]1=[O:31])([OH:16])=[O:15]
Reactant: CCOC(=O)CCc1c(C=O)[nH]c(C(=O)OCC)c1C
Reactant: O=C1Cc2ccc(Cl)cc2N1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(C(=O)O)[nH]c(C=C2C(=O)Nc3cc(Cl)ccc32)c1CCC(=O)O
Temperature: 95 °C
Yield: 72.1 %

Procedure:
5-Formyl-4-(2-ethoxycarbonylethyl)-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (281 mg), 6-chloro-2-oxindole (168 mg) and piperidine (2 drops) in ethanol (2 mL) were stirred at 90° C. for 2 hours. Potassium hydroxide (537 mg) was added to the mixture and it was then stirred at 95° C. for and additional hour. The reaction mixture was cooled and concentrated. The residue was dissolved into water and acidified with 2 N hydrochloric acid to pH 2. The precipitate was filtered, washed with water, and dried in a vacuum oven overnight to give 270 mg (72%) of 4-(2-carboxy-ethyl)-3-methyl-5-(6-chloro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-2-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[C:7](Br)=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.[K+].C(O[C:14]([S-:16])=[S:15])C.O.C(O)(=O)C>CN1CCCC1=O>[Cl:9][C:5]1[CH:6]=[C:7]2[S:15][C:14]([SH:16])=[N:1][C:2]2=[N:3][CH:4]=1
Reactant: Nc1ncc(Cl)cc1Br
Reactant: CCOC(=S)[S-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Solvent: CN1CCCC1=O
Product: Sc1nc2ncc(Cl)cc2s1
Temperature: 25 °C
Yield: 97.9 %

Procedure:
A solution of 133 g (0.64 mol) of 2-amino-3-bromo-5-chloropyridine from Example 1.1 in 1.02 l of N-methylpyrrolidone was admixed with 205 g (1.28 mol) O-ethylxanthic acid potassium salt. The reaction mixture was refluxed for 6 h and then allowed to cool to ambient temperature. 2.7 l of demineralized water were added then acetic acid to adjust the reaction mixture to pH 4.5. The resulting precipitate was filtered, washed with demineralized water (2×600 ml). The solid was triturated in succession with demineralized water (2×4.2 l) and ethanol, (1.5 l), filtered, washed with ethanol (2×300 ml) followed by hexane (2×400 ml) and dried in vacuo at 45° C. to give 127 g (yield: 98%) of 6-chloro-2-mercaptothiazolo[4,5-b]pyridine used without further purification.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]1[N:22]([CH3:23])[CH:21]=[N:20][CH:19]=1>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]([S:8][CH2:17][C:18]2[N:22]([CH3:23])[CH:21]=[N:20][CH:19]=2)[N:5]=[C:4]([OH:9])[CH:3]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: Cn1cncc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(O)nc(SCc2cncn2C)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 42.2 %

Procedure:
6-methyl-2-sulfanylpyrimidin-4-ol (846 mg, 5.9 mmol) was dissolved in anhydrous DMF (40 mL), then potassium carbonate (2.46 g, 17.8 mmol) and 5-(bromomethyl)-1-methyl-1H-imidazole (1.56 g, 8.9 mmol) were added. The mixture was stirred for 4 hours at room temperature. The solid was removed by filtration, washed with methanol, and the filtrate was evaporated. The residue was dissolved in DCM/MeOH and purified on silica gel using 10% DCM in MeOH to afford 6-methyl-2-{[(1-methyl-1H-imidazol-5-yl)methyl]sulfanyl}pyrimidin-4-ol (589 mg, 42% yield for 2 steps); 1H NMR (400 MHz, DMSO-d6): δ 2.22 (s, 3H), 3.61 (s, 3H), 4.44 (s, 2H), 6.02 (s, 1H), 6.88 (s, 1H), 7.56 (s, 1H); LRMS (ES+) m/z 237 (100%, M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:9])[CH:8]=1)[NH2:5].[C:10]([C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1)([OH:12])=[O:11].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C>C1(C)C=CC=CC=1>[C:10]([C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[N:5][C:4]2[CH:3]=[C:2]([Cl:1])[CH:8]=[C:7]([Cl:9])[CH:6]=2)=[CH:15][CH:14]=1)([OH:12])=[O:11]
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(O)c1ccc(C=Nc2cc(Cl)cc(Cl)c2)cc1

