Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[NH2:15])=[CH:5][C:4]=1[O:16][CH3:17].[CH2:18]1[O:29][C:28]2[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][C:20]=2[O:19]1>C(Cl)Cl.C(N(CC)CC)C>[CH3:17][O:16][C:4]1[CH:5]=[C:6]([C@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:28]3[O:29][CH2:18][O:19][C:20]=3[CH:21]=2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc([C@@H]2CCCC[C@@H]2N)cc1OC
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc([C@H]2CCCC[C@H]2NC(=O)c2ccc3c(c2)OCO3)cc1OC
Reaction time: 8 h
Yield: 95.1 %

Procedure:
4.0 g of (−)-cis-1,2-dimethoxy-4-(2-aminocyclohexyl)benzene (compound B2) are dissolved in 100 ml of methylene chloride and 5.0 ml of triethylamine. A solution of 3.8 g of 3,4-methylenedioxybenzoyl chloride in 50 ml of methylene chloride is added dropwise at RT and the mixture is extracted with 100 ml each of water, 2N hydrochloric acid, satd. sodium hydrogencarbonate solution and water again after stirring overnight. The organic phase is dried using sodium sulfate and concentrated. 6.2 g of the title compound are obtained.
Reaction SMILES: [CH:1]([N:4]([CH:31]([CH3:33])[CH3:32])[CH2:5][CH2:6][C@@H:7]([C:14]1[CH:19]=[C:18]([C:20](=[O:22])[CH3:21])[CH:17]=[CH:16][C:15]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH:31]([N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6][C@@H:7]([C:14]1[CH:19]=[C:18]([CH:20]([OH:22])[CH3:21])[CH:17]=[CH:16][C:15]=1[O:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([CH3:33])[CH3:32]
Reactant: CC(=O)c1ccc(OCc2ccccc2)c([C@H](CCN(C(C)C)C(C)C)c2ccccc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(O)c1ccc(OCc2ccccc2)c([C@H](CCN(C(C)C)C(C)C)c2ccccc2)c1
Reaction time: 2 h
Yield: 78 %

Procedure:
N,N-Diisopropyl-3(R)-(5-acetyl-2-benzyloxyphenyl)-3-phenylpropanamine, prepared as described in Example 13.1, (3.5 g, 7.90 mmol) dissolved in dry THF was added to LiAlH4 (0.2 g, 5.41 mmol). After 2 hours of stirring, additional LiAlH4 (50 mg, 1.32 mmol) was added and the reaction mixture was stirred for 1.5 hours. The reaction was quenched and the solvent evaporated. The residue was chromatographed on silica (toluene-E3N 90:10) to give 2.74 g (78%) of an oil that crystallised slowly upon storage at room temperature.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:11][C:10]3[CH:12]=[C:13]([O:19][CH3:20])[C:14]([N+:16]([O-])=O)=[CH:15][C:9]=3[N:8]([CH3:21])[C:7](=[O:22])[CH2:6]2)[CH2:3][CH2:2]1.C(O)C.C(OCC)(=O)C>[Pd]>[NH2:16][C:14]1[C:13]([O:19][CH3:20])=[CH:12][C:10]2[CH2:11][N:5]([CH2:4][CH:1]3[CH2:2][CH2:3]3)[CH2:6][C:7](=[O:22])[N:8]([CH3:21])[C:9]=2[CH:15]=1
Reactant: COc1cc2c(cc1[N+](=O)[O-])N(C)C(=O)CN(CC1CC1)C2
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cc2c(cc1N)N(C)C(=O)CN(CC1CC1)C2
Yield: 78.1 %

Procedure:
4-Cyclopropylmethyl-7-methoxy-1-methyl-8-nitro-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (0.5 g, 0.002 mol) was hydrogenated in Ethanol (40 mL, 0.7 mol) and Ethyl acetate (40 mL, 0.4 mol) with 10% Pd/C (10:90, Palladium:carbon black, 0.082 g) in an analogous manner to example N26-F to give 8-Amino-4-cyclopropylmethyl-7-methoxy-1-methyl-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one as an oil (0.43 g, 90%). LCMS (m/e) 276 (M+1); 1H-NMR (DMSO, 400 MHz) δ 6.76 (s, 1H), 6.57 (s, 1H), 4.88 (s, 2H), 3.77 (s, 3H), 3.44 (s, 2H), 3.05 (s, 3H), 2.89 (s, 2H), 2.38-2.37 (d, 2H, J=15.41 Hz), 1.26-1.24 (m, 1H), 0.85-0.75 (m, 2H), 0.49-0.47 (d, 2H, J=7.83 Hz), 0.16-0.15 (d, 2H, J=4.80 Hz).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([CH3:14])([CH3:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:4][C:3]=1I.[CH2:16]([O:23][CH2:24][C@@H:25]([CH3:35])[C:26]#[C:27][Si:28]([CH2:33][CH3:34])([CH2:31][CH3:32])[CH2:29][CH3:30])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[Na+].[Na+]>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].C(Cl)Cl.CN(C)C=O>[CH2:16]([O:23][CH2:24][C@H:25]([C:26]1[C:3]2[C:2](=[N:7][CH:6]=[C:5]([C:8]([CH3:14])([CH3:13])[C:9]([O:11][CH3:12])=[O:10])[CH:4]=2)[NH:1][C:27]=1[Si:28]([CH2:33][CH3:34])([CH2:29][CH3:30])[CH2:31][CH3:32])[CH3:35])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC[Si](C#C[C@H](C)COCc1ccccc1)(CC)CC
