Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:22][CH2:21][C:12]2=[C:13](Cl)[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[CH:17][CH:16]=[N:15]3)=O)(C)(C)C.[C:23]1([CH:29]2[CH2:32][CH2:31][NH:30]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:23]1([CH:29]2[CH2:32][CH2:31][N:30]2[C:13]2[N:14]3[C:18]([N:19]=[C:11]4[CH2:10][CH2:9][NH:8][CH2:22][CH2:21][C:12]=24)=[CH:17][CH:16]=[N:15]3)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: c1ccc(C2CCN2)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2nc3ccnn3c(Cl)c2CC1
Product: c1ccc(C2CCN2c2c3c(nc4ccnn24)CCNCC3)cc1

Procedure:
The product was prepared using 10-chloro-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester in route 1 (step e and f), in step e (route 1) 2-phenyl-azetidine was used as the amine.
Reaction SMILES: CC(=NO)C(C)=NO.[BH4-].[Na+].[CH3:11][C:12]1([CH2:18][O:19][C:20]2[CH:33]=[CH:32][C:23]([CH:24]=[C:25]3[S:29][C:28](=[O:30])[NH:27][C:26]3=[O:31])=[CH:22][CH:21]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(O)(=O)C>O.[OH-].[Na+].C1COCC1.CN(C=O)C>[CH3:11][C:12]1([CH2:18][O:19][C:20]2[CH:33]=[CH:32][C:23]([CH2:24][CH:25]3[S:29][C:28](=[O:30])[NH:27][C:26]3=[O:31])=[CH:22][CH:21]=2)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: CC1(COc2ccc(C=C3SC(=O)NC3=O)cc2)CCCCC1
Agent: CC(=NO)C(C)=NO
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: CC1(COc2ccc(CC3SC(=O)NC3=O)cc2)CCCCC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To the suspension containing CoCl2.6H2O (4.5 mg, 0.016 mmol) and dimethylglyoxime (70.1 mg, 0.6 mmol) in 10 ml of water, 4 drops of 1.0N NaOH and NaBH4 (384.6 mg, 10 mmol) were subsequently added. The mixture was cooled to 0° C., and 5-(4-((1-methylcyclohexyl)methoxy)benzylidene)thiazolidine-2,4-dione (1 g, 3.0 mmol) in 15 ml of THF-DMF (2:1) was then added thereto over 20 minutes. The mixture was stirred at room temperature for 18 hours, to which acetic acid was then added until the pH thereof reached about 6. The mixture was diluted with water, and extracted with ethyl acetate and water. The organic layer was washed with water several times, dried with anhydrous magnesium sulfate, filtered and solvent-evaporated. The residual oil was chromatographed on silica gel to afford 5-(4-((1-methylcyclohexyl)methoxy)benzyl)thiazolidine-2,4-dione (Derivative 112 of the above formula) as white solid (0.8 g, yield: 80%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:21](Cl)(=[O:25])[C:22]([CH3:24])=[CH2:23]>O1CCCC1.CN(C)C1C=CN=CC=1>[CH3:24][C:22](=[CH2:23])[C:21]([O:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1)=[O:25]
Reactant: C=C(C)C(=O)Cl
Reactant: COC(=O)C=Cc1ccc(O)cc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)Oc1ccc(/C=C/C(=O)OC)cc1
Temperature: 15 °C
Reaction time: 8 h
Yield: 70.9 %