Procedure:
To a reaction flask, equipped with a Dean-Stark trap, is added 3,5-dichloroaniline (16.2 g., 0.10 mole), p-carboxybenzaldehyde (0.10 moles), p-toluenesulfonic acid monohydrate (0.2 g), and toluene (100 ml.). The reaction mixture is then warmed to reflux and the water (1.65 ml.) collected by azeotroping. The cooled reaction mixture is treated with charcoal and the filtrate reduced to vacuo to give an amber oil that crystallizes on standing to give N-(p-carboxybenzylidene)-3,5-dichloroaniline which is recrystallized from pentane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@H:17]3[N:8]([C:9](=[O:21])[C@@H:10]4[C@H:15]([CH2:16]3)[NH:14][CH2:13][CH2:12][CH2:11]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1.C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl.CCCCCC>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@H:17]3[N:8]([C:9](=[O:21])[C@@H:10]4[C@H:15]([CH2:16]3)[N:14]([S:30]([CH3:29])(=[O:32])=[O:31])[CH2:13][CH2:12][CH2:11]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc2c(c1)CCN1C(=O)[C@H]3CCCN[C@H]3C[C@@H]21
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2c(c1)CCN1C(=O)[C@H]3CCCN(S(C)(=O)=O)[C@H]3C[C@@H]21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 11 g of (8aS,12aS,13aS)-3-methoxy-5,6,8a,9,10,11,12,12a,13,13a-decahydroisoquino[2,1-g][1,6]naphthyridin-8-one (I), obtained as shown in Example 4, in 300 ml of methylene chloride and 10 ml of triethylamine was cooled in an ice bath and 5 ml of methanesulfonyl chloride was added. The mixture was stirred at room temperature for 30 minutes, diluted with 100 ml of hexane, and extracted with water. The organic layer was dried over sodium sulfate and the solvent removed under reduced pressure. The residue was crystallized from isopropanol, to give 11 g of (8aS,12aS,13aS)-3-methoxy-12-methanesulfonyl5,6,8a,9,10,11,12,12a,13,13a-decahydroisoquino[2,1-g][1,6]naphthyridin-8-one, m.p. 138°-140° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([S:16][CH2:17][CH2:18][CH3:19])=[C:14]([C:20]([OH:22])=O)[CH:13]=[N:12]2)=[CH:7][CH:6]=1)=[O:4].[CH3:23][NH:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C.C(OCC)(=O)C>[CH:25]1([N:24]([CH3:23])[C:20]([C:14]2[CH:13]=[N:12][N:11]([C:8]3[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:10][CH:9]=3)[C:15]=2[S:16][CH2:17][CH2:18][CH3:19])=[O:22])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CNC1CCCCC1
Reactant: CCCSc1c(C(=O)O)cnn1-c1ccc(C(=O)OC)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCSc1c(C(=O)N(C)C2CCCCC2)cnn1-c1ccc(C(=O)OC)cc1
Reaction time: 18 h
Yield: 78 %

Procedure:
1-(4-methoxycarbonylphenyl)-5-propylsulfanyl-pyrazole-4-carboxylic acid (Intermediate #7), (160 mg, 0.5 mmol), N-methylcyclohexylamine (57 mg, 0.5 mmol), HOBT (81 mg, 0.6 mmol) and DIPEA (174 μL, 1.0 mmol) were dissolved in DMF (5 mL) and treated at ambient temperature with EDCI (115 mg, 0.6 mmol). The mixture was stirred at ambient for 18 h and then diluted with ethyl acetate (50 mL), washed with water (3×20 mL) and brine, dried (MgSO4) and volatiles removed by evaporation. The residue was purified by chromatography on silica gel (12 g silica 0-70% EtOAc/isohexane) to give the title compound as a colourless gum (162 mg, 78%).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]#[N:21])[CH:15]=2)[C:9]1=[O:22])(C)(C)C.[ClH:24]>CCOC(C)=O>[ClH:24].[NH2:7][C@H:8]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=2)[C:20]#[N:21])[C:9]1=[O:22]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(Cc2cccc(C#N)c2)C1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: N#Cc1cccc(CN2CC[C@H](N)C2=O)c1
Reaction time: 4 h

Procedure:
To a solution of [1-(3-cyanobenzyl)-2-oxo-pyrrolidin-3-(S)-yl]-carbamic acid tert-butyl ester (9.1 g, 29 mmol) in 150 mL of EtOAc at 0° C. is bubbled HCl gas for 10 min. After this time, the solution is stirred for 4 h. The solution is then concentrated to afford the title compound (7.3 g, 29 mmol) as a white solid.