Reactant: COC(=O)C(C)(C)c1cnc(N)c(I)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)c1[nH]c2ncc(C(C)(C)C(=O)OC)cc2c1[C@H](C)COCc1ccccc1
Temperature: 90 °C
Yield: 88.3 %

Procedure:
A vigorously stirred suspension of methyl 2-(6-amino-5-iodopyridin-3-yl)-2-methylpropanoate (4.61 g, 14.4 mmol), (S)-(4-benzyloxy-3-methylbut-1-ynyl)triethylsilane (4.98 g, 17.3 mmol), Pd(dppf)Cl2·CH2Cl2 (0.59 g, 0.72 mmol) LiCl (0.61 g, 14.4 mmol), Na2CO3 (3.82 g, 36.0 mmol) and N,N-dimethylformamide (60 mL) was degassed via three vacuum/nitrogen ingress cycles and the resulting mixture was heated at approximately 90° C. overnight. After cooling to ambient temperature, the reaction mixture was diluted with ethyl acetate and filtered through celites washing copiously with ethyl acetate. The filtrate was poured into water and extracted with ethyl acetate (x3). The combined organic extract was washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (gradient elution; 20-25% ethyl acetate/hexanes as eluent) to give the title compound as a viscous oil (6.11 g).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:20][CH2:19][C:18]3[C@:13]([C:31]([C:33]4[S:34][CH:35]=[CH:36][N:37]=4)=[O:32])([CH2:14][C:15]4[CH:23]=[N:22][N:21]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)[C:16]=4[CH:17]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1>C(#N)C>[F:30][C:27]1[CH:26]=[CH:25][C:24]([N:21]2[C:16]3[CH:17]=[C:18]4[C@:13]([C:31]([C:33]5[S:34][CH:35]=[CH:36][N:37]=5)=[O:32])([CH2:14][C:15]=3[CH:23]=[N:22]2)[CH2:12][N:11]([S:8]([C:5]2[CH:6]=[N:7][C:2]([N:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH2:20][CH2:19]4)=[CH:29][CH:28]=1
Reactant: C1CCNC1
Reactant: O=C(c1nccs1)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(Cl)nc1)C2
Solvent: CC#N
Product: O=C(c1nccs1)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(N3CCCC3)nc1)C2
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
A mixture of (R)-(6-((6-chloropyridin-3-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone (100 mg, 0.180 mmol) and pyrrolidine (37.5 μL, 0.450 mmol) in acetonitrile (2 mL) was stirred at 40° C. for 0.5 hour. The reaction mixture was cooled to room temperature and concentrated in vacuo to give a yellow oil. The crude product was purified by column chromatography on silica gel (gradient: 0-100% ethyl acetate in isohexane) to give a white solid. This was further purified by preparative HPLC (Gilson, Acidic (0.1% Formic acid), Agilent Prep C-18, 5 μm, 21.2×50 mm column, 30-95% acetonitrile in water) to afford (R)-(1-(4-fluorophenyl)-6-((6-(pyrrolidin-1-yl)pyridin-3-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone as a white solid (51 mg). LCMS (Method F, ES-API): RT 2.43 min, m+H=590.9; 1H NMR (400 MHz, CDCl3): δ 8.45 (1H, dd, J=2.0, 0.5 Hz), 8.01 (1H, d, J=3.1 Hz), 7.63-7.59 (2H, m), 7.46-7.41 (2H, m), 7.29 (1H, s), 7.19-7.13 (2H, m), 6.51 (1H, d, J=2.1 Hz), 6.27 (1H, d, J=9.1 Hz), 5.47 (1H, dd, J=12.2, 2.1 Hz), 4.20 (1H, d, J=16.8 Hz), 3.87-3.83 (1H, m), 2.91-2.82 (2H, m), 2.71 (1H, d, J=12.3 Hz), 2.53-2.46 (2H, m), 2.06-2.04 (4H, m), 1.33-1.24 (2H, m), 1.17-1.07 (2H, m).