Procedure:
10.5 g (59 mmol) of methyl 3-(4-hydroxy-phenyl)-acrylate were dissolved in 170 ml of tetrahydrofuran and treated in succession with 9.1 ml (65 mmol) of triethylamine and 0.079 g (0.65 mmol) of 4-dimethylamino-pyridine (DMAP). 6.8 g (65 mmol) of methacryloyl chloride were added dropwise to the solution, cooled to about 15° C., over a period of 30 minutes. The reaction batch was stirred at room temperature overnight and subsequently filtered over a thin silica gel layer. The silica gel layer was rinsed thoroughly with THF. After evaporation of the solvent the crude product was recrystallized from about 200 ml of ethanol. It was filtered off, dried and recrystallized once more from ethanol. Filtration and drying at 50° C. in a water-jet vacuum gave 10.3 g of 4-[(E)-2-methoxycarbonyl-vinyl]-phenyl 2-methyl-acrylate as white crystals with a melting point of 76-80° C. and an absorption maximum of λmax. (in CH2Cl2)=281.7 nm (ε=24290 l/mol cm).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([Cl:11])=[C:9]([NH2:12])[N:8]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([O:20][CH3:21])[C:14]=2[F:22])[N:6]=1)=[O:4].[OH-].[Na+].Cl>CO>[NH2:12][C:9]1[N:8]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([O:20][CH3:21])[C:14]=2[F:22])[N:6]=[C:5]([C:3]([OH:4])=[O:2])[C:10]=1[Cl:11]
Reactant: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)nc(N)c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1c(Cl)ccc(-c2nc(N)c(Cl)c(C(=O)O)n2)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.9 %

Procedure:
6-Amino-5-chloro-2-(4-chloro-2-fluoro-3-methoxyphenyl)-pyrimidine-4-carboxylic acid methyl ester (156 mg, 0.45 mmol) was dissolved in 15 mL methanol and 1 mL of 2N sodium hydroxide (2 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours and then acidified with a slight excess of 2N HCl. The resulting solution was concentrated under a nitrogen stream and several crops of crystals were collected during this process yielding 6-amino-5-chloro-2-(4-chloro-2-fluoro-3-methoxyphenyl)pyrimidine-4-carboxylic acid (100 mg, 66.7% yield): mp 172-173° C.: 1H NMR (DMSO-d6): δ 8.0 (br, 1H), 7.63 (dd, 1H), 7.43 (dd, 1H), 3.92 (s, 3H).
Reaction SMILES: [CH3:1][S:2][CH3:3].ClN1C(=O)CCC1=O.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[O:22])[CH:19]=2)C=[CH:13]1>ClCCl>[CH3:1][S:2][C:3]1[C:15]2[C:20](=[CH:19][C:18]([C:21]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[O:22])=[CH:17][CH:16]=2)[NH:12][CH:13]=1
Reactant: CSC
Reactant: O=C(c1ccc2cc[nH]c2c1)N1CCOCC1
Agent: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: CSc1c[nH]c2cc(C(=O)N3CCOCC3)ccc12
Temperature: -20 °C
Reaction time: 1 h
Yield: 58.3 %

Procedure:
Dimethylsulfane (8.17 mL, 109.32 mmol, 1.1 eq) was added dropwise to a stirred suspension of N-chlorosuccinimide (14.53 g, 109.32 mmol, 1.1 eq) in dichloromethane (50 mL) at 0° C. The reaction mixture was cooled to −20° C. and (1H-indol-6-yl)(morpholino)methanone (16.0 g, 99.37 mmol, 1.0 eq) in dichloromethane (120 mL) was added dropwise. After stirring for 1 h at room temperature, the solvent was evaporated and replaced by xylene (100 mL). The mixture was refluxed for 1 h, cooled to ambient temperature and then passed through a silica gel column [100-200 mesh, methanol/dichloromethane=1:19]. The product (16.0 g) obtained was used without further purification.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][CH2:13][O:14][C:15]1[CH:30]=[CH:29][C:18]([CH:19]=[C:20]([C:25]([O:27][CH3:28])=[O:26])[C:21]([O:23][CH3:24])=[O:22])=[CH:17][CH:16]=1.[H][H]>CO.O1CCOCC1.[Pd]>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][CH2:13][O:14][C:15]1[CH:30]=[CH:29][C:18]([CH2:19][CH:20]([C:25]([O:27][CH3:28])=[O:26])[C:21]([O:23][CH3:24])=[O:22])=[CH:17][CH:16]=1
Reactant: COC(=O)C(=Cc1ccc(OCCOc2ccc3ccccc3c2)cc1)C(=O)OC
Reactant: [H][H]
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)C(Cc1ccc(OCCOc2ccc3ccccc3c2)cc1)C(=O)OC
Yield: 94 %