Reaction SMILES: ClC1C=[C:10]2[C:5]([CH2:6][CH2:7][N:8](C3C=NC=CC=3)[C:9]2=O)=[CH:4]C=1.[F:19][C:20]1[CH:21]=[CH:22][C:23]2[S:31][C:30]3[CH2:29][CH2:28][NH:27][C:26](=[O:32])[C:25]=3[C:24]=2[CH:33]=1.IC1C=NC=CC=1C.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[F:19][C:20]1[CH:21]=[CH:22][C:23]2[S:31][C:30]3[CH2:29][CH2:28][N:27]([C:6]4[CH:7]=[N:8][CH:9]=[CH:10][C:5]=4[CH3:4])[C:26](=[O:32])[C:25]=3[C:24]=2[CH:33]=1
Reactant: O=C1NCCc2sc3ccc(F)cc3c21
Reactant: O=C1c2cc(Cl)ccc2CCN1c1cccnc1
Agent: I[Cu]I
Agent: Cc1ccncc1I
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCc2sc3ccc(F)cc3c2C1=O
Yield: 67.37 %

Procedure:
Using analogous conditions and workup as described for the preparation of Compound 1A, 8-Fluoro-3,4-dihydro-2H-benzo[4,5]thieno[3,2-c]pyridin-1-one (I-50 g: 100 mg, 0.452 mmol) was reacted with 3-iodo-4-methylpyridine (99.09 mg, 0.452 mmol), 1,4-dioxane (5 mL), copper iodide (8.64 mg, 0.0452 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (19.25 mg, 0.1356 mmol) and potassium phosphate (287.44 mg, 1.356 mmol) at 115° C. overnight under nitrogen atmosphere to afford the crude product. Purification by column chromatography on silica gel (1.5% methanol in CHCl3) afforded 95 mg of the product (67.37% yield).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[NH:12][C@H:11]([C:13]([OH:15])=[O:14])[CH2:10][S:9]1.C(N(CC)CC)C.[C:23]1(=[O:29])[O:28][C:26](=[O:27])[CH2:25][CH2:24]1>CC(C)=O>[C:26]([CH2:25][CH2:24][C:23]([N:12]1[C@H:11]([C:13]([OH:15])=[O:14])[CH2:10][S:9][CH:8]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[OH:1])=[O:29])([OH:28])=[O:27]
Reactant: O=C(O)[C@@H]1CSC(c2ccccc2O)N1
Reactant: O=C1CCC(=O)O1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: O=C(O)CCC(=O)N1C(c2ccccc2O)SC[C@H]1C(=O)O
Reaction time: 3 h
Yield: 75.4 %

Procedure:
To a stirred solution of (4R)-2-(2-hydroxyphenyl)-4-thiazolidinecarboxylic acid (4.5 g) and triethylamine (4.0 g) in acetone (100 ml), succinic anhydride (2.0 g) was added at room temperature, and stirred for 3 hours at the same temperature. The reaction mixture was concentrated in vacuo, and acidified with dilute hydrochloric acid. The separated oil was extracted with ethyl acetate, and the organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and evaporated in vacuo to give 4.9 g (75%) of the titled compound: mp 190°-191° C. (dec.) (ethyl acetate-methanol); [α]D27 +181.6° (c=1.0, methanol). IR (nujol, cm-1): 3210 (OH), 1720 (COOH), 1618 (CON), 1602 (aromatic), 1245, 1173, 940, 763. NMR (DMSO-6, δ): 2.0-2.7 (4H, m, --CH2CH2 --), 3.03 (1H, ABq (A part), d, J=11.0, 10.0 Hz, C5 --HA), 3.36 (1H, ABq (B part), d, J=11.0, 7.0 Hz, C5 --HB), 4.61 and 5.07 (1H, dd, J=10.0, 7.0 Hz and m, C4 --H), 6.36 (1H, s, C2 --H), 6.5-8.0 (4H, arom. H). TLC: Rf value* 0.35.
Reaction SMILES: S(Cl)(Cl)=O.Cl.[C:6]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([CH3:20])([CH3:19])[NH2:18])=[CH:11][CH:10]=1)([OH:8])=[O:7].[CH3:21]O>>[C:6]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([CH3:20])([CH3:19])[NH2:18])=[CH:11][CH:10]=1)([O:8][CH3:21])=[O:7]
Reactant: CO
Reactant: CC(C)(N)CCc1ccc(C(=O)O)cc1
Agent: Cl
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(CCC(C)(C)N)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Thionyl chloride (31 ml) was added dropwise to methanol (210 ml) at -70°. The solution was stirred for 10 mins and then 3-(4-carboxyphenyl)-1, 1-dimethylpropanamine hydrochloride (20 g) in methanol was added dropwise. The reaction mixture was allowed to warm to ambient temperature and then heated under reflux for 1 h. The solvent was evaporated, the residue partitioned between potassium carbonate and ether and the organic layer dried. Removal of the solvent gave the title compound, as an oil.
Reaction SMILES: CO.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[CH3:20][O:21][N:22]=[C:23]([C:37]1[CH:41]=[C:40]([CH3:42])[O:39][N:38]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][O:31]C(OCC)C>[Cl-].[Na+].O>[CH3:20][O:21][N:22]=[C:23]([C:37]1[CH:41]=[C:40]([CH3:42])[O:39][N:38]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][OH:31]
Reactant: CCOC(C)OCc1ccccc1C(=NOC)c1cc(C)on1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CON=C(c1cc(C)on1)c1ccccc1CO
Yield: 92.1 %

Procedure:
Methanol (26 ml) and pyridinium p-toluene-sulfonate (0.33 g, 0.0013 mol) were added to 2-(1-ethoxyethyl)oxymethylphenyl 5-methylisoxazol-3-yl ketone O-methyloxime (4.14 g, 0.013 mol), and the mixture was stirred under reflux for 0.5 hour. After completion of the reaction, half-saturated brine (300 ml) was added, and the mixture was extracted with dichloromethane (100 ml) twice. The extracts were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-hydroxymethylphenyl 5-methylisoxazol-3-yl ketone O-methyloxime (2.95 g, yield: 92.1%) as a colorless oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([C:11]3[N:12]=[C:13](O)[C:14]4[C:19]([CH:20]=3)=[CH:18][C:17]([O:21][CH3:22])=[CH:16][CH:15]=4)[CH:9]=[CH:10][C:2]1=2.O=P(Cl)(Cl)[Cl:26]>>[Cl:26][C:13]1[C:14]2[C:19](=[CH:18][C:17]([O:21][CH3:22])=[CH:16][CH:15]=2)[CH:20]=[C:11]([C:8]2[CH:9]=[CH:10][C:2]3[O:1][CH2:6][CH2:5][O:4][C:3]=3[CH:7]=2)[N:12]=1
Reactant: COc1ccc2c(O)nc(-c3ccc4c(c3)OCCO4)cc2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(Cl)nc(-c3ccc4c(c3)OCCO4)cc2c1
Yield: 75.5 %

Procedure:
A solution of 3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-6-methoxyisoquinolin-1-ol (250 mg, 0.808 mmol) in POCl3 (5 mL, 53.6 mmol) was refluxed for 14 h. Concentrated the solvent. The residue was taken into a mixture of DCM and 4N NaOH solution. Adjust pH to 7. The organic phase was collected and dried over sodium sulfate, filtered, then concentrated under vacuum. The crude material was purified by silica gel chromatography using 10% EtOAc/Hexanes as eluent to give 200 mg of the desired product 1-chloro-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-6-methoxyisoquinoline as a solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.18 (d, J=9.3 Hz, 1H), 7.77 (s, 1H), 7.65-7.55 (m, 2H), 7.21 (dd, J=9.2, 2.4 Hz, 1H), 7.08 (d, J=2.3 Hz, 1H), 6.95 (d, J=8.3 Hz, 1H), 4.30 (s, 4H), 3.95 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([NH:20][C:21](=[O:33])[CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)[CH:14]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[S-:34][C:35]#[N:36].