Procedure:
To a solution of dimethyl 4-[2-(2-naphthoxy)ethoxy]benzylidenemalonate (2.22 g, 5.47 mmol) in a mixture of methanol (20 ml) and 1,4-dioxane (150 ml) is added 5% palladium on charcoal (1.20 g). Then the mixture is stirred under an atmosphere of hydrogen at room temperature until hydrogen uptake ceased. The solution is filtered through Celite, and the filtrate is evaporated under a vacuum. The residue is crystallized from ethyl acetate to give the title compound (2.10 g, 94%). HRMS calcd for C24H24O6: 408.4476. Found: 408.4475. MA calcd for C24H24O6: C, 70.58%; H, 5.92%. Found: C, 70.71%; H, 5.89%.
Reaction SMILES: [Br:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]([NH:16][CH:17]([CH3:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[N:7][C:8]3[C:9](I)=[CH:10][NH:11][C:12](=[O:14])[C:13]=3[C:4]=2[CH:3]=1.[CH3:25][S:26]([O-:28])=[O:27].[Na+].N1CCCC1C(O)=O.[OH-].[Na+]>[Cu]I>[Br:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]([NH:16][CH:17]([CH3:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[N:7][C:8]3[C:9]([S:26]([CH3:25])(=[O:28])=[O:27])=[CH:10][NH:11][C:12](=[O:14])[C:13]=3[C:4]=2[CH:3]=1
Reactant: CC(Nc1nc2c(I)c[nH]c(=O)c2c2cc(Br)ccc12)C(C)(C)C
Reactant: CS(=O)[O-]
Agent: [Cu]I
Agent: O=C(O)C1CCCN1
Agent: [Na+]
Product: CC(Nc1nc2c(S(C)(=O)=O)c[nH]c(=O)c2c2cc(Br)ccc12)C(C)(C)C
Temperature: 90 °C
Reaction time: 72 h

Procedure:
9-bromo-4-iodo-6-[(1,2,2-trimethylpropyl)amino]benzo[c]-1,6-naphthyridin-1(2H)-one (50 mg, 0.10 mmol), sodium methanesulfinate (13.27 mg, 0.130 mmol), DL-proline (2.302 mg, 0.020 mmol), copper(I) iodide (1.904 mg, 10.00=01) and NaOH (0.800 mg, 0.020 mmol) were combined in a 2-dram vial that was then flushed with nitrogen and kept under a nitrogen atmosphere. DMSO (500 μl) was then added and the reaction was heated to 90° C. and stirred for 72 h. Then, the reaction was purified by preparative HPLC reverse phase (C-18), eluting with Acetonitrile/Water+0.05% TFA, to give the title compound as a pale yellow solid. LRMS (ESI) calc'd for (C19H23BrN3O3S) [M+H]+ 452.1; found 452.0.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[O:12][C:13]([C:17]([O:19]CC)=[O:18])=[C:14]([I:16])[N:15]=2)[C:8]([CH3:22])=[CH:7][N:6]=1)(=[O:3])[CH3:2].[Li+].[OH-]>C1COCC1.O>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[O:12][C:13]([C:17]([OH:19])=[O:18])=[C:14]([I:16])[N:15]=2)[C:8]([CH3:22])=[CH:7][N:6]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1oc(-c2cc(NC(C)=O)ncc2C)nc1I
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Nc1cc(-c2nc(I)c(C(=O)O)o2)c(C)cn1
Reaction time: 5 h
Yield: 80.7 %