[K+].BrBr>C(O)(=O)C>[NH2:36][C:35]1[S:34][C:11]2[C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([O:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([NH:20][C:21](=[O:33])[CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:30])[F:31])[CH:24]=4)[CH:14]=3)[CH:4]=[CH:3][C:2]=2[N:1]=1
Reactant: N#C[S-]
Reactant: COC(=O)c1cc(N)ccc1Oc1ccc(F)c(NC(=O)Cc2cccc(C(F)(F)F)c2)c1
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: COC(=O)c1c(Oc2ccc(F)c(NC(=O)Cc3cccc(C(F)(F)F)c3)c2)ccc2nc(N)sc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87.9 %

Procedure:
To a solution of methyl 5-amino-2-[4-fluoro-3-({[3-(trifluoromethyl)phenyl]acetyl}amino)phenoxy]benzoate (3.00 g, 6.09 mmol) in acetic acid (70 mL) was added potassium thiocyanate (2.37 g, 24.4 mmol), and the mixture was stirred at room temperature for 10 min. A solution of bromine (1.27 mg, 7.92 mmol) in acetic acid (35 mL) was added dropwise to the obtained solution over 20 min. After the completion of the dropwise addition, the mixture was stirred at room temperature for 36 hr. Insoluble material was filtered off and washed with ethyl acetate (200 mL). The filtrate and washings were combined and the mixture was concentrated under reduced pressure. The obtained residue was suspended in ethyl acetate (100 mL), and the suspension was washed successively with saturated aqueous sodium hydrogen carbonate solution (2×100 mL) and saturated brine (100 mL), and dried over anhydrous magnesium sulfate. Insoluble material was filtered off, the filtrate was purified by basic silica gel column chromatography (eluate: ethyl acetate), and the obtained solution was concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate/n-hexane (1:1) to give the title compound (2.78 g, 88%) as a white powder.
Reaction SMILES: [OH:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([C:12]2[O:13][C:14]3[C:15]([N:20]=2)=[N:16][CH:17]=[CH:18][CH:19]=3)[CH:3]=1.[H-].[Na+].[CH2:23](I)[CH2:24][CH3:25]>CN(C)C=O>[CH2:23]([O:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([C:12]2[O:13][C:14]3[C:15]([N:20]=2)=[N:16][CH:17]=[CH:18][CH:19]=3)[CH:3]=1)[CH2:24][CH3:25]
Reactant: CCCI
Reactant: Oc1cc(-c2nc3ncccc3o2)cc2c1CCCC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCOc1cc(-c2nc3ncccc3o2)cc2c1CCCC2
Reaction time: 0.17 h

Procedure:
A solution of 5.0 mmoles of product from Step D in 5 ml. of dimethylformamide is treated with 5.0 mmoles of sodium hydride/mineral oil emulsion. After stirring 10 minutes 1.0 g. of propyl iodide is added. After stirring 2 hours, the mixture is concentrated in vacuo to remove the dimethylformamide. Water (10 ml.) is added to the residue and the solids are collected and recrystallized from cyclohexane to give 2-(4-propoxy-5,6,7,8-tetrahydronaphth-2-yl)oxazolo[4,5-b]pyridine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:44]=[C:43]([O:45][CH3:46])[CH:42]=[C:41]([O:47][CH3:48])[C:4]=1/[CH:5]=[CH:6]/[CH:7]([S:16]([CH:18](/[CH:27]=[CH:28]/[C:29]1[C:34]([O:35][CH3:36])=[CH:33][C:32]([O:37][CH3:38])=[CH:31][C:30]=1[O:39][CH3:40])[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)=[O:17])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.[OH:49]O>C(O)(=O)C>[CH3:36][O:35][C:34]1[CH:33]=[C:32]([O:37][CH3:38])[CH:31]=[C:30]([O:39][CH3:40])[C:29]=1/[CH:28]=[CH:27]/[CH:18]([S:16]([CH:7](/[CH:6]=[CH:5]/[C:4]1[C:41]([O:47][CH3:48])=[CH:42][C:43]([O:45][CH3:46])=[CH:44][C:3]=1[O:2][CH3:1])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)(=[O:49])=[O:17])[C:19]1[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=1
Reactant: OO
Reactant: COc1ccc(C(/C=C/c2c(OC)cc(OC)cc2OC)S(=O)C(/C=C/c2c(OC)cc(OC)cc2OC)c2ccc(OC)cc2)cc1
Solvent: CC(=O)O
Product: COc1ccc(C(/C=C/c2c(OC)cc(OC)cc2OC)S(=O)(=O)C(/C=C/c2c(OC)cc(OC)cc2OC)c2ccc(OC)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(E)-2,4,6-trimethoxystyryl-4-methoxybenzyl sulfoxide (3 g) is dissolved in glacial acetic acid (30 mL) and cooled to 0° C. To the cooled solution is added hydrogen peroxide (7.5 mL of a 30% solution) to form a reaction mixture. The reaction mixture is heated to reflux temperature and maintained at reflux for 1 hour. After 1 hour, the heated reaction mixture is poured onto crushed water ice (200 g). A solid precipitate is formed. The precipitate is separated by filtration, dried, and recrystallized from 2-propanol to yield the desired (E)-2,4,6-trimethoxystyryl-4-methoxybenzyl sulfone.
Reaction SMILES: C(O[C@H:5]1[C@H:10]([NH:11][C:12]([NH:14][C:15]([O:17][CH2:18][CH:19]2[C:31]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:25]3[C:20]2=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:16])=[S:13])[C@@H:9]([O:32][C:33](=[O:35])[CH3:34])[C@H:8]([O:36][C:37](=[O:39])[CH3:38])[C@@H:7]([CH2:40][O:41][C:42](=[O:44])[CH3:43])[O:6]1)(=O)C.Cl[Sn](Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:37]([O:36][C@@H:8]1[C@@H:7]([CH2:40][O:41][C:42](=[O:44])[CH3:43])[O:6][C@H:5]2[C@H:10]([N:11]=[C:12]([NH:14][C:15]([O:17][CH2:18][CH:19]3[C:31]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:25]4[C:20]3=[CH:21][CH:22]=[CH:23][CH:24]=4)=[O:16])[S:13]2)[C@H:9]1[O:32][C:33](=[O:35])[CH3:34])(=[O:39])[CH3:38]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](NC(=S)NC(=O)OCC2c3ccccc3-c3ccccc32)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H]2SC(NC(=O)OCC3c4ccccc4-c4ccccc43)=N[C@@H]2[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 69 %

Procedure:
The thiourea from above (200 mg, 0.32 mmol) was dissolved in CH2Cl2 (4 mL) and SnCl4 (0.5 mL, 4.0 mmol) was added. Then the resulting mixture was stirred at room temperature for 16 h. The solution was diluted saturated aqueous NaHCO3 (20 mL), then the resulting mixture was extracted with CH2Cl2 (3×10 mL) and the combined organic extracts were dried (Na2SO4) and concentrated. Flash chromatography of the residue (EtOAc:hexanes 2:3) gave (3aR,5R,6S,7R,7aR)-5-(acetoxymethyl)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diyl diacetate as a pale colourless foam (125 mg, 69% yield). 1H NMR 500 MHz, CDCl3) δ 1.88 (s, 3H), 2.04 (s, 3H), 2.12 (s, 3H), 3.69 (m, 1H), 3.81 (ddd, 1H, J=2.5, 5.5, 6.5 Hz), 4.12 (dd, 1H, J=2.5, 12.5 Hz), 4.21-4.26 (m, 2H), 4.55 (dd, 1H, J=6.0, 12.5 Hz), 4.72-4.75 (dd, 1H, J=6.5, 6.5 Hz), 4.95 (dd, 1H J=5.5, 9.5 Hz), 5.24 (dd, 1H J=6.5, 9.5 Hz), 6.01 (d, 1H, J=6.5 Hz), 7.35 (dd, 2H, J=7.1, 7.8 Hz), 7.44 (dd, 2H, J=7.0, 7.8 Hz), 7.59 (d, 2H, J=7.1 Hz), 7.81 (d, 2H, J=7.0 Hz). 