Procedure:
To a solution of ethyl 2-(2-acetamido-5-methylpyridin-4-yl)-4-iodo-1,3-oxazole-5-carboxylate (33.0 g, 80.0 mmol) in THF (660 mL) was added an aqueous solution of LiOH (1M in water, 80 mL). The reaction mixture was allowed to stir for 5 h and then diluted with water. The organic solvent was removed by evaporation and the pH of the remaining aqueous solution was adjusted to 3-4. The mixture was filtered and the solid was collected, washed with water, and dried to give 2-(2-acetamido-5-methylpyridin-4-yl)-4-iodo-1,3-oxazole-5-carboxylic acid (25.0 g, 81%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:43]([NH2:45])=[O:44])[CH:24]=[C:25]([C:28]4[CH:33]=[C:32]([CH2:34][NH:35][CH2:36][C@@H:37]5[CH2:41][CH2:40][CH2:39][O:38]5)[CH:31]=[C:30]([F:42])[CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].O1CCC[C@H]1CN>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:14][CH2:15][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:43]([NH2:45])=[O:44])[CH:24]=[C:25]([C:28]4[CH:33]=[C:32]([CH2:34][NH:35][CH2:36][C@H:37]5[CH2:41][CH2:40][CH2:39][O:38]5)[CH:31]=[C:30]([F:42])[CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:17][CH2:18]1)(=[O:12])=[O:11])[CH3:9]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(F)cc(CNC[C@@H]5CCCO5)c4)cc23)CC1
Agent: NC[C@@H]1CCCO1
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(F)cc(CNC[C@H]5CCCO5)c4)cc23)CC1
Yield: 47.4 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-furanylmethyl]amino}methyl)phenyl]-1H-indole-7-carboxamide trifluoroacetate, substituting 1-[(2R)-tetrahydro-2-furanyl]methanamine (53 mg, 0.525 mmol) for 1-[(2S)-tetrahydro-2-furanyl]methanamine to afford 27.1 mg of the title compound (47.4%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([CH3:17])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[O:39][N:38]=[C:37]([CH3:40])[CH:36]=2)[CH:30]=1)=[O:28])(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:15])[CH3:16])[C:11]([CH3:17])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[O:39][N:38]=[C:37]([CH3:40])[CH:36]=2)[CH:30]=1)=[O:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(N)c(NC(=O)OC(C)(C)C)cc1N(C)C
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)on1
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C)c(N(C)C)cc3NC(=O)OC(C)(C)C)c2)on1

Procedure:
The title compound was prepared from (2-amino-5-dimethylamino-4-methyl-phenyl)-carbamic acid tert-butyl ester (Example J22) (265 mg, 1.0 mmol) and 3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K4) (301 mg, 1.0 mmol) according to the general procedure M. Obtained as a brown foam (330 mg, 67%).
Reaction SMILES: Cl.[CH:2]12[CH:9]([C:10]([O:12][CH3:13])=[O:11])[CH:6]([CH2:7][CH2:8]1)[CH2:5][NH:4][CH2:3]2.Cl[C:15]1[N:20]=[CH:19][C:18]([B:21]([OH:23])[OH:22])=[CH:17][N:16]=1>>[CH3:13][O:12][C:10]([CH:9]1[C@@H:2]2[CH2:8][CH2:7][C@H:6]1[CH2:5][N:4]([C:15]1[N:20]=[CH:19][C:18]([B:21]([OH:23])[OH:22])=[CH:17][N:16]=1)[CH2:3]2)=[O:11]
Reactant: COC(=O)C1C2CCC1CNC2
Reactant: OB(O)c1cnc(Cl)nc1
Agent: Cl
Product: COC(=O)C1[C@@H]2CC[C@H]1CN(c1ncc(B(O)O)cn1)C2
Yield: 122.7 %

Procedure:
Prepared from methyl 3-azabicyclo[3.2.1]octane-8-carboxylate hydrochloride (0.57 g, 2.8 mmol) and (2-chloropyrimidin-5-yl)boronic acid (0.45 g, 2.8 mmol) in accordance with General Method C to afford the title compound (1 g) as an off-white gum. LCMS (pH 3) MH+ 292, RT 0.79 minutes.
Reaction SMILES: C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.CC1CCNCC1C(OCC)=O.C(N(CC)CC)C.[CH3:35][CH:36]1[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH:37]1[C:49]([O:51][CH2:52][CH3:53])=[O:50]>ClCCl>[CH3:35][C@H:36]1[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:46])[CH3:47])=[O:43])[CH2:38][C@H:37]1[C:49]([O:51][CH2:52][CH3:53])=[O:50]
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCC1C
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CCOC(=O)C1CNCCC1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.3 %