13C NMR (125 MHz, CDCl3) δ 20.62, 20.71, 21.35, 46.78, 57.91, 63.70, 67.92, 69.46, 71.88, 72.52, 90.23, 120.71, 120.89, 123.83, 124.04, 125.15, 127.76, 127.97, 129.61, 129.72, 130.08, 141.31, 142.86, 152.11, 161.43, 169.11, 169.63, 170.23.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH:11]2[CH2:20][CH2:19][C:14]3([O:18][CH2:17][CH2:16][O:15]3)[CH2:13][CH2:12]2)[CH:3]=1.[NH3:21]>CO.C(Cl)Cl>[O:18]1[C:14]2([CH2:19][CH2:20][CH:11]([C:4]3[CH:3]=[C:2]([NH2:21])[N:7]4[N:8]=[CH:9][CH:10]=[C:6]4[N:5]=3)[CH2:12][CH2:13]2)[O:15][CH2:16][CH2:17]1
Reactant: Clc1cc(C2CCC3(CC2)OCCO3)nc2ccnn12
Reactant: N
Solvent: CO
Solvent: ClCCl
Product: Nc1cc(C2CCC3(CC2)OCCO3)nc2ccnn12
Temperature: 100 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
7-chloro-5-(1,4-dioxaspiro[4.5]decan-8-yl)pyrazolo[1,5-a]pyrimidine (5.58 mmol, 1.64 g) is charged to 10-20 mL microwave vessel. To this vessel is added 10 mL ˜7N NH3 in methanol. The vessel was sealed and heated at 100° C. for 18 hours. After 18 hours, the reaction mixture was cooled to room temperature and diluted with 100 mL DCM. The resulting solution is washed with saturated NaHCO3(aq) and extracted with DCM twice more. The combined organics were dried over Na2SO4 and the solvent removed in vacuo to yield 5-(1,4-dioxaspiro[4.5]decan-8-yl)pyrazolo[1,5-a]pyrimidin-7-amine (1.52 g, 99% yield) as pale orange solid.
Reaction SMILES: [C:1]([O:4][CH2:5]Br)(=[O:3])[CH3:2].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([F:43])=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]([CH2:37][C@@H:38]([OH:42])[C:39]([OH:41])=[O:40])[NH:22][C:23]([C:25]3[O:29][N:28]=[C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[F:36])[CH:26]=3)=[O:24])=[CH:16][CH:15]=2)[CH:13]=1.CCN(CC)CC.CC(C)=O>>[C:1]([O:4][CH2:5][O:41][C:39](=[O:40])[C@H:38]([OH:42])[CH2:37][N:21]([CH2:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[CH:13]=[C:8]([Cl:7])[CH:9]=[CH:10][C:11]=2[F:43])=[CH:15][CH:16]=1)[NH:22][C:23]([C:25]1[O:29][N:28]=[C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[F:36])[CH:26]=1)=[O:24])(=[O:3])[CH3:2]
Reactant: O=C(NN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)C[C@@H](O)C(=O)O)c1cc(-c2ccccc2F)no1
Reactant: CC(=O)OCBr
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(=O)OCOC(=O)[C@H](O)CN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)c1cc(-c2ccccc2F)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.6 %

Procedure:
Bromomethyl acetate (11.9 mL, 121 μmol) was added to a mixture of (R)-3-{N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)-N′-[3-(2-fluorophenyl)isoxazole-5-carbonyl]hydrazino}-2-hydroxypropionic acid (40.0 mg, 76 μmol) and Et3N (21.1 mL, 152 μmol) in acetone (1.0 mL, 14 mmol). The resulting mixture was stirred at room temperature for 1 hour. The mixture was then concentrated and the residue was dissolved in AcOH (2 mL), filtered, and purified by reverse phase prep HPLC. The desired fractions were frozen and lyophilized to yield the title compound (8.5 mg, purity 98.5%) as a TFA salt. MS m/z [M+H]+ calc'd for C29H24ClF2N3O7, 600.13. found 600.1.