Procedure:
Di-tert-butyl dicarbonate (3.26 g, 15.20 mmol) was added to a solution of ethyl 4-methylpiperidine-3-carboxylate (2.0 g, 11.68 mmol) and triethylamine (3.9 mL, 28.05 mmol) in anhydrous dichloromethane (50 mL) at 0° C. The reaction mixture was stirred at room temperature for 18 h. The mixture partitioned between dichloromethane and water. The organics were dried over sodium sulfate, filtered and concentrated under reduced pressure to afford a mixture of the cis and trans diastereomers of 1-tert-butyl 3-ethyl 4-methylpiperidine-1,3-dicarboxylate (3.0 g). The crude material was purified via column chromatography (5-10% ethyl acetate in petroleum ether) to afford cis-1-tert-butyl 3-ethyl 4-methylpiperidine-1,3-dicarboxylate (2.5 g).
Reaction SMILES: [F:1][C:2]([F:35])([CH2:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:3][CH2:4][C@H:5]1[C@H:9]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH2:8][C@H:7]([OH:17])[C@@H:6]1[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C(Cl)Cl>[F:35][C:2]([F:1])([CH2:27][O:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH2:3][CH2:4][C@H:5]1[C@H:9]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH2:8][C:7](=[O:17])[C@@H:6]1[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25]
Reactant: O=C(O)CCC/C=C\C[C@@H]1[C@@H](CCC(F)(F)COc2ccccc2)[C@H](OC2CCCCO2)C[C@@H]1O
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=C(O)CCC/C=C\C[C@H]1C(=O)C[C@@H](OC2CCCCO2)[C@@H]1CCC(F)(F)COc1ccccc1
Temperature: 0 °C

Procedure:
(Z)-7-((1R,2R,3R,5S)-2-(3,3-Difluoro-4-phenoxybutyl)-5-hydroxy-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl)hept-5-enoic acid (limiting reagent, prepared in Step G) is dissolved in DCM (0.05 M) and cooled to 0° C. PCC (2 molar equivalents) is added and the reaction mixture is allowed to warm to room temperature with stirring. Upon completion by as indicated by TLC, the crude product is purified by flash chromatography on regular silica gel using ethyl acetate-hexane-acetic acid as eluent to afford the title intermediate.
Reaction SMILES: [C:1]([NH:6][C:7]1[NH:8][C:9](=[O:42])[C:10]2[N:11]=[CH:12][N:13]([C@@H:16]3[O:28][C@H:27]([CH2:29][O:30][C:31]4(C(=O)C(C)C)[CH2:36][CH2:35][CH2:34][CH2:33][O:32]4)[C@@H:19]([O:20][CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][O:22]4)[C@@H:17]3[OH:18])[C:14]=2[N:15]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].[OH-].[Na+].C(O)(=O)C.C([O-])(O)=O.[Na+]>N1C=CC=CC=1.CO.O.CCO.CO>[C:1]([NH:6][C:7]1[NH:8][C:9](=[O:42])[C:10]2[N:11]=[CH:12][N:13]([C@@H:16]3[O:28][C@H:27]([CH2:29][O:30][CH:31]4[CH2:36][CH2:35][CH2:34][CH2:33][O:32]4)[C@@H:19]([O:20][CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][O:22]4)[C@@H:17]3[OH:18])[C:14]=2[N:15]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C(=O)Nc1nc2c(ncn2[C@@H]2O[C@H](COC3(C(=O)C(C)C)CCCCO3)[C@@H](OC3CCCCO3)[C@@H]2O)c(=O)[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: CO
Solvent: O
Product: CC(C)C(=O)Nc1nc2c(ncn2[C@@H]2O[C@H](COC3CCCCO3)[C@@H](OC3CCCCO3)[C@@H]2O)c(=O)[nH]1
Temperature: 0 °C
Reaction time: 2 h
Yield: 78.3 %

Procedure:
N2-Isobutyryl-9-(2′-isobutyryl-3′,5′-di-O-[tetrahydropyran-2-yl]-β-D-arabinofuranosyl)guanine (5.58 g) was dissolved in pyridine-MeOH—H2O (65:30:15, 52 mL) at room temperature. The solution was cooled to 0° C. and 52 mL of 2 N NaOH in EtOH-MeOH (95:5) was added slowly, followed by stirring for 2 hours at 0° C. Glacial acetic acid was added to pH 6, and saturated NaHCO3 was added to pH 7. The reaction mixture was evaporated under reduced pressure and the residue coevaporated with toluene. The residue was then dissolved in EtOAc (150 mL) and washed 3× with saturated NaHCO3. The organic phase was evaporated and the residue purified by silica gel column chromatography using EtOAc-MeOH (95:5) as the eluent, yielding 3.85 g (78.3%) of product.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][C@@H:14]([CH3:19])[C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[NH2:20][C:21]([CH3:29])([CH2:24][S:25]([CH3:28])(=[O:27])=[O:26])[C:22]#[N:23]>>[C:22]([C:21]([NH:20][C:10]([C:7]1[CH:6]=[C:5]([O:13][C@@H:14]([CH3:19])[C:15]([F:18])([F:17])[F:16])[C:4]([CH:1]2[CH2:2][CH2:3]2)=[CH:9][N:8]=1)=[O:12])([CH3:29])[CH2:24][S:25]([CH3:28])(=[O:27])=[O:26])#[N:23]
Reactant: C[C@H](Oc1cc(C(=O)O)ncc1C1CC1)C(F)(F)F
Reactant: CC(N)(C#N)CS(C)(=O)=O
Product: C[C@H](Oc1cc(C(=O)NC(C)(C#N)CS(C)(=O)=O)ncc1C1CC1)C(F)(F)F

Procedure:
The title compound was synthesized in analogy to Example 78e, using 5-Cyclopropyl-4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-pyridine-2-carboxylic acid (Example 68a) and 2-Amino-3-methanesulfonyl-2-methyl-propionitrile (Example 80a) as starting materials and isolated (503 mg, 54%) as a white solid; MS (ESI, m/z): 420.4 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH:25]([F:27])[F:26])=[C:6]([C:8]2[N:12]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:11]=[CH:10][C:9]=2[N+:21]([O-])=O)[CH:7]=1.O.[Cl-].[NH4+]>C(O)C.[Fe]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH:25]([F:26])[F:27])=[C:6]([C:8]2[N:12]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:18])[CH3:19])[N:11]=[CH:10][C:9]=2[NH2:21])[CH:7]=1
Reactant: C[Si](C)(C)CCOCn1ncc([N+](=O)[O-])c1-c1cc(Cl)ccc1OC(F)F
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: C[Si](C)(C)CCOCn1ncc(N)c1-c1cc(Cl)ccc1OC(F)F
Temperature: 80 °C
Yield: 53.4 %

Procedure:
To a solution of 5-(5-chloro-2-difluoromethoxyphenyl)-4-nitro-1-(2-trimethylsilanylethoxymethyl)-1H-pyrazole (62 g, 148 mmol) in ethanol (600 mL) was added water (200 mL), ammonium chloride (32 g, 590 mmol) and iron powder (41 g, 740 mmol). The mixture was heated at 80° C. for 2 hours then allowed to cool to room temperature. The residual solid was removed by filtration through Celite®. The filtrate was evaporated under reduced pressure, diluted with water and extracted twice with DCM. The combined organic extracts were washed with water and brine, dried (MgSO4) and evaporated to afford a dark oil. The oil was purified by flash chromatography on silica eluting with 0-25% EtOAc in DCM. Appropriate fractions were collected and the solvent removed in-vacuo to afford 5-(5-chloro-2-difluoromethoxyphenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazol-4-ylamine as a brown oil (30.8 g, 54%). 1H NMR (400 MHz, CDCl3) δ: (ppm) 7.56 (d, 1H), 7.44 (dd, 1H), 7.34 (s, 1H), 7.30-7.25 (m, 1H), 6.37 (t, 1H), 5.29 (s, 2H), 3.56 (t, 2H), 0.88 (dd, 2H), 0.00 (s, 9H).
Reaction SMILES: [CH3:1][C@:2]12[C@H:12]([CH2:13]/[CH:14]=[C:15]3\[C@H:16]([OH:21])[CH2:17][O:18][C:19]\3=[O:20])[C:10](=[CH2:11])[CH2:9][CH2:8][C@@H:7]1[C@@:6]([CH2:23][OH:24])([CH3:22])[C@H:5]([OH:25])[CH2:4][CH2:3]2.CO[C:28](OC)([CH3:30])[CH3:29].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(N(CC)CC)C>C1C=CC=CC=1.CS(C)=O>[CH3:1][C@:2]12[C@H:12]([CH2:13]/[CH:14]=[C:15]3\[C@H:16]([OH:21])[CH2:17][O:18][C:19]\3=[O:20])[C:10](=[CH2:11])[CH2:9][CH2:8][C@@H:7]1[C@:6]1([CH3:22])[CH2:23][O:24][C:28]([CH3:30])([CH3:29])[O:25][C@@H:5]1[CH2:4][CH2:3]2
Reactant: C=C1CC[C@@H]2[C@](C)(CO)[C@H](O)CC[C@@]2(C)[C@@H]1C/C=C1/C(=O)OC[C@H]1O
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: C=C1CC[C@@H]2[C@]3(C)COC(C)(C)O[C@@H]3CC[C@@]2(C)[C@@H]1C/C=C1/C(=O)OC[C@H]1O
Temperature: 25 °C

Procedure:
A mixture of andrographolide (15 g), 2,2-dimethoxy propane (20 ml) and a catalytic amount of pyridinium p-toluene sulphonate in benzene/dimethyl sulphoxide (300 ml/40 ml) was refluxed for 30 min. After completion of the reaction (checked by TLC), the contents were cooled to room temperature and treated with excess triethylamine (10 ml) to quench the remaining catalyst. The reaction mixture was diluted with benzene (200 ml) and washed with water (3×300 ml). The organic layer was separated, dried over Na2SO4 and concentrated to obtain a yellow coloured solid which on maceration with diethyl ether gave 3,19-isopropylidene andrographolide as a pale yellow product (16.5 g). m.p. 194.5° C., m/z 390.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:7][CH:6]([CH2:8][OH:9])[CH:5]=[CH:4]1.[OH-].[Na+].[C:12]([O:16][C:17](F)=[O:18])([CH3:15])([CH3:14])[CH3:13].Cl>O.O1CCOCC1.C(OCC)C>[C:17]([C:3]1([NH2:2])[CH2:7][CH:6]([CH2:8][OH:9])[CH:5]=[CH:4]1)([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18]
Reactant: CC(C)(C)OC(=O)F
Reactant: NC1C=CC(CO)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)C1(N)C=CC(CO)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56 %

Procedure:
15 g of crude (±)-1-amino-4-hydroxymethyl-2-cyclopentene hydrochloride (prepared as described in J. Org. Chem. 1981, 46, 3268) were dissolved in a mixture of 150 ml of water and 150 ml of dioxane at room temperature under nitrogen. The solution was adjusted to pH 14 with 1N NaOH, then a diethyl ether solution of tert-butyloxycarbonyl fluoride (BOC-F, 20% excess) was added, and the mixture was stirred for a further 3 h at room temperature (BOC-F prepared as disclosed in Synthesis 1975, 599). The pH was adjusted to 2 with conc. HCl. After distillation of the organic solvents, 50 ml of water were added to the residue, and the mixture was extracted with 3×100 ml of ethyl acetate. The combined organic phases were completely evaporated. The residue was crystallized in a mixture of 110 ml of diisopropyl ether and 80 ml of n-hexane. 11.95 g of title compound were obtained. The yield was